ACCP Farmakoterapi 2013

AMERICAN COLLEGE OF CLINICAL PHARMACY
Pharmacotherapy Review Program for

Advanced Clinical Pharmacy Practice
March 2022, 2013

Surabaya, Indonesia
American College of Clinical Pharmacy
Pharmacotherapy Review Program for

Advanced Clinical Pharmacy Practice
March 2022, 2013

Surabaya, Indonesia

Lenexa, Kansas
United States of America
Executive Director: Michael S. Maddux, Pharm.D., FCCP

Director of Professional Development: Nancy M. Perrin, M.A., CAE
Associate Director of Professional Development: Wafa Y. Dahdal, Pharm.D., BCPS
Publications Project Manager: Janel Mosley
Project Coordinator: Carla Scarborough
Desktop Publisher/Graphic Designer: Jen DeYoe, B.F.A.
Medical Editor: Kimma Sheldon, Ph.D., M.A.
Material appearing in this workbook is adapted from matter originally published in the following chapters:
Coyle EA. Infectious diseases. In: Bainbridge JL, Barbour SY, Coyle EA et al. Updates in Therapeutics: The Ambulatory Care Pharmacy
Preparatory Review Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(2):43-82.
Dopp AL. Policy, practice, and regulatory issues. In: Dugan J, El-Ibiary S, Foote EF, et al. Updates in Therapeutics: The Pharmacotherapy
Preparatory Review and Recertification Course, 2012 ed. Lenexa, KS: American College of Clinical Pharmacy, 2012:275-94.
Foote EF. Nephrology. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy Preparatory Review and
Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(1):449-80.
Harris IM. Ambulatory care. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy Preparatory
Review and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2012(1):231-280.
Hemstreet BA. Gastrointestinal disorders. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy
Preparatory Review and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2012(1):69-144.
Irons BK. Endocrine and metabolic disorders. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy
Mueller BA. Nephrology. In: Bainbridge JL, Barbour SY, Coyle EA et al. Updates in Therapeutics: The Ambulatory Care Pharmacy
Preparatory Review Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(1):43-70.
Page RL. Cardiology III. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy Preparatory Review
and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(2):269-306.
Rodgers JE. Cardiology I. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy Preparatory Review
Smith CL. Infectious diseases. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy Preparatory
Review and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(1):365-406.
Sowinski KM. Biostatistics: a refresher. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy
Sowinski KM. Clinical trials: fundamentals of design and interpretation. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in
Therapeutics: The Pharmacotherapy Preparatory Review and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy,
2011(1):163-86.
Wiggins BS. Cardiology II. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy Preparatory Review
For order information or questions, contact:
13000 West 87th Street Parkway, Suite 100
Lenexa, Kansas 66215
(913) 492-3311
(913) 492-4922 (fax)
accp@accp.com
Copyright 2013 by American College of Clinical Pharmacy. No part of this publication may be reproduced, stored in a retrieval system,
or transmitted, in any for or by any means, electronic or mechanical, including photocopy, without prior written permission of the American
College of Clinical Pharmacy.
Printed in the United States of America
Table of Contents
Nephrology .............................................................................................................................. 1
Endocrinology ......................................................................................................................29
Biostatistics ...........................................................................................................................56
Clinical Trials ......................................................................................................................... 71
Policy, Practice and Regulatory Issues ..................................................................... 89
Infectious Diseases in the Ambulatory Care Setting .......................................... 113
Infectious Diseases in the Acute Care Setting .................................................... 139
Gastroenterology ............................................................................................................. 156
Cardiology ........................................................................................................................... 199
Pulmonary Diseases .......................................................................................................260
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Pharmacotherapy Review Program for Advanced Clinical Pharmacy Practice 2013 American College of Clinical Pharmacy
iii
Program Goals
The Pharmacotherapy Review Program for Advanced Clinical Pharmacy Practice is designed to help
pharmacists who are preparing for the Board of Pharmacy Specialties certification examination in the
pharmacotherapy specialty as well as those seeking a general review and refresher on
pharmacotherapeutics and clinical skills.
Program goals are to:
1. present a high-quality, up-to-date overview of pharmacotherapeutics;
2. provide a framework to help participants prepare for the pharmacotherapy specialty certification
examination; and
3. engage participants in an interactive, case-based learning experience to advance the clinical
judgment and problem-solving skills required in clinical practice.
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iv
Faculty
G. Robert DeYoung, Pharm.D., BCPS
Clinical Pharmacist, Ambulatory Care
Advantage Health Physicians
St. Marys Health Care
Grand Rapids, Michigan
Brian A. Hemstreet, Pharm.D., BCPS
Associate Professor
University of Colorado
Skaggs School of Pharmacy and Pharmaceutical Sciences
Aurora, Colorado
Alan H. Lau, Pharm.D., FCCP
Professor
Director, International Clinical Pharmacy Education
College of Pharmacy
University of Illinois at Chicago
Chicago, Illinois
Professional Development Associate International Programs
Lenexa, Kansas
Zachary A. Stacy, Pharm.D., BCPS
Associate Professor of Pharmacy Practice
St. Louis College of Pharmacy
St. Louis, Missouri
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v
Program Agenda
March 20, 2013
Introduction and Welcome
Nephrology
Dr. Lau
Break
Nephrology (cont.)
Dr. Lau
Lunch
How to Prepare for the Certification Examination
Faculty Panel
Endocrinology
Dr. Stacy
Break
Endocrinology (cont.)
Dr. Stacy
March 21, 2013
Biostatistics and Clinical Trials
Dr. DeYoung
Break
Biostatistics and Clinical Trials
Dr. DeYoung
Policy, Practice and Regulatory Issues
Dr. Lau
Lunch
Infectious Diseases in the Ambulatory Care Setting
Dr. DeYoung
Break
Infectious Diseases in the Acute Care Setting
Dr. Hemstreet
March 22, 2013
Gastroenterology
Dr. Hemstreet
Lunch
Cardiology
Dr. Stacy
Break
Cardiology (cont.)
Dr. Stacy
Pulmonary Diseases
Dr. Hemstreet
9:00 a.m.9:30 a.m.

9:30 a.m.10:30 a.m.
10:30 a.m.10:45 a.m.
10:45 a.m.12:15 p.m.
12:15 p.m.1:45 p.m.
1:45 p.m.2:15 p.m.
2:15 p.m. 3:15 p.m.
3:15 p.m.3:30 p.m.
3:30 p.m.5:30 p.m.
9:00 a.m.10:30 a.m.
10:30 a.m.10:45 a.m.
10:45 a.m.11:45 a.m.
11:45 a.m. 12:15 p.m.
12:15 p.m.1:45 p.m.
1:45 p.m.3:15 p.m.
3:15 p.m.3:30 p.m.
3:30 p.m.5:00 p.m.
9:00 a.m.11:00 a.m.
11:00 a.m.1:00 p.m.
1:00 p.m.3:00 p.m.
3:00 p.m.3:15 p.m.
3:15 p.m.4:15 p.m.
4:15 p.m.5:15 p.m.
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vi
NEPHROLOGY
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Nephrology
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Learning Objectives:
1. Categorize acute kidney injury (AKI) as prerenal, intrinsic, or postrenal on the basis of patient history,
physical examination, and laboratory values.
2. List risk factors for AKI and formulate strategies to decrease risk of AKI in specific patient populations.
3. Formulate a therapeutic plan to manage AKI.
4. Identify medications and medication classes associated with acute and chronic kidney damage.
5. Discuss factors that determine the efficiency of dialysis of drugs.
6. Identify the stage of chronic kidney disease (CKD) on the basis of patient history, physical examination,
and laboratory values.
7. List risk factors for the progression of CKD and formulate strategies to slow the progression of CKD.
8. Describe the common complications of CKD.
9. Develop a care plan to manage the common complications observed in patients with CKD (e.g., anemia,
secondary hyperthyroidism).
I. ACUTE KIDNEY INJURY (ACUTE RENAL FAILURE)

A. Definitions and Background
1. Acute kidney injury (AKI) is defined as an acute decrease in kidney function (GFR) over a period
of hours, days, or even weeks. Associated with an accumulation of waste products and (usually)
volume
a. Definitions vary. A commonly used definition is an increase in serum creatinine (SCr) of 0.5
mg/dL or greater or a decrease of 25% or greater in the glomerular filtration rate (GFR) of
patients with previous normal kidney function OR an increase of 1 mg/dL or greater in SCr in
patients with chronic kidney disease (CKD). It is also defined on the basis of urine output
(less than 0.5 mL/kg/hour for at least 6 hours). The Acute Kidney Injury Network (AKIN):
An abrupt (48 hours) absolute increase in SCr of more than 0.3 mg/dL or a 50% increase in
baseline OR urine output less than 0.5 mL/kg/hour for more than 6 hours. Can further classify
into stages 13 given the degree of SCr rise and urine output
b. RIFLE criteria (AKIN). Uses change in baseline of SCr/GFR and/or urine output. Categorized
as risk, injury, failure, loss, or end-stage renal disease (ESRD)
c. Common complications include fluid overload as well as acid-base and electrolyte
abnormalities.
d. Urine output classification
i. Anuric: Less than 50 mL/24 hoursAssociated with worse outcomes
ii. Oliguric: 50500 mL/24 hours
iii. Nonoliguric: More than 500 mL/24 hoursAssociated with better patient outcomes.
Easier to manage because of fewer problems with volume overload
2. Community-acquired AKI
a. Low incidence (0.02%) in otherwise healthy patients. As high as 13% in patients with CKD
b. Usually has a very high survival rate (70%95%)
c. Single insult to the kidney, often drug induced
d. Often reversible
3. Hospital-acquired AKI
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a. Has a moderate incidence (2%5%) and moderate survival rate (30%50%)

b. Single or multifocal insults to the kidney
c. Can still be reversible
4. Intensive care unitacquired AKI: 5%6% of patients in intensive care have AKI during unit
stay. Low survival rate (10%30%)
5. Estimating kidney function in AKI
a. Difficult because commonly used equations (Cockcroft-Gault and MDRD [Modification of
Diet in Renal Disease]) are not appropriate (need stable SCr)
b. Equations by Brater and Jeliffe are probably more accurate than the Cockcroft-Gault equation,
but they have not been rigorously tested.
c. Can do a urine collection in non-oliguria. Obtain an SCr before and after the collection, and
average them for the calculation.
B. Risk Factors Associated with AKI
1. Preexisting CKD (estimated GFR [eGFR]) less than 60 mL/minute/1.73m2)
2. Volume depletionVomiting, diarrhea, poor fluid intake, fever, diuretic use. Effective volume
depletion congestive heart failure (CHF), liver disease with ascites
3. Use of nephrotoxic agents/medications (intravenous radiographic contrast, aminoglycosides,
amphotericin, nonsteroidal anti-inflammatory drugs [NSAIDs] and cyclooxygenase-2 [COX-2]
inhibitors, angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin II receptor blockers
[ARBs], cyclosporine, and tacrolimus)
4. Obstruction of the urinary tract
C. Classifications of AKI (Table 1)
1. Prerenal AKI
a. Initially, the kidney is undamaged.
b. Characterized by hypoperfusion to the kidney
i. Systemic hypoperfusion: Hemorrhage, volume depletion, drugs, CHF
ii. Isolated kidney hypoperfusion: Renal artery stenosis, emboli
c. Urinalysis will initially be normal (no sediment) but concentrated.
d. Physical examination: Hypotension, volume depletion
2. Functional AKI
a. Kidney is undamaged. Often lumped with prerenal in classification
b. Caused by reduced glomerular hydrostatic pressure
c. In general, medication related (cyclosporine, ACEIs and ARBs, and NSAIDs). Seen in
patients with underlying effective bloodflow (patients with CHF, patients with liver disease,
and elderly patients) who cannot compensate for alterations in afferent/efferent tone.
Concentrated urine
d. Small increases in SCr (less than 1 mg/dL) after initiation of ACEI/ARB are acceptable.
3. Intrinsic AKI
a. Kidney is damaged. Damage can be linked to structure involved: Small blood vessels,
glomeruli, renal tubules, and interstitium
b. Most common cause is ATN. Other causes include AIN, vasculitis, and acute
glomerulonephritis.
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c. Urinalysis will reflect damage. Urine generally not concentrated

d. Physical examination: Normotensive, euvolemic, or hypervolemic; check for signs of allergic
reactions or embolic phenomenon
e. History: Identifiable insult, drug use, infections
4. Postrenal AK
a. Kidney is initially undamaged. Bladder outlet obstruction is the most common cause of
postrenal AKI. Lower urinary tract obstruction may be caused by calculi. Ureteric
obstructions may be caused by clots or intraluminal obstructions. Extrarenal compression can
also cause postrenal disease. Increased intraluminal pressure upstream of the obstruction will
result in damage if obstruction is not relieved.
b. Urinalysis may be nonspecific.
c. Physical examination: Distended bladder, enlarged prostate
d. History: Trauma, benign prostatic hypertrophy (BPH), cancers
Table 1. Classifications of Acute Kidney Injury
Prerenal and Functional
Volume depletion
Renal artery stenosis
CHF
Hypercalcemia
NSAID/ACEI use
Cyclosporin
Intrinsic (ATN and AIN)

Long-standing renal
hypoperfusion
Nephrotoxins (e.g., contrast
or antibiotics)
Vasculitis
Glomerulonephritis
Postrenal
Kidney stones
BPH
Cancers
Physical examination
Hypotension
Dehydration
Petechia if thrombotic
Ascites
Rash, fever (with AIN)
Distended bladder
Enlarged prostate
Serum BUN/SCr ratio

Urine concentrated?
> 20:1
Yes
Low urine sodium (< 20
mEq/L)
Low FENa (< 1)
High urine osmolarity
15:1
No
Urine sodium > 40 mEq/L
FENa > 2
Low urine osmolarity
15:1
No
Urine sodium > 40
mEq/L
FENa > 2
Low urine osmolarity
Urine sediment
Normal
Variable, may be normal
Urinary WBC
Urinary RBC
Proteinuria
Negative
Negative
Negative
Muddy-brown granular casts;

tubular epithelial casts
24+
24+
Positive
History/presentation
Variable
1+
Negative
ACEI = angiotensin-converting enzyme inhibitor; AIN = acute interstitial nephritis; ATN = acute tubular necrosis; BPH = benign
prostatic hypertrophy; BUN = blood urea nitrogen; CHF = congestive heart failure; FENa = fractional excretion of sodium; GFR
= glomerular filtration rate; NSAID = nonsteroidal anti-inflammatory drug; SCr = serum creatinine; RBC = red blood cell
(count); W BC = white blood cell (count).
D. Prevention of AKI
1. Avoid nephrotoxic drugs when possible.
2. Ensure adequate hydration.
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3. Patient education
4. Drug therapies to decrease incidence of contrast-induced nephropathySee Drug
Nephrotoxicity section.
E. Treatment and Management of Established AKI
1. Prerenal azotemia: Correct primary hemodynamics.
a. Normal saline if volume depleted
b. Pressure management if needed
c. Blood products if needed
2. Postrenal azotemia: Relieve obstruction. Early diagnosis is important. Consult urology and/or
radiology.
3. Intrinsic: No specific therapy universally effective
a. Eliminate the causative hemodynamic abnormality or toxin.
b. Avoid additional insults.
c. Fluid and electrolyte management. Prevent volume depletion or overload and electrolyte
imbalance.
d. Nutrition support. Important, but no specific recommendations are widely accepted
e. Medical therapy
i. Fenoldopam. May reduce need for renal replacement therapy (RRT) and in-hospital
mortality (based on systematic review)
ii. Atrial natriuretic peptide. May reduce need for renal RRT
iii. Loop diuretics. Consider loop diuretics for patients who are oliguric and euvolemic or
hypervolemic. Loop diuretics do not reduce mortality or improve renal recovery but may
assist in fluid/electrolyte management. In general, given intravenously at relatively high
doses
iv. Low-dose dopamine: Ineffective; avoid
4. Renal replacement therapyIndications
a. Blood urea nitrogen (BUN) greater than 100
b. Volume overload unresponsive to diuretics
c. Uremia or encephalopathy
d. Life-threatening electrolyte imbalance
e. Refractory acidosis
II. DRUG-INDUCED KIDNEY DAMAGE

A. Introduction: Drugs are responsible for kidney damage through many mechanisms. Evaluate potential
drug-induced nephropathy on the basis of the period ingested, patient risk factors, and the propensity
of the suspected agent to cause kidney damage.
1. Risk factors
a. History of CKD
b. Increased age
2. Epidemiology
a. 7% of all drug toxicities
b. 18%27% of AKI in hospitals
c. 1%5% of NSAID users in community
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d. Most implicated medications: Aminoglycosides, NSAIDs, ACEIs, contrast dye, amphotericin

3. Kidney at risk of toxicity because:
a. High exposure to toxin: Kidney receives 20%25% of cardiac output.
b. Autoregulation and specialized bloodflow through glomerulus
c. High intrarenal drug metabolism
d. Tubular transport processes
e. Concentration of solutes (i.e., toxins) in tubules
f. High-energy requirements of tubule epithelial cells
g. Urine acidification
4. Pseudodrug-induced nephropathy
a. Drugs that inhibit Cr tubular secretion: Triamterene; cimetidine
b. Drugs that increase BUN: Corticosteroids; tetracycline
c. Drugs that interfere with Cr assay: Cefoxitin and other cephalosporins
B. Acute Tubular Necrosis
1. Most common drug-induced kidney disease in the inpatient setting
2. Aminoglycoside nephrotoxicity
a. Incidence: 1.7%58% of patients
b. Pathogenesis
i. Caused by proximal tubular damage leading to obstruction of the lumen
ii. Cationic charge of drug leads to binding to tubular epithelial cells and uptake into those
cells.
iii. Accumulation of phospholipids and toxicity
c. Presentation
i. Gradual rise in SCr concentrations and decrease in GFR after about 610 days of therapy
ii. Patients usually have nonoliguric kidney failure.
iii. Wasting of potassium (K+) and magnesium (Mg2+) may occur.
d. Risk factors
i. Related to dosing: Large total cumulative dose, prolonged therapy, trough concentration
exceeding 2 mg/L, recent previous aminoglycoside therapy
ii. Concurrent use of other nephrotoxins (cyclosporine, amphotericin B, and diuretics)
iii. Patient related: Preexisting kidney disease/damage, increased age, poor nutrition, shock,
gram-negative bacteremia, liver disease, hypoalbuminemia, obstructive jaundice,
dehydration, and K/Mg deficiencies
e. Prevention
i. Avoid in high-risk patients.
ii. Maintain adequate hydration.
iii. Limit the total cumulative aminoglycoside dose.
iv. Avoid other nephrotoxins.
v. Use extended-interval (once daily) dosing. (Not as useful in patients with severe kidney
disease; need to monitor these and other high-risk patients closely)
3. Radiographic contrast media nephrotoxicity (intravenous contrast). Consists of isoosmolar (300
mOsm/kg), low-osmolar (780800 mOsm/kg), and high-osmolar (more than 1000 mOsm/kg)
agents. Also categorized as ionic versus nonionic
a. Incidence
i. Third leading cause of inpatient AKI
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b.
c.
d.
e.
f.
ii. Less than 2% and up to 50% of patients, depending on risk

iii. Associated with a high (34%) in-hospital mortality rate
Pathogenesis
i. Direct tubular toxicity caused by reactive oxygen species
ii. Also may cause renal ischemia (prerenal picture from volume depletion) because of
intrarenal hemodynamic alterations. Most contrast agents are hyperosmolar (more than
900 mOsm/kg), which leads to an osmotic diuresis and dehydration. Some contrast agents
also cause systemic hypotension on injection and renal vasoconstriction.
Presentation
i. Initial transient osmotic diuresis, followed by tubular proteinuria
ii. SCr rises and peaks after about 25 days.
iii. 50% of patients develop oliguria, and some will require dialysis.
Risk factors for toxicity
i. Preexisting kidney disease (SCr more than 1.5 mg/dL or creatinine clearance [CrCl] less
than 60 mL/minute)
ii. Diabetes mellitus
iii. Volume depletion
iv. Age older than 75 years
v. Anemia (hematocrit less than 39% of men, less than 36% of women)
vi. Conditions with decreased bloodflow to the kidney (e.g., CHF)
vii. Hypotension
viii. Other nephrotoxins
ix. Large doses of contrast (more than 140 mL) and/or hyperosmolar contrast agents
Prevention
i. Hydration. Intravenous isotonic saline considered more effective than half-isotonic saline
in prevention of contrast-induced nephropathy. Begin 612 hours before procedure.
Maintain urine output greater than 150 mL/hour. Sodium bicarbonate is widely used, but
there are conflicting data on efficacy.
ii. Use an alternative imagining study if possible.
iii. Discontinue nephrotoxic agents. Avoid diuretics.
iv. Use low-osmolar or iso-osmolar contrast agents in patients at risk (more expensive).
v. Medications used to prevent contrast-induced nephropathy:
(a) AcetylcysteineAntioxidant and vasodilatory mechanism. Accumulation of
glutathione takes time, so it may not be as effective in emergency cases. Various
dosing recommendations. Widely used. Lots of conflicting evidence. Considered safe
(b) Ascorbic acidAntioxidant. One large study showed benefit when used immediately
before. Not confirmed. Give ascorbic acid 3 g before procedure and
2 g 2 times/day two doses after procedure. May have role in emergency cases
(c) TheophyllineMay reduce contrast-induced nephropathy
(d) FenoldopamAvoid, given the CONTRAST (Controlled Multicenter Trial
Evaluating Fenoldopam Mesylate for the Prevention of Contrast-Induced
Nephropathy) trial, which showed no benefit on contrast-induced nephropathy and an
increased incidence of hypotension.
(e) Others not worth mentioning
Joint Commission on Accreditation of Healthcare Organizations
i. Treated as a drug
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ii. Subject to all the standards for medication management in a health system
g. Nephrogenic systemic fibrosis also known as nephrogenic fibrosing dermopathy
i. Rare. Associated with gadolinium-based agents used in high doses for magnetic
resonance angiogram
ii. Occurs in patients with moderate CKD to ESRD given contrast. Systemic acidosis seems
to be a risk factor. Magnevist, Omniscan, and OptiMARK considered inappropriate for
use in patients with AKI or CKD
iii. Onset 218 days after exposure
iv. Presents as burning, itching, swelling/hardening/tightening of skin, skin patches, spots on
eyes, joint stiffness, and muscle weakness
v. Can cause organ damage. Deaths have occurred.
vi. In 2010, the U.S. Food and Drug Administration (FDA) required an added warning
to prescribing information.
4. Cisplatin and carboplatin nephrotoxicity
a. Incidence: 6%13% with appropriate dosing and administration
b. Pathogenesis Complex. Direct tubular toxin
c. Presentation
i. SCr peaks 1012 days after starting therapy but may continue to rise with subsequent
cycles of therapy.
ii. Renal Mg wasting is common (may be severe with central nervous system symptoms)
and may be accompanied by hypokalemia and hypocalcemia.
iii. May result in irreversible kidney damage
d. Risk factors for toxicity: Many courses of cisplatin, patient age, dehydration, concurrent
nephrotoxins, kidney irradiation, alcohol abuse
e. Prevention
i. Avoid concurrent use of nephrotoxins.
ii. Use smallest dose possible, and decrease frequency of administration.
iii. Aggressive intravenous hydration: 14 L within 24 hours of high-dose cisplatin or
carboplatin
iv. Amifostine: Cisplatin-chelating agent. Should be considered in patients at risk of
nephrotoxicity
5. Amphotericin B nephrotoxicity
a. Incidence
i. Increases as cumulative dose increases
ii. Approaches 80% with cumulative doses of 4 g or more
b. Pathogenesis
i. Direct proximal and distal tubular toxicity
ii. Arterial vasoconstriction
c. Presentation
i. Manifests after 23 g
ii. Loss of tubular function leads to electrolyte wasting (especially K+, Na+, and Mg2+)
and distal tubular acidosis.
iii. Patients may require substantial K+ and Mg2+ replacement.
iv. SCr increases and GFR decreases because of a decrease in kidney bloodflow from
vasoconstriction caused by amphotericin.
d. Risk factors for toxicity: Existing kidney dysfunction, high average daily doses, diuretic use,
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volume depletion, concomitant nephrotoxins, rapid infusion

e. Prevention
i. Avoid other nephrotoxins (especially cyclosporine), and limit the total cumulative dose.
ii. Intravenous hydration with at least 1 L/day of 0.9% NaCl before each dose
iii. Use a liposomal product in high-risk patients.
C. Hemodynamically Mediated Kidney Failure
1. Results from a decrease in intraglomerular pressure through the vasoconstriction of afferent
arterioles or the vasodilation of efferent arterioles
2. ACEIs and ARBs
a. Pathogenesis
i. Vasodilation of the efferent arteriole
ii. Leads to a decrease in glomerular hydrostatic pressure and a resultant decrease in GFR
b. Presentation
i. Exerts a predictable dose-related reduction in GFR
ii. SCr is usually expected to rise by up to 30%.
(a) Usually occurs within 25 days
(b) Usually stabilizes in 23 weeks
(c) Increases greater than 30% may be detrimental.
(d) Usually reversible on drug discontinuation
c. Risk factors for toxicity: Patients with bilateral (unilateral with a solitary kidney) renal artery
stenosis, decreased effective kidney bloodflow (CHF, cirrhosis), preexisting kidney disease,
and volume depletion
d. Prevention
i. Initiate therapy with low doses of short-acting agents and gradually titrate upward.
ii. Switch to long-acting agents once tolerance is established.
iii. Initially, monitor kidney function and SCr concentrations often: daily for inpatients,
weekly for outpatients.
iv. Avoid use of concomitant diuretics, if possible, during therapy initiation.
3. Nonsteroidal anti-inflammatory drugs
a. Incidence: Estimates indicate that 500,0002.5 million people develop NSAID-induced
nephrotoxicity annually in the United States.
b. Pathogenesis
i. Vasodilatory prostaglandins help maintain glomerular hydrostatic pressure by afferent
arteriolar dilation, especially in times of decreased kidney bloodflow.
ii. Administration of an NSAID in the setting of decreased kidney perfusion reduces this
compensatory mechanism by decreasing the production of prostaglandins, resulting in
afferent vasoconstriction and reduced glomerular bloodflow.
c. Presentation
i. Can occur within days of starting therapy
ii. Patients generally have low urine volume and Na and an increase in BUN, SCr, K+,
edema, and weight.
d. Risk factors for toxicity: Preexisting kidney disease, systemic lupus erythematosus, high
plasma renin activity (e.g., CHF, hepatic disease), diuretic therapy, atherosclerotic disease,
and advanced age
e. Prevention
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i.
Use therapies other than NSAIDs when appropriate (e.g., acetaminophen for
osteoarthritis).
ii. Sulindac is a potent NSAID that may affect prostaglandin synthesis in the kidney to a
lesser extent than other NSAIDs.
iii. Question the utility of COX-2specific inhibitors. They have not been found to prevent
kidney dysfunction, and they increase cardiovascular complications.
f. If NSAID-induced AKI is suspected, discontinue drug and give supportive care.
Recovery is usually rapid.
4. Cyclosporine and tacrolimus
a. Incidence
i. The 5-year risk of developing CKD after transplantation of a nonrenal organ ranges from
7% to 21%.
ii. The occurrence of kidney failure in the transplant patient population has a 4-fold
increased risk of death.
b. Pathogenesis
i. Results from a dose-related hemodynamic mechanism
ii. Causes vasoconstriction of afferent arterioles through possible increased activity of
various vasoconstrictors (thromboxane A2, endothelin, sympathetic nervous system) or
decreased activity of vasodilators (nitric oxide, prostacyclin)
iii. Increased vasoconstriction from angiotensin II may also contribute.
iv. Effects usually resolve with dose reduction.
c. Presentation
i. Can occur within days of starting therapy
ii. SCr rises and GFR decreases.
iii. Patients often have hypertension, hyperkalemia, and hypomagnesemia.
iv. A biopsy is often needed for kidney transplant patients to distinguish this from acute
allograft rejection.
d. Risk factors for toxicity: Increased age, high initial cyclosporine dose, kidney graft rejection,
hypotension, infection, and concomitant nephrotoxins
e. Prevention
i. Monitor serum cyclosporine and tacrolimus concentrations closely.
ii. Use lower doses in combination with other nonnephrotoxic immunosuppressants.
iii. Calcium channel blockers may help antagonize the vasoconstrictor effects of cyclosporine
by dilating afferent arterioles.
D. Tubulointerstitial Disease
1. Involves the renal tubules and the surrounding interstitium
2. Onset can be acute or chronic.
a. Acute onset generally involves interstitial inflammatory cell infiltrates, rapid loss of kidney
function, and systemic symptoms (i.e., fever and rash).
b. Chronic onset shows interstitial fibrosis, slow decline in kidney function, and no systemic
symptoms.
3. Acute allergic interstitial nephritis
a. Cause of up to 3% of all cases of AKI. Results from an allergic hypersensitivity reaction that
affects the interstitium of the kidney
b. Many medications and medication classes can cause this type of kidney failure. The most
commonly implicated are the -lactams and the NSAIDs (although the presentations are
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different).
i. Penicillins: Classic presentation of acute allergic interstitial nephritis. Signs/symptoms
occur about 12 weeks after therapy initiation and include fever, maculopapular rash,
eosinophilia, pyuria, hematuria, and proteinuria. Eosinophiluria may also be present.
ii. NSAIDs: Onset much more delayed, typically begins about 6 months into therapy.
Usually occurs in elderly patients on chronic NSAID therapy. Patients usually do not have
systemic symptoms.
c. Kidney biopsy may be needed to confirm diagnosis.
d. Treatment includes discontinuing the offending agent and possibly initiating steroid therapy.
4. Chronic interstitial nephritis
a. Often progressive and irreversible
b. Lithium
i. Toxicity results from a dose-related decrease in response to an antidiuretic hormone.
ii. AKI from lithium usually occurs during acute lithium intoxication.
Patients become dehydrated secondary to nephrogenic diabetes insipidus. There is also
direct damage to the proximal and distal tubules.
iii. Risks include elevated serum concentrations and repeated episodes of AKI from
lithium toxicity.
iv. Prevention is accomplished by maintaining the lowest serum lithium concentrations
possible, avoiding dehydration, and monitoring kidney function closely.
c. Cyclosporine: Presents later in therapy (about 612 months) than hemodynamically mediated
toxicity
5. Papillary necrosis
a. Form of chronic interstitial nephritis affecting the papillae, causing necrosis of the collecting
ducts
b. Results from the long-term use of analgesics
i. Classic example was with products that contained phenacetin.
ii. Occurs more often with combination products
iii. Products containing caffeine may also pose an increased risk.
c. Evolves slowly as time progresses
d. Affects women more often than men
e. Difficult to diagnose, and much controversy remains regarding risk, prevention, and cause
E. Obstructive Nephropathy
1. Results from obstruction of the flow of urine after glomerular filtration
2. Renal tubular obstruction
a. Caused by intratubular precipitation of tissue degradation products or precipitation of drugs or
their metabolites
i. Tissue degradation products
(a) Uric acid intratubular precipitation after tumor lysis after chemotherapy
(b) Drug-induced rhabdomyolysis leading to intratubular precipitation of myoglobin
(c) Results in rapid decline in kidney function, with resultant oliguric or anuric kidney
failure
ii. Drug precipitation: Sulfonamides, methotrexate, acyclovir, ascorbic acid; can be
diagnosed by observing needlelike crystals in leukocytes found on urinalysis
b. Prevention includes pretreatment hydration, maintenance of high urinary volume, and
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alkalinization of the urine.

3. Extrarenal urinary tract obstruction
a. Anticholinergics can worsen BPH.
b. Bladder outlet or ureteral obstruction from fibrosis after cyclophosphamide for hemorrhagic
cystitis
4. Nephrolithiasis
a. Usually does not affect GFR, so does not have the classic signs/symptoms of nephrotoxicity
b. Some medications contribute to the formation of kidney stones: Triamterene, sulfadiazine,
indinavir, and ephedrine derivatives.
F. Glomerular Disease
1. Proteinuria is the hallmark sign of glomerular disease and may occur with or without a decrease in
GFR.
2. A few distinct drugs can cause glomerular disease.
a. NSAIDs: Associated with acute allergic interstitial nephritis
b. Heroin: Can be caused by direct toxicity, toxicity from additives, or infection from injection.
End-stage renal disease develops in most cases.
c. Parenteral gold: Results from immune complex formation along glomerular capillary loops
III. CHRONIC KIDNEY DISEASE

A. Background
1. Prevalence: Difficult to assess, according to NHANES (19992004); 16.8% of adults (20 years or
older) have CKD. There were 382,343 prevalent dialysis patients in 2008 (up 3.6% from 2007)
and 165,639 prevalent transplant patients. Incidence rate is relatively flat, so growth in population
of ESRD is mainly because of the longer life span of these patients.
2. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) Advisory
Board recommends a definition of CKD and staging guidelines.
a. Definition
i. Kidney damage for more than 3 months, as defined by structural or functional
abnormality of the kidney, with or without decreased GFR, manifested by either
pathologic abnormalities or markers of kidney damage, including abnormalities in the
composition of blood or urine or abnormalities in imaging tests
ii. GFR less than 60 mL/minute/1.73m2 for 3 months, with or without kidney damage
b. Stages of CKD
i. Stage 1 kidney damage with normal or increased GFR (90 mL/minute/1.73m2 or more)
ii. Stage 2 kidney damage with mild decrease in GFR (6089 mL/minute/1.73m2)
iii. Stage 3 moderate decrease in GFR (3059 mL/minute/1.73m2)
iv. Stage 4 severe decrease in GFR (1529 mL/minute/1.73m2)
v. Stage 5 kidney failure (less than 15 mL/minute/1.73m2 or on dialysis
B. Etiology
1. Diabetes (40% of new ESRD cases in the United States)
2. Hypertension (25% of new cases)
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3. Glomerulonephritis (10%)
4. OthersUrinary tract disease, polycystic kidney disease, lupus, analgesic nephropathy, unknown
C. Risk Factors
1. Susceptibility (associated with an increased risk, but not proved to cause CKD): Advanced age,
reduced kidney mass, low birth weight, racial/ethnic minority, family history, low income or
education, systemic inflammation, and dyslipidemia. Mostly not modifiable
2. Initiation (directly cause CKD): Diabetes, hypertension, autoimmune disease, polycystic kidney
diseases, and drug toxicity. Modifiable by drug therapy
3. Progression (result in faster decline in kidney function): Hyperglycemia, elevated BP, proteinuria,
and smoking
D. Albuminuria/Proteinuria
1. Marker of kidney damage, progression factor, and cardiovascular risk factor. Can be classified as
follows
a. Normal: Albumin excretion less than 30 mg/24 hours
b. Microalbuminuria: 30300 mg/24 hours
c. Macroalbuminuria: (overt proteinuria) more than 300 mg/24 hours. Nephrotic range
proteinuria: More than 3 g/24 hours
2. Assessment for proteinuriaUsually assessed by measurement of urinary albumin-to-creatinine
ratio. Spot urine: Untimed sample is adequate for adults and children (screening test).
E. Assessment of Kidney Function
1. Serum creatinine
a. Avoid use as the sole assessment of kidney function.
b. Depends on age, sex, weight, and muscle mass
c. All laboratories now use standardized Cr traceable to IDMS (isotope dilution mass
spectrometry), which will decrease variability in results between laboratories.
2. Measurement of GFR. Inulin, iothalamate, and others are not routinely used.
3. Measurement of CrCl through urine collection
a. Reserve for vegetarians, patients with low muscle mass, patients with amputations, and
patients needing dietary assessment, as well as when documenting need to start dialysis.
b. Urine collection will give a better estimate in patients with very low muscle mass. In most
cases, equations will overestimate kidney function because Cr concentrations will be low in
patients with very low muscle mass.
4. Estimated using Cockcroft-Gault equation (mL/minute CrCl) Overestimates GFR [(140 age)
body weight]/[SCr 72] (x 0.85 if female)
5. Estimated GFR with MDRD study data equation
a. Estimated GFR (mL/minute/1.73m2) in patients with known CKD (less than 90 mL/minute)
b. Abbreviated MDRD formula correlates well with the original MDRD formula, simpler to use
GFR (mL/minute/1.73m2) = 186 SCr1.154 age0.203 (0.742 if female) (1.21 if African
American). This equation and an adjusted equation for use with standardized creatinine are
available at www.nkdep.nih.gov or www.kidney.org.
c. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Alternative
equation to estimate GFR. See www.kidney.org.
6. CKD-EPI. Relatively new formula. More accurate than MDRD in patients with eGFR greater
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than 60 mL/minute/1.73m2
7. For children, Schwartz and Counahan-Barratt formulas
F. Diabetic Nephropathy
1. Pathogenesis
a. Hypertension (systemic and intraglomerular)
b. Glycosylation of glomerular proteins
c. Genetic links
2. Diagnosis
a. Long history of diabetes
b. Proteinuria
c. Retinopathy (suggests microvascular disease)
3. Monitoring
a. Type IBegin annual monitoring for microalbuminuria 5 years after diagnosis.
b. Type IIBegin annual monitoring for proteinuria immediately (do not know how long they
have had diabetes mellitus).
4. Management/slowing progression
a. Aggressive BP management
i. In patients with diabetes and CKD, target BP is less than 130/80 mm Hg.
ii. ACEIs and ARBs are preferred and should be used with any degree of proteinuria, even if
the patient is not hypertensive. Use moderate to high doses with proteinuria. Hold ACE/
ARB if K is greater than 5.6 or there is a rise in SCr greater than 30% after initiation.
iii. Most patients will require diuretic in combination. (Thiazide with stages 13 and loop in
stages 45.) If BP is greater than 160/100 mm Hg, start with two-drug regimen.
iv. Calcium channel blockers (nondihydropyridine) are second line to ACEIs/ARBs. Data are
emerging for combined therapy.
v. Dietary sodium less than 2.4 g/day. Modify DASH to limit K.
b. Intensive blood glucose control. Glycosylated hemoglobin less than 7%. Less aggressive with
more advanced CKD
c. Protein restrictionThere are insufficient data in diabetes, but 0.8 g/kg day might slightly
reduce progression and decrease risk of ESRD. Patients should avoid high-protein diets.
G. Nondiabetic Nephropathy
1. Manage hypertension. If proteinuric and hypertensive, use ACE and ARB. Often need to add (or
start with) combination. Diuretic is usual second drug.
2. Minimize protein in diet. Controversial. May slow progression on the basis of MDRD study but
may also impair nutrition. Very low-protein diet may increase mortality.
H. Other Guidelines to Slow Progression
1. Manage hyperlipidemia. Follow National Cholesterol Education Program guidelines. Goal is lowdensity lipoprotein less than 100. Statins are first line.
2. Stop smoking.
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IV. RENAL REPLACEMENT THERAPY

A. Indications for RRT
1. A acidosis (not responsive to bicarbonate)
2. E electrolyte abnormality (hyperkalemia; hyperphosphatemia)
3. I intoxication (boric acid; ethylene glycol; lithium; methanol; phenobarbital; salicylate;
theophylline)
4. O fluid overload (symptomatic [pulmonary edema])
5. U uremia (pericarditis and weight loss)
B. Two Primary Modes of Dialysis
1. HemodialysisMost common modality
2. Peritoneal dialysis
C. Hemodialysis (intermittent for ESRD)
1. Access
a. Arteriovenous fistulaPreferred access
i. Natural, formed by anastomosis of artery and vein
ii. Lowest incidence of infection and thrombosis, lowest cost, longest survival
iii. Takes weeks/months to mature
b. Arteriovenous graft
i. Synthetic (polytetrafluoroethylene)
ii. Often used in patients with vascular disease
c. Catheters
i. Commonly used if permanent access not available
ii. Problems include high infection and thrombosis rates. Low bloodflow leads to inadequate
dialysis.
2. Dialysis membranes
a. ConventionalNot used much anymore. Small pores. Made of cuprophane
b. High flux and high efficiencyLarge pores. Can remove drugs that were impermeable to
standard membranes (vancomycin). Large amounts of fluid removal (ultrafiltrate)
3. Adequacy
a. Kt/VUnitless parameter. K = clearance, t = time on dialysis, and V = volume of distribution
of urea. The KDOQI set goal of 1.2 or more.
b. URRUrea reduction ratio. URR = BUN post/BUN pre 100%. Goal is URR greater than
65%.
4. Common complications of HD
a. Intradialytic
i. HypotensionPrimarily related to fluid removal. Common in people who are elderly and
people with diabetes mellitus. Treatment: Limit fluid gains between sessions; give normal
or hypertonic saline, midodrine. Less well-studied agents include fludrocortisone,
selective serotonin reuptake inhibitors
ii. CrampsVitamin E or quinine (controversial because of adverse effect profile)
iii. Nausea/vomiting
iv. Headache/chest pain/back pain
b. Vascular access complicationsMost common with catheters
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i. InfectionS. aureus. Need to treat aggressively. May need to remove catheter

ii. ThrombosisSuspected with low bloodflow. Oral antiplatelets for prevention not used
because of lack of efficacy. Can treat with alteplase 1 mg per lumen
5. Factors that affect efficiency of HD
a. Type of dialyzer used (changes in membrane surface area and pore size)
b. Therapy length
c. Dialysis flow rate
d. Bloodflow rate
D. Continuous HD for AKI
1. CAVH/CVVH (continuous arteriovenous hemofiltration/continuous veno-venous hemofiltration).
Removes fluid and solutes by dialysis. CAVH differs from CVVH because VV access requires
an in-line pump. Used primarily when fluid removal is most important
2. CVVHD/CAVHD: D is dialysate, which flows in countercurrent to bloodflow. Fluid and solute
removal are greater with this procedure. Used when there is a need for fluid removal and better
solute clearance
E. Peritoneal Dialysis
1. Peritoneal dialysis membrane is 12 m2 (approximates the body surface area) and consists of the
vascular wall, the interstitium, the mesothelium, and the adjacent fluid films. From 1.5 to 3 L of
peritoneal dialysate fluid may be instilled in the peritoneum (fill), allowed to dwell for a specified
time, and then drained.
2. Solutes and fluid diffuse across the peritoneal membrane.
3. Peritoneal dialysis is usually not used to treat AKI in adults.
4. Peritonitis
a. Infection of the peritoneal cavity. Patient technique and population variables influence the
infection rate. Elderly patients or those with diabetes have a higher infection rate. Peritonitis
is a major cause of failure of peritoneal dialysis.
b. Treatment
i. Most common gram-positive organisms include Staphylococcus epidermis, S. aureus,
and streptococci. Most common gram-negative organisms include Escherichia coli and
Pseudomonas aeruginosa.
ii. Empiric treatment should cover gram-positive and gram-negative bacteria. Adjust as
needed.
5. Types of peritoneal dialysis
a. Continuous ambulatory peritoneal dialysis. Classic. Requires mechanical process, which
requires many manual changes throughout the day. Can be interruptive to daytime routine
b. Automated peritoneal dialysis. Many variants exist, but continuous cycling peritoneal dialysis
is the most common. Patient undergoes many exchanges during sleep by a cycling machine.
May have one or two dwells during day. Minimizes potential contamination. Lowest
incidence of peritonitis
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V. COMPLICATIONS OF CKD
A. Anemia
1. Several factors are responsible for anemia in CKD: Decreased erythropoietin production (most
important), shorter life span of red blood cells (RBCs), blood loss during dialysis, iron deficiency,
anemia of chronic disease, and renal osteodystrophy
2. Prevalence: 26% of patients with a GFR greater than 60 mL/minute have anemia versus 75%
of patients with a GFR less than 15 mL/minute.
3. Signs and symptoms. Symptoms of anemia of CKD are similar to anemia associated with other
causes.
4. TreatmentTreatment of anemia in CKD can decrease morbidity/mortality, reduce left
ventricular hypertrophy, increase exercise tolerance, and increase quality of life. Recent studies
have suggested that treatment to high hemoglobin concentrations (greater than 13 g/dL) increases
cardiovascular events. Most recently, TREAT (Trial to Reduce Cardiovascular Events with
Aranesp Therapy) failed to show a benefit in outcomes but was associated with increased stroke
(N Engl J Med 2009;361).
a. Anemia workupInitiate evaluation when CrCl is less than 60 mL/minute or hemoglobin is
less than 10 g/dL.
i. Hemoglobin/hematocrit
ii. Mean corpuscular volume
iii. Reticulocyte count
iv. Iron studies
(a) Transferrin saturation (total iron/total iron-binding capacity)Assesses available iron
(b) FerritinMeasures stored iron
v. Stool guaiac
b. Erythropoiesis-stimulating agents (ESAs). Note: ESAs are now under the FDAs Risk
Evaluation and Mitigation Strategy program.
i. Epoetin-
(a) Same molecular structure as human erythropoietin (recombinant DNA technology)
(b) Binds to and activates erythropoietin receptor
(c) Administered subcutaneously or intravenously
ii. Darbepoetin-
(a) Molecular structure of human erythropoietin has been modified from 3 N-linked
carbohydrate chains to 5 N-linked carbohydrate chains; increased duration of activity.
The advantage is less-frequent dosing.
(b) Binds to and activates erythropoietin receptor
(c) May be administered subcutaneously or intravenously. Initial dose 0.45 mcg/kg/week;
typically 40 mcg
c. Goal hemoglobin. Because of concern about high hemoglobin concentrations, the 2007 update
to the KDOQI guidelines suggests a goal of 1112 g/dL and the avoidance of a hemoglobin
concentration greater than 13 g/dL. Since June 2011, the FDA-approved product prescribing
information has recommended using the lowest dose sufficient to reduce the need for red
blood cell transfusions. The product label further states that in controlled trials with CKD
patients, patients experienced greater risks for death, serious adverse cardiovascular reactions,
and stroke when administered ESAs to target a hgb level of > 11 g/dL. More recently, the
KDIGO guidelines recommend that for CKD ND (non-dialysis) patients, ESA therapy not be
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d.
e.
f.
g.
initiated with Hb concentration 10 g/dL. With Hb Concentration <10 g/dL, decision to start
ESA should be individualized based on the rate of Hb concentration, prior response to iron
therapy, risk of needing a transfusion, the risks related to ESA therapy and the presence of
symptoms attributable to anemia. For CKD 5D (dialysis) patients, ESA therapy should be
started when the Hb is between 9 and 10 g/dL. Individualization of therapy is reasonable for
improvement of quality of life in some patients with Hb >10 g/dL.
ESA dose adjustment is based on hemoglobin response.
i. Adjustment parameters are the same for epoetin- and darbepoetin-.
ii. Dosage adjustments upward should not be made more often than every 4 weeks. In
general, dose adjustments are made in 25% intervals.
ESA monitoring
i. Hemoglobin concentrations initially every 12 weeks and then every 24 weeks when
stable
ii. Monitor BP because it may rise (treat as necessary).
iii. Iron stores
(a) Ferritin: HD target is 200500, and peritoneal dialysis/CKD target is 100500.
(b) Transferrin saturation target is greater than 20% (upper limit of 50% removed
from recent guidelines).
Common causes of inadequate response to ESA therapy:
i. Iron deficiency is the most common cause of erythropoietin resistance. Increased use of
intravenous iron products has reduced this problem, however.
ii. Infection and inflammation
iii. Other causes include chronic blood loss, renal bone disease, aluminum toxicity, folate or
vitamin B12 deficiency, malignancies, malnutrition, hemolysis, and vitamin C deficiency.
Iron therapy
i. Most patients with CKD who are receiving erythropoietic therapy require parenteral iron
therapy to meet needs (increased requirements, decreased oral absorption).
ii. For CKD patients not on iron or ESA therapy, KDIGO guidelines recommend a trial of
IV iron (or in CKD ND patients, alternatively, a 1-3 month trial of oral iron therapy) if an
increase of Hb without starting ESA is desired and when the TSAT is 30% and ferritin is
500 ng/mL.(guideline 2.1.2)
iii. For CKD patients on ESA therapy, KDIGO guidelines recommend a trial of IV iron (or in
CKD ND patients, alternatively, a 1-3 month trial of oral iron therapy) if an increase of
Hb or reduction in ESA dose is desired and when the TSAT is 30% and ferritin is 500
ng/mL. (guideline 2.1.3)
iv. Follow transferrin saturation and ferritin as noted during erythropoietic therapy.
v. Four commercial iron preparations are approved in the United States (Table 2).
vi. IV iron therapy is more effective in CKD 5 patients (both HD and PD). Oral iron
therefore not recommended for these patients. For CKD ND patients, the advantage of IV
over oral therapy is rather small. The route of iron administration can therefore be IV or
oral.
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Table 2. Iron Therapy

Iron Dextran
Replacement therapy IVP: 100 mg IV 3 times/ week
%TSAT
during HD for 10 doses (1 g)
< 20% and ferritin
IVPB: 5001000 mg in 250
< 100 200 mg/dL
mL of NSS infused for at
least 1 hour (option for nonHD patients)
Ferric Gluconate
125 mg IV 3
times/week during
HD for eight
doses (1 g)
Iron Sucrose
100 mg IV 3
times/week during
HD for 10 doses
(1 g)
For nondialysis
CKD, 200 mg IV
5 doses
Ferumoxytol
510 mg at up to
30 mg/second,
followed by a
second 510-mg IV
dose 38 days later
(all CKD)
Maintenance
therapy (iron stores
in goal)
25100 mg/week IV
10 weeks
31.25125 mg/
week IV 10
weeks
25100 mg/week
IV 10 weeks
N/A
Iron overload
%TSAT > 50% and/
or ferritin > 500
Hold therapy
Hold therapy
Hold therapy
Hold therapy
Initial test dose
Yes; 25-mg one-time test dose
No
No
No
CKD = chronic kidney disease; HD = hemodialysis; IV = intravenous; IV P = IV push; IV PB = IV piggyback; N/A = not
applicable; NSS = normal saline solution; TSAT = transferrin saturation.
B. CKD-Mineral Bone Disorder and Secondary Hyperparathyroidism

1. Pathophysiology: Calcium and phosphorus homeostasis is complex, involving the interplay of
hormones affecting the bone, gastrointestinal (GI) tract, kidneys, and parathyroid hormone (PTH).
Process may begin as early as GFR 60 mL/minute. The most important driving force behind the
process is hyperphosphatemia. Nephron loss: Decreased production of 1,25-dihydroxyvitamin D3
and phosphate retention. Increased phosphorus concentrations cause 1) an inhibition of vitamin D
activation, reducing absorption of calcium in the gut; 2) a decrease in ionized (free) calcium
concentrations; and 3) direct stimulation of PTH secretion. Elevated PTH concentrations cause
decreased reabsorption of phosphorus and increased reabsorption of calcium in the proximal tube.
This adaptive mechanism is lost as the GFR falls below 30 mL/minute. Important: Calcium is not
well absorbed through the gut at this point, and calcium concentrations are maintained by
increased bone resorption through elevated PTH. Unabated calcium loss from the bone results in
renal osteodystrophy.
2. Prevalence
a. Major cause of morbidity and mortality in patients undergoing dialysis
b. Very common
3. Signs and symptoms
a. Insidious onset: Patients may experience fatigue and musculoskeletal and GI pain;
calcification may be visible on radiography; bone pain and fractures can occur if progression
is left untreated.
b. Laboratory abnormalities
i. Phosphorus
ii. Corrected calcium
iii. Intact PTH
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4. Treatment
a. Therapy goalsTable 3
Table 3. KDOQI Guidelines for Calcium, Phosphorus, Ca x PO4 Product, and PTH in CKD Stages 35
Calcium (mg/dL)
Phosphorus (mg/dL)
Ca PO4 product
PTH (pg/mL)
a
CKD Stage 3
Normal
2.74.6
< 55
3570
CKD Stage 4
Normal
2.74.6
< 55
70110
CKD Stage 5
8.49.5
3.55.5
< 55
150300
a
Use corrected calcium = serum calcium + (0.8 [4.0 patient albumin]).
CKD = chronic kidney disease; KDOQI = Kidney Disease Outcomes Quality Initiative; PO4 = phosphate; PTH = parathyroid
hormone.
b. Nondrug therapy
i. Dietary phosphorus restriction 8001200 mg/day in stage 3 CKD or higher
ii. Dialysis removes various amounts of phosphorus depending on treatment modalities but,
by itself, is insufficient to maintain phosphorus balances in most patients.
iii. Parathyroidectomy. Reserved for patients with unresponsive hyperparathyroidism
c. Drug therapy
i. Phosphate binders: Take with meals to bind phosphorus in the gut; products from
different groups may be used together for additive effect.
(a) Aluminum-containing phosphate binders (aluminum hydroxide, aluminum carbonate,
and sucralfate). Effectively lowers phosphorus concentrations. In general, avoid. Not
used as often because of aluminum toxicity (adynamic bone disease, encephalopathy,
and erythropoietin resistance)
(b) Calcium-containing phosphate binders (calcium carbonate and calcium acetate)
(1) Widely used phosphate binder. Calcium binders are initial binder of choice
for stage 3 and 4 CKD. Calcium (or nonionic binders) is considered initial binder
of choice in stage 5 CKD. Carbonate salt is relatively inexpensive.
(2) Carbonate is also used to treat hypocalcemia, which sometimes occurs in patients
with CKD, and can decrease metabolic acidosis.
(3) Calcium acetate: 667-mg capsule contains 167 mg of elemental calcium.
Better binder than carbonate, so less calcium given
(4) Use may be limited by development of hypercalcemia.
(5) Total elemental calcium is 2000 mg/day (1500-mg binder; 500-mg diet).
(c) Sevelamer: A nonabsorbable phosphate binder
(1) Effectively binds phosphorus
(2) As with calcium, considered primary therapy in CKD stage 5. In particular,
consider if calcium x phosphorus product is greater than 55 mg2/dL2 or if
calcium intake exceeds recommended dose with calcium-containing binders.
(3) Decreases low-density lipoprotein cholesterol and increases high-density
lipoprotein cholesterol
(4) Hypocalcemia may occur if sevelamer is sole phosphate binder. Metabolic
acidosis may worsen with sevelamer HCl.
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(5) Available as sevelamer HCl (Renagel) and sevelamer carbonate (Renvela)

(d) Lanthanum carbonate:
(1) As effective as aluminum in phosphate-binding capability. Not widely used, but
indications similar to sevelamer
(2) Tasteless, chewable wafer
(3) Consider using if calcium phosphorus is more than 55 mg2/dL2.
(e) There are no data to support that any phosphate binder is superior to another in
clinical outcomes (mortality or hospitalization). However, sevelamer and lanthanum
do cause less hypercalcemia and reduce calcium burden.
ii. Vitamin D analogs: Suppress PTH synthesis and reduce PTH concentrations; therapy is
limited by resultant hypercalcemia, hyperphosphatemia, and elevated calcium x
phosphorus product. Products include calcitriol, doxercalciferol, and paricalcitol.
(a) Calcitriol, the pharmacologically active form of 1,2-hydroxyvitamin D3, is FDA label
approved for the management of hypocalcemia and the prevention and treatment of
secondary hyperparathyroidism.
(1) Oral and parenteral formulations
(2) Does not require hepatic or renal activation
(3) Low-dose daily oral therapy reduces hypocalcemia but does not reduce PTH
concentrations significantly.
(4) High incidence of hypercalcemia limiting PTH suppression
(5) Dose adjustment at 4-week intervals
(b) Paricalcitol: Vitamin D analog; FDA label approved for the treatment and prevention
of secondary hyperparathyroidism
(1) Parenteral and oral formulation
(2) Does not require hepatic or renal activation
(3) Lower incidence of hypercalcemia (decreased mobilization of calcium from the
bone and decreased absorption of calcium from the gut)
(c) Doxercalciferol: Vitamin D analog; FDA label approved for the treatment and
prevention of secondary hyperparathyroidism
(1) Parenteral and oral formulations
(2) Prodrug, requires hepatic activation; may have more physiologic levels
(3) Lower incidence of hypercalcemia (decreased mobilization of calcium from the
bone and decreased absorption of calcium from the gut)
iii. Cinacalcet HCl: A calcimimetic that attaches to the calcium receptor on the parathyroid
gland and increases the sensitivity of receptors to serum calcium concentrations, thus
reducing PTH. Especially useful in patients with high calcium/ phosphate concentrations
and high PTH concentrations when vitamin D analogs cannot be used
(a) The initial dose is 30 mg, irrespective of the patients PTH concentration.
(b) Monitor serum calcium every 12 weeks (risk of hypocalcemia is about 5%); do not
start therapy if serum calcium is less than 8.4 mg/dL.
(c) Can be used in patients irrespective of phosphate binder or vitamin D analog use
(d) Caution in patients with seizure disorder (hypocalcemia may exacerbate)
(e) Adverse effects are nausea (30%) and diarrhea (20%).
(f ) Cinacalcet inhibits cytochrome P450 (CYP) 2D6 metabolism, thereby inhibiting the
metabolism of CYP2D6 substrates such that dose reductions in drugs
with narrow therapeutic indexes may be required (e.g., flecainide, tricyclic
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antidepressants, thioridazine).
(g) Cinacalcet is primarily metabolized by CYP3A, so drugs that are potent inhibitors of
CYP3A (ketoconazole) may increase cinacalcet concentrations up to 2-fold
VI. ASSESSMENT OF RENAL FUNCTION

A. Tubular Secretion Is Usually Maintained Even as Kidney Function Declines.
B. GFR is the most important aspect of kidney function with respect to adjustment of drug dosing, and it
cannot be measured easily by direct measures.
C. Creatinine
1. Creatinine is a product of creatine metabolism from the muscle.
2. Production is dependent on muscle mass.
3. Creatinine is freely filtered and not reabsorbed.
a. A small quantity of creatinine is secreted (about 10%) in healthy adults.
b. Secretion is maintained even at lower GFRs; consequently, creatinine secretion
accounts for a larger percentage of creatinine in urine at lower GFRs (which leads to an
overestimation of GFR).
4. Several factors affect creatinine.
a. Age Less muscle tissue as we age; hence, less creatinine produced. A little old lady with
an SCr of 0.2 mg/dL does NOT have great renal function; rather, she has little muscle mass.
b. Body mass Controversy is related to this aspect. Increased muscularity means more
creatinine, but fat does not produce creatinine.
i. Obese individuals often have a little more muscle to haul around their extra fat.
ii. Nonetheless, most CrCl estimates use IBW (see Cockcroft-Gault below).
iii. Special equations have been developed for special populations (e.g., obese individuals,
paraplegics, children [because of their differing muscle masses]).
c. Sex Men typically have more muscle mass than do women.
d. Diets high in meats Creatinine from ingested muscle can appear in the urine.
e. Drugs affecting creatinine secretion (e.g., cimetidine, trimethoprim, probenecid) will raise SCr
values, resulting in falsely low estimates of CrCl when only SCr is used in the calculation.
D. Equation-Based Methods to Estimate CrCl and/or GFR
1. All equations assume that a patient is at a steady state and that renal function usually is not
changing rapidly. In the ambulatory care setting, this is usually a reasonable assumption; in the
critical care environment, it is not.
a. Cockcroft-Gault:
[(140-age (years)) x IBW (kg) / 72 x SCr (mg/dL)] 0.85 for females = CrCl
IBW
Male IBW = 50 kg + 2.3 (for every inch greater than 5 feet tall)
Female IBW = 45 kg + 2.3 (for every inch greater than 5 feet tall)
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b. MDRD 4-factor equation

GFR (mL/minute/1.73m2) = 186 (SCr)-1.154 (age) - 0.203 (0.742 if female) (1.212 if
African American) (conventional units)
i. MDRD is usually the basis for the estimated GFR (eGFR) that appears in patient charts.
For the past few years, laboratories have included an eGFR in all patient charts.
ii. The equation does not require weight because the results are reported normalized to
1.73m2 of body surface area, which is an accepted average adult surface area. MDRD
underestimates eGFR for heavy people and overestimates it for underweight people.
MDRD tends to underestimate the GFR in healthy patients with GFRs greater than 60
mL/minute.
c. CKD-EPI equation (Ann Intern Med 2009;150:60412) The CKD-EPI equation, expressed as
a single equation, is:
GFR = 141 min(SCr/,1) max(SCr/,1)-1.209 0.993Age 1.018 [if female] 1.159 [if
African American]
where SCr is serum creatinine (mg/dL), is 0.7 for females and 0.9 for males, is 0.329 for
females and 0.411 for males, min indicates the minimum of SCr/ or 1, and max indicates
the maximum of SCr/ or 1.
d. Jeliffe Use when height and weight in adults are unavailable.
CrCl (male) = 98 0.8(age in years 20)/SCr
CrCl (female) = 88 0.7(age in years 20)/SCr
e. Salazar-Corcoran This equation was developed from data derived from obese individuals.
Drug-dosing guidelines do not mention using this method to dose drugs, but it is provided
here for when data from a morbidly obese patient yield non-believable results with one of the
above methods.
Estimating CrCl (milliliters per minute)
For men:
[137 age] [(0.285 weight (kg)) + (12.1 height (m)2)]
-----------------------------------------------------------------------(51 SCr)
For women:
[146 age] [(0.287 weight (kg)) + (9.74 height (m)2)]
----------------------------------------------------------------------(60 SCr)
Units: Weight: kg; height: meters
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f.
Schwartz equation Preferred pediatric method to estimate CrCl
CrCl = (k* Ht (cm))

SCr (mg/dL)
*k = is dependent on
Infant (low birth weight less than 1 year), k = 0.33
Infant (term less than 1 year), k = 0.45
Child or adolescent girl, k = 0.55
Adolescent boy, k = 0.70
Original Schwartz Equation

Updated Schwartz Equation: Bedside Schwartz Equation
GFR (mL/minute/1.73m2) = (0.41 height in cm)/SCr in mg/dL
http://nkdep.nih.gov/professionals/gfr_calculators/idms_schwartz.htm
2. Most drug doses have been designed using the Cockcroft-Gault equation, even though this method
is likely less accurate than the MDRD equation, creating confusion regarding which method to
use clinically (Dowling TC, et al. Evaluation of renal drug dosing: prescribing information and
clinical pharmacist approaches. Pharmacotherapy 2010;30:77686).
E. Direct Measurements of CrCl
1. Direct measurements require a timed urine collection, often 1224 hours. This is usually not
practical, especially in the ambulatory care environment.
2. Sources of error even in timed urine measurements are incomplete urine collection and
mistimed collection.
3. Some creatinine is secreted; consequently, directly measured urinary CrCl probably overestimates
GFR, especially at lower GFRs (secretion is relatively well maintained even at low GFRs).
4. Cystatin C is a protein secreted by many cells (an inhibitor of cysteine protease) that is freely
filtered at the glomerulus and not reabsorbed. Some studies have shown the utility of cystatin C
measurement in the urine, but all the problems associated with a timed collection of urine will
remain.
5. Inulin (administered exogenously) Seldom done anymore except in research application
VII. DOSAGE ADJUSTMENTS IN KIDNEY DISEASE

A. Dosages of many drugs will require adjustment to prevent toxicity in patients with CKD; adjustment
strategies will vary, depending on whether the patient is receiving RRT and, if so, the type of RRT.
The National Kidney Disease Education Program of the National Institutes of Health/National
Institute of Diabetes and Digestive and Kidney Diseases suggests that either eGFR or eCrCl be used
for drug dosing. If using eGFR in very large or small patients, the eGFR should be multiplied by the
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actual body surface area to obtain eGFR in milliliters per minute.

B. Pharmacokinetic Principles Can Guide Therapy Adjustments.
1. Absorption Oral absorption can be decreased.
a. Nausea and vomiting
b. Increased gastric pH (uremia)
c. Edema
d. Physical binding of drugs to phosphate binders
2. Distribution
a. Changes in concentrations in highly water-soluble drugs occur as extracellular fluid status
changes.
b. Acidic and neutral protein-bound drugs are displaced by toxin buildup. Other mechanisms
include conformational changes of the plasma proteinbinding site. Phenytoin is a classic
example. The normal free fraction of phenytoin is 10%. Free fraction can be as high as
25%30% in patients with ESRD and hypoalbuminemia.
i. Hypoalbuminemia correction
Concentration adjusted = concentration measured/[(0.2 measured albumin) + 0.1]
ii. Renal failure adjustment
Concentration adjusted = concentration measured/[(0.1 measured albumin) + 0.1]
iii. Patients will have lower total concentrations despite having adequate free concentrations.
(Increased free fraction)
iv. Dosage adjustment of phenytoin not needed, just a different approach to evaluating
concentrations
3. Metabolism. Variable changes can occur with uremia. Metabolites can accumulate.
4. Excretion Decreased
C. Pharmacodynamic Changes Can Also Occur (e.g., patients with CKD can be more sensitive to
benzodiazepines).
D. General Recommendations:
1. Patient history and clinical data
2. Estimate CrCl ( Jeliffe or Brater in AKI; Cockcroft-Gault or MDRD study equations in stable
kidney function).
3. Identify medications that require modification (Table 4).
Table 4. Dose Adjustments in Decreased Kidney Function
Agent
Antibiotics
Dose Adjustment
Almost all antibiotics will require dosage adjustment (exceptions: cloxacillin, clindamycin,
linezolid, metronidazole, and macrolides)
Cardiac
medications
Atenolol, ACEIs, digoxin, nadolol, sotalol; avoid potassium-sparing diuretics if CrCl

< 30 mL/minute
Lipid-lowering
h
Narcotics
Clofibrate, fenofibrate, statins

Codeine, avoid meperidine; other agents may also accumulate
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Table 4. Dose Adjustments in Decreased Kidney Function

Agent
Dose Adjustment
Antipsychotic/
antiepileptic
Chloral hydrate, gabapentin, lithium, paroxetine, primidone, topiramate, trazodone, vigabatrin
Hypoglycemic
Antiretrovirals
Acarbose, chlorpropamide, glyburide, glipizide, insulins, and metformin

Individualize therapy: Monitor CD4 counts, viral load, and adverse effects (agents requiring dose
adjustment: lamivudine, adefovir, didanosine, stavudine, tenofovir, zalcitabine, and zidovudine)
Miscellaneous
Allopurinol, colchicine, H2-receptor antagonists, diclofenac, ketorolac, and terbutaline
ACEIs = angiotensin-converting enzyme inhibitors; CrCl = creatinine clearance.
4. Calculate drug doses individualized for the patient.

a. Published data
b. Rowland-Tozer estimate
i. Q = 1 [Fe(1 KF)]
ii. Q = kinetic parameter or drug dose adjustment factor
iii. Fe = fraction of drug excreted unchanged in the urine
iv. KF = ratio of patients CrCl to normal (120 mL/minute)
5. Monitor patient (e.g., kidney function, clinical parameters) and drug concentration (if applicable).
6. Revise regimen as appropriate.
E. Drug Dosing in HD
1. Dosing changes in HD patients may be necessary because of accumulation caused by kidney
failure AND/OR because the procedure may remove the drug from the circulation.
2. Drug-related factors affecting drug removal during dialysis:
a. Molecular weightWith high-flux membranes, larger molecules (such as vancomycin)
can be removed.
b. Water solubleNon-soluble drugs not likely removed
c. Protein bindingBecause albumin cannot pass through membranes, protein-bound drugs
cannot either.
d. Volume of distributionDrugs with a small Vd (less than 1 L/kg) available in central
circulation for removal. Drugs with large Vd cannot be removed (digoxin and tricyclic
antidepressants), even if the protein binding is very low.
3. Procedure-related factors affecting drug removal
a. Type of dialyzerHigh flux widely used now
b. Bloodflow rate. Increased rates will increase delivery and maintain gradient across membrane.
c. Duration of dialysis session
d. Dialysate flow rate. High rates of flow will increase removal by maintaining the gradient
across membranes
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REFERENCES
1.
2.
3.
National Kidney Foundations Kidney Disease

Outcomes Quality Initiative (NKF
KDOQI) Guidelines. Available at
http://www.kidney.org/professionals/KDOQ/
guidelines_commentaries.cfm.
Accessed February 18, 2013.
Kidney Disease Improving Global Outcomes
(KDIGO) Clinical Practice Guide lines.
Available at http://www.kdigo.org/clinical_
practice_guidelines/index.php. Accessed February
18, 2013.
National Kidney Disease Education Program.
Available at www.nkdep.nih.gov/.Accessed
February 18, 2013.
EBSCO Publishing, 2010. Available at http://dynaweb.ebscohost.com/

Detail?id=AN+566508&sid=83c84372-f322416d-97d3e545dcf064d4@sessionmgr10.
Subscription required.
Drug-Induced Kidney Damage
1. Nolin TD, Himmelfarb J. Drug-induced kidney
disease. In: DiPiro JT, Talbert RL, Yee GC, et al,
eds. Pharmacotherapy: A Pathophysiologic
Approach, 8th ed. New York: McGraw-Hill,
2011:81936.
2. Schweiger MJ, Chambers CE, Davidson
CJ, et al. Prevention of contrast induced nephropathy: recommendations for the high risk
patient undergoing cardiovascular procedures.
Catheter Cardiovasc Interv 2007;69:13540.
Acute Kidney Injury

1. Dager W, Halilovic J. Acute renal failure. In:
DiPiro JT, Talbert RL, Yee GC, et al, eds.
Pharmacotherapy: A Pathophysiologic Approach, 8th ed. New York: McGraw-Hill,
2008:74165.
2. Bellomo R, Ronco C, Kellum JA, et al; the ADQI
workgroup. Acute renal failure definition,
outcome measures, animal models, and
information technology needs: the Second
International Consensus Conference of the Acute
Dialysis Quality Initiative (ADQI) Group. Crit
Care 2004;8:R204R212.
3. Kellum JA. Acute kidney injury. Crit Care
Med 2008;36:S141S145.
4. Mehta RL, Kellum JA, Shah SV, et al. Acute
kidney injury network: report of an initiative to
improve outcomes in acute kidney injury. Crit
Care 2007;11:R31.
5. Stamatakis MK. Acute kidney injury. In:
Chisholm-Burns MA, Wells BG, Schwinghammer TL, et al, eds. Pharmacotherapy:
Principles and Practice. New York: McGrawHill, 2010:chap 25.
6. Ympa YP, Sakr Y, Reinhart K, Vincent JL.
Has mortality from acute kidney injury decreased? A systematic review of the literature.
Am J Med 2005;118:82732.
7. Acute Renal Failure. In: DynaMed [database on the Internet]. Ipswich, MA:
Chronic Kidney Disease

1. Derebail VK, Kshirsagar AV, Joy MS. Chronic
kidney disease: progression-modifying therapies.
In: DiPiro JT, Talbert RL, Yee GC, et al, eds.
Pharmacotherapy: A Pathophysiologic Approach,
8th ed. New York: McGraw-Hill,
2011:76786.
2. Hudson JQ. Chronic kidney disease: management of complications. In: DiPiro JT, Talbert RL,
Yee GC, et al, eds. Pharmacotherapy:
A Pathophysiologic Approach, 8th ed. New
York: McGraw-Hill, 2011:787816.
3. Schonder KS. Chronic and end-stage renal disease.
In: Chisholm-Burns MA, Wells BG,
Schwinghammer TL, et al, eds. Pharmacotherapy:
Principles and Practice. New York: McGraw-Hill,
2010:chap 26.
4. National Kidney Foundation. KDOQI.
Clinical Practice Guidelines and Clinical
Practice Recommendations for diabetes and
chronic kidney disease. Am J Kidney Dis
2007;49(Suppl 2):S1S180.
5. National Kidney Foundation. KDOQI. Clinical
Practice Guidelines on hypertension and
antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004;43(Suppl 5):S1.
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Nephrology
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Renal Replacement Therapy

1. Sowinski KM, Churchwell MD. Hemodialysisand
peritoneal dialysis. In: DiPiro JT, Talbert RL, Yee
GC, et al, eds. Pharmacotherapy: A
Pathophysiologic Approach, 8th ed. New York:
McGraw-Hill, 2011:8178.
2. Li PK, Szeto CC, Piraino B, et al.
Peritoneal dialysis-related infections
recommendations: 2010 update. Perit Dial
Int 2010;30:393423.
Drug Therapy Adjustment in CKD

1. Kappel J, Calissi P. Nephrology: 3. Safe drug
prescribing for patients with renal insufficiency.
Can Med Assoc J 2002;166:4737.
2. Matzke GR, Frye RF. Drug therapy individualization for patients with chronic kidney disease.
In: DiPiro JT, Talbert RL, Yee GC, et
al, eds. Pharmacotherapy: A Pathophysiologic
Approach, 8th ed. New York: McGraw-Hill,
2011:86172.
3. Chronic Kidney Disease and Drug Dosing.
Information for Providers. Available at www.
nkdep.nih.gov/resources/CKD-drug-dosing.
shtml. Accessed June 11, 2012.
Complications of CKD
1. Hudson JQ. Chronic kidney disease: management
of complications. In: DiPiro JT, Talbert RL, Yee
GC, et al, eds. Pharmacotherapy:
A Pathophysiologic Approach, 8th ed. New
2. Schonder KS. Chronic and end-stage renal
disease. In: Chisholm-Burns MA, Wells BG,
Schwinghammer TL, et al, eds. Pharmacotherapy: Principles and Practice. New York:
McGraw-Hill, 2010:chap 26.
Assessment of Renal Function
1. Dowling TC, Matzke GR, Murphy JE,
Burckart GJ. Evaluation of renal drug dosing:
prescribing information and clinical
pharmacist approaches. Pharmacotherapy
2010;30:77686.
2. Nyman HA, Dowling TC, Hudson JQ , Peter WL,
Joy MS, Nolin TD. Comparative evaluation of the
Cockcroft-Gault equation and
the Modification of Diet in Renal Disease
(MDRD) study equation for drug dosing: an
opinion of the Nephrology Practice and
Research Network of the American College of
Clinical Pharmacy. Pharmacotherapy
2011;31:113044.
3. Mueller BA, Smoyer WE. Challenges in developing evidence-based drug dosing guidelines
for adults and children receiving renal
replacement therapy. Clin Pharmacol Ther
2009;86:47982.
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ENDOCRINOLOGY
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Endocrinology
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1. Differentiate between the diagnostic and classification criteria for various metabolic and endocrine
disorders including type 1 and 2 diabetes mellitus, disorders of the thyroid gland, and syndrome of
inappropriate antidiuretic hormone secretion.
2. Compare and contrast the various therapeutic agents used in treating endocrine and metabolic disorders.
3. Select appropriate treatment and monitoring options for a given patient presenting with one of the
above disorders.
4. Recommend appropriate therapeutic management for secondary complications from diabetes or thyroid disorders.
I. DIABETES MELLITUS
A. Consensus Recommendations
1. American Diabetes Association. Updated yearly in the January supplement of Diabetes Care
(www.diabetes.org)
2. American College of Endocrinology/American Association of Clinical Endocrinologists
(ACE/AACE)
3. Canadian Diabetes Association
4. Various European groups
5. For the remainder of this section, unless otherwise noted, we will follow the American
Diabetes Association recommendations.
B. Classification
1. Type 1 diabetes mellitus (DM)
a. Attributable to cellular-mediated -cell destruction leading to insulin deficiency (insulin
required for survival)
b. Accounts for 5%10% of DM
c. Formerly known as insulin-dependent diabetes, juvenile-onset diabetes
d. Prevalence in the United States: 0.12%, 340,000 in the United States
e. Usually presents in childhood or early adulthood but can present in any stage of life
f. Usually symptomatic with a rapid onset in childhood but can be slower in older adults
2. Type 2 DM
a. Result of insulin resistance with subsequent defect in insulin secretion
b. Accounts for 90%95% of DM
c. Formerly known as noninsulin-dependent diabetes, adult-onset diabetes
d. Prevalence in the United States: 7.8%, 23.6 million (and growing!)
e. Often relatively asymptomatic with a slow onset. Cause for improved screening (below)
and assessment for complications at diagnosis
f. Disturbing trends in type 2 DM in children and adolescents attributable to increase in
obesity
3. MODY (maturity-onset diabetes of the young)
a. Result of genetic disorder leading to impaired secretion of insulin with little or no
impairment in insulin action
b. Onset usually before age 25 and may mimic either type 1 or 2 DM
4. Gestational diabetes
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Endocrinology
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a. Glucose intolerance occurring during pregnancy

b. Prevalence: 1%14% of pregnancies (complicates about 4% of pregnancies)
c. New diagnostic criteria (see below) will likely increase the prevalence.
d. Most common in third trimester
5. Prediabetes
a. Impaired glucose tolerance
b. Impaired fasting glucose
6. Other DM types
a. Genetic defects in -cell function or insulin action
b. Diseases of the pancreas (e.g., pancreatitis, neoplasia, cystic fibrosis)
c. Drug or chemical induced (e.g., glucocorticoids, nicotinic acid, protease inhibitors,
atypical antipsychotics)
C. Screening for DM
1. Type 1 DM
a. Symptomatic patients
b. Asymptomatic patients at higher risk
i. History of transient hyperglycemia or relatives with type 1 DM
ii. Measure islet autoantibodies to assess for risk of type 1 DM.
2. Type 2 DM
a. Age 45 or older, repeat every 3 years if normal
b. Younger age if body mass index (BMI) of 25 kg/m2 or greater and one of the following
risk factors:
i. History of cardiovascular disease
ii. Impaired glucose tolerance or impaired fasting glucose
iii. History of PCOS (polycystic ovary syndrome)
iv. High-density lipoprotein cholesterol (HDL-C) less than 35 mg/dL and/or
triglycerides (TG) greater than 250 mg/dL
v. Hypertension
vi. Women with a diagnosis of gestational diabetes or women who delivered a baby
weighing more than 4.1 kg (9 lb)
vii. High-risk ethnicity: African American, Latino, Native American, Asian American,
Pacific Islander
viii. First-degree relative with DM
ix. Physical inactivity
3. Gestational DM
a. Screen at 2428 weeks of gestation using a 75-g oral glucose tolerance test (OGTT).
b. If gestational DM is the diagnosis, screen for diabetes 612 weeks after delivery.
D. DM Diagnosis
1. Type 1 and 2 DM diagnosis
a. Glycemic parameters in nonpregnant patients
i. Fasting plasma glucose (FPG)
(a) Easy and preferred method
(b) 126 mg/dL or greater
ii. Random plasma glucose
(a) 200 mg/dL or greater with symptoms of hyperglycemia
(b) Common hyperglycemia symptoms include polyuria, polydipsia, and
unexplained weight loss
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(c) Prudent to obtain hemoglobin A1c (A1c) concentration as well

iii. Oral glucose tolerance test
(a) Plasma glucose concentration obtained 2 hours after ingestion of 75 g of oral
glucose
(b) 200 mg/dL or greater
(c) More sensitive and specific than FPG but more cumbersome to perform
iv. With an abnormal test result, the patient should be tested again (preferably with the
same test, but it can be any of the above on a subsequent day or by obtaining an A1c
unless unequivocal hyperglycemia is noted)
v. A1c (glycated hemoglobin)
(a) 6.5% or greater
(b) Confirmed by repeating (unless unequivocal hyperglycemia is noted), though
interval for repeating test is not provided
(c) May be less sensitive than FPG but does not require fasting and has less
variability from day to day
(d) A1c values may be inaccurate in patients with hemolytic anemia, chronic
malaria, or significant blood loss and/or recent blood transfusion
b. Other useful diagnostic tests if type of DM present is in question
i. C-peptide (measure of insulin secretion, usually negligible in type 1 DM and normal
or elevated in type 2 DM)
ii. Presence of islet cell autoantibodies, autoantibodies to insulin, glutamic acid
decarboxylase, or tyrosine phosphatase (all suggest autoimmune activity)
2. Gestational diabetes diagnosis: Glycemic parameters in pregnancy
a. 2011 American Diabetes Association updated and simplified diagnosis criteria
b. 75-g OGTT at weeks 2428 of gestation
i. Fasting: 92 mg/dL or greater
ii. 1 hour post-OGTT: 180 mg/dL or greater
iii. 2 hours post-OGTT: 153 mg/dL or greater
3. Prediabetes diagnosis
a. Impaired fasting glucose: FPG between 100 and 125 mg/dL
b. Impaired glucose tolerance: 2-hour plasma glucose post-OGTT (75 g) between 140 and
199 mg/dL
c. A1c between 5.7% and 6.4%
E. Goals of Diabetes Management in Nonpregnant Adults
1. Primary goal is to prevent the onset of acute or chronic complications.
2. Acute complications: Hypoglycemia, diabetic ketoacidosis (DKA), hyperglycemic
hyperosmolar nonketotic syndrome
3. Chronic complications
a. Microvascular: Retinopathy, nephropathy, and neuropathy
b. Macrovascular: Cardiovascular, cerebrovascular, and peripheral vascular diseases
4. Glycemic therapy goals
a. A1c less than 7.0%. (Note: The ACE/AACE guidelines recommend 6.5% or less.)
i. Obtain every 6 months in patients at goal and quarterly in uncontrolled patients.
ii. Less-stringent A1c targets may be appropriate in those with shorter life expectancy,
advanced diabetes complications, long-standing diabetes that is difficult to control, or
extensive other comorbidities.
b. FPG 70130 mg/dL. Frequency of monitoring very dependent on regimen, type of DM,
and current glycemic control
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c. Peak postprandial glucose (12 hours after a meal) less than 180 mg/dL
5. Nonglycemic therapy goals
a. Blood pressure less than 130/80 mm Hg (updated 2011 American Diabetes Association
guidelines suggest higher or lower systolic blood pressure goals are appropriate in some
patients but do not specifically define who these patients are)
b. Lipids
i. Low-density lipoprotein cholesterol (LDL-C) less than 100 mg/dL; less than 70 mg/
dL an option in those with existing cardiovascular disease
ii. TG less than 150 mg/dL
F. Goals for Gestational Diabetes
1. Primary goal is to prevent complications to mother and child.
2. Glycemic therapy goals (more stringent)
a. FPG 95 mg/dL or less
b. 1-hour postprandial glucose 140 mg/dL or less
c. 2-hour postprandial glucose 120 mg/dL or less
3. Potential complications of hyperglycemia during pregnancy
a. Mother: Hypertension, preeclampsia, type 2 DM after pregnancy
b. Fetus/child: Macrosomia, hypoglycemia, jaundice, respiratory distress syndrome
G. Benefits of Optimizing Diabetes Management in Nonpregnant Adults
1. Glycemic control
a. Reduce the risk of developing retinopathy, nephropathy, and neuropathy in type 1 and 2
DM.
b. Prospective studies specifically designed to assess optimizing glycemic control, as well
as its effect on cardiovascular events, have not shown reduced cardiovascular outcomes.
c. However, the legacy effect seen in the Diabetes Control and Complications Trial of
type 1 DM and the United Kingdom Prospective Diabetes study of type 2 DM suggests
early control has future cardiovascular benefit.
d. No profound benefit of very aggressive glycemic control in type 2 DM (A1c less than
6.5%)
2. Blood pressure control: Reduction in both macrovascular and microvascular complications
3. Lipid control: Reduction in LDL-C with statin therapy reduces cardiovascular complications.
H. Oral Diabetes Agents in Type 2 DM
1. Sulfonylureas
a. Mechanism of action: Bind to receptors on pancreatic -cells, leading to membrane depolarization with subsequent stimulation of insulin secretion (insulin secretagogue)
b. First-generation agents seldom used today (e.g., chlorpropamide, tolbutamide)
c. Second-generation agents (e.g., glyburide, glipizide, glimepiride). Dose titration: Can increase at weekly intervals as necessary
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Table 1.Second-Generation Sulfonylurea Dosing Strategies

Drug
Initial Dose
Maximal Daily Dose (mg)
Glyburide
(nonmicronized)
2.55.0 mg once or twice daily
20
Glyburide (micronized)
1.53 mg once or twice daily
12
Glipizide
5 mg once or twice daily

(once daily with extended
release)
Glimepiride
12 mg once daily
40
(little improved efficacy above 20
mg/day)
8
d. Adverse effects
i. Common: Hypoglycemia, weight gain
ii. Less common: Rash, headache, nausea, vomiting, photosensitivity
e. Contraindications/precautions
i. Hypersensitivity to sulfonamides
ii. Patients with hypoglycemic unawareness
iii. Poor renal function (glipizide may be a better option than glyburide or glimepiride in
elderly patients or in those with renal impairment because drug or active metabolites
are not renally eliminated)
f. Efficacy
i. 1%2% A1c reduction
ii. Note: For this and all medications used to treat hyperglycemia, the absolute decrease
in A1c is larger for higher baseline A1c values and smaller for lower A1c values.
2. Metformin (biguanide)
a. Mechanism of action: Reduces hepatic gluconeogenesis. Also has favorable effects on
insulin sensitivity and intestinal absorption of glucose
b. Dosing
i. Initial: 500 mg once or twice daily (once daily with extended-release formulations)
ii. Maximal daily dose: 2550 mg (more commonly 2000 mg/day)
iii. Can increase at weekly intervals as necessary
iv. Small initial dosage and slow titration secondary to gastrointestinal (GI) disturbances
c. Adverse effects
i. Common: Nausea, vomiting, diarrhea, epigastric pain
ii. Less common: Decrease in vitamin B12 levels, lactic acidosis (rare)
iii. Signs or symptoms of lactic acidosis include acidosis, nausea, vomiting, increased respiratory rate, abdominal pain, shock, and tachycardia.
d. Contraindications/precautions
i. Renal impairment: Serum creatinine 1.5 mg/dL or greater in men and 1.4 mg/dL or
greater in women or reduced creatinine clearance (CrCl) (CrCl cutoff is not well established, but it may be as low as 30 mL/minute). Renal insufficiency increases risk
of lactic acidosis.
ii. Age 80 years or older
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iii.
iv.
v.
vi.
High risk of cardiovascular event or hypoxic state

Hepatic impairment
Congestive heart failure (especially if prone to exacerbations)
Interrupt therapy if undergoing procedures using iodinated contrast dye because of its
nephrotoxicity. Reinitiate after 48 hours and achievement of normal serum creatinine
concentrations.
e. Efficacy
i. 1%2% A1c reduction
ii. Some benefit in TG reduction and weight loss
iii. Considered first-line therapy unless contraindicated on the basis of adverse effect
profile, reduction in A1c, cost, and limited data on reduction of cardiovascular events
in overweight patients
3. Meglitinides
a. Mechanism of action: Very similar to that of sulfonylureas in increasing insulin secretion
from the pancreas but with a more rapid onset and shorter duration of activity
b. Glucose-dependent activity
c. Two currently available: Repaglinide and nateglinide
d. Dosing
i. Repaglinide
(a) Initial: 0.51 mg 15 minutes before meals
(b) Maximal daily dose: 16 mg
ii. Nateglinide
(a) 120 mg before meals
(b) 60 mg if A1c near goal
iii. Repaglinide can be increased in weekly intervals if needed.
e. Adverse effects: Hypoglycemia (though less than with sulfonylureas), weight gain, upper
respiratory infection
f. Contraindications/precautions
i. Hypersensitivity
ii. Caution in concomitant use of repaglinide and gemfibrozilcan lead to greatly
increased repaglinide levels
g. Efficacy
i. 0.5%1.5% A1c reduction (repaglinide shown to reduce A1c more than nateglinide)
ii. Most effective on postprandial glucose excursions
4. Thiazolidinediones (often called TZDs or glitazones)
a. Mechanism of action
i. Peroxisome proliferator-activated receptor agonist
ii. Increases expression of genes responsible for glucose metabolism, resulting in
improved insulin sensitivity
b. Two agents available: Pioglitazone and rosiglitazone
i. In September 2010, the U.S. Food and Drug Administration initiated restricted access
to rosiglitazone secondary to continued concerns about its cardiovascular safety.
ii. When fully implemented, rosiglitazone will be restricted to patients unable to obtain
glycemic control with other agents and in situations in which pioglitazone is not used
for medical reasons.
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c. Dosing
i. Pioglitazone
(a) Initial: 15 mg once daily
ii. Rosiglitazone
(a) Initial: 12 mg once daily
iii. Dose titration is slower with these agents, and the maximal effect of a dose change
may not be observed for 812 weeks.
d. Adverse effects
i. Weight gain
ii. Fluid retention (particularly peripheral edema), worse with insulin use (manufacturer
of rosiglitazone states that it should no longer be used with insulin). Edema less
responsive to diuretic therapy
iii. Risk of bone fractures
iv. Increased risk of heart failure
(a) Both have a black box warning.
(b) More than 2-fold higher relative risk, though absolute risk is quite small
v. Controversial increase in myocardial infarction and cardiovascular death with
rosiglitazone
i. Hepatic impairment
ii. Class III/IV heart failure iii. Existing fluid retention
f. Efficacy
i. 0.5%1.4% A1c reduction
ii. Both increase HDL-C, but pioglitazone has better effects on reducing LDL-C and TG
compared with rosiglitazone.
5. -Glucosidase inhibitors
a. Mechanism of action: Slows the absorption of glucose from the intestine into the
bloodstream by slowing the breakdown of large carbohydrates into smaller absorbable
sugars
b. Two agents available: Acarbose and miglitol
c. Dosing (both agents dosed similarly)
i. Initial: 25 mg 3 times/day at each meal
ii. Maximal daily dose: 300 mg
iii. Slow titration, increasing as tolerated every 48 weeks to minimize GI adverse
effects
d. Adverse effects
i. Flatulence, diarrhea, abdominal pain
ii. Increased liver enzymes observed with high doses of acarbose
e. Contraindications/precautions: Inflammatory bowel disease, colonic ulcerations,
intestinal obstruction
f. Efficacy
i. 0.5%0.8% reduction in A1c
ii. Targets postprandial glucose excursions
iii. May not be as effective in patients using low-carbohydrate diets
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6. Dipeptidyl peptidase-4 inhibitors

a. Mechanism of action: Inhibits the breakdown of glucagon-like peptide-1 (GLP-1)
secreted during meals, which in turn increases pancreatic insulin secretion, limits
glucagon secretion, slows gastric emptying, and promotes satiety
b. Two agents available (sitagliptin and saxagliptin)
c. Dosing
i. Sitagliptin: 100 mg once daily
(a) Reduce with CrCl between 30 and 50 mL/minute to 50 mg once daily.
(b) Reduce with CrCl less than 30 mL/minute to 25 mg once daily.
ii. Saxagliptin: 5 mg once daily. (Reduce with CrCl equal to 50 mL/minute or less to 2.5
mg once daily.)
d. Adverse effects
i. Upper respiratory and urinary tract infections, headache
ii. Hypoglycemia with monotherapy is minimal, but frequency increases with
concurrent sulfonylurea therapy (can lower dose of sulfonylurea when initiating).
iii. Sitagliptin has had some postmarketing reports of acute pancreatitis, angioedema,
Stevens-Johnson syndrome, and anaphylaxis.
i. Previous hypersensitivity to the agents
ii. History of pancreatitis
f. Efficacy: 0.5%0.8% reduction in A1c
7. Bile acid sequestrantColesevelam is the only studied drug in this class.
a. Mechanism of action
i. Bile acid sequestrant used primarily for cholesterol management. Its mechanism to
reduce serum glucose concentrations is unknown.
ii. Used in conjunction with insulin or oral DM medications
b. Colesevelam is the only studied and approved drug in this class.
c. Dosing: Six 625-mg tablets once daily or three 625-mg tablets twice daily
d. Adverse effects: Constipation, dyspepsia, nausea, myalgia
i. Contraindicated in patients with a history of bowel obstruction, serum TG
concentration greater than 500 mg/dL
ii. Caution in patients with swallowing disorders (large pill), dysphasia, gastric mobility
disorders, and serum TG concentrations greater than 300 mg/dL
f. Efficacy: A 0.3%0.5% reduction in A1c
8. Bromocriptine
a. Mechanism of action: Not clearly understood. inAgonist for dopamine D2 receptor
thought to reset circadian rhythm that may reduce caloric intake and storage. Other
effects maybe through antagonism, agonistic properties, and modulation of serotonin
and prolactin.
b. Dosing
i. Initial: 0.8 mg once daily on waking, take with food (increases bioavailability)
ii. Maximal daily dose: 4.8 mg
iii. Titrate weekly by 0.8 mg/day as tolerated and on the basis of response.
iv. Tablet strength is different from that of generic formulations currently on the market.
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c. Adverse effects: Nausea, somnolence, fatigue, dizziness, vomiting, headache, orthostatic

hypotension, syncope
d. Contraindications/precautions
i. Can limit the effectiveness of agents used to treat psychosis or can exacerbate
psychotic disorders
ii. Should not be used in nursing mothers or patients with syncopal migraines
iii. Concomitant use with dopamine antagonists (e.g., neuroleptic agents) may limit the
efficacy of both agents.
e. Efficacy: 0.1%0.6% reduction in A1c
9. Combination products
a. Metformin with: Glyburide, glipizide, sitagliptin, saxagliptin, repaglinide, pioglitazone,
or rosiglitazone
b. Glimepiride with: Pioglitazone or rosiglitazone
I.
Incretin Analogs
1. GLP-1 analog
a. Mechanism of action: Synthetic analog of human GLP-1 that binds to GLP-1 receptors,
resulting in glucose-dependent insulin secretion, reduction in glucagon secretion, and
reduced gastric emptying; promotes satiety
b. Two agents available (exenatide and liraglutide)
c. Dosing
i. Exenatide
(a) Initial: 5 mcg subcutaneously twice daily administered no more than 60 minutes
before morning and evening meals
(b) Maximal daily dose: 20 mcg/day
(c) Dose titration from 5 to 10 mcg twice daily after 1 month if tolerated
ii. Liraglutide
(a) 0.6 mg subcutaneously once daily for 1 week (regardless of mealtime)
(b) Dose titration from 0.6 to 1.2 mg/day if tolerated
(c) Maximal daily dose: 1.8 mg/day
iii. Both agents available in prefilled, multidose syringes
d. Adverse effects
i. Nausea, vomiting, diarrhea very common
ii. Hypoglycemia common with concurrent sulfonylurea (consider reduction in
sulfonylurea dose if adding exenatide)
iii. Postmarketing reports of pancreatitis, acute renal failure, or impairment
i. Impaired renal function, CrCl less than 30 mL/minute
ii. History of severe GI tract disorder
iii. History of pancreatitis
iv. For liraglutide: Contraindicated in patients with a personal or family history of
medullary thyroid carcinoma (adverse effect found in rodent studies but not in
humans)
f. Efficacy
i. A 0.5%1.1% reduction in A1c
ii. Effects on postprandial hyperglycemia better than fasting glucose concentrations
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iii. Modest weight loss

2. Amylin analog
a. Mechanism of action: Synthetic analog of human amylin. Amylin is cosecreted with
insulin and has effects similar to those of GLP-1, previously described.
b. Pramlintide is currently the only agent in this class available in the United States. Can be
used in either type 1 or type 2 DM as adjunctive therapy in patients receiving insulin
c. Dosing
i. Type 1 DM
(a) Initial: 15 mcg subcutaneously immediately before main meals
(b) Must reduce dose of preprandial rapid-acting, short-acting, or combination
insulin products by 50%
(c) Maximal daily dose: 60 mcg with each meal
(d) Dose should be titrated in 15-mcg increments, as tolerated, no more rapidly than
every 3 days.
ii. Type 2 DM
(a) Initial: 60 mcg subcutaneously immediately before main meals
(b) As above, must reduce preprandial insulins by 50%
(c) Maximal daily dose: 120 mcg with each meal
(d) Dose should be titrated in 60-mcg increments, as tolerated, no more rapidly than
every 37 days.
iii. Use of prefilled pens is strongly recommended, when possible, versus using a syringe
and vial to reduce the risk of dosing errors (dosing instructions with U-100 syringes
and vial in package insert).
iv. Cannot be mixed with insulin products, requires increased frequency of daily
injections
d. Adverse effects
i. Black box warning for severe hypoglycemia, especially in patients with type 1 DM
ii. Nausea, vomiting, anorexia, headache
i. Substantial gastroparesis
ii. History of poor adherence or monitoring of blood glucose
iii. A1c greater than 9%
iv. Hypoglycemia unawareness or frequent bouts of hypoglycemia
f. Efficacy
i. A 0.5%1% reduction in A1c
ii. Very effective at controlling postprandial glucose excursions
J.
Insulin
1. Categorized on the basis of therapy duration after injection
a. Short acting: Regular human insulin
b. Rapid acting: Insulin aspart, lispro, and glulisine
c. Intermediate acting: Neutral protamine Hagedorn (NPH)
d. Long acting: Insulin glargine and detemir; cannot be mixed with other insulins
2. Combination products (NPH/either regular or rapid-acting insulin): 70/30, 75/25
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Table 2. Insulin Characteristics
Category
Injection Time
Before Meal
(minutes)
Peak
(hours)
Duration
(hours)
Drug Name
Clarity
Onset
Short acting
Regular
Clear
3060
minutes
30
23
46
Rapid acting
Aspart/lispro/glu
lisine
Clear
520 minutes
15
13
35
Intermediate
acting
NPH
Cloudy
12 hours
N/A
48
1020
Long acting
Detemir
Glargine
Clear
24 hours
12 hours
N/A
68
peakless
624
~24
Note: The above times are dependent on the source of data and intersubject variability.
N/A = not applicable; NPH = neutral protamine Hagedorn.
3. Glycemic target
a. Regular and short-acting insulins target postprandial glucose concentrations.
b. Intermediate- and long-acting insulins target fasting glucose concentrations.
K. Therapeutic Insulin Management of Type 1 DM
1. First step is to estimate total daily insulin (TDI) requirements.
2. Weight-based estimate if insulin naive
a. 0.30.6 unit/kg/day
b. Requirements higher if treating DKA near initial diagnosis of DM
c. Honeymoon phase shortly after treatment initiation often requires lower daily insulin
needs.
3. One common approach is to use older insulin formulations (NPH and regular insulins).
a. Two-thirds of TDI given before morning meal. Two-thirds of this given as NPH and
one-third as regular insulin
b. One-third of TDI given before evening meal (or regular given before meal and NPH at
bedtime). Again, two-thirds of this given as NPH and one-third as regular insulin
c. Advantages: Daily insulin injection frequency 2 or 3 times/day and inexpensive
d. Disadvantages: Does not mimic natural insulin secretion pattern, prone to hypoglycemic
events
4. Another approach is basal/bolus insulin therapy (aka physiologic insulin therapy).
a. Use of newer insulin analogs to better mimic natural insulin secretion patterns
b. Provides day-long basal insulin to prevent ketosis and control FPG
c. Provides bolus insulin to control postprandial hyperglycemia
d. Basal insulins: Insulin glargine once daily or insulin detemir once or twice daily
e. Bolus insulins: Rapid-acting insulin
f. Basal requirements are 50% of estimated TDI.
g. Bolus requirements are 50% of estimated TDI split three ways before meals.
i. Provides initial estimate about prandial insulin needs
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ii. Typically, patients will begin to estimate bolus requirements on the basis of the
amount of carbohydrates to be ingested.
h. Advantages over NPH plus regular approach: More physiologic, less hypoglycemia, more
flexible to patient mealtimes
i. Disadvantages: Cost and increased frequency of daily injections
Note: The same process of basal/bolus insulin therapy can apply to a patient with
type 2 DM who is receiving intensive insulin therapy with or without oral DM
medications.
5. Correctional insulin needs
a. Occasionally, a need to correct for hyperglycemic excursions despite optimal basal/bolus
therapy
b. 1800 Rule: 1800/TDI = No. of mg/dL of glucose 1 unit of rapid-acting insulin will
lower
i. For example: If TDI is 60 units, 1800/60 = 30, suggesting 1 unit of rapid-acting
insulin will reduce blood glucose concentrations by 30 mg/dL.
ii. Some advocate the 1500 Rule when using regular human insulin.
c. More patient-specific than traditional sliding-scale insulin
6. Continuous subcutaneous insulin infusion (insulin pump)
a. Device allows very patient-specific hourly basal dosing and bolus insulin dosing.
b. Uses rapid-acting insulins
c. Requires considerable patient education and carbohydrate counting
7. Assessing therapy and dosage adjustment
a. Know the goals for fasting and postprandial glucose concentrations.
b. Identify when patient is at goal and not at goal (hypo- or hyperglycemia). Look for
consistent trends rather than isolated events.
c. Identify which insulin affects problematic glucose concentrations.
d. Adjust insulin dose or patient behavior accordingly.
e. The same process for treating type 2 DM applies (see below).
L. Therapeutic Management of Type 2 DM
1. Given the progressive nature of type 2 DM, a stepwise approach is usually required.
2. American Diabetes Association tier 1 (well-validated core therapies: best established, most
clinically effective, and most cost-effective)
a. Step 1: Unless contraindicated, metformin and lifestyle modifications to improve diet and
exercise
b. Step 2: With inadequate glycemic control with metformin therapy
i. Add sulfonylurea or
ii. Use basal insulin (intermediate- or long-acting insulin: 10 units/day or 0.2
unit/kg).Titrate basal insulin to obtain FPG between 70 and 130 mg/dL.
c. Step 3: With inadequate glycemic control with combination therapy: Lifestyle,
metformin, and intensive insulin therapy
i. Add rapid-acting insulin preprandially to basal insulin therapy.
ii. Which meals to target depends on patient-specific glucose concentrations.
3. American Diabetes Association tier 2 (less well-validated therapies: less well established,
may be used when risk of hypoglycemia is more undesirable than usual [e.g., those with
hazardous jobs])
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a. Step 1: As above
b. Step 2: Either a or b below
i. Add pioglitazone.
(a) If inadequate control, add sulfonylurea
(b) If inadequate control with metformin-pioglitazone-sulfonylurea, change to
metformin-basal insulin combination
ii. Add exenatide. If inadequate control, change to metformin-pioglitazone-sulfonylurea
combination or change to metformin-basal insulin combination
c. Step 3: As above
4. Initial insulin therapy: Use insulin early with any of the following baseline characteristics:
a. A1c greater than 10%
b. Random glucose greater than 300 mg/dL or fasting glucose greater than 250 mg/dL
c. Hyperglycemic symptoms
d. Presence of urine ketones
5. Changing from oral DM medications to insulin-only management (e.g., because of adverse
effects, contraindications, lack of efficacy of oral medications)
a. Can follow NPH/regular insulin or basal/bolus approach similar to that in type 1 DM as
previously described
b. The TDI requirements in type 2 DM are usually higher than those in type 1 DM.
6. Changing from NPH to long-acting insulin (either insulin glargine or detemir)
a. If adequate glycemic control already obtained, initiate insulin glargine at 80% of total
daily NPH dose
b. Detemir may be initiated on a unit-to-unit basis, and it may require higher daily insulin
dosages after conversion; however, this is determined by glycemic response.
II. TREATMENT OF DM COMPLICATIONS

A. Hypoglycemia
1. Degree of intervention depends on glucose concentrations and presence of symptoms.
2. Symptoms are very patient-specific.
3. Definition: Plasma glucose less than 70 mg/dL with or without symptoms
4. Mild to moderate hypoglycemia
a. Oral ingestion of 1520 g of glucose or equivalent
b. Repeat glucose concentration in 15 minutes and, if still less than 70 mg/dL, repeat.
5. Severe hypoglycemia (altered consciousness, requires assistance from others)
a. Glucagon 1 mg intramuscularly
b. Intravenous dextrose if patient does not respond to glucagon
B. Diabetic Ketoacidosis
1. More common in type 1 DM but can occur in type 2 DM
2. Usually occurs because of a precipitating factor that considerably stresses the body, resulting
in increased counterregulatory hormones
a. Inappropriate (including nonadherence) or inadequate insulin therapy and infection are
the two most common causes.
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b. Other causes: Myocardial infarction, pancreatitis, stroke, drugs (e.g., corticosteroids)

3. Results in significant hyperglycemia, dehydration, and ketoacidosis
4. Common signs/symptoms: Polyuria, polydipsia, vomiting, dehydration, weakness, altered
mental status, coma, abdominal pain, Kussmaul respirations, tachycardia, hyponatremia,
hyperkalemia
5. Treatment
a. Treat underlying cause if known.
b. Fluid replacement
i. 0.45%0.9% sodium chloride depending on baseline concentrations of serum sodium
ii. Change to 5% dextrose (D5W ) with 0.45% sodium chloride when serum glucose is
less than 200 mg/dL.
c. Insulin
i. Goal is to stop ketosis, not to get glucose concentrations to normal.
ii. Intravenous bolus: 0.1 unit/kg
iii. Intravenous infusion:
(a) 0.1 unit/kg/hour (increase if not a 50- to 75-mg/dL drop in serum glucose in the
first hour)
(b) Alternatively, 0.14 unit/kg/hour if no insulin bolus is given
(c) If not at least a 10% decrease in serum glucose obtained in first hour, give a 0.14
unit/kg intravenous bolus
(d) Reduce infusion rate to 0.020.05 unit/kg/hour when serum glucose reaches 200
mg/dL, and keep glucose between 150 and 200 mg/dL until DKA resolves.
iv. Interrupt insulin treatment if baseline serum potassium is less than 3.3 mEq/L and
until corrected.
d. Potassium
i. 2030 mEq/L of intravenous fluid if baseline serum potassium greater than 3.3 but
less than 5.3 mEq/L
ii. Hold if 5.3 mEq/L or greater
iii. 2030 mEq potassium per hour if baseline less than 3.3 mEq/L (while holding
insulin)
e. Intravenous bicarbonate if serum pH less than 6.9
f. DKA considered resolved and can be converted to subcutaneous insulin when serum
glucose is less than 200 mg/dL and at least two of the following:
i. Venous pH is greater than 7.3.
ii. Serum bicarbonate is 15 mEq/L or greater.
iii. Calculated anion gap of 12 mEq/L or less
C. Nephropathy
1. Screen annually with random spot collection of urine albumin-to-creatinine ratio starting at
diagnosis in type 2 DM and after 5 or more years in type 1 DM.
a. Normal: Less than 30 mg/g (or micrograms per milligram)
b. Microalbuminuria: 30299 mg/g
c. Macroalbuminuria: 300 mg/g or greater
2. Estimate CrCl yearly as well.
3. With type 1 DM, hypertension, and any degree of nephropathy: Angiotensin-converting
enzyme (ACE) inhibitor therapy
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4. With type 2 DM, hypertension, and microalbuminuria: ACE inhibitor or angiotensin receptor
blocker (ARB) therapy
5. With type 2 DM, hypertension, macroalbuminuria, and serum creatinine greater than 1.5
mg/dL: ARB therapy
6. The above differences in choice of drug class reflect what is documented in the literature.
7. ACE inhibitors and ARBs are often used regardless of whether the patient has hypertension.
8. Dietary protein restriction as renal function declines
D. Retinopathy
1. Screen annually with dilated and comprehensive eye examinations starting at diagnosis in
type 2 DM and after 5 or more years in type 1 DM.
2. Frequency can be reduced to every 23 years after one or more normal examinations.
3. No specific pharmacotherapy recommended except to adequately control glucose
concentrations
E. DM Neuropathies
1. Can have nerve damage in any area of the body
2. Screen for distal polyneuropathy using monofilament once yearly.
a. Screen after 5 years of type 1 DM and at diagnosis with type 2 DM.
b. Diminished sensitivity is a significant risk factor for diabetes-related foot ulcer and
increases the need for frequent visual inspection by patients if it exists.
3. Treatment of neuropathies is for symptomatic improvement and does not prevent progression.
4. Symptoms are patient-specific but may include numbness, burning, and a tingling sensation.
5. Neuropathic pain
a. Tricyclic antidepressants (amitriptyline, desipramine)
i. Effective but limited because of anticholinergic effects (some recommend using
secondary amine tricyclic antidepressants (e.g., desipramine, nortriptyline) because
they may have a lower anticholinergic effect than tertiary amines (e.g., amitriptyline,
imipramine)
ii. Daily dose is less than doses used for depression.
b. Anticonvulsants (gabapentin, lamotrigine, pregabalin)
i. Comparative data of gabapentin and pregabalin against tricyclic antidepressants show
similar efficacy with fewer adverse effects. Adverse effect profile is still significant
(fatigue, dizziness, etc.).
ii. Pregabalin is the only anticonvulsant approved for use in DM neuropathic pain.
c. Selective serotonin reuptake inhibitor/selective serotonin and norepinephrine reuptake
inhibitor (duloxetine, paroxetine, citalopram)
i. Duloxetine is the only approved agent in this category.
ii. No comparative data with other agents
d. Tramadol/acetaminophen
e. As effective as gabapentin, different adverse effect profile
6. Gastroparesis
a. Autonomic neuropathy causes considerable nausea/vomiting after meals because of
delayed gastric emptying.
b. Nonpharmacologic strategies
i. More frequent but smaller meals
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ii. Homogenize food.

c. Pharmacologic treatment
i. Metoclopramide: 10 mg before meals: Risk of tardive dyskinesia or extrapyramidal
reactions
ii. Erythromycin: 40250 mg before meals
F. Cardiovascular Disease
1. Most common cause of morbidity and mortality as well as health care expenditures in DM
2. Proper DM management should always focus on cardiovascular disease risk reduction
3. Stress and continually assess the blood pressure and lipid goals previously described.
4. Blood pressure management
a. Given lower goal than for essential hypertension, often requires more antihypertensive
medications
b. Hypertensive regimen should include an ACE inhibitor or ARB.
5. Lipid management
a. Assess fasting lipid profile annually.
b. Statin therapy recommended regardless of baseline lipid levels for:
i. Established cardiovascular disease
ii. No history of cardiovascular event but older than 40 years with at least one
cardiovascular risk factor other than DM
c. A 30%40% reduction in LDL-C can be an alternative goal in those who do not attain an
LDL-C less than 100 mg/dL.
d. TG goal: Less than 150 mg/dL
e. HDL-C goal: Greater than 40 mg/dL for men, greater than 50 mg/dL for women
6. Antiplatelet therapy
a. Low-dose aspirin (75162 mg/day)
i. With existing cardiovascular disease
ii. For primary prevention, if 10-year risk is greater than 10% (includes most men older
than 50 and women older than 60 who have at least one cardiovascular risk factor)
b. Clopidogrel for those intolerant of aspirin therapy
G. Preventive Immunizations
1. Annual influenza vaccine
2. Pneumococcal polysaccharide vaccine
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III. THYROID DISORDERS
Figure 1. Hypothalamus-pituitary-thyroid axis.a

aT4 is converted to T3 by peripheral tissue. Only unbound (free) thyroid hormone is biologically active.
T3 = triiodothyronine; T4 = thyroxine; TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone; - ve =

negative feedback loop.
A. Classification
1. Hyperthyroid disorders (thyrotoxicosis)
a. Toxic diffuse goiter (Graves disease): Most common hyperthyroid disorder
i. Autoimmune disorder
ii. Thyroid-stimulating antibodies directed at thyrotropin receptors mimic thyroid-stimulating hormone (TSH) and stimulate triiodothyronine/thyroxine (T3/T4) production.
b. Pituitary adenomas: Excessive TSH secretion that does not respond to normal T3
feedback
c. Toxic adenoma: Hot nodule in thyroid, autonomous of pituitary and TSH
d. Toxic multinodular goiter (Plummer disease): Autonomous follicles, if large enough,
cause excessive thyroid hormone secretion.
e. Painful subacute thyroiditis: Self-limiting thyroiditis caused by viral invasion of the
thyroid parenchyma, resulting in release of stored hormone
f. Drug induced (e.g., excessive thyroid hormone use, amiodarone)
2. Hypothyroid disorders
a. Hashimoto disease: Most common hypothyroid disorder
i. Autoimmune-induced thyroid injury resulting in decreased thyroid secretion
ii. Disproportionately affects women more than men
b. Surgery or radioiodine induced (iatrogenic)
c. Iodine deficiency or excessive intake
d. Secondary causes
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i. Pituitary insufficiency (lack of TSH secretion)

ii. Drug induced (e.g., amiodarone, lithium)
B. Diagnosis
1. Hyperthyroid disorders
a. Elevated total T4 and free T4 serum concentrations
b. Suppressed TSH concentrations (except in TSH-secreting adenomas)
c. If examination and history do not provide exact etiology, radioactive iodine uptake may
be employed.
i. Radioactive iodine uptake is elevated if thyroid gland actively and excessively
secretes T4 and/or T3: Graves disease, TSH-secreting adenoma, toxic adenoma,
multinodular goiter
ii. Radioactive iodine uptake is suppressed in disorders caused by thyroiditis or
hormone ingestion.
d. Can also assess thyroid-stimulating antibodies, thyroglobulin, thyroid biopsy, etc.
a. Decreased total T4 and free T4 serum concentrations
b. Elevated TSH concentrations (normal or low if secondary cause etiology)
c. Thyroid antibodies: Antithyroid peroxidase and antithyroglobulin autoantibodies
C. Clinical Presentation
1. Hyperthyroid disorders
a. Weight loss/increased appetite
b. Lid lag
c. Heat intolerance
d. Goiter
e. Fine hair
f. Heart palpitations/tachycardia
g. Nervousness, anxiety, insomnia
h. Menstrual disturbances (lighter or more infrequent menstruation, amenorrhea)
i. Sweating or warm, moist skin
j. Exophthalmos, pretibial myxedema in Graves disease
a. Cold intolerance
b. Dry skin
c. Fatigue, lethargy, weakness
d. Weight gain
e. Bradycardia
f. Slow reflexes
g. Coarse skin and hair
h. Periorbital swelling
i. Menstrual disturbances (more frequent or longer menstruation, painful menstruation,
menorrhagia)
D. Therapy Goals for Both Hyperthyroid and Hypothyroid Disorders
1. Minimize or eliminate symptoms, improve quality of life
2. Minimize long-term damage to organs.
3. Normalize free T4 and TSH concentrations.
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E. Pharmacotherapy
1. Hyperthyroidism
a. Treatment of choice for Graves disease, toxic nodule, multinodular goiter: Radioactive
iodine ablative therapy and surgical resection for adenomas based on patient preferences
or comorbidities. Ablative therapy often results in hypothyroidism.
b. Pharmacotherapy usually reserved for the following:
i. Awaiting ablative therapy or surgical resection
(a) Depletes stored hormone
(b) Minimizes risk of posttreatment hyperthyroidism because of thyroiditis
ii. Not an ablative or surgical candidate
iii. When ablative therapy or surgical resection fails to normalize thyroid function
c. Thioureas (i.e., propylthiouracil [PTU], methimazole)
i. Mechanism of action: Inhibits iodination and synthesis of thyroid hormones; PTU
may block T4-to-T3 conversion in the periphery as well
ii. Dosing
(a) Propylthiouracil
(1) Initial: 100 mg by mouth 3 times/day
(2) Maximal: 400 mg 3 times/day
(b) Methimazole
(1) Initial: 510 mg by mouth 3 times/day
(2) Maximal: 40 mg 3 times/day
(c) Either drug can be given once daily if tolerated (disparity between
pharmacokinetics and pharmacodynamics).
(d) Monthly dose titrations as needed (on the basis of symptoms/TSH)
iii. Adverse effects
(a) Hepatotoxicity issue with PTU (black box warning)
(b) Transient leucopenia (white blood cell count less than 4000 cells/m3)
(c) Rash
(d) Arthralgias, lupuslike symptoms
(e) Fever
(f ) Granulocytosis early in therapy
iv. Efficacy
(a) Slow onset in reducing symptoms (weeks). Maximal effect may take 46 months.
(b) Neither drug appears superior to the other in efficacy.
(c) On a milligram-to-milligram basis, methimazole is 10 times more potent than
PTU.
(d) Remission rates low: 40%50%
d. -Blockers (primarily propranolol, sometimes nadolol)
i. Mechanism of action: Block many hyperthyroidism manifestations mediated by
-adrenergic receptors. Also may block T4-to-T3 conversion
ii. Dosing
(a) Initial: 2040 mg by mouth 3 or 4 times/day
(b) Maximal: 240480 mg/day
iv. Efficacy
(a) Primarily used for symptomatic relief (e.g., palpitations, tachycardia, tremor,
anxiety)
(b) Poor remission rates: 20%35%
(c) Primary role is treatment of thyroiditis and during thyroid storm.
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(d) Alternatives to -blockers: Clonidine, calcium channel blocker known as

nondihydropyridine
e. Iodines (e.g., Lugol solution, saturated solution of potassium iodide)
i. Mechanism of action: Inhibits the release of hormone. Minimal effect on hormone
synthesis. Helps decrease vascularity and size of gland before surgery
ii. Dosing
(a) Lugol solution (6.3 mg of iodide per drop)
(b) Saturated solution of potassium iodide (38 mg of iodide per drop)
(c) Usual daily dose: 120400 mg mixed with juice or water, split 3 times/day
(a) Hypersensitivity
(b) Metallic taste
(c) Soreness or burning in mouth or tongue
iv. Efficacy
(a) Limited efficacy after 714 days of therapy because thyroid hormones will begin
to be released
(b) Primary use is temporary before surgery (714 days) to shrink the size of the
gland.
(c) Used as postablative therapy (37 days) to inhibit thyroiditis-mediated release of
stored hormone
(d) Used acutely in thyroid storm
2. Hypothyroidism
a. Levothyroxine (drug of choice)
i. Mechanism of action: Synthetic T4
ii. Dosing
(a) Initial: 5075 mcg by mouth once daily (25 mcg once daily in the elderly or in
those with existing cardiovascular disease)
(b) Dose titration on the basis of response (symptoms, TSH, free T4)
(c) 6 weeks is appropriate to assess patient response (about a 7-day half-life).
(d) Use free T4 rather than TSH if secondary cause of hypothyroidism
(e) Average maintenance dose about 1.61.7 mcg/kg/day or 125 mcg
(a) Hyperthyroidism
(b) Cardiac abnormalities (angina, myocardial infarction)
iv. Efficacy: If levothyroxine is properly dosed, most patients will maintain TSH and
free T4 in the normal ranges and experience symptomatic relief.
v. Considered drug of choice secondary to its adverse effect profile, cost, antigenicity
profile, and uniform potency
vi. Bioequivalence
(a) The AACE recommends the brand levothyroxine (none of the following thyroid
preparations is supported by AACE).
(b) Although legal, most clinicians recommend against changing from brand to
generic and vice versa. Staying with one product throughout therapy is
recommended.
(c) TSH concentrations in bioequivalence testing never performed; small changes in
T4 between products may result in significant changes in TSH; pharmacokinetic
studies were in normal subjects with normal thyroid function
b. Liothyronine
i. Mechanism of action: Synthetic T3
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ii. Dosing
(a) Initial: 25 mcg/day
(b) Average maintenance dose: 2575 mcg/day
iii. Adverse effects: May be higher incidence of cardiac adverse effects than
levothyroxine
iv. Efficacy: If properly dosed, efficacy should be similar to levothyroxine. Has shorter
halflife than levothyroxine
c. Liotrix
i. Mechanism of action: Synthetic T4/T3 in 4:1 ratio. Mimics bodys natural ratio
ii. Seldom used. No actual need because T4 is easily converted to T3
d. Desiccated thyroid (Thyroid USP)
i. Mechanism of action: Hog-, beef-, or sheep-derived levothyroxine, liothyronine in
specific ratios to thyroglobulin
ii. Used less secondary to potential risk of hypersensitivity reactions
iii. Dosed in grains: 1 grain of Armour Thyroid equals 100 mcg of levothyroxine.
F. Subclinical Hypothyroidism
1. Definition: Elevated TSH (above upper limit of reference range) with normal T4. Often the
result of early Hashimoto disease
2. Risk?
a. TSH greater than 7.0 mIU/L in the elderly associated with increased risk of heart failure
b. TSH greater than 10 mIU/L associated with increased risk of coronary heart disease
3. Treatment of subclinical hypothyroidism is controversial because benefits in identified
patients are inconclusive.
4. Whom to treat
a. Patients with symptoms
b. TSH greater than 10 mIU/L
c. TSH between 5 and 10 mIU/L and goiter or antithyroid peroxidase antibodies present
5. If untreated, screen regularly for the development of overt hypothyroidism (decreased free T4
concentrations).
G. Thyroid Storm
1. Severe and life-threatening decompensated thyrotoxicosis. Mortality rate may be as high as
20%.
2. Precipitating cause (trauma, infection, antithyroid agent withdrawal, severe thyroiditis, postablative therapy)
3. Presentation: Fever, tachycardia, vomiting, dehydration, coma, tachypnea, delirium
4. Pharmacotherapy
a. PTU: 300400 mg 3 times/day
b. Iodide therapy after PTU initiation (dosed as previously described)
c. -Blocker therapy: Esmolol commonly used (can use other agents [e.g., propranolol])
d. Antipyretic therapy: Acetaminophen (avoid nonsteroidal anti-inflammatory drugs
[NSAIDs] because of displacement of protein-bound thyroid hormones)
e. Corticosteroid therapy: Prednisone 25100 mg/day in divided doses (or equivalent doses
of dexamethasone, hydrocortisone, etc.)
H. Myxedema Coma
1. Severe and life-threatening decompensated hypothyroidism; mortality rate 30%60%
2. Precipitating causes: Trauma, infections, heart failure, medications
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3. Presentation: Coma is not required and is uncommon despite terminology, altered mental
state (very common), diastolic hypertension, hypothermia, hypoventilation
4. Pharmacotherapy
a. Intravenous thyroid hormone replacement
i. T4: 100- to 500-mcg loading dose, followed by 75100 mcg/day, until patient can
tolerate oral therapy. Lower initial dose in frailer patients or in patients with established cardiovascular disease
ii. Some advocate the use of T3 over T4 given that T3 is more biologically active and
T4-to-T3 conversion may be suppressed in myxedema coma. Cost and availability
limit intravenous T3 use.
b. Antibiotic therapy: Given common cause, some advocate empiric therapy with broadspectrum antibiotics.
c. Corticosteroid therapy
i. Hydrocortisone 100 mg every 8 hours (or equivalent steroid)
ii. Can be discontinued if random cortisol concentration not found to be depressed
IV. SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION
Figure 2. Normal total body sodium content and small increases in extracellular fluid volume.
Na = sodium.
A. Drug-Induced Syndrome of Inappropriate of Antidiuretic Hormone (SIADH) Secretion:
1. Thiazide diuretics
2. Sulfonylureas: Chlorpropamide
3. Antineoplastics: Cyclophosphamide, cisplatin, vinca alkaloids
4. Antidepressants: Selective serotonin reuptake inhibitors
5. Analgesics: NSAIDs, narcotics
6. Antiepileptics: Carbamazepine, Clofibrate
B. Mechanism: Increased release of antidiuretic hormone (ADH) from the posterior pituitary or increased responsiveness of the collecting duct to ADH
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Figure 3. General approach to treatment of SIADH.

D/C = discontinue; NaCl = sodium chloride; SIADH = syndrome of inappropriate antidiuretic hormone secretion
C. Intravenous Fluid Administration

1. Choice of intravenous fluids: Large-volume intravenous fluids are usually dispensed as 1-L
bags. Hypertonic saline (3% sodium chloride) is usually dispensed in 500-mL increments.
Table 3. Intravenous Fluid Administration
Sodium
(mEq/L)
Chloride
(mEq/L)
Normal saline
(0.9% NaCl)
154
154
308
3% NaCl
514
514
1028
Fluid
Potassium
(mEq/L)
Calcium
Lactate
Osmolality
(mOsm/L)
NaCl = sodium chloride.
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2. Rate of administration
3. Use of diuretics in the treatment of SIADH
a. Mechanism of action of diuretics
b. When to use loop diuretics

i. Serum sodium has not been corrected by the administration of intravenous fluid
alone.
ii. Measured urine osmolality is high.
iii. Patient has hypervolemic hyponatremia.
c. Dosing/administration
i. Furosemide 4080 mg orally or intravenously every 6 hours; management of chronic
hyponatremia secondary to SIADH.
ii. Demeclocycline: Mechanism of action: Antagonizes the action of ADH at the
collecting duct.
iii. Conivaptan
(a) Mechanism of action: Conivaptan is a dual vasopressin receptor antagonist (V1A
and V2) that increases free water excretion and urine output and decreases urine
osmolality.
(b) Dosing/administration:
(1) Loading dose: Conivaptan 20 mg in 100 mL of D5W infused over 30
minutes
(2) Continuous infusion: 20 mg in 250 mL of D5W infused over 24 hours (10
mL/hour)
(3) May be increased to 40 mg in 250 mL of D5W infused over 24 hours
(4) May be continued for up to 4 days
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REFERENCES
10. Holman R, Paul S, Bthel M, Matthews D,
Neil H. 10-year follow-up of intensive
glucose control in type 2 diabetes. N Engl J
Med 2008;359:157789.
11. The Diabetes Control and Complications
Trial/Epidemiology of Diabetes
Interventions and Complications
(DCCT/EDIC) Study Research Group.
Intensive diabetes treatment and
cardiovascular disease in patients with type
1 diabetes. N Engl J Med
2005;353:264353.
12. Nathan D, Buse J, Davidson M, et al.
Medical management of hyperglycemia in
type 2 diabetes: a consensus algorithm for the
initiation and adjustment of therapy. Diabetes
Care 2009;32:193203.
13. Boyle P, Zrebiec J. Management of
diabetes-related hypoglycemia. South Med J
2007;100:18394.
14. Kitabchi A, Umpierrez G, Miles J, Fisher J.
Hyperglycemic crises in adult patients with
diabetes. Diabetes Care 2009;32:133543.
15. Camilleri M. Diabetic gastroparesis. N Engl
J Med 2007;356:8209.
16. Boulton A, Vinik A, Arezzo J, et al. Diabetic
neuropathies. A statement by the American
Diabetes Association. Diabetes Care
2005;28:95662.
Diabetes
1. American Diabetes Association. Diagnosis
and classification of diabetes mellitus.
Diabetes Care 2010;33(Suppl 1):S62S69.
2. American Diabetes Association. Standards
of medical care in diabetes 2011. Diabetes
Care 2011;34(Suppl 1):S11S61.
3. Lebovitz H, Austin M, Blonde L, et al.
ACE/AACE consensus conference on the
implementation of outpatient management
of diabetes mellitus: consensus conference
recommendations. Endocr Pract
2006;12:612.
4. The International Expert Committee.
International Expert Committee report on
the role of the A1c assay in the diagnosis of
diabetes. Diabetes Care 2009;32:18.
5. UK Prospective Diabetes Study Group.
Tight blood pressure control and risk of
macrovascular and microvascular
complications in type 2 diabetes: UKPDS
38. BMJ 1998;317:70313.
6. UK Prospective Diabetes Study Group.
Intensive blood-glucose control with
sulphonylureas or insulin compared with
conventional treatment and risk of
complications in patients with type 2
diabetes (UKPDS 33). Lancet
1998;352:83753.
7. Skyler J, Bergenstal R, Bonow R, et al.
Intensive glycemic control and the
prevention of cardiovascular events:
implications of the ACCORD, ADVANCE,
and VA Diabetes trials. Diabetes Care
2009;32:18792.
8. Heart Protection Study Collaborative Group.
MRC/BHF Heart Protection Study of
cholesterol-lowering with simvastatin in
5963 people with diabetes: a randomized
placebo-controlled trial. Lancet
2003;361:200516.
9. Calhoun H, Betteridge D, Durrington P, et
al. Primary prevention of cardiovascular
disease with atorvastatin in type 2 diabetes
in the Collaborative Atorvastatin Diabetes
study (CARDS): multicentre randomized
placebo-controlled trial. Lancet
2004;364:68596.
Thyroid
1. American Association of Clinical
Endocrinologists Thyroid Task Force.
American Association of Clinical
Endocrinologists medical guidelines for
clinical practice for the evaluation and
treatment of hyperthyroidism and
hypothyroidism. Endocr Pract
2002;8:45769.
2. Singer P, Cooper D, Levy E, et al.
Treatment guidelines for patients with
hyperthyroidism and hypothyroidism.
JAMA 1995;273:80812.
3. Surks M, Ortiz E, Daniels G, et al. Subclinical
thyroid disease: scientific review and
guidelines for diagnosis and management.
JAMA 2004;291:22838.
4. Sherman S, Talbert R. Thyroid disorders. In:
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5.
6.
7.
8.
9.
DiPiro J, Talbert R, Yee G, Matzke G, Wells

B, Posey L, eds. Pharmacotherapy: A
Pathophysiologic Approach, 7th ed. New
Roos A, Linn-Rasker S, van Domburg R,
Tijssen J, Berghout A. The starting dose of
levothyroxine in primary hypothyroidism
treatment. Arch Intern Med
2005;165:171420.
Pearce E, Farwell A, Braverman L.
Thyroiditis. N Engl J Med
2005;348:264655.
Rodondi N, Newman A, Vittinghoff E, et al.
Subclinical hypothyroidism and the risk of
heart failure, other cardiovascular events,
and death. Arch Intern Med
2005;165:24606.
Walsh J, Bremner A, Bulsara M, et al.
Subclinical thyroid dysfunction as a risk
factor for cardiovascular disease. Arch
Intern Med 2005;165:246772.
Wall C. Myxedema coma: diagnosis and
treatment. Am Fam Physician
2000;62:248590.
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BIOSTATISTICS
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Biostatistics
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1. Describe differences between descriptive and inferential statistics.
2. Identify different types of data (nominal, ordinal, continuous [ratio and interval]) to determine an
appropriate type of statistical test (parametric vs. nonparametric).
3. Describe strengths and limitations of different types of measures of central tendency (mean, median
mode) and data spread (standard deviation, standard error of the mean, range, interquartile range).
4. Describe the concepts of normal distribution and the associated parameters that describe the
distribution.
5. State the types of decision errors that can occur when using statistical tests and the conditions under
which they can occur.
6. Describe hypothesis testing and state the meaning of and distinguish between p-values and confidence
intervals.
7. Describe areas of misuse or misrepresentation that are associated with various statistical methods.
8. Select appropriate statistical tests on the basis of the sample distribution, data type, and study design.
9. Interpret statistical significance for results from commonly used statistical tests.
10. Describe the similarities and differences between correlation and regression; learn how to apply them
appropriately.
11. Identify the use of survival analysis and different ways to perform and report it.
I.
INTRODUCTION TO STATISTICS
A. Method for Collecting, Classifying, Summarizing, and Analyzing Data
B. Useful Tools for Quantifying Clinical and Laboratory Data in a Meaningful Way
C. Assists in Determining Whether and by How Much a Treatment or Procedure Affects a Group
of Patients
D. Why Pharmacists Need to Know Statistics
E. As It Pertains to Most of You:
Pharmacotherapy Specialty Examination Content Outline
Domain 2: Retrieval, Generation, Interpretation, and Dissemination of Knowledge in
Pharmacotherapy (25%)
Interpret biomedical literature with respect to study design and methodology, statistical analysis,
and significance of reported data and conclusions.
Knowledge of biostatistical methods, clinical and statistical significance, research hypothesis
generation, research design and methodology, and protocol and proposal development
F. Several papers have investigated the various types of statistical tests used in the biomedical literature.
The data from one paper are illustrated below.
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Biostatistics
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1. Statistical content of original articles in The New England Journal of Medicine, 20042005
Statistical Procedure
No statistics/descriptive
statistics
t-tests
Contingency tables
Nonparametric tests
Epidemiologic statistics
Pearson correlation
Simple linear regression
Analysis of variance
Transformation
Nonparametric correlation
Survival methods
Multiple regression
Multiple comparisons
% of Articles
Containing
Methods
13
26
53
27
35
3
6
16
10
5
61
51
23
% of Articles
Containing Methods
Statistical Procedure
Adjustment and standardization
Multiway tables
Power analyses
Cost-benefit analysis
Sensitivity analysis
Repeated-measures analysis
Missing-data methods
Non-inferiority trials
Receiver-operating
characteristics
Resampling
Principal component and cluster

analyses
Other methods
1
13
39
<1
6
12
8
4
2
2
2
4
2. Statistical content of original articles from six major medical journals from January to March
2005 (n=239 articles). Papers published in American Journal of Medicine, Annals of Internal
Medicine, BMJ, JAMA, Lancet, and The New England Journal of Medicine. Table modified from
JAMA 2007;298:101022.
Statistical Test
Descriptive statistics
(mean, median, frequency, SD, and
IQR)
Simple statistics
Chi-square analysis ttest
Kaplan-Meier analysis
Wilcoxon rank sum test
Fisher exact test Analysis
of variance Correlation
Multivariate analysis
Cox proportional hazards
Multiple logistic regression
Multiple linear regression
Other regression analysis
None
No. (%)
219 (91.6)
120 (50.2)
70 (29.3)
48 (20.1)
48 (20.1)
38 (15.9)
33 (13.8)
21 (8.8)
16 (6.7)
164 (68.6)
64 (26.8)
54 (22.6)
7 (2.9)
38 (15.9)
5 (2.1)
Statistical Test
Others
Intention-to-treat analysis
Incidence/prevalence Relative risk
/risk ratio Sensitivity analysis
Sensitivity/specificity
No. (%)
42 (17.6)
39 (16.3)
29 (12.2)
21 (8.8)
15 (6.3)
IQR = interquartile range; SD = standard deviation.

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Biostatistics
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II. TYPES OF VARIABLES/DATA

A. Definition: Data: A variable whose observed values may be considered outcomes of an experiment
and whose values cannot be anticipated with certainty before the experiment is conducted
B. Two Types of Random Variables
1. Discrete variables (e.g., dichotomous, categorical)
2. Continuous variables
C. Discrete Variables
1. Can only take a limited number of values within a given range
2. Nominal: Classified into groups in an unordered manner, with no indication of relative severity (e.g., sex, mortality, disease state)
3. Ordinal: Ranked in a specific order but with no consistent level of magnitude of difference
between ranks (e.g., NYHA [New York Heart Association] functional class describes the
functional status of patients with heart failure, and subjects are classified in increasing order
of disability: I, II, III, IV )
4. COMMON ERROR: Measure of central tendency: In most cases, means and SDs should not
be reported with ordinal data. What is a common incorrect use of means and SDs to show
ordinal data?
D. Continuous Variables, Sometimes Referred to as Counting Variables
1. Continuous variables can take on any value within a given range.
2. Interval: Data are ranked in a specific order with a consistent change in magnitude between
units; the zero point is arbitrary (e.g., degrees Fahrenheit).
3. Ratio: Like interval but with an absolute zero (e.g., degrees Kelvin, heart rate, blood
pressure, time, distance)
III. TYPES OF STATISTICS
A. Descriptive Statistics: Used to summarize and describe data that are collected or generated in
research studies. This is done both visually and numerically.
1. Visual methods of describing data
a. Frequency distribution
b. Histogram
c. Scatterplot
2. Numeric methods of describing data: Measures of central tendency
a. Mean (i.e., average)
i. Sum of all values divided by the total number of values
ii. Should generally be used only for continuous and normally distributed data
iii. Very sensitive to outliers and tend toward the tail, which has the outliers
iv. Most commonly used and most well-understood measure of central tendency
v. Geometric mean
b. Median
i. Midpoint of the values when placed in order from highest to lowest. Half of the observations are above and below.
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Biostatistics
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ii. Also called 50th percentile

iii. Can be used for ordinal or continuous data (especially good for skewed populations)
iv. Insensitive to outliers
c. Mode
i. Most common value in a distribution
ii. Can be used for nominal, ordinal, or continuous data
iii. Sometimes, there may be more than one mode such as bimodal and trimodal.
iv. Does not help describe meaningful distributions with a large range of values, each of
which occurs infrequently
3. Numeric methods of describing data: Measures of data spread or variability
a. Standard deviation
i. Measure of the variability about the mean, most common measure used to describe this
ii. Square root of the variance (average squared difference of each observation from the
mean) returns variance back into original units (non-squared).
iii. Appropriately applied only to continuous data that are normally or near-normally
distributed or that can be transformed to be normally distributed
iv. By the empiric rule, 68% of the sample values are found within 1 SD, 95% are found
within 2 SD, and 99% are found within 3 SD.
v. The coefficient of variation relates the mean and the SD (SD/mean 100%).
b. Range
i. Difference between the smallest and largest value in a data set does not give a tremendous
amount of information by itself.
ii. Easy to compute (simple subtraction)
iii. Size of range is very sensitive to outliers.
iv. Often reported as the actual values rather than the difference between the two extreme
values
c. Percentiles
i. The point (value) in a distribution in which a value is larger than some percentage of the
other values in the sample. Can be calculated by ranking all data on a data set
ii. The 75th percentile lies at a point at which 75% of the other values are smaller.
iii. Does not assume the population has a normal distribution (or any other distribution)
iv. The interquartile range (IQR) is an example of the use of percentiles to describe the
middle 50% values. It encompasses the 25th75th percentile.
4. Presenting data using only measures of central tendency can be misleading without some
idea of data spread. Studies that report only medians or means without their accompanying
measures of data spread should be closely scrutinized. What are the measures of spread that
should be used with means and medians?
B. Inferential Statistics
1. Conclusions or generalizations made about a population (large group) from a study of a
sample of that population
2. Choosing and evaluating statistical methods depend, in part, on the type of data used.
3. An educated statement about an unknown population is commonly referred to in statistics as
an inference.
4. Statistical inference can be made by estimation or hypothesis testing.
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IV. POPULATION DISTRIBUTIONS

A. Discrete Distributions
1. Binomial distribution
2. Poisson distribution
B. Normal (Gaussian) Distribution
1. Most common model for population distributions
2. Symmetric or bell-shaped frequency distribution
3. Landmarks for continuous, normally distributed data
a. : Population mean is equal to zero.
b. : Population SD is equal to 1.
c. x and s represent the sample mean and SD.
4. When measuring a random variable in a large-enough sample of any population, some values will
occur more often than others.
5. A visual check of a distribution can help determine whether it is normally distributed or whether it
appears symmetric and bell shaped. Need the data to perform these checks
a. Frequency distribution and histograms (visually look at the data; you should do this anyway)
b. Median and mean will be about equal for normally distributed data (most practical and easiest
to use).
c. Formal test: Kolmogorov-Smirnov test
d. More challenging to evaluate this when we do not have access to the data (when we are
reading a paper) because most papers do not present all data or both the mean and median?
6. The parameters mean and SD completely define a normally distributed population. As such,
normally distributed data are termed parametric.
7. Probability: The likelihood that any one event will occur given all the possible outcomes
8. Estimation and sampling variability
a. One method that can be used to make an inference about a population parameter
b. Separate samples (even of the same size) from a single population will give slightly different
estimates.
c. The distribution of means from random samples approximates a normal distribution.
i. The mean of this distribution of means = the unknown population mean, .
ii. The SD of the means is estimated by the standard error of the mean (SEM).
iii. Like any normal distribution, 95% of the sample means lie within 2 SEM of the
population mean.
d. The distribution of means from these random samples is about normal regardless of the
underlying population distribution (central limit theorem). You will get slightly different
mean and SD values each time you repeat this experiment.
e. The SEM is estimated using a single sample by dividing the SD by the square root of the
sample size (n). The SEM quantifies uncertainty in the estimate of the mean, not variability in
the sample. Important for hypothesis testing and 95% confidence interval (CI) estimation
f. Why is all of this worth knowing about the difference between the SEM and SD?
i. Application of CIs (95% CI is about mean 2 times the SEM.)
ii. Hypothesis testing
iii. Deception (e.g., makes results look less variable, especially when used in graphic
format)
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V. CONFIDENCE INTERVALS
A. Commonly Reported as a Way to Estimate a Population Parameter

1. In the medical literature, 95% CIs are the most commonly reported CIs. In repeated samples,
95% of all CIs include true population value (i.e., the likelihood/confidence [or probability] that
the population value is contained within the interval). In some cases, 90% or 99% CIs are
reported. Why are 95% CIs most often reported?
2. The differences between the SD, SEM, and CIs should be noted when interpreting the literature
because they are often used interchangeably. Although it is common for CIs to be confused with
SDs, the information that each provides is quite different and needs to be assessed correctly.
B. CIs can also be used for any sample estimate. Estimates derived from categorical data such as risk, risk
differences, and risk ratios are often presented with the CI and will be discussed later.
C. CIs Instead of Hypothesis Testing

1. Hypothesis testing and calculation of p-values tell us (ideally) whether there is, or is not, a
statistically significant difference between groups, but they do not tell us anything about the
magnitude of the difference.
2. CIs help us determine the importance of a finding or findings, which we can apply to a situation.
3. CIs give us an idea of the magnitude of the difference between groups as well as the statistical
significance.
4. CIs are a range, together with a point estimate of the difference.
5. Wide CIs
a. Many results are possible, either larger or smaller than the point estimate provided by the
study.
b. All values contained in the CI are statistically plausible.
6. If the estimate is the difference between two continuous variables: A CI that includes zero (no
difference between two variables) can be interpreted as not statistically significant (a p-value of
0.05 or greater). There is no need to show both the 95% CI and the p-value.
7. The interpretation of CIs for odds ratios and relative risks is somewhat different. In that case, a
value of 1 indicates no difference in risk, and if the CI includes 1, there is no statistical difference.
(See the discussion of case-control/cohort in other sections for how to interpret CIs for odds ratios
and relative risks.)
VI. HYPOTHESIS TESTING
A. Set up the hypothesis to be tested.

1. Null hypothesis (H0): No difference between groups being compared (treatment A = treatment B)
2. Alternative hypothesis (Ha): Opposite of null hypothesis; states that there is a difference (treatment
A treatment B)
3. The structure or the manner in which the hypothesis is written will depend on the statistical test
being used and the variables being compared. Two-sample t-test: H0: mean 1 = mean 2
4. Used to assist in determining whether any observed differences between groups can be explained
by chance
5. Tests for statistical significance (hypothesis testing) determine whether the data are consistent
with H0 (no difference).
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6. The results of the hypothesis testing will indicate whether enough evidence exists for H0 to be
rejected.
a. If H0 is rejected = statistically significant difference between groups (unlikely attributable to
chance)
b. If H0 is not rejected = no statistically significant difference between groups (any apparent
differences may be attributable to chance). Note that we are not concluding that the treatments are equal.
B. To determine what is sufficient evidence to reject H0: Set the a priori significance level () and generate
the decision rule.
1. Developed after the research question has been stated in hypothesis form
2. Used to determine the level of acceptable error caused by a false positive (also known as level of
significance)
a. Convention: A priori is usually 0.05.
b. Critical value is calculated, capturing how extreme the sample data must be to reject H0.
C. Perform the experiment and estimate the test statistic.
1. A test statistic is calculated from the observed data in the study, which is compared with the critical
value.
2. Depending on this test statistics value, H0 is not-rejected (often referred to as fail to reject) or
rejected.
3. In general, the test statistic and critical value are not presented in the literature; instead, p-values
are usually reported and compared with a prior values to assess statistical significance.
p-value: Probability of making an observation as extreme as or more extreme than the one actually
observed (more informally [and incorrect], the probability that observation is attributable to chance)
4. Because computers are used in these tests, this step is often transparent; the p-value estimated in the
statistical test is compared with the a priori (usually 0.05), and the decision is made.
VII. STATISTICAL TESTS AND CHOOSING A STATISTICAL TEST
A. Which Tests Do You Need to Know?
B. Choosing the Appropriate Statistical Test Depends on

1. Type of data (nominal, ordinal, or continuous)
2. Distribution of data (normal, etc.)
3. Study design (parallel, crossover, etc.)
4. Presence of confounding variables
5. One-tailed versus two-tailed test
6. Parametric versus nonparametric tests
a. Parametric tests assume
i. Data being investigated have an underlying distribution that is normal or near- normal. Or
more correctly: Randomly drawn from a parent population with a normal distribution.
Remember that one way to estimate or evaluate this is to compare the mean and median.
ii. Data measured are continuous data, measured either on an interval or a ratio scale.
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iii. Parametric tests assume that the data being investigated have variances that are
homogeneous between the groups investigated. This is often referred to as
homoscedasticity.
b. Nonparametric tests are used when data are not normally distributed or do not meet other
criteria for parametric tests (e.g., discrete data).
C. Parametric Tests
1. Student t-test: Several different types
a. One-sample test: Compares the mean of the study sample with the population mean
Group 1
Known population mean
b. Two-sample, independent samples, or unpaired test: Compares the means of two independent
samples
i. This is an independent samples test.
Group 1 Group 2
ii. Equal variance and unequal variance

(a) Rule of thumb for variances: If the ratio of larger variance to smaller variance is greater
than 2, we generally conclude that the variances are different.
(b) Formal test for differences in variances: F test
(c) Adjustments can be made for cases of unequal variance.
c. Paired test: Compares the mean difference of paired or matched samples. This is a related samples test.
Group 1
Measurement 1
Measurement 2
d. Common error: Use of multiple t-tests with more than two groups
2. Analysis of variance (ANOVA): A more generalized version of the t-test that can apply to more than
two groups
a. One-way ANOVA: Compares the means of three or more groups in a study. Also known as a
single-factor ANOVA. This is an independent samples test.
Group 1
Group 2
Group 3
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b. Two-way ANOVA: Additional factor (e.g., age) added

Young Groups
Group 1 Group 2 Group 3
Old Groups
Group 1 Group 2 Group 3
c. Repeated-measures ANOVA: This is a related samples test.

Related Measurements
Group 1
Measurement 1
Measurement 2
Measurement 3
d. Many more complex factorial ANOVAs can be used.

e. Several comparison procedures are used to determine which groups actually differ
from each other. Post hoc tests: Tukey HSD (Honestly Significantly Different),
Bonferroni, Scheff, Newman-Keuls
3. Analysis of covariance: Provides a method to explain the influence of a categorical variable
(independent variable) on a continuous variable (dependent variable) while statistically controlling for other variables (confounding)
4. Pearson correlation (discussed later)
5. Simple regression (discussed later)
D. Nonparametric Tests
1. These tests may also be used for ordinal data and continuous data that do not meet the
assumptions of the t-test or ANOVA.
2. Tests for independent samples
a. Wilcoxon rank sum and Mann-Whitney U-test, compares two independent samples
(related to a t-test)
b. Kruskal-Wallis one-way ANOVA by ranks
i. Compares three or more independent groups (related to a one-way ANOVA)
ii. Post hoc testing
3. Tests for related or paired samples
a. Sign test and Wilcoxon signed rank test: Compares two matched or paired samples
(related to a paired t-test)
b. Friedman ANOVA by ranks: Compares three or more matched/paired groups
E. Nominal Data
1. Chi-square (2) test: Compares expected and observed proportions between two or more
groups
a. Test of independence
b. Test of goodness of fit
2. Fisher exact test: Specialized version of chi-square test for small groups (cells) containing
fewer than five observations
3. McNemar: Paired samples
4. Mantel-Haenszel: Controls for the influence of confounders
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2 Samples
Type of Variable (independent)
2 or Fisher exact test
Nominal
Wilcoxon rank sum
Ordinal
Mann-Whitney U-test
Continuous
No factors
1 factor

Equal variance t-test

Unequal variance
t-test
ANCOVA
2 Samples
(related)
McNemar test
Wilcoxon signed
rank
Sign test
Paired t-test
> 2 Samples
(independent)
2
Kruskal-Wallis
(MCP)
> 2 Samples
(related)
Cochran Q
Friedman ANOVA
1-way ANOVA
(MCP)
Repeated-measures
ANOVA
2-way repeatedmeasures ANOVA
2-way ANOVA
(MCP)
2-way repeatedmeasures ANOVA
ANCOVA = analysis of covariance; ANOVA = analysis of variance; MCP = multiple comparison procedures.
F. Correlation and Regression (see section IX)

VIII. DECISION ERRORS

A. Summary of Decision Errors

Test result
Accept H0 (no difference)
Reject H0 (difference)
Underlying Truth or Reality

H0 Is True (no difference)
H0 Is False (difference)
No error (correct decision)
Type II error (beta error)
Type I error (alpha error)
No error (correct decision)
B. Type I Error: The probability of making this error is defined as the significance level .
1. Convention is to set to 0.05, effectively meaning that, 1 in 20 times, a type I error will occur
when the H0 is rejected. So, 5.0% of the time, a researcher will conclude there is a statistically
significant difference when actually, one does not exist.
2. The calculated chance that a type I error has occurred is called the p-value.
3. The p-value tells us the likelihood of obtaining a given (or a more extreme) test result if the
H0 is true. When the level is set a priori, H0 is rejected when p is less than . In other words,
the p-value tells us the probability of being wrong when we conclude that a true difference
exists (false positive).
4. A lower p-value does not mean the result is more important or more meaningful, but only
that it is statistically significant and not likely attributable to chance.
C. Type II Error: The probability of making this error is termed .
1. Concluding that no difference exists when one truly does (not rejecting H0 when it should
be rejected)
2. It has become a convention to set to between 0.20 and 0.10.
D. Power (1 )
1. The probability of making a correct decision when H0 is false, the ability to detect differences
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between groups if any actually exist

2. Dependent on the following factors:
a. Predetermined : The risk of error you will tolerate when rejecting H0
b. Sample size
c. The size of the difference between the outcomes you wish to detect. Often unknown
before conducting the experiment, so to estimate the power of your test, you will have to
specify how large a change is worth detecting
d. The variability of the outcomes that are being measured
e. Items c and d are generally determined from previous data and/or the literature.
3. Power is decreased by (in addition to the above criteria)
a. Poor study design
b. Incorrect statistical tests (use of nonparametric tests when parametric tests are appropriate)
4. Statistical power analysis and sample size calculation
a. Related to above discussion of power and sample size
b. Should be performed in all studies a priori
c. Necessary components for estimating appropriate sample size
i. Acceptable type II error rate (usually 0.100.20)
ii. Observed difference in predicted study outcomes that is clinically significant
iii. The expected variability in item ii
iv. Acceptable type I error rate (usually 0.05)
5. Statistical significance versus clinical significance
a As previously stated, the size of the p-value is not related to the importance of the result.
Smaller values mean only that chance is less likely to explain observed
differences.
b. Statistically significant does not necessarily mean clinically significant.
c. Lack of statistical significance does not mean results are not important.
d. When considering nonsignificant findings, consider sample size, estimated power, and
observed variability.

IX. CORRELATION AND REGRESSION
A. Introduction: Correlation vs. Regression

1. Correlation examines the strength of the association between two variables. It does not necessarily assume that one variable is useful in predicting the other.
2. Regression examines the ability of one or more variables to predict another variable.
B. Pearson Correlation
1. The strength of the relationship between two variables that are normally distributed, ratio or
interval scaled, and linearly related is measured with a correlation coefficient.
2. Often referred to as the degree of association between the two variables
3. Does not necessarily imply that one variable is dependent on the other (regression analysis
will do that)
4. Pearson correlation (r) ranges from 1 to +1 and can take any value in between:
1
perfect negative linear
relationship
0
no linear relationship
+1
perfect positive linear
relationship
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5. Hypothesis testing is performed to determine whether the correlation coefficient is different

from zero. This test is highly influenced by sample size.
C. Pearls About Correlation
1. The closer the magnitude of r to 1 (either + or ), the more highly correlated the two variables.
The weaker the relationship between the two variables, the closer r is to 0.
2. There is no agreed-on or consistent interpretation of the value of the correlation coefficient. It
is dependent on the environment of the investigation (laboratory vs. clinical experiment).
3. Pay more attention to the magnitude of the correlation than to the p-value because it is
influenced by sample size.
4. Crucial to the proper use of correlation analysis is the interpretation of the graphic
representation of the two variables. Before using correlation analysis, it is essential to
generate a scatterplot of the two variables to visually examine the relationship.
D. Spearman Rank Correlation: Nonparametric test that quantifies the strength of an association
between two variables and does not assume a normal distribution of continuous data. Can be used
for ordinal data or nonnormally distributed continuous data
E. Regression
1. A statistical technique related to correlation. There are many different types; for simple linear
regression: one continuous outcome (dependent) variable and one continuous independent
(causative) variable
2. Two main purposes of regression: (1) development of prediction model and (2) accuracy of
prediction
3. Prediction model: Making predictions of the dependent variable from the independent
variable; Y = mx+ b (dependent variable = slope independent variable + intercept)
4. Accuracy of prediction: How well the independent variable predicts the dependent variable.
Regression analysis determines the extent of variability in the dependent variable that can be
explained by the independent variable.
a. Coefficient of determination (r2) measured describing this relationship. Values of r2 can
range from 0 to 1.
b. An r2 of 0.80 could be interpreted as saying that 80% of the variability in Y is explained
by the variability in X.
c. This does not provide a mechanistic understanding of the relationship between X and Y,
but rather, a description of how clearly such a model (linear or otherwise) describes the
relationship between the two variables.
d. Like the interpretation of r, the interpretation of r2 is dependent on the scientific arena
(e.g., clinical research, basic research, social science research) to which it is applied.
5. For simple linear regression, two statistical tests can be employed.
a. To test the hypothesis that the y-intercept differs from zero
b. To test the hypothesis that the slope of the line is different from zero
6. Regression is useful in constructing predictive models. The literature is full of examples of
predictions. The process involves developing a formula for a regression line that best fits the
observed data.
7. Like correlation, there are many different types of regression analysis.
a. Simple linear regression: One continuous independent (response) variable, one
continuous or categorical dependent (explanatory) variable
b. Multiple linear regression: One continuous response variable and two or more continuous
or categorical response variables
c. Simple logistic regression: One categorical response variable and one continuous or
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categorical explanatory variable

d. Multiple logistic regression: One categorical response variable and two or more
continuous or categorical explanatory variables
e. Nonlinear regression: Variables are not linearly related (or cannot be transformed into a
linear relationship).
f. Polynomial regression: Any number of response and continuous variables with a
curvilinear relationship (e.g., cubed, squared)
X. SURVIVAL ANALYSIS
A. Studies the Time Between Entry in a Study and Some Event (e.g., death, myocardial infarction)
B. Censoring makes survival methods unique, takes into account that some subjects leave the study
for reasons other than the event (e.g., lost to follow-up, end of study period)
C. Considers that all subjects do not enter the study at the same time
D. Standard methods of statistical analysis such as t-tests and linear or logistic regression cannot be
applied to survival data because of censoring.
E. Estimating the survival function: Kaplan-Meier method Most common method
1. Uses survival times (or censored survival times) to estimate the proportion of people who
would survive a given length of time under the same circumstances
2. Allows the production of a table (life table) and a graph (survival curve)
3. We can visually evaluate the curves, but we need a test to formally evaluate them.
F. Log-rank test Compares the survival distributions between (two or more) groups
1. This test precludes an analysis of the effects of several variables or the magnitude of
difference between groups or the CI (see below for Cox proportional hazards model).
2. H0: No difference in survival between the two populations
3. Log-rank test uses several assumptions:
a. Random sampling and subjects chosen independently
b. Consistent criteria for entry or end point
c. Baseline survival rate does not change as time progresses.
d. Censored subjects have the same average survival time as uncensored subjects.
G. Cox proportional hazards model
1. Most popular method to evaluate the impact of covariates, reported (graphically) like KaplanMeier
2. Investigates several variables at a time
3. Actual method of construction/calculation is complex.
4. Compares survival in two or more groups after adjusting for other variables
5. Allows calculation of a hazard ratio (and CI)
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REFERENCES
1. Strassels SA. Biostatistics. In: Dunsworth
2.
3.
4.
5.
6.
7.
8.
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11. Gaddis ML, Gaddis GM. Introduction

to biostatistics. Part 4, statistical inference techniques in hypothesis testing. Ann
Emerg Med 1990;19:8205.
12. Gaddis ML, Gaddis GM. Introduction to
biostatistics. Part 5, statistical inference
techniques for hypothesis testing with
nonparametric data. Ann Emerg Med
1990;19:10549.
13. Gaddis ML, Gaddis GM. Introduction to
biostatistics. Part 6, correlation and regression.
Ann Emerg Med 1990;19:14628.
14. Kusuoka H, Hoffman JIE. Advice on statistical
analysis for circulation research. Circ Res
2002;91:66271.
15. Larson MG. Descriptive statistics and
graphical displays. Circulation
2006;114:7681.
16. Sullivan LM. Estimation from samples.
Circulation 2006;114:4459.
17. Davis RB, Mukamal KJ. Hypothesis testing:
means. Circulation 2006;114:107882.
18. Larson MG. Analysis of variance. Circulation
2008;117:11521.
19. Crawford SL. Correlation and regression.
20. Rao SR, Schoenfeld DA. Survival methods.
21. Tsuyuki RT, Garg S. Interpreting data in
cardiovascular disease clinical trials: a biostatistical toolbox. In: Richardson MM, Chant C,
Cheng JWM, et al, eds. Pharmacotherapy SelfAssessment Program, 7th ed. Kansas City, MO:
ACCP, 2010.
22. Windish DM, Huot SJ, Green ML. Medicine
residents understanding of the biostatistics and
results in the medical literature. JAMA
2007;298:101022.
23. Jones SR, Carley S, Harrison M. An introduction to power and sample size estimation.
Emerg Med J 2003;20:4538.
TS, Richardson MM, Chant C, et al, eds.

Pharmacotherapy Self-Assessment Program, 6th
ed. Kansas City, MO: ACCP,
2007.
DeYoung GR. Understanding biostatistics: an
approach for the clinician. In: Zarowitz B,
Shumock G, Dunsworth T, et al, eds.
Pharmacotherapy Self-Assessment Pro- gram,
5th ed. Kansas City, MO: ACCP,
2005.
Harper ML. Biostatistics for the clinician.
In: Zarowitz B, Shumock G, Dunsworth
T, et al, eds. Pharmacotherapy Self-Assessment
Program, 4th ed. Kansas City, MO: ACCP, 2002.
Hayney MS, Meek PD. Essential clinical
concepts of biostatistics. In: Carter BL, Lake
KD, Raebel MA, et al, eds. Pharmacotherapy
Self-Assessment Program, 3rd ed. Kansas City,
MO: ACCP, 1999.
Rector TS, Hatton RC. Statistical concepts and
methods used to evaluate pharmacotherapy. In:
Zarowitz B, Shumock G, Dunsworth T, et al, eds.
Pharmacotherapy Self-Assessment Program, 2nd
ed. Kansas City, MO: ACCP, 1997.
Overholser BR, Sowinski KM. Biostatistics
primer: part 1. Nutr Clin Pract
2007;22:62935.
Overholser BR, Sowinski KM. Biostatistics
primer: part 2. Nutr Clin Pract
2008;23:7684.
Gaddis ML, Gaddis GM. Introduction to
biostatistics. Part 1, basic concepts. Ann Emerg
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biostatistics. Part 2, descriptive statistics. Ann
Emerg Med 1990;19:30915.
biostatistics. Part 3, sensitivity, specificity,
predictive value, and hypothesis testing. Ann
Emerg Med 1990;19:5917.
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1. Define, compare, and contrast the concepts of internal and external validity, bias, and confounding in
clinical study design.
2. Identify potential sources of bias in clinical trials; select strategies to eliminate or control for bias.
3. Outline the hierarchy of evidence generated by various study designs.
4. Compare and contrast the advantages and disadvantages of various study designs (e.g., prospective;
retrospective; case-control; cohort; cross-sectional; randomized controlled clinical trials; systematic
review; meta-analysis).
5. Select from various biostatistical tests to appropriately compare groups or their assessments from
various study designs and use their findings/output to interpret results.
6. Define and evaluate odds, odds ratio, risk /incidence rate, risk ratio/relative risks, and other risk
estimates. Compute and evaluate number needed to treat and number needed to harm.
I. INTRODUCTION
A. Why Do Pharmacists Need to Know About Study Design and Interpretation?
B. Glossary of Clinical Evidence (http://clinicalevidence.bmj.com/ceweb/resources/glossary.jsp)
C. Online Statistical and Study Design Tools (www.graphpad.com/quickcalcs/)
D. Pharmacotherapy Specialty Examination Content Outline
Domain 2: Retrieval, Generation, Interpretation, and Dissemination of Knowledge in
Pharmacotherapy (25%)
Interpret biomedical literature with respect to study design and methodology, statistical analysis,
and significance of reported data and conclusions
Knowledge of: Biostatistical methods, clinical and statistical significance, research hypothesis
generation, research design and methodology, and protocol and proposal development
II. VARIOUS ISSUES IN STUDY DESIGN

A. Validity in Study Design
1. Internal validity
a. Validity within the confines of the study methods
b. Does the study design adequately and appropriately test/measure what it purports to test/
measure?
c. Does the study adequately and appropriately address bias, confounding, and measurement
of end points?
2. External validity
a. Validity related to generalizing the study results outside the study setting
b. Can the results be applied to other groups, patients, or systems?
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c. Addresses issues of representativeness

B. Bias in Study Design
1. Definition: Systematic, nonrandom variation in study methodology and conductance,
ultimately introducing error in outcome interpretation. Bias can occur in all aspects of the
study design.
2. Examples of bias:
a. Selection bias
b. Observation or information bias
c. Recall bias: Classic example: Studies of birth defects secondary to medications
d. Interviewer bias: Classic example: Interviews are not conducted in a uniform manner (or
by the same person) for all study participants.
e. Misclassification bias example: A patient is thought (classified) to have a disease but does not.
3. Controlling for bias
a. Design: For example, selection of study population
b. Means of collecting data
c. Sources of information (regarding disease and exposure)
d. Analysis: May be difficult to interpret
C. Confounding in Study Design
1. A variable that affects the independent or dependent variable, altering the ability to determine
the true effect on the measured outcome. These factors may hide or exaggerate a true
association.
2. To minimize the potential for missing a confounding variable, all relevant information should
be collected and evaluated.
3. Controlling for confounding
a. During the design of a study
i. Randomization
ii. Restriction
iii. Matching
b. Analysis
i. Stratification
ii. Multivariate analysis
D. Relative Strength of Evidence: Hierarchy of Study Designs
Descriptive
Ideas,
opinions, and
reviews
Case Report
Obser vational Studies
Case Series
Case-control
Cohort
Crosssectional
Experimental/
Inter ventional
RDBCT
Systemic Reviews and Meta-analysis
Figure 1.
RDBCT = randomized double-blind, placebo-controlled clinical trial.
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E. Prospective vs. Retrospective Design (discussed later in this chapter)

1. Prospective: Begin in the present and progress forward, collecting data from subjects whose
outcome lies in the future.
2. Retrospective: Begin and end in the present; however, this design involves a major
backward look to collect information about events that occurred in the past. There is a
common misconception that only case-control studies are retrospective.
III. CASE REPORTS/CASE SERIES

A. Document and Describe Experiences, Novel Treatments, and Unusual Events. Allows hypothesis
generation that can be tested with other study designs. Note that the title does not state study.
1. Possible adverse drug reactions in one or more patients: QT-interval prolongation associated
with fluoroquinolone antibiotics
2. Case report: One patient
3. Case series: More than one patient with a similar experience or many case reports combined
into a descriptive review
4. Reports should provide sufficient detail to allow readers to recognize same/similar cases at
their center/practice.
5. Is IRB (institutional review board) approval required?
B. Advantages: Hypotheses are formed, which is may be the first step in describing an important
clinical problem. Easy to perform and inexpensive
Disadvantages: Does not provide explanation other than conjecture and does not establish
causality or association
IV. OBSERVATIONAL STUDY DESIGNS

A. Design Does Not Involve Investigator Intervention, Only Observation. It is essential to
remember that observational study designs investigate associations, not, in most cases,
causes.
B. Case-Control Study: Study Exposure in Those With and Without the Outcome of Interest
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Figure 2. Case control study design.

1. Determine the association between exposures/risk factors and disease/condition. Classic
example: Aspirin use and Reye syndrome
2. Often referred to as retrospective studies
3. Useful method (and perhaps the only practical way) to study exposures in rare diseases or
diseases that take long periods to develop
4. Critical assumptions to minimize bias:
a. Cases are selected to be representative of those who have the disease (challenge:
tertiary care vs. community hospital).
b. Controls are representative of the general population that does not have the disease and
are as identical as possible to the cases, minus the presence of the disease.
c. Information is collected from cases and controls in the same way.
5. Advantages
a. Inexpensive and can be conducted quickly
b. Allows investigation of several possible exposures or associations
6. Disadvantages
a. Confounding must be controlled for.
b. Observation and recall bias: Looking back to remember
c. Selection bias: Case selection and control matching are difficult.
7. Measure of association: Odds ratio: In some cases, this can be an estimate of the RR. The OR
is interpreted as the odds (and its ratio) of exposure to a factor in those with a condition or
disease, compared with those who do not have the condition or disease.
C. Cohort Study
1. Determine the association between exposures/factors and disease/condition development.
Allows an estimation of the risk of outcome (and the RR between the exposure groups).
Study outcome of interest in those with and without the exposure of interest. Classic
examples:
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a. Framingham Study. A cohort of subjects from Framingham, Massachusetts, were

(and are) studied over time to evaluate the relationship between a variety of conditions
(exposures) on the development of cardiovascular disease.
b. Nurses Health Study: Investigate the potential long-term consequences of the use of oral
contraceptives
2. Describes the incidence or natural history of a disease/condition and measures it in time
sequence
3. Retrospective: Begins and ends in the present but involves a major backward look to collect
information about events that occurred in the past
Figure 3. Retrospective cohort study design
a. Advantages: Less expensive and time-consuming; no loss to follow-up, ability

to investigate issues not amenable to a clinical trial or ethical or safety issues
b. Disadvantages: Only as good as the data available, little control of confounding
variables through nonstatistical approaches, recall bias
4. Prospective or longitudinal: Begin in the present and progress forward, collecting data from
subjects whose outcome lies in the future.
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Figure 4. Prospective cohort study design.

a. Example: Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and
secondary prevention of coronary events in the nurses health study. A prospective,
observational study. Ann Intern Med 2001;135:18.
b. Advantages: Better able to control for confounding factors, easier to plan for data
collection
c. Disadvantages: More expensive and time-intensive, loss of subject follow-up, difficult
to study rare diseases/conditions at a reasonable cost
5. Measure of association: Relative risk or risk ratio: The risk of an event or development of
a condition relative to exposure; the risk of developing a condition when exposed
compared with someone who has not been exposed
D. Cross-sectional (a.k.a. prevalence study)
1. Identify the prevalence or characteristics of a condition in a group of individuals.
2. Examples:
a. Reidy A, et al. Prevalence of serious eye disease and visual impairment in a north London
population: population based, cross sectional study. BMJ 1998;316:16437
b. Nezvalova K, et al. Maternal characteristics and migraine pharmacotherapy during
pregnancy: cross sectional analysis of data from a large cohort study. Cephalgia
2009;29:126776
3. Advantages: Easy design, snapshot in time, all data collected at one time, studies
are accomplished by questionnaire, interview, or other available biomedical
information (laboratory values, etc.)
4. Disadvantages: Does not allow a study of factors in individual subjects over time, just at the
time of assessment; difficult-to-study rare conditions
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V. INCIDENCE, PREVALENCE, RELATIVE RISKS, AND ODDS RATIOS

A. Incidence
1. Measure of the instantaneous rate of developing a disease so that it reflects the rate of disease
development
2. Divide the number of individuals who develop a disease by the total amount of time these
individuals were at risk of developing a disease (measured in persons/year).
B. Prevalence: Measure of the number of individuals who have a condition or disease at any given
time
C. Interpreting Relative Risks/Odds Ratios
1. Estimate the magnitude of association between exposure and disease. Key point: This is not
cause and effect but association.
2. The incidence of disease in the exposed group divided by the incidence of disease in the
unexposed group
3. The relative risk (a.k.a. risk ratio) cannot be directly calculated for most case-control studies;
instead, the OR is usually an estimate of the RR.
4. The RR and OR are interpreted on the basis of their difference from unity (1.0). If the 95%
confidence interval (CI) includes unity, no statistical difference is indicated. The CI also
gives us an idea of the spread within which the true effect lies.
5. Interpretation of the index of risk
a. Direction of risk
RR
<1
OR
<1
=1
=1
>1
>1
Interpretation
Negative association
Risk is lower in the exposed group
No association
Risk between the two groups is the same
Positive association
Risk is greater in the exposed group
OR = odds ratio; RR = relative risk /risk ratio.
b. Magnitude of risk
RR
0.75
1.0
1.5
3.0
OR
0.75
1.0
1.5
3.0
Interpretation
25% reduction in the risk /odds
No difference in the risk /odds
50% increase in the risk /odds
3-fold (or 300%) increase in the risk /odds
OR = odds ratio; RR = relative risk /risk ratio.
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6. Calculating RR /OR /contingency tables

Yes
Exposure?
Yes
No
Disease?
No
A
C
B
D
D. Causation
1. REMEMBER: In general, we do not prove or show causality with observation studies, but
there is some general guidance to consider when evaluating them. It is important to
recognize that in many situations, the conduct of studies to establish causality is not possible
or practical.
2. Questions used to evaluate causality
a. Was statistical significance observed?
b. What was the strength of the association, as measured by the OR or the RR?
c. Were dose-response relationships evaluated?
d. Was there a temporal relationship between exposure and disease/outcome?
e. Have the results been consistently shown?
f. Is there biologic plausibility to the association?
g. Is there any experimental (animal, in vitro, etc.) evidence?
VI. RANDOMIZED CONTROLLED TRIAL DESIGN

A. Characteristics
1. Experimental or interventional, investigator makes intervention and evaluates cause and
effect. Examine etiology, cause, efficacy, etc., using comparative groups.
2. Some information should exist to suggest that the intervention employed will likely be
beneficial.
3. Design allows assessment of causality.
4. Minimizes bias through randomization and/or stratification
5. May use parallel or crossover design
a. Crossover provides practical and statistical efficiency.
b. Crossover is not appropriate for certain types of treatment questions. Effect of treatment
on a disease that worsens quickly over time or worsens during the study period
6. Examples:
a. Clinical trial: Comparison of two drugs, comparison of two behavioral modifications, etc.
b. Educational intervention: Online course versus lecture class format
c. Health care intervention: Pharmacist-based health care team versus nonpharmacistbased health care team
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B. Randomized Controlled Trial: Parallel Design
Figure 5. Randomized controlled trial: parallel design.
Figure 6. Randomized controlled trial: crossover design
D. Examples of Considerations for Controlled Trials

1. Are the results of the study valid?
a. Were the subjects randomized, and what was the randomization technique? Did the
randomization process result in equal baseline characteristics?
b. Were all subjects who entered the trial accounted for? Was follow-up complete? If not,
how many were lost to follow-up, from which groups did they leave, and why?
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c. Were subjects analyzed in the groups to which they were randomized? Was intention-totreat, per-protocol, or actual treatment analysis used?
d. How was blinding conducted (subject, investigator, etc.), if applicable?
e. Were the inclusion and exclusion criteria appropriate, or were they too restrictive or
inclusive? Were the groups similar at the start of the trial?
f. Was the sample size sufficient, and was a power calculation included?
g. Were the groups handled the same way, aside from the intervention(s)?
h. Were the statistical tests appropriate and understandable?
i. Were surrogate markers or true outcomes assessed? Were a priori subgroup
analyses performed?
2. What were the results?
a. How large was the treatment effect?
b. How precise was the effect (were the CIs)?
c. Did the authors properly interpret the results?
3. Can I apply the results of this study to my patient population? Will they help me care for my
patients?
a. Can the results of this study be applied to general practice?
b. Was a representative population studied? Can I apply this to my setting?
c. Do the patients I care for fill the enrollment criteria for this study?
d. Do the patients I care for fill the subgroup criteria evaluated?
e. Do the expected benefits outweigh the expected and/or unanticipated risks?
VII. OTHER ISSUES TO CONSIDER IN CONTROLLED TRIALS

A. Subgroup Analysis
1. Important part of controlled clinical trials (if set a priori)
2. Many times, they are overused and over-interpreted, leading to unnecessary research,
misinterpretation of results, and/or suboptimal patient care.
3. Qualitative versus quantitative interactions or differences
a. Quantitative: Studied treatment is superior for both subgroups (ex. male and female).
b. Qualitative: Studied treatment is superior in only ONE of the subgroups (ex. male or
female). These types of differences should be viewed with caution.
4. Many potential pitfalls in identifying and interpreting:
a. Failure to account for several comparisons or to adjust p-values
b. Problems with sample size (power), classification, and lack of assessment of interaction
B. Composite End Points: Often, the Impression Is that This Practice Is Not a Good Practice.
1. The primary end point is one of the most important decisions to make in the design of a
clinical study.
2. A composite end point combines several end points:
a. For example, cardiovascular death, nonfatal myocardial infarction (MI), and cardiac
arrest with resuscitation
b. Usually combines measures of morbidity and mortality
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c. What does the following statement mean?

Our findings show that ramipril reduces the rate of death, MI, stroke,
revascularization, cardiac arrest, heart failure, complications related to diabetes, and new
cases of diabetes in a broad spectrum of high-risk patients. Treating 1000 patients with
ramipril for 4 years prevents about 150 events in around 70 patients.
i. Was there a reduction in all the end points or just some?
ii. Are all the outcomes just as likely to occur?
iii. Why would this trial have been interested in all of these outcomes?
3. What are the positives for using composite end points?
a. No single primary outcome
b. Alleviate problems of multiple testing.
c. Increase number of events, which decreases sample size and cost.
4. What are the problems?
a. Difficulties in interpreting composite end points; consider the example above
b. Misattribution of statistically beneficial effects of composite measure to each of its
component end points
c. Dilution of effects, negative results for relatively common component of composite end
point hide real differences in other end points. Undue influence exerted on composite
end point by softer component end points
d. Averaging of overall effect problems when component end points move in
opposite directions
e. Should all end points be weighed the same, or should death weigh more?
5. The results for each individual end point should be reported together with the results for the
composite.
C. Surrogate End Points
1. Parameters thought to be associated with clinical outcomes
a. Blood pressure and stroke prevention
b. Low-density lipoprotein cholesterol reduction and cardiovascular death reduction
i. Statins: Yes
ii. Hormone replacement therapy: No
c. PVC (premature ventricular contraction) suppression and reduced mortality
2. Surrogate outcomes do not always predict clinical outcomes.
3. Short-duration studies that evaluate surrogate end points may not be large enough to detect
uncommon adverse events.
D. Superiority vs. Equivalence vs. Non-inferiority
1. Superiority trial is designed to detect a difference between experimental treatments. This is
the typical design in a clinical trial.
2. An equivalence trial is designed to confirm the absence of meaningful difference(s) between
treatments. The key is the definition of the specified margin. What difference is important?
One example is a bioequivalence trial.
3. A non-inferiority trial is designed to investigate whether a treatment is not clinically worse
(no less effective, or inferior) than an existing treatment.
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a. It may be the most effective, or it may have a similar effect.

b. Useful when placebo administration is not possible because of ethical reasons
c. ONTARGET trial
i. Designed to evaluate telmisartan, ramipril, or the combination of them in patients
with a high risk of vascular disease
ii. Objective was to determine whether telmisartan was non-inferior to ramipril in the
incidence of cardiovascular deaths.
iii. Non-inferior difference was defined as 13% or less.
iv. Essentials of non-inferiority design
(a) Control group (ramipril) must be effective.
(b) Current study similar to previous study with control (HOPE) and with equal
doses, clinical conditions, and design employed
(c) Adequate power is essential, and usually, larger sample sizes are required.
VIII. CONTROLLED CLINICAL TRIALS: QUESTIONS TO CONSIDER IN THE

EVALUATION AND INTERPRETATION OF A CLINICAL TRIAL
A. Study design
1. Was the studied sample representative of the population or the individual to whom the
results were being applied?
2. Were the inclusion/exclusion criteria appropriate, or were they overly restrictive or inclusive?
3. Sufficient sample size, power, etc.? Was a power analysis included?
4. Is a study objective and/or hypothesis provided?
5. Was the study blinded and to whom? (subject, investigator, study personnel, or all?)
6. Was a run-in phase employed? If so, why? Did it affect the interpretation of the trial?
7. What type of randomization method was performed? Did the randomization process produce
equal baseline characteristics between all groups?
B. Outcomes/Assessments
1. Are the primary and/or secondary outcomes identified, are they reasonable, and do they
apply to clinical practice?
2. Is a composite outcome employed, and are all the individual components identified and
clearly stated in the methods and results?
3. Are surrogate markers employed instead of (or in addition to) clinically relevant
outcomes?
C. Analysis
1. What analysis technique was used: intention-to-treat, actual treatment, or per-protocol?
2. Are the statistical tests appropriate?
D. Interpretation: Is the authors interpretation appropriate and within the confines of the study
design?
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E. Extrapolation
1. Are you applying the results to similar patients in a similar setting?
2. Are there possible additional adverse effects that are not measured in this study?
IX. COMMON APPROACHES TO ANALYZING CLINICAL TRIALS

A. Intention-to-Treat Analysis
1. Compares outcomes on the basis of initial group assignment or as randomized. The
allocation to groups was how they were intended to be treated, even though they may not
have taken the medication for the full duration of the study or they dropped out, etc.
2. Determines effect of treatment under usual conditions of use. Analogous to routine clinical
practice in which a patient receives a prescription but may not adhere to the drug
3. Gives a conservative estimate of differences in treatments; may underestimate treatment benefits
4. Most common approach to assessing clinical trial results
B. Per-Protocol Analysis
1. Subjects who do not adhere to allocated treatment are not included in the final analysis; only
those who completed the trial and adhered to the protocol (based on some predetermined
definition [e.g., 80% adherence])
2. Provides additional information about treatment effectiveness and provides more generous
estimates of differences between treatments
3. Subject to several issues because of factors such as lower sample size and definitions
of adherence. Results are more difficult to interpret.
C. As-Treated Analysis
1. Subjects are analyzed by the actual intervention received. If subjects were in the active
treatment group but did not take active treatment, the data would be analyzed as if they were
in the placebo group.
2. This analysis essentially ignores the randomization process for those who did not adhere to
the study design.
X. SYSTEMATIC REVIEW/META-ANALYSIS
A. Introduction
1. Dramatic increase in the number of this type of papers
2. First meta-analysis probably published in 1904: Assessment of typhoid vaccine effectiveness
B. Systematic Review
1. Summary that uses explicit methods to perform a comprehensive literature search, critically
appraise it, and synthesize the world literature on a specific topic. Instead of the subjects being
human subjects, the individual studies are the study subjects (i.e., the subjects are studies).
2. Differs from a standard literature review: The study results are more
comprehensively synthesized and reviewed.
3. As with a controlled clinical trial (or other studies), the key is a well-documented and
described systematic review.
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4. Some systematic reviews will attempt to statistically combine results from many studies.
5. Differs from other reviews, which combine evaluation with opinions
C. Meta-analysis
1. Systematic review that uses mathematical/statistical techniques to summarize the results of
the evaluated studies
2. These techniques may improve on:
a. Calculation of effect size
b. Increase statistical power
c. Interpretation of disparate results
d. Reduce bias
e. Answers to questions that may not be addressable with additional study
D. Issues Related to Meta-analysis
1. Reliant on criteria for inclusion of previous studies and statistical methods to ensure validity.
Details of included studies are essential.
2. Assessment of trial methodology
a. Is there a focused research question?
b. What types of studies were included?
c. How was the literature search conducted, and how were trials included/excluded?
d. How was quality assessed, and how many reviewers were there?
e. How was heterogeneity assessed?
i. Statistical heterogeneity
ii. c2 and Cochrane Q are common tests for heterogeneity.
f. Sensitivity analysis
g. Assessment of risk
3. Forest plots
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XI. SUMMARY MEASURES OF EFFECT

A. Absolute and Relative Differences
1. Absolute differences or absolute changes
2. Relative differences or relative changes
3. Absolute differences are more important than relative differences, although the authors of
many clinical studies highlight the differences observed in their trials with relative
differences because they are larger. Why? Larger numbers are more convincing to
practitioners and patients. Most drug advertisements (both directly to patients and to health
care professionals) quote relative differences.
B. Number Needed to Treat
1. Another means to characterize changes or differences in absolute risk
2. Definition: The reciprocal of the ARR
a. NNT = 1/(ARR).
b. Rounded to the next highest whole number is most conservative approach
3. Applied to clinical outcomes with dichotomous data (yes/no, alive/dead, MI/no MI, etc)
4. Cautions: Assumes the baseline risk is the same for all patients (or that it is unrelated to RR)
5. Extrapolation beyond studied time points
6. NNTs should only be provided for significant effects because of the difficulty of interpreting
the CIs for nonsignificant results.
7. Number needed to harm
XII. PHARMACOECONOMIC STUDIES

A. Cost-minimization Analysis
1. Outcome: Equal, only cost is addressed
2. Determines the lowest cost alternative
B. Cost-benefit Analysis
1. Outcome: Monetary; is a treatment worth the cost?
2. Determines the greatest net benefit alternative
C. Cost-effectiveness Analysis
1. Clinical units
2. Determines the most cost-effective alternative
D. Cost-utility Analysis
1. Utility
2. Determines the greatest benefit alternative
XIII. SENSITIVIT Y/SPECIFICIT Y/PREDICTIVE VALUES

A. Sensitivity: Proportion of True Positives That Are Correctly Identified by a Test
B. Specificity: Proportion of True Negatives That Are Correctly Identified by a Test
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C. Positive Predictive Value: Proportion of Patients with a Positive Test Who Are Given a Correct
Diagnosis
D. Negative Predictive Value: Proportion of Patients with a Negative Test Who Are Given a Correct
Diagnosis
E. Example: Relationship Between Test and Correct Diagnosis Identified by Pathology (data from: J
Nucl Med 1972;13:90815)
Test
Abnormal (positive test)
Normal (negative test)
Total
Pathology
Normal
32
54
86
Abnormal
231
27
258
Total
263
81
344
1. Sensitivity: True positives: 258; correct diagnosis 231/258.0.90 or 90%

2. Specificity: True negatives: 86; correct diagnosis: 54/860.63 or 63%
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REFERENCES
1. Strassels SA, Wilson JP. Pharmacoepidemi-
2.
3.
4.
8.
ology. In: Dunsworth TS, Richardson MM, Chant

C, et al, eds. Pharmacotherapy Self- Assessment
Program, 6th ed. Lenexa, KS: ACCP, 2007.
Shermock KM. Secondary data analysis/
observational research. In: Dunsworth TS,
Richardson MM, Chant C, et al, eds. Pharmacotherapy Self-Assessment Program, 5th ed.
Kansas City, MO: ACCP, 2005.
Smith GH, Mays DA. Clinical study design and
literature evaluation. In: Zarowitz B, Shumock G,
Dunsworth T, et al, eds. Phar- macotherapy SelfAssessment Program, 4th ed. Kansas City, MO:
ACCP, 2002.
Quilliam BJ, Barbour MM. Evaluating druginduced cardiovascular disease: a
pharmacoepidemiologic perspective. In:
Richardson MM, Chant C, Cheng JWM,
et al, eds. Pharmacotherapy Self-Assessment
Program, 7th ed. Lenexa, KS: ACCP, 2010.
Mann CJ. Observational research methods.

Research design II: cohort, cross sectional and
case-control studies. Emerg Med J
2003;20:5460.
9.
Dasgupta A, Lawson K A, Wilson JP. Evaluating equivalence and noninferiority trials. Am

J Health Syst Pharm 2010;67:133743.
10. Lesaffre E. Superiority, equivalence and noninferiority trials. Bull NY U Hosp Jt Dis
2008;66:1504.
11. Lagakos SW. The challenge of subgroup
analyses reporting without distorting. N Engl
J Med 2006;354:16679.
12. Tomlinson G, Detsky AS. Composite endpoints in randomized trials: there is no free
lunch. JAMA 2010;303:2678.
13. Neely JG, Magit AE, Rich JT, et al. A practical
guide to understanding systematic reviews and
meta-analysis. Otolaryngol Head Neck Surg
2010;142:614.
14. DiPietro NA. Methods in epidemiology:
observational study designs. Pharmacother- apy
2010;30:97384.
15. Koretz RL. Methods of meta-analysis: an
analysis. Curr Opin Clin Nutr Metab Care
2002;5:46774.
5. Tsuyuki RT, Garg S. Interpreting data in

cardiovascular disease clinical trials: a biostatistical toolbox. In: Richardson MM, Chant
C, Cheng JWM, et al, eds. Pharma- cotherapy
Self-Assessment Program, 7th ed. Lenexa, KS:
ACCP, 2010.
6. Windish DM, Huot SJ, Green ML. Medi- cine
residents understanding of the biostatistics and
results in the medical literature. JAMA
2007;298:101022.
7. Clancy MJ. Overview of research designs.
Emerg Med J 2002;19:5469.
16. Altman DG, Bland JM. Diagnostic tests 1:

sensitivity and specificity. BMJ
1994;308:1552.
17. Altman DG, Bland JM. Diagnostic tests 2:
predictive values. BMJ 1994;309:102.
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POLICY, PRACTICE AND

REGULATORY ISSUES
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1. Explain the prescription drug approval process of the U.S. Food and Drug Administration.
2. Identify implications for clinical research while adhering to institutional review board requirements.
3. List the purpose and function of an investigational drug service.
4. Describe national efforts aimed at improving and ensuring health care quality in the United States,
including the Joint Commission, National Committee for Quality Assurance, National Quality Forum, and
Agency for Healthcare Research and Quality.
5. Interpret legislative activity and regulatory opportunities for pharmacists.
OVERVIEW
The purpose of this review of policy, practice, and regulatory issues is to highlight areas of importance for
clinical pharmacists as they pertain to patient care outcomes and clinical research activity. Specifically, the
rules and regulations set forth by several agencies within the U.S. Department of Health and Human Services
will be outlined.
I. THE U.S. FOOD AND DRUG ADMINISTRATION AND THE PRESCRIPTION DRUG
APPROVAL PROCESS
A. Basics
1. The U.S. Food and Drug Administration (FDA) is the agency within the U.S. Department of
Health and Human Services (DHHS) responsible for the safety of most foods (human and animal)
and cosmetics, and it regulates both the safety and effectiveness of human drugs, biologics (e.g.,
vaccines, blood and blood components), medical devices, and animal drugs.
2. Most federal laws giving the FDA this authority are provisions in and amendments to the Federal
Food, Drug, and Cosmetic Act (FD&C Act), and they are organized in the Code of Federal
Regulations (CFR) Title 21. The FDA is funded through discretionary spending every fall in
Congresss Appropriations bill written by the Senate and House Appropriations Committees, but
the Senate Health, Education, Labor, and Pensions and the House Energy and Commerce
Committees have jurisdiction over its reauthorization.
3. It is organized by two offices, one research center, and six product centers:
a. Office of the Commissioner conducts overall agency coordination; the FDAs top official, the
Commissioner, requires Senate confirmation.
b. Office of Regulatory Affairs, the largest office, regulates all inspection and enforcement
activities.
c. National Center for Toxicological Research supports the six product centers with scientific
technology, training, and technical expertise.
d. Center for Drug Evaluation and Research (CDER) regulates prescription and
nonprescription drugs.
e. Center for Biologics Evaluation and Research regulates vaccines, blood, and gene therapy.
f. Center for Devices and Radiological Health regulates medical devices.
g. Center for Food Safety and Applied Nutrition regulates most foods, food additives, infant
formulas, dietary supplements, and cosmetics.
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h. Center for Tobacco Products regulates tobacco-containing products.

i. Center for Veterinary Medicine regulates feed, drugs, and devices used in pets, farm animals,
and other animals.
B. Definitions
1. The Abbreviated New Drug Application (ANDA) contains data that, when submitted to the FDAs
CDER, Office of Generic Drugs, allows the review and ultimate approval of a generic drug
product.
2. An authorized generic drug is a listed drug that is marketed, sold, or distributed directly or
indirectly to retail class of trade with labeling, packaging (other than repackaging as the listed
drug in blister packs, unit doses, or similar packaging for use in institutions), product code, labeler
code, trade name, or trademark that differs from that of the listed drug.
3. A biologics license application (BLA) is a submission that contains specific information on the
manufacturing processes, chemistry, pharmacology, clinical pharmacology, and medical effects of
a biologic product (monoclonal antibodies, enzymes, immunomodulators, growth factors, and
cytokines) seeking approval to market in the United States.
4. A clinical trial is a research study of humans conducted to answer specific questions about
vaccines, new therapies, or new ways of using known treatments. Clinical trials required by the
FDA seek to determine whether new drugs or treatments are both safe and effective.
5. An Investigational New Drug (IND) application is used for a new drug, a new indication, or offlabel use that will be used in a clinical investigations preclinical development in order for that
new drug to be distributed across state lines before undergoing full FDA review.
6. A New Drug Application (NDA) is the vehicle through which drug sponsors formally propose that
the FDA approve a new pharmaceutical for sale and marketing in the United States.
C. History of the Regulation of Drugs and Human Subjects Research
1. Drug Importation Act of 1848, which prohibited the importation of unsafe or adulterated drugs at
key ports of entry
2. Biologics Control Act of 1902
a. Mandated annual licensing of establishments to manufacture and sell vaccines, sera,
antitoxins, and similar products in interstate commerce
b. Authorized Hygienic Laboratory, precursor to the National Institutes of Health (NIH), to
conduct regular inspections for purity and potency
3. Pure Food and Drug Act of 1906
a. Prohibited interstate commerce of adulterated or misbranded drugs
b. Required labeling of selected dangerous and addictive substances
c. Identified United States Pharmacopoeia and the National Formulary as official standards for
drugs
4. Food, Drug, and Cosmetic Act of 1938
a. Required that firms prove evidence of safety to the FDA before marketing
b. Placed drug advertising under the jurisdiction of the Federal Trade Commission
5. Durham-Humphrey Amendment of 1951: Amended the FD&C Act of 1938 to statutorily
differentiate prescription and nonprescription drugs
6. Kefauver-Harris Amendments of 1962
a. Established the requirement for drug firms to demonstrate efficacy as well as safety
b. Statutory requirement to obtain informed consent for research subjects
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7.
8.
9.
10.
11.
12.
13.
14.
15.
c. Authorized the FDA to regulate advertising of prescription drugs and establish good
manufacturing practices
The Orphan Drug Act of 1983 established grants, federal assistance for research, and tax
incentives to develop drugs targeted for a patient population of less than 200,000.
The Food and Drug Administration Act of 1988 officially established the FDA as an agency in
DHHS.
Prescription Drug User Fee Act (PDUFA) of 1992
a. Requires drug, biologics, and medical device (MDUFA) manufacturers to pay fees for product
applications, supplements, and other services
b. Reauthorized every 5 years (1997, 2002, 2007)
The Dietary Supplement Health and Education Act of 1994 allows nutritional supplements and
vitamins to be regulated.
FDA Modernization Act of 1997
a. Streamline clinical research on drugs and devices
b. Exclusivity provisions for pediatric drugs
c. Authorizes the creation of a databank (ClinicalTrials.gov) to provide easy access to
information on federally and privately supported clinical trials for a wide range of diseases
and conditions
i. Provides abstracts of clinical study protocols that investigators are required to submit
(a) Summary and purpose of study
(b) Recruiting status
(c) Criteria for patient participation
(d) Location for trial and specific contact information
(e) Research study design
(f) Phase of trial
(g) Disease or condition and drug or therapy under study
ii. More than 115,000 clinical trials have been listed in over 170 countries.
Food and Drug Administration Amendments Act of 2007 (FDAAA)
a. Vehicle for reauthorizing PDUFA
b. Statutory authority to require Risk Evaluation Mitigation Strategies (REMS)
The Family Smoking Prevention and Tobacco Control Act of 2009 gave the FDA authority to
regulate tobacco products.
The Patient Protection and Affordable Care Act of 2010 established a regulatory approval
pathway for biosimilars or follow-on biologics.
The Reducing Prescription Drug Shortages Executive Order was signed by President Barack
Obama on October 31, 2011. It requires the FDA to:
a. Broaden reporting of manufacturing discontinuances that may lead to shortages of drugs that
are life supporting or life sustaining or that prevent debilitating disease;
b. Expedite regulatory review to avoid or mitigate existing or potential drug shortages. Reviews
may include new drug suppliers, manufacturing sites, and manufacturing changes; and
c. Communicate to the Department of Justice any evidence of or behaviors by market
participants that have contributed to stockpiling or exorbitant prices.
D. Prescription Drug Approval Path

1. Preclinical studies
a. Laboratory and animal studies that assess safety and biologic activity in various model system
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2.
3.
4.
5.
b. Toxicologic studies completed

i. Effects on the fetus in pregnant mice, rats, rabbits, or baboons
ii. May or may not translate into human fetal adverse effects
iii. Fetal effects in humans may occur that were not observed in animal studies. iv. Basis for
pregnancy categories B, C, and some D
c. An IND application is drafted and submitted to the FDA.
Phase I drug trial
a. Initial introduction of an IND into humans, typically 20100 healthy volunteers
b. Goal is to garner information on the pharmacokinetic and pharmacodynamic properties of the
investigational drug to design a well-controlled and robust phase II trial.
Phase II drug trial
a. Controlled clinical studies conducted in no more than several hundred subjects
b. Goal is to evaluate the drugs effectiveness for a particular indication in patients with the
disease or condition under investigation and to determine the common short-term adverse
effects and risks associated with the drug.
Phase III drug trial
a. Involves the administration of the investigational drug to a range of several hundred to several
thousand patient subjects in different clinical settings to determine its safety, efficacy, and
appropriate dosage
b. Goal is to gather necessary additional information about effectiveness and safety for
evaluating the overall benefit-risk relationship of the drug and to provide an adequate basis for
physician labeling.
c. The step before the sponsors submitting an NDA to the FDA for approval to market the drug
d. Once an NDA is submitted, it is classified with a code that reflects both the type of drug being
submitted and its intended uses. The numbers 17 are used to describe the type of drug:
i. New Molecular Entity (1)
ii. New Salt of Previously Approved Drug (2)
iii. New Formulation of Previously Approved Drug (3)
iv. New Combination of Two or More Drugs (4)
v. Already Marketed Drug Product (i.e., new manufacturer) (5)
vi. New indication for currently marketed drug or switch from prescription to over the
counter (6)
vii. Already marketed drug product without a previously approved NDA (7)
e. Letter code describes the review priority of the drug
i. S = standard review for drug similar to currently available drugs
ii. P = priority review for drugs that represent significant advances over existing treatments
f. Not all phase III drugs are approved, and the FDA can impose a clinical hold at any stage.
Phase IV drug trial
a. Also referred to as postmarketing studies
b. May be required by the FDA to identify additional information about the drugs risks,
benefits, andoptimal use
c. Verify effectiveness or focus treatment on special populations
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Box 1. Components of the NDAa

Index
Summary
Chemistry, manufacturing, and control
Samples, methods, and labeling
Safety update reportb
Statistical analysis
Case report tabulations
Other pertinent information
Nonclinical pharmacology and toxicology
Human pharmacokinetics and bioavailability
Microbiology (for antimicrobial drugs only)
Clinical data
Case report forms
Patent information
Patent certification
a
NDA = New Drug Approval.

The safety update report is usually submitted 120 days after the NDA submission.
E. Generic Drugs
1. Around 69% of all drugs dispensed are generic.
2. A generic drug product is one that is identical (bioequivalent) to an innovator drug product in
dosage form, strength, route of administration, quality, performance characteristics, and intended
use. The Drug Price Competition and Patent Term Restoration Act of 1984, also known as the
Hatch-Waxman Act, defined bioequivalence statutorily as a means to approve a generic drug.
3. Once an ANDA is submitted to and approved by CDERs Office of Generic Drugs, the applicant
can manufacture and market the generic drug as a safe, effective, and low-cost option to the
public.
4. All approved products are listed in the FDAs Approved Drug Products with Therapeutic
Equivalence Evaluations (Orange Book).
5. ANDAs generally do not require preclinical or clinical data, but rather, they must demonstrate bioequivalence.
6. Pharmaceutical equivalents
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Box 2. Criteria for Medications to be Pharmaceutical Equivalents

Three criteria:
Must contain the same active ingredient
Must be the same dosage form
Must be of identical strength or concentration
Differences allowed:
Shape
Releasing mechanism
Labeling (limited differences)
Scoring
Excipients (colors, flavors, preservatives)
7. Therapeutic equivalents can be substituted with the expectation that the substituted product will
produce the same clinical effect and safety profile as the prescribed product.
a. Criteria
i. Pharmaceutical equivalent
ii. Therapeutic equivalence codes rated A by the FDA
b. Assigns therapeutic equivalence code on the basis of data submitted in an ANDA to
demonstrate bioequivalence
i. ANDA contains adequate scientific evidence establishing through in vivo and/or in vitro
studies of bioequivalence of the product to the reference listed drug.
ii. Products deemed by the FDA not therapeutically equivalent are B rated.
8. An authorized generic is a prescription drug produced by the brand pharmaceutical company and
marketed at generic prices during and after the 180-day exclusivity period that is identical to the
brand alternative both in active and inactive ingredients.
9. At-risk launch of a generic occurs when a generic drug manufacturer challenges the validity of the
existing patent of a brand drug.
10. Follow-on biologics or biosimilars are drugs or vaccines that have been produced in living cells.
a. Biosimilars are approved new versions of an innovator biopharmaceutical product after patent
expiration; this is a fairly controversial area between the government, industry, and patient
advocacy organizations.
b. Legislation has created a statutory pathway for the FDA to approve these products after 12
years of data exclusivity for the manufacturer of a new biologic product.
F. Medical Devices
1. An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other
similar or related article, including a component part, or accessory that is:
a. Recognized in the official National Formulary, or the United States Pharmacopoeia, or any
supplement to them
b. Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation,
treatment, or prevention of disease, in humans or other animals
c. Intended to affect the structure or any function of the body of humans or other animals that
does not achieve any of its primary intended purposes through chemical action within or on
the body
of human beings or other animals and that is not dependent on being metabolized for the
achievement of any of its primary intended purposes
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2. Regulated by the Center for Devices and Radiological Health (CDRH)

a. To be approved, a medical device company must submit a premarket approval (PMA)
application ensuring the devices safety and efficacy.
b. If a medical device is substantially equivalent to an existing, legally marketed device, a 510(k)
is submitted for premarket notification.
c. An investigational device exemption (IDE) allows an investigational device to be used in a
clinical study to collect the safety and effectiveness data required to support a PMA
application or a premarket notification 510(k) submission to the FDA.
3. Classified according to the risks associated with the device:
a. Class I Deemed low risk and therefore subject to the least regulatory control
b. Class II Higher-risk devices than class I that require greater regulatory controls to ensure
reasonable safety and efficacy
c. Class III Highest-risk devices, subject to the greatest regulatory control; must be approved
by the FDA before marketing
G. Risk Evaluation and Mitigation Strategies
1. Replaces the Risk Minimization Action Plans (RiskMAPs)
2. Requirements that a drug be dispensed with one of the following:
a. Medication guide and/or patient package inserts
b. Communication plan to health care providers
c. Elements to ensure safe use
Box 3. Risk Evaluation and Mitigation Strategies Requirements of Elements to Ensure Safe Use
Elements to Ensure Safe Use may include one of the following:
Health care providers who prescribe the drug have particular training or experience or are specially certified
Pharmacies, practitioners, or health care settings that dispense the drug are specially certified
Drug dispensed only in certain health care settings
Drug dispensed to patients with evidence of safe-use conditions, such as laboratory test results
Each patient using the drug is subject to monitoring
Each patient using the drug is enrolled in a registry
The FDA does not have the authority to impose penalties on pharmacies and pharmacists not in
compliance with REMS requirements, but there may be legal implications such as misbranding
violations or civil liability issues.
H. MedWatch Through the FDA Is a Voluntary Safety Information and Adverse Event Reporting
Program.
I. Critical Path Initiative
1. Created in response to a significant decline in NDAs, BLAs, and medical device applications
because of the widening gap between basic science discovery and the challenging, inefficient, and
costly development of medical product development
2. Prioritizes the most pressing development problems and identifies areas that provide the greatest
opportunities for rapid improvement and public health benefit through three dimensions:
3.
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Table 1. U.S. Food and Drug Administrations Critical Path Initiative
II.
Dimension
Definition
Example of Activities
Assessing safety
Show that the product is

adequately safe for each
stage of development
Preclinical: Show that product is safe enough for human testing

Eliminate products with safety problems early
Clinical: Show that the product is safe enough for commercial
distribution
Demonstrating
medical utility
Show that the product

benefits people
Preclinical: Select appropriate design (devices) or candidate

(drugs) with high probability of effectiveness
Clinical: Show effectiveness in people
Product
industrialization
Go from laboratory concept

or prototype to a
manufacturable product
Design a high-quality product

- Physical design, characterization, specifications
Develop mass production capacity
- Manufacturing scale-up, quality control
INSTITUTIONAL REVIEW BOARD (IRB) IMPLICATIONS FOR CLINICAL PRACTICE AND

RESEARCH
A. Basics
1. Every institution that conducts or supports biomedical or behavioral research involving human
participants must, by federal regulation, have an IRB that initially approves and periodically
reviews research protocols to protect the rights of human participants.
2. Governed by DHHS Office for Human Research Protections (OHRP) regulations at Title 45 CFR
Part 46; requires the IRB or ethics committee to protect the rights, safety, and well-being of all
study subjects. Specifically, Subpart A constitutes the Federal Policy (Common Rule) for the
Protection of Human Subjects.
3. IRB approval is required for interventional and observational studies, and applications must be
reviewed annually.
B. Definitions
1. The Health Insurance Portability and Accountability Act (HIPAA) of 1996 provides protection for
the privacy of certain individually identifiable health data, referred to as protected health
information (PHI).
2. Human subject means a living individual about whom an investigator conducting research obtains
1) data through intervention or interaction with the individual or 2) identifiable private
information.
3. Informed consent is the process of learning the key facts about a clinical trial before deciding
whether to participate.
4. An informed consent document describes the rights of the study participants and includes details
about
the study including purpose, duration, required procedures, risks, benefits, and key contacts.
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5. An IRB is a committee of physicians, statisticians, researchers, community advocates, and others

that ensures that a clinical trial is ethical and the rights of study participants are protected.
6. Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the
research are not greater in and of themselves compared with those ordinarily encountered in daily
life or during the performance of routine physical or psychological examinations or tests.
C. The IRB is composed of at least five members with varying backgrounds to promote complete and
adequate review of research activities while adhering to institutional commitments and regulations,
applicable law, and standards of professional conduct and practice.
1. The committee must be sufficiently qualified through the experience, expertise, and diversity of its
members, including race, gender, cultural background, and sensitivity to issues such as community
attitudes, to promote respect for its advice and counsel.
2. At least one member whose primary concerns are in scientific areas
3. At least one member whose primary concerns are in nonscientific areas
4. At least one member who is not affiliated with the institution and who is not an immediate family
member of a person affiliated with the institution
D. Human Subjects Training
1. Institution-specific
2. A Collaborative Institutional Training Initiative (CITI) program is a subscription-based service
that provides research ethics training to its members.
E. Research Exempt from IRB Requirements
1. Research conducted in established or commonly accepted educational settings, involving normal
educational practices, such as
a. Research on regular or special education instructional strategies
b. Research on the effectiveness of the comparison among instructional techniques, curricula, or
classroom management methods
2. Research involving the use of educational tests (cognitive, diagnostic, aptitude, or achievement),
survey procedures, interview procedures, or observation of public behavior, unless:
a. Information obtained is recorded in a manner that human subjects can be identified, directly or
through identifiers linked to the subjects, and
b. Any disclosure of the human subjects responses outside the research could reasonably place
the subjects at risk of criminal or civil liability or be damaging to the subjects financial
standing, employability, or reputation
3. Research involving the collection or study of existing data, documents, records, pathologic
specimens, or diagnostic specimens; if these sources are publicly available or if the information is
recorded by the investigator in a manner such that subjects cannot be identified, directly or
through identifiers linked to the subjects
4. Research involving no more than minimal risk, and minor changes made to approved research
protocols, may be considered for expedited review.
F. The HIPAA Privacy Rule Supplements and Expands the Common Rule Regulation of Human
Subjects Research.
1. Protections for the confidentiality of PHI used in clinical practice, research, and the operation of
health care facilities
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2. PHI includes information that:

a. Is created or received by a covered entity, which includes a health care provider, and
b. Pertains to the past, present, or future physical or mental health, or condition of the
individual, or
c. Pertains to payment for the individuals health care, or
d. Pertains to the provision of health care in the past, present, or future, and
e. Identifies an individual or could be used for identifying an individual
3. To use or disclose PHI for research purposes, one or more of the following actions must be taken:
a. Written authorization specifically for the use and disclosure of PHI for research purposes
involving human subjects;
b. Waiver of authorization approved by an IRB Use of de-identified information or limited
data sets (limited data set [45 CFR 164.514(e)] defined for research, public health, and health
care operations);
c. Preparatory to research certifications; and/or
d. Database registration
4. A provision within HIPAA also mandated the adoption of a standard unique identifier for health
care providers. The National Plan & Provider Enumeration System of the Center for Medicare &
Medicaid Services (CMS) collects information from providers and assigns each a unique National
Provider Identifier.
G. Typical Documents Submitted to the IRB for an Initial Review. Examples of these documents can be
found at NIHs National Institute on Aging Clinical Study Investigators Toolbox.
Box 4. Documents That May Need to Be Submitted to an IRB for Initial Review
Cover sheet
Conflict of interest assessment
Application
Formal protocol
Informed consent forms
HIPAA authorization forms
Recruitment materials
Surveys, questionnaires, other instruments
Federal grant, if applicable
Documentation of IRB approval from another institution
Data and safety monitoring plan
Additional supportive documents as requested by IRB
HIPAA = Health Insurance Portability and Accountability Act; IRB = institutional review board.
H. Informed Consent
1. Basic elements
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a. A statement that the study involves research, an explanation of the purposes of the research,
the expected duration of the subjects participation, a description of the procedures to be
followed, and the identification of any procedures that are experimental
b. A description of any reasonably foreseeable risks or discomforts to the subject
c. A description of any benefits to the subject or to others that may reasonably be expected from
the research
d. A disclosure of appropriate alternative procedures or courses of treatment that might be
advantageous to the subject
e. A statement describing the extent to which confidentiality of records identifying the subject
will be maintained
f. For research involving more than minimal risk, an explanation regarding whether there is any
compensation and an explanation regarding whether any medical treatments are available if
injury occurs and, if so, what they consist of, or where further information may be obtained
g. An explanation of whom to contact for answers to pertinent questions about the research and
research subjects rights and of whom to contact in the event of a research-related injury to the
subject
h. A statement that participation is voluntary, refusal to participate will involve no penalty or
loss of benefits to which the subject is otherwise entitled, and the subject may discontinue
participation at any time without penalty or loss of benefits to which the subject is otherwise
entitled
2. Waiver will be considered if
a. Research involves no more than minimal risk to subjects;
b. The waiver or alteration will not adversely affect the rights and welfare of subjects;
c. The research could not practicably be carried out without the waiver or alteration; and
d. Where appropriate, the subjects will be provided with additional pertinent information after
participation.
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Template for Combined Informed Consent and HIPAA Authorization Form
NAME OF INSTITUTION
Subject CONSENT to Participate in Research
And
AUTHORIZATION to Use and/or Disclose Identifiable Health information for Research
Title of the Study: Title of Research Protocol

Principal Investigator: Include name of PI (PI contact telephone number) (PI contact e-mail)
Mailing Address: Provide PI contact mailing address
INVITATION
You are invited to participate in this research study about: Provide brief description of research in terms understandable to a layperson.
You are invited to take part because you: Describe why the person is being asked to participate as a research
subject in the study. Give an approximation of the number of individuals who will participate in the study.
Your participation in this research study is voluntary. If you decide not to participate, the health care provided
to you by the insert institution name will not be affected in any way.
A. WHAT IS THE PURPOSE OF THIS STUDY?
Provide a clear explanation of the purpose of the research
B. WHAT WILL MY PARTICIPATION INVOLVE?
Describe in lay terms what procedures the research participant will be required to take part in during the
research. List how many questionnaires, surveys, or interviews they will be required to complete and the
amount of time it may take.
We will also collect the following information about you for this research study:
1.
From you: List the demographic information that you will collect from the subject (i.e., birth date, home
address, phone number, e-mail address). List the health information that you will collect from the subject
(i.e. diet, exercise habits, use of tobacco, use of alcohol).
2.
From your medical records, health records (such as x-rays), and/or billing records: List the information
from the subjects medical or other health or billing records that will be used for this research.
3.
From medical tests or other procedures performed for this study: List the medical tests or other procedures
that will be performed for this study and the information generated by each (e.g., white blood cell count
from blood test).
C. ARE THERE ANY BENEFITS TO ME?

List any benefits to the subject in a way that is not coercive, enticing, or self-serving. This section should include a statement that there may be no benefit to the subject.
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D. WILL I BE PAID FOR MY PARTICIPATION?

Describe compensation for participating in this study.
E. ARE THERE ANY SIDE EFFECTS OR RISKS TO ME?
Describe, in terms understandable to a layperson, any risks to research participants. This could include health
risks and/or psychosocial risks including breach of confidentiality resulting in legal issues, and insurability and
employability problems. Example: The main risk of taking part in this study is that your study information could
become known to someone who is not involved in performing or monitoring this study.
F. HOW WILL MY PRIVACY BE PROTECTED AND WHO WILL USE MY HEALTH
INFORMATION?
Sample statement: The information collected from you during this study and from your medical records will be
used by the researchers and research staff of at this institution for this study. It may also be shared with others
outside of this institution.
Describe how research data will be kept confidential by the investigator. Specify the measures that will be
implemented by your research group to safeguard the PHI from unauthorized use or disclosure. For paper forms
of PHI, your plan should address, at least, the following: Locking up your research files while they are
unsupervised, shredding excess copies of paper documents, protections for codes that link patients to their data.
For electronic forms of PHI, plan should address, at least, the following: Workstation locks that secure a users
computer from unauthorized access when not in use, defining the electronic location where PHI will be stored
and the technical security measures in place to protect the data while it is stored there, authentication
requirements to access the PHI, including whether authentication occurs at the network, device, folder or file
level, audit trails to record accesses or changes to data, and transmission protocols that assure data cannot be
intercepted while in transit If PHI is to be disclosed outside your institution, describe the plans of any research
collaborators to protect the PHI you will share with them.
List others inside and outside the institution of record who may need to use PHI in the course of the research
protocol (i.e. Institutional regulatory and research oversight boards and offices, Accounting and billing perso nel)
Certificate of Confidentiality
Sample statement: To help us protect your privacy, we have obtained a Certificate of Confidentiality from the
National Institutes of Health. With this Certificate, the researchers cannot be forced to disclose information that
may identify you, even by a court subpoena, in any federal, state, or local civil, criminal, administrative,
legislative, or other proceedings. The researchers will use the Certificate to resist any demands for information
that would identify you, except as explained below.
The Certificate cannot be used to resist a demand for information from personnel of the United States
Government that is used for auditing or evaluation of Federally funded projects or for information that must be
disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA).
You should understand that a Certificate of Confidentiality does not prevent you or a member of your family from
voluntarily releasing information about yourself or your involvement in this research. If an insurer, employer, or
other person obtains your written consent to receive research information, then the researchers may not use the
Certificate to withhold that information.
The Certificate of Confidentiality does not prevent the researchers from disclosing voluntarily, without your
consent, information that would identify you as a participant in the research project in certain circumstances.
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G. IS MY PERMISSION VOLUNTARY AND MAY I CHANGE MY MIND?

Your permission is voluntary. You do not have to sign this form and you may refuse to do so. If you refuse to sign
this form, however, you cannot take part in this research study.
You may completely withdraw from the study at any time. You also may choose to cease participation or skip any
questions that you do not feel comfortable answering.
H. HOW LONG WILL MY PERMISSION TO USE MY HEALTH INFORMATION LAST?
By signing this form you are giving permission for your health information to be used by and shared with the
individuals, companies, or institutions described in this form. Unless you withdraw your permission in writing to
stop the use of your health information, there is no end date for its use for this research study. You may withdraw
your permission at any time by writing to the person whose name is listed below:
Include name of PI and PI contact mailing address
Beginning on the date you withdraw your permission, no new information about you will be used. Any
information that was shared before you withdrew your permission will continue to be used. If you withdraw your
permission, you can no longer actively take part in this research study.
I. WHO SHOULD I CONTACT IF I HAVE QUESTIONS?
Please take as much time as you need to think over whether or not you wish to participate. If you have any
questions about this study at any time, contact the Principal Investigator: Include name of PI and contact
telephone number.
If you are not satisfied with response of research team, have more questions, or want to talk with someone about
your rights as a research participant, contact: Insert institutions patient relations representative (or title specific
to the institution) and provide telephone number
AGREEMENT TO PARTICIPATE IN THIS STUDY AND

PERMISSION TO USE AND/OR DISCLOSE MY HEALTH INFORMATION
I have read this consent and authorization form describing the research study procedures, risks, and benefits, what
health information will be used, and how my health information will be used. I have had a chance to ask questions
about the research study, including the use of my health information, and I have received answers to my questions.
I agree to participate in this research study, and permit the researcher to use my health information as described
above.
Name of Participant (please print):
YOU WILL RECEIVE A COPY OF THIS FORM AFTER SIGNING IT.
Signature of participant:
Date:
Signature of person obtaining consent and authorization:
Date:
Include date of version and leave room for IRB stamp of approval according to institutions specifications
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III. INVESTIGATIONAL DRUG SERVICE (IDS)

A. Basics
1. The American Society of Health-System Pharmacists Policy on Institutional Review Boards and
Investigational Use of Drugs (0711) strongly supports pharmacists management of the control
and distribution of drug products used in clinical research.
2. The purpose of an IDS is to procure, manage, prepare, dispense, and dispose of investigational
drugs according to protocol and in compliance with the state and federal requirements that govern
investigational drug activities.
B. Definitions Drugs, as defined by the FD&C Act, are (A) articles intended for use in the diagnosis,
cure, mitigation, treatment, or prevention of disease, and (B) articles (other than food) intended to
affect the structure or any function of the body of man or other animals [FD&C Act, sec. 201(g)(1)].
An investigational drug is a chemical or biologic substance that has been tested in a laboratory and
been approved by the FDA to be tested in human subjects. An investigational (also referred to as
experimental) drug may be:
1. A new chemical or compound that has not been approved by the FDA for general use or
2. An approved drug undergoing further investigation for an approved or unapproved indication,
dose, dosage form, administration schedule, or under an IND application in a controlled,
randomized, or blinded clinical trial
C. In addition to the regulations outlined by the Office of Human Research Protection (Common Rule)
and the FDA to conduct research in accordance with the principles of good clinical practice and
human subjects protection, there are federal and state requirements of an IDS:
1. The Joint Commission Standards require policies for the use of investigational drugs that
specifically
address their storage, dispensing, labeling, and distribution.
2. The Environmental Protection Agency and Occupational Safety and Health Administration
regulate the disposal of investigational drugs.
3. The American Society of Health-System Pharmacists provides practice standards.
4. The local IRB
5. State-specific laws may vary.
D. A Study-Specific Notebook Is Maintained Where Study Drugs Are Stored. It contains the following
files and contents:
Table 2. Example of Documents Stored in Study-Specific Notebooks Maintained by an Investigational Drug
Service
File Section
Contents
Protocol
Copy of the research protocol
Drug information
Investigators brochure, drug data sheet, package inserts (if commercially available)
Pharmacy procedures
Study-specific pharmacy procedure information
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Table 2. Example of Documents Stored in Study-Specific Notebooks Maintained by an Investigational

Drug Service
File Section
Contents
Logs/forms/labels
Study-specific materials
Procurement details
Receipt and disposition records
Correspondence
Correspondence
Computer matters
Copies of order entry codes
Billing
Financial agreements with investigator
IRB
IRB submission application, approval, and consent forms
Miscellaneous
Miscellaneous documentation
Master patient log
Record of patients enrolled
Drug accountability records
Data accountability record for each drug/dosage form/package size/strength
IRB = institutional review board.
E. In addition to managing the activities outlined under the purpose of an IDS, an investigational drug
pharmacists duties may include
1. Participating in IRB as a voting member
2. Maintaining a working relationship with the IRB, Pharmacy and Therapeutics Committee,
principal investigators, and the pharmacy department
3. Reviewing new and existing investigational drug study protocols
4. Meeting with investigators, study monitors, and other study personnel responsible for coordinating
the logistics of a clinical trial
5. Receiving, organizing, and maintaining the contents of study notebooks
6. Providing randomization, blinding, or control functions of a clinical trial
7. Conducting the training of IDS staff and personnel regarding investigational protocols and study
drug procedures
IV. THE JOINT COMMISSION, NATIONAL COMMITTEE FOR QUALITY ASSURANCE

(NCQA), NATIONAL QUALITY FORUM (NQF), AGENCY FOR HEALTHCARE RESEARCH
AND QUALITY (AHRQ), AND PHARMACY QUALITY ALLIANCE (PQA)
A. The programs outlined in this section are not federal regulatory programs, but they play an important
role in the pharmacists ability to provide patient-centered, safe, and effective care.
B. The Joint Commission is a not-for-profit, independent organization that sets standards for accrediting
health care facilities through its mission to continuously improve health care for the public, in
collaboration with other stakeholders, by evaluating health care organizations and inspiring them to
excel in providing safe and effective care of the highest quality and value.
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1. Basics
a. Accredits and certifies more than 19,000 health care organizations in the United States
b. Standards address an organizations performance in functional areas of patient rights, patient
treatment, medication safety, and infection control. Hospitals provide data from a selection of
57 inpatient measures.
2. Definitions
a. National Patient Safety Goals were established to help accredited organizations address
specific areas of concern in patient safety in the areas of ambulatory health care, behavioral
health care, critical access hospital, home care, hospital, laboratory, long-term care,
Medicare/Medicaid long- term care, and office-based surgery.
b. ORYX is a Joint Commission performance measurement and improvement initiative
implemented to integrate outcomes with accountability measures in the areas of acute
myocardial infarction, heart failure, pneumonia, surgical care improvement project, childrens
asthma care, perinatal, hospital outpatient measures, venous thromboembolism, hospital-based
inpatient psychiatric services, and stroke in its accreditation process.
i. Common standardized measures between the Joint Commission and the CMS are called
National Hospital Quality Measures.
ii. Accountability measures and processes that result in the greatest improvement in patient
outcomes have been identified by the Joint Commission. These measures and processes
must be of sound scientific evidence, have close proximity between process and outcome,
accurately measure the process, and minimize adverse effects without inducing
unintended consequences. Measures are updated frequently. Examples of current
inpatient measures are listed below. (a) Acute myocardial infarction
(1) Aspirin at arrival
(2) Aspirin at discharge
(3) Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker
(ARB) at discharge
(4) -Blocker at discharge
(5) Fibrinolytic therapy within 30 minutes
(6) Primary PCI (percutaneous coronary intervention) balloon within 90 minutes
(7) Smoking cessation advice/counseling
(b) Heart failure care requiring an ACE inhibitor or ARB at discharge
(c) Pneumonia care
(1) Pneumococcal vaccination
(2) Blood culture in emergency department
(3) Antibiotics for immunocompetent patients
(4) Influenza vaccination
(d) Surgical care (Surgical Care Improvement Project [SCIP]) (1) Antibiotics within 1
hour before the first surgical cut (2) Appropriate prophylactic antibiotics
(3) Discontinuing antibiotics within 24 hours
(4) Cardiac patients with controlled 6 a.m. postoperative blood glucose
(5) Patients with appropriate hair removal
(6) -Blocker patients who received -blocker perioperatively
(7) Prescribing venous thromboembolism prophylaxis
(8) Receiving venous thromboembolism prophylaxis
(e) Childrens asthma care
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(1) Relievers for inpatient asthma

(2) Systemic corticosteroids for inpatient asthma
(3) Home management plan of care given to patient/caregiver
c. Targeted Solutions Tool, created by the Joint Commission Center for Transforming
Healthcare, provides a process for accredited hospitals to measure performance, identify
barriers to excellent performance, and implement proven solutions.
d. Tracer methodology is a process used by an on-site surveyor to evaluate a patients medical
record as a road map to move through a health care organization to assess and evaluate its
compliance with standards and systems to provide care and services. First-generation tracers
follow a patient through care areas, whereas second-generation tracers focus on major
organizational areas such as high-alert medications or medication shortages.
C. The NCQA is a private, not-for-profit organization with a mission to improve the quality of health
care through measurement, transparency, and accountability.
1. Basics
a. Offers accreditation programs, certification programs, physician recognition programs, and
distinctions that apply to health plans, such as health maintenance organizations, preferred
provider organizations, and consumer-directed health plans, physician networks, medical
groups, and individual physicians.
b. Produces several public reports including The State of Health Care Quality, which is an
overall assessment of the performance of the American health care system; Americas Best
Health Plans in collaboration with U.S. News & World Report; and the online Health Plan
Report Card with a searchable database detailing health plans accreditation and performance
ratings.
2. Definitions
a. The Healthcare Effectiveness Data and Information Set (HEDIS) is a tool that consists of 75
measures across eight domains of care that health plans use to measure performance and focus
improvement efforts.
i. Measures are developed by identifying the clinical area to evaluate; conducting an
extensive literature review; developing the measure; vetting it with various stakeholders;
and performing a field test that evaluates feasibility, reliability, and validity.
ii. Domains
(a) Asthma medication use
(b) Persistence of -blocker treatment after a heart attack
(c) Controlling high blood pressure
(d) Comprehensive diabetes care
(e) Breast cancer screening
(f) Antidepressant medication management
(g) Childhood and adolescent immunization status
(h) Advising smokers to quit
b. NCQA will establish criteria for Accountable Care Organizations (ACOs), created by the
Patient Protection and Affordable Care Act of 2010. Principles of ACOs include:
i. Strong foundation of primary care;
ii. Reliable reporting of measures to support quality improvement and to eliminate waste and
inefficiencies to reduce cost;
iii. Commitment to improving quality and patient experience while reducing per capita costs;
iv. Collaborate with stakeholders in a community or region; and
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v. Create and support a sustainable workforce.

D. NQF is a nonprofit organization that aims to improve quality through a three-part mission: setting
national priorities and goals for performance improvement; endorsing national consensus standards for
measuring and publicly reporting on performance; and promoting the attainment of national goals
through education and outreach programs. Basics:
1. Membership includes stakeholders from consumer organizations, public and private purchasers,
physic cians, nurses, accrediting and certifying bodies, supporting industries, and health care
research and quality improvement organizations.
2. Through the passing of the Medicare Improvements for Patients and Providers Act of 2008,
DHHS entered into a contract with NQF to establish a portfolio of quality and efficiency measures
for use in reporting on and improving health care quality for the federal government to determine
a return on investment on health care spending.
a. Formulation of a national strategy and priorities for health care performance measurement in
order to review and synthesize evidence related to 20 high-priority conditions identified by
CMS that account for more than 95% of their costs
b. Implementation of a consensus process for endorsement of health care quality measures
c. Maintenance of consensus-endorsed measures
d. Promotion of electronic health records (EHRs)
e. Focused measurement of the development, harmonization, and endorsement efforts to fill
critical gaps in performance measurements
E. The Agency for Healthcare Research and Quality
1. Basics
a. The agency within DHHS that supports research that helps people make more informed
decisions and improves the quality of health care services through its mission to improve the
quality, safety, and effectiveness of health care for all Americans
b. Health services research provides clinical, health care system, and public policy decisionmakers evidence-based information on health outcomes, quality, cost, use, and access to
improve the quality of health care services.
2. Definitions
a. Comparative effectiveness research (CER) is the conduct and synthesis of systematic research
comparing different interventions and strategies to prevent, diagnose, treat, and monitor health
conditions. The concept of CER was introduced in the Medicare Modernization Act of 2003,
but it received more funding and attention in the American Recovery Act of 2009 when the
Federal Coordinating Council for Comparative Effectiveness was established. It is composed
of members from DHHS agencies such as the AHRQ, FDA, NIH, CMS, Centers for Disease
Control and Prevention, Office of Minority Health, Office of the National Coordinator, Health
Resources and
Services Administration, and Substance Abuse and Mental Health Services and from the
Veterens Health Administration and Department of Defense.
b. Consumer Assessment of Healthcare Providers and Systems (CAHPS)
c. The Effective Health Care Program funds individual researchers, research centers, and
academic organizations to work together with the AHRQ to produce effectiveness and the
CER for clinicians, consumers, and policy-makers.
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d. Health services research, according to the Institute of Medicine, is a multidisciplinary field of

inquiry, both basic and applied, that examines the use, costs, quality, accessibility, delivery,
organization, financing, and outcomes of health care services to increase knowledge and
understanding of the structure, processes, and effects of health services for individuals and
populations.
F. The PQA
1. Basics
a. The mission of PQA is to improve the quality of medication use across health care settings
through a collaborative process in which key stakeholders agree on a strategy for measuring
and reporting performance information related to medications.
b. Developed performance measures including proportion of days covered, gap in medication
therapy, diabetes medication dosing, suboptimal treatment of hypertension in patients with
diabetes, use of high-risk medications in the elderly, drug-drug interactions, and medication
therapy for individuals with asthma.
2. Demonstration projects have been funded across the country.
V. LEGISLATIVE ACTIVITY INTO REGULATORY POLICY

A. The American Recovery and Reinvestment Act (ARRA) of 2009 provided a vehicle for passing
the Health Information Technology for Economic and Clinical Health (HITECH) Act, which
authorized DHHS to create programs to improve health care quality, safety, and efficiency through
the promotion of HIT, including EHRs.
1. Created the Office of the National Coordinator to coordinate nationwide implementation efforts
2. The Standards and Certification Criteria Final Rule is the initial approach to adopting standards,
implementing specifications, and providing certification criteria to enhance the interoperability,
functionality, utility, and security of HIT and to support its meaningful use.
3. The Incentive Program for Electronic Health Records was issued by CMS to provide a financial
incentive to eligible professionals, eligible and critical access hospitals, and Medicare Advantage
Organizations that are meaningful users of EHRs.
a. ARRA 2009 specified three main components for Meaningful Use:
i. Use of certified EHRs in a meaningful manner (i.e., e-Prescribing)
ii. Use of certified EHR technology for electronic exchange of health information to improve
quality of health care
iii. Use of certified EHR technology to submit clinical quality and other measures
b. Incentive payments began in fiscal year 2011 and will gradually decrease until fiscal year
2015, when penalties are put into effect.
B. The Patient Protection and Affordable Care Act of 2010 contains several provisions, ranging from
protecting consumers to improving health care quality and lowering costs to increasing access to care.
As the law translates into regulation, unique opportunities exist for pharmacists to become engaged.
1. Funding opportunities will be available for pharmacists to demonstrate their contributions as
providers of medication therapy management.
2. The patient-centered medical home model emphasizes primary care as a central role in managing
the chronic conditions of patients using a team-based care approach.
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3. ACOs are a set of providers associated with a defined population of patients accountable for the
quality and cost of care delivered to that population.
4. Independence at Home Demonstration Program promotes the interdisciplinary collaboration of
clinicians to provide home-based medical care for Medicare beneficiaries.
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REFERENCES
The Food And Drug Administration and The
Prescription Drug Approval Process
1. FDA Web site. Available at www.fda.gov.
Accessed January 28, 2012.
2. FDA Web site: How Is FDA Organized?
Available at
www.fda.gov/AboutFDA/Transparency/Basics/
ucm194884.htm. Accessed January 28, 2012.
3. The Past, Present, and Future of FDA Human
Drug Regulation. Available at
www.fda.gov/Training/
ForHealthProfessionals/ucm209538.htm.
4. Presidential Actions, Executive Orders.
Available at www.whitehouse.gov/briefingroom/presidential- actions/executive-orders.
5. FDA REMS. Available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf.
6. Clinical Trials. Available at
http://clinicaltrials.gov. Accessed January 28,
2012.
7. National Cancer Institute Clinical Trial Information. Available at www.cancer.gov/clinicaltrials/.
8. Generic Pharmaceutical Association. Available
at www.gphaonline.org/about-gpha/aboutgenerics/ facts. Accessed January 28, 2012.
3.
4.
5.
6.
va.gov/vhapublications/ViewPublication.asp?pu
b_ ID=1333. Accessed January 28, 2012.
National Cancer Institute Clinical Trial Information. Available at
http://www.cancer.gov/clinicaltrials/. Accessed
January 28, 2012.
University of Pittsburgh Cancer Institute Investigational Drug Service. Available at Comparative
Effectiveness Research (CER): www.upci.upmc.
edu/ids/index.cfm. Accessed January 28, 2012.
Brigham and Womens Hospital Investigational
Drug Service. Available at
www.brighamandwomens.org/research/CCI/IDS.aspx. Accessed
January 28, 2012.
Seattle Childrens Hospital Investigational Drug
Service. Available at
www.seattlechildrens.org/research/cores/ids/.
The Joint Commission, National Committee For

Quality Assurance, National Quality Forum, And
Agency For Healthcare Research And Quality
1. Chassin MR, Loeb JM, Schmaltz SP, Wachter
RM. Accountability measures using
measurement to promote quality improvement. N
Engl J Med 2010;363:6838.
2. The Joint Commission. Available at www.jointcommission.org/. Accessed January 28, 2012.
3. Joint Commission Center for Transforming
Health- care Targeted Solutions Tool. Available
at centerfortransforminghealthcare.org. Accessed
Jan- uary 28, 2012.
4. The National Committee for Quality Assurance.
Available at www.ncqa.org/. Accessed January
28, 2012.
5. The National Quality Forum. Available at www.
qualityforum.org. Accessed January 28, 2012.
6. The Agency for Healthcare Research and
Quality. Available at www.ahrq.gov. Accessed
January 28, 2012.
7. Effective Health Care Program, AHRQ.
Available at http://effectivehealthcare.ahrq.gov/.
8. Pharmacy Quality Alliance. Available at
www.PQAAlliance.org. Accessed January 28,
2012.
Institutional Review Board Implications For

Clinical Practice And Research
1. Title 45 Code of Federal Regulations Part 46.
Avail- able at
http://ohsr.od.nih.gov/guidelines/45cfr46. html.
2. National Institute on Aging Clinical Study Investigators Toolbox. Available at
http://www.nia.nih. gov/research/dgcg/clinicalresearch-study-investigators-toolbox. Accessed
January 28, 2012.
Investigational Drug Service
1. American Society of Health-System Pharmacists
Policy Position: On Institutional Review Boards
and Investigational Use of Drugs. Available
at w w w.a shp.org / DocLibr a r y/ Best P r a ct
ices/ Re - searchPositions.aspx. Accessed
January 28, 2012.
2. Department of Veterans Affairs Investigational
Drugs and Supplies Handbook. Available at
www1.
Legislative Activity Into Regulatory Policy

1. The Office of the National Coordinator for
Health Information Technology. Available at
http://heal- thit.hhs.gov. Accessed January 28,
2012.
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2. 42 CFR Parts 412, 413, 422, et al. Medicare and

Medicaid Programs; Electronic Health Record
Incentive Program Final Rule. Available at
http:// edocket.access.gpo.gov/2010/pdf/201017207.pdf. Accessed January 28, 2012.
3. Lipton HL. Pharmacists and health reform: go
for it. Pharmacotherapy 2010;30:96772.
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INFECTIOUS DISEASES IN THE

AMBULATORY CARE SETTING
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1. Be able to design appropriate pharmacologic and nonpharmacologic treatment regimens for various patient
populations with urinary tract infections, prostatitis, community-acquired pneumonia, influenza, upper
respiratory tract infections, skin and soft tissue infections, and sexually transmitted diseases.
2. Recognize and recommend appropriate immunizations to meet the requirements of CDC (Centers for
Disease Control and Prevention) recommendations for routinely recommended immunizations for infants
and children.
3. Identify risk factors and clinical circumstances in which antimicrobial resistance is a risk, and be able to
appropriately design antimicrobial regimens to treat resistant infections and prevent future development.
4. Be able to apply patient and clinical factors to design antimicrobial regimens that are appropriate and costeffective for the patient.
I. COMMUNITY-ACQUIRED PNEUMONIA
A. Introduction: Community-Acquired Pneumonia (CAP)

1. Affects about 5.6 million people annually in the United States
a. One of the top 10 causes of mortality
b. Most patients can be treated as outpatients.
2. Annual total costs are about $8 million dollars.
a. $8 billion attributed to patients admitted to hospital
b. Major costs can be avoided by appropriate outpatient treatment.
3. Most patients with CAP are treated by outpatient practitioners such as primary care physicians,
family practice, hospitalists, and emergency medicine.
B. CAP Description
1. CAP is a lower respiratory tract infection in patients who are not hospitalized or who have not
been in a health care nonambulatory setting, with infiltrates on chest radiographs or consistent
with auscultatory findings.
2. Risk factors
a. Age older than 65 years
b. Asthma
c. Chronic obstructive pulmonary disease
d. Diabetes
e. Smokers
f. Congestive heart failure
g. Chronic renal failure
h. Immunocompromised/HIV (human immunodeficiency virus)
i. Recent antibiotic therapy
j. Alcohol abuse
3. Pathogenesis: Organisms gain entry to lower respiratory tract through:
a. Inhalation of aerosolized particles
b. Entrance to the lung through the bloodstream from an extrapulmonary infection site
c. Aspiration of oropharyngeal contents
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C. Etiology
1. Streptococcus pneumoniaeAbout 75% of CAP cases
2. Haemophilus influenzae
3. Mycoplasma pneumoniae
a. About 20% of CAP cases
b. Atypical pneumonia pathogen
4. Chlamydia pneumoniae
a. Atypical pneumonia pathogen
b. 5%15% of CAP cases
5. Legionella pneumophila
a. 2%15% of CAP cases
b. Atypical pneumonia pathogen
6. Respiratory viruses: Influenza A and B, adenovirus, respiratory syncytial virus, and parainfluenza
7. Less common: Methicillin-resistant Staphylococcus aureus (MRSA) and community-acquired
MRSA (CA-MRSA), Pseudomonas, Acinetobacter
a. Mainly in the elderly or in patients with severe comorbidities such as alcoholism and diabetes
b. Patients who have been recently hospitalized or in nursing homes; in these instances, it is
referred to as health careassociated pneumonia
D. Diagnosis
a. CAP diagnosis is primarily based on clinical signs and symptoms, with the most common
symptoms being fever (temperature greater than 38C/100.4F) and cough with or without
sputum.
b. Symptoms may be nonspecific in older patients.
c. Other symptoms
i. Dyspnea
ii. Pleuritic chest pain
iii. Wheezing
iv. Myalgia, sweats, rigors
2. Diagnostic and laboratory tests
a. Physical examination
i. Rales, rhonchi, inspiratory crackles
ii. Dullness to percussion
iii. Increased tactile fremitus, egophony
b. Positive chest radiograph: False negatives can be seen in severe dehydration, early pneumonia,
neutropenia
c. Microbiologic testing
i. Not routinely done in outpatient practice
(a) The Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS)
2007 guidelines recommend testing if the result is likely to change individual
treatment.
(b) May be indicated if previous antibiotic therapy has failed
ii. Sputum Gram stain usually reveals many polymorphonuclear cells, with the predominance
of a bacterial pathogen.
iii. Blood and sputum cultures are more likely to be performed in severe cases
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3. Scoring systems/site-of-care decisions

a. Important in determining whether the patient can be treated in the outpatient setting or
whether he or she needs to be hospitalized in the ICU (intensive care unit) or hospital ward
because inpatient costs can be as high as 25 times the costs of outpatient care
b. CURB-65 (severity-of-illness scoring)
i. Score of 05 is given, using 1 point for each of the following:
(a) Confusion caused by pneumonia
(b) Urea nitrogen greater than 7 mmol/L (blood urea nitrogen greater than 19 mg/dL)
(c) Respiratory rate of 30 breaths/minute or greater
(d) Blood pressure less than 90 mm Hg systolic or 60 mm Hg or less diastolic
(e) Age 65 or older
ii. Score of 2 or greater indicates a need for more intense treatment and hospitalization.
c. Pneumonia severity index prognostic model
i. Uses many demographic and historical findings, physical findings, and laboratory data to
calculate a total score
ii. On the basis of score, patients are categorized into one of five classes, each with a
different risk of mortality.
iii. Tool was designed to predict mortality so that those with low risk of death from CAP
could be treated in the outpatient setting.
E. Treatment
1. Therapy goals: Eradicate infecting organism, prevent complications, and prevent resistance.
2. The IDSA/ATS guidelines suggest treatment protocols because they have been shown to decrease
mortality.
3. Initial treatment will be empiric and should target the most likely organisms. Ability to cover both
typical bacterial pathogens (S. pneumoniae, H. influenzae) and atypical pathogens (M.
pneumoniae, C. pneumoniae, and Legionella)
a. -Lactams do not cover atypical pathogens.
b. Macrolides and fluoroquinolones cover both typical and atypical pathogens.
c. Doxycycline covers both typical and atypical pathogens, but it may not adequately cover more
resistant pathogens such as penicillin-resistant S. pneumoniae.
4. Antimicrobials should have the ability to reach adequate concentrations within the respiratory
secretions.
5. Risk factors and where patient is to be treated (outpatient or inpatient) should be considered in
therapy decisions.
6. Treatment duration should be for 710 days unless otherwise noted (i.e., azithromycin package
dosing of 5 days).
7. Outpatient treatment based on IDSA/ATS guidelines
a. Previously healthy and no antimicrobials in past 3 months
i. Macrolide (azithromycin, clarithromycin)
ii. Doxycycline
b. Presence of comorbidities such as diabetes; alcoholism; immunosuppression; asplenia; chronic
heart, lung, or liver disease; use of antimicrobial in past 3 months (be sure to choose an
antimicrobial from a class that differs from that previously administered)
i. Respiratory fluoroquinolone (levofloxacin 750 mg, moxifloxacin, gemifloxacin)
ii. -Lactam(high-dose amoxicillin 1 g three times/day; amoxicillin/clavulanate 2 g two
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times/day; or ceftriaxone, cefpodoxime, and cefuroxime 500 mg two times/day) plus a

macrolide
c. Suspected aspiration
i. Amoxicillin/clavulanate
ii. Clindamycin
d. Regions with a high rate (greater than 25%) of macrolide-resistant S. pneumoniae
(erythromycin minimum inhibitory concentration [MIC] of 16 mg/L or greater): Use an
alternative agent such as fluoroquinolone.
e. If MRSA or CA-MRSA is suspected
i. Add vancomycin or linezolid.
ii. Patient may need to be hospitalized.
F. Resistance
1. Resistance patterns vary geographically, and empiric antibiotic selections should consider local
susceptibility patterns.
2. Drug-resistant S. pneumoniae
a. Penicillin
i. Current breakpoints for nonmeningeal infections set in 2008 by the Clinical and
Laboratory Standards Institute (CLSI)
(a) Susceptibility of 2 mg/L or less
(b) Intermediate 4 mg/L
(c) Resistant 8 mg/L or greater
ii. Although MICs have risen during the past 20 years for penicillin, data suggest the
clinically relevant level of resistance is greater than 4 mg/L.
b. Macrolides and fluoroquinolones i. Continue to rise
ii. Resistance is associated with more clinical failures.
c. Multidrug resistant
i. In the late 1990s, there was an increase in -lactam plus macrolide-resistant S.
pneumoniae.
ii. A 2008 study found less than 5% multidrug resistance in Europe; the decreased number
probably reflects changes in CLSI susceptibility breakpoints for penicillin.
3. Risk factors for resistance
a. Age younger than 2 years or older than 65 years
b. Previous -lactam, macrolide, or fluoroquinolone exposure
c. Alcoholism
d. Medical comorbidities
e. Immunosuppression
f. Exposure to children in a day care setting
II. INFLUENZA
A. Overview
1. Influenza caused by RNA viruses, predominantly influenza A or B
2. Each year, 5%20% of the population is infected.
3. Very large impact on outpatient health services
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4. Influenza season is defined as when influenza viruses are circulating in the community, anywhere
from about September to April in the Northern Hemisphere; usually most predominant in winter
months (December to March)
5. Associated with high morbidity and mortality rates in the United States each year
a. Average of 36,000 deaths
b. Greater than 200,000 hospitalizations
6. Most infections are self-limited and resolve without complications.
7. Severe disease can lead to hospitalization and even death, especially in high-risk patients.
a. Elderly
b. Very young
c. Comorbid medical conditions
8. Vaccination is the best method for prevention, and it should be administered to all who are at risk.
B. Diagnosis
a. Sudden onset of fever and cough is the most predictive (sensitivity greater than 70%).
b. Headache
c. Myalgias
d. Tiredness, weakness, exhaustion
e. Chest discomfort
f. Symptoms often seen, but they are not as specific, and they may be more consistent than those
for the common cold
i. Stuffy nose
ii. Sneezing iii. Sore throat
g. Diarrhea
i. Up to 28% seen in infants and young children
ii. Not as commonly seen in adults
h. Presentation can vary by age, comorbidities, immune status
2. Diagnostic specimens
a. Diagnosis is often made by clinical presentation only.
b. Nasopharyngeal aspirates and swabs preferably taken within 5 days of illness onset; if taken
after more than 5 days, false-negative tests may result because of decreased viral shedding
c. Tests available for influenza
i. Reverse transcriptase-polymerase chain reaction (RT-PCR)
(a) Most sensitive and specific
(b) Will differentiate influenza type (i.e., H1N1, H5N1)
ii. Commercial rapid influenza tests
(a) Results in 1030 minutes
(b) Less sensitive than RT-PCR
(c) Performance depends on patient age, illness duration, and sample type.
(d) A follow-up with RT-PCR may be needed.
iii. Immunofluorescence
(a) Antigen detection
(b) Performance depends greatly on laboratory expertise.
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C. Pathophysiology
1. Type A
a. Grouped by variations in hemagglutinin and neuraminidase (i.e., H1N1, H5N1, H1N2)
b. Can see epidemics every 13 years; for example, the H1N1 epidemic of 20092010
2. Type B
a. Carries one form of hemagglutinin and one form of neuraminidase
b. Can see epidemics less often than in type A, every 5 years
D. Treatment
1. Recommended for adults and children with the following:
a. Patients having highly suspected or laboratory-confirmed influenza who are within 48 hours of
symptom onset
b. Patients with high risk of complications
c. Patients who require hospitalization
d. Patients with persistent moderate to severe symptoms more than 48 hours after initial onset
2. Current recommendations and susceptibilities should always be checked when initiating therapy
because antiviral susceptibility can vary from year to year, depending on the years predominant
pathogen. Information is available on the Centers for Disease Control and Preventions (CDC)
influenza Web site (www.cdc.gov/flu).
3. Adamantanes: Amantadine (Symmetrel) and rimantadine (Flumadine)
a. Work by inhibiting viral uncoating and release of viral nucleic acid by inhibiting M2 protein
b. Work only against influenza A virus
c. Therapy is preferably initiated within 48 hours of symptom onset.
d. Adverse effects
i. Central nervous system
ii. Peripheral edema
iii. Orthostatic hypotension
e. Rimantadine tends to have a more favorable adverse effect profile and is preferred in the 2009
influenza IDSA guidelines.
f. Dose
i. 100 mg orally two times/day for 37 days
ii. Adjust in renal disease.
iii. Should decrease to 100 mg/day in elderly
4. Oseltamivir (Tamiflu)
a. Works by inhibiting neuraminidase, thereby decreasing viral shedding
b. Effective against influenza A and B
c. Therapy preferably initiated within 48 hours of symptom onset
d. Dose
i. 75 mg orally two times/day for 5 days
ii. If creatinine clearance less than 30 mL/minute, decrease dose to 75 mg/day
e. Tolerated relatively well, but can be associated with nausea and vomiting
5. Zanamivir (Relenza)
a. Works by inhibiting neuraminidase, thereby decreasing viral shedding
b. Effective against influenza A and B
c. Therapy preferably initiated within 48 hours of symptom onset
d. Associated with bronchospasm (50%) if not used with 2-agonist
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e. Dose (e.g., 2 inhalations [5 mg/inhalation] two times/day for 5 days)

f. Tolerated well, but cough, sore or dry throat, dizziness, headache, diarrhea, and vomiting can
be seen
E. Prevention
1. Vaccination is the best means of prevention.
2. For patients older than 1 year who are unable to be vaccinated (severely immunocompromised,
lack or shortage of vaccine), chemoprophylaxis is an option.
a. The CDCs influenza Web site (www.cdc.gov/flu) will give the most up-to-date
recommendations based on current influenza susceptibilities and outbreaks.
b. Oseltamivir, zanamivir, and rimantadine are the only recommended agents.
c. Duration
i. If vaccination is given, chemoprophylaxis should be fine to discontinue at 2 weeks
enough time to allow peak immune response.
ii. If vaccination is unable to be given, patients at high risk of complications from
chemoprophylaxis should be continued as long as influenza viruses are circulating in the
community.
III. UPPER RESPIRATORY TRACT INFECTIONS
A. Introduction
1. Upper respiratory tract infections are responsible for most antibiotics prescribed in ambulatory
practice.
2. Most infections are caused by viral pathogens and are self-limiting; this can lead to a great deal of
unnecessary antibiotic use.
3. Studies have shown that antibiotic exposure for upper respiratory infections can lead to the
development of resistance to that antibiotic.
a. Effect is greatest in the month immediately after exposure.
b. Resistance risk can persist for up to 12 months.
(Guideline: IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Adults and Children.
CID, March 21, 2012.)
B. Acute Sinusitis
1. Inflammation and/or infection of the paranasal and nasal mucosa
2. Viral respiratory infections usually precede sinusitis.
3. Primarily viral in origin, but differentiation between viral and bacterial causes can be difficult
a. Viral infections tend to resolve after 710 days.
b. Persistence or worsening of sinusitis may indicate bacterial infection.
4. Other things that can present like sinusitis
a. Allergies
b. Trauma
c. Environmental exposures
d. Anatomic abnormalities
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5. Very rare complications

a. Orbital cellulitis
b. Meningitis
c. Brain abscess
a. Nasal discharge and/or congestion
b. Facial, sinus, and maxillary tooth pain
7. Etiology
a. Viruses in most cases
b. Bacterial pathogens similar to otitis media
i. S. pneumoniae and H. influenzae in about 70% of cases
ii. Moraxella catarrhalis (frequently in children)
iii. Less frequentlyStreptococcus pyogenes, S. aureus, fungi/yeast, anaerob
8. Treatment
a. Goals are to reduce the signs and symptoms, minimize duration, prevent complications, and
reduce bacterial resistance by limiting antimicrobial treatment to those who need it.
b. Most infections are self-limiting, and patients will recover on their own.
c. Supportive therapy
i. Nasal decongestant sprays to reduce inflammationLimit to the recommended duration
ii. Oral decongestants
iii. Saline irrigations and/or steam inhalations
iv. Mucolytics such as guaifenesin may decrease the viscosity of nasal secretions.
v. Avoid antihistamines because they may dry nasal mucosa.
d. Antimicrobial therapy may be warranted when symptom duration has progressed beyond a
viral infection (35 days), when symptoms worsen, or when sinus discharge becomes more
purulent and discolored.
i. First lineAmoxicillin
(a) Proven efficacy and safety
(b) Low cost
ii. Penicillin-allergic patients
(a) Trimethoprim/sulfamethoxazole
(b) Azithromycin or clarithromycin
(c) Second-generation cephalosporins (cefprozil, cefuroxime, cefpodoxime)
(d) Respiratory fluoroquinolones (levofloxacin, moxifloxacin, gemifloxacin)
iii. Treatment failure
(a) High-dose amoxicillin/clavulanate
(b) Second-generation cephalosporin
(c) Respiratory fluoroquinolone
iv. Resistant S. pneumoniae
(a) High-dose amoxicillin
(b) Clindamycin
(c) Respiratory fluoroquinolone
v. Treatment is for 1014 days unless otherwise note
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Table 1.
Antimicrobial
Amoxicillin
Adult Dose
500 mg three times/day (low dose)
1 g three times/day (high dose)
Amoxicillin/clavulanate
500/125 mg three times/day (low dose)

2 g/125 mg two times/day (high dose)
Cefprozil
Cefuroxime
Cefpodoxime
Cefdinir
Trimethoprim/sulfamethoxazole
Azithromycin
Clarithromycin
Clindamycin
Levofloxacin
Moxifloxacin
Gemifloxacin
250500 mg two times/day

600 mg/day
160/800 mg two times/day
500 mg once on day 1, followed by 250 mg/day for 25 days
150450 mg every 6 hours
500 mg/day
400 mg/day
320 mg/day for 5 days
C. Pharyngitis
1. Acute inflammation of the oropharynx or nasopharynx
2. Viruses cause most cases (rhinovirus, coronavirus, influenza, parainfluenza, Epstein-Barr).
3. Group A Streptococcus (S. pyogenes) is the most common bacterial etiology in 15%30% of all
cases.
a. Predominantly seen in children 515 years old
b. Parents of school-aged children
4. Spread by direct contact with droplets of infected saliva or nasal secretions
(Guideline: Clinical Practice Guideline for the Diagnosis and Management of Group A Streptococcal Pharyngitis: 2012
Update by the Infectious Diseases Society of America. CID, September 9, 2012.)
D. Clinical Presentation
1. Difficult to differentiate viral from bacterial etiology
a. Acute onset of sore throat
b. Pain with swallowing
c. Fever
d. Erythema and inflammation of tonsils and pharynx with or without exudates
e. Tender and swollen lymph nodes
3. Diagnosis
a. Need to determine whether viral or group A Streptococcus infection; definitive diagnosis cannot
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be made by clinical presentation alone

b. Throat swab to do a culture or the rapid antigen detection test (RADT)
i. The RADT, which gives a very rapid result, can be done in the clinic.
ii. Culture usually takes 2448 hours.
iii. The RADT and/or culture should only be done in patients with presenting signs and
symptoms of pharyngitis.
c. Clinical scoring systems
i. Can still result in overprescribing of antimicrobials
ii. The RADT is suggested for all patients with presenting symptoms.
4. Treatment
a. Supportive care
i. Resolve pain and fever with acetaminophen or nonsteroidal anti-inflammatory drugs.
ii. Topical analgesics/lozenges
iii. Salt water gargles
b. Antimicrobial therapy for group A Streptococcus
i. Will allow bacterial eradication within 4872 hours
ii. Penicillin is the drug of choice because group A Streptococcus remains exquisitely sensitive
to penicillin.
(a) Penicillin VK for 10 days, 500 mg two times/day for adults, 50 mg/kg/day in three doses
for pediatrics
(b) Penicillin benzathine 1.2 million units intramuscularly once for adults and 0.6 million
unit intramuscularly (for less than 27 kg) once for pediatrics
(c) Amoxicillin 500 mg three times/day for adults, 4050 mg/kg/day for pediatrics for 10
days of treatment
iii. Other options include macrolides and first-generation cephalosporins.
c. The treatment goal (supportive and/or antimicrobial) is the eradication of symptoms or
organisms. This usually takes place in 4872 hours. Patients should be able to return to work or
school after being fever free for 2448 hours.
IV. UNCOMPLICATED SKIN AND SOF T TISSUE INFECTIONS
A. Introduction
1. Skin and soft tissue infections (SSTIs) involve any of the skin layers.
a. Epidermis
b. Dermis
c. Fascia
d. Muscle
2. Categorized as complicated or uncomplicated; complicated infections:
a. Involve deeper structures (fascia, muscle)
b. Require significant surgical intervention
c. Occur in immunocompromised patients
3. SSTIs are among the most common infections seen in the community setting.
4. Obtaining a detailed patient history is imperative to aid in diagnosis.
a. Immune status information
b. Geographic locale
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c. Travel history
d. Recent trauma or surgery
e. Previous or current antimicrobial therapy
f. Hobbies
g. Animal exposure or bites
5. Issues with SSTIs
a. Diagnosis
b. Severity of infection
c. Pathogen and antibiotic resistance patterns; CA-MRSA
i. Although MRSA is traditionally considered a nosocomial infection, in recent years, it has
been isolated from patients without typical risk factors such as prior hospitalization or
exposure to a long-term care facility.
ii. CA-MRSA differs genetically and in susceptibility from nosocomial MRSA.
(a) Strains often carry genes for toxins such as Panton-Valentine leukocidin, responsible for
tissue necrosis and virulence.
(b) Usually susceptible to agents such as clindamycin, doxycycline, and
trimethoprim/sulfamethoxazole
(c) Health care providers need to be aware of geographic patterns and outbreaks of CAMRSA when assessing patients for SSTIs.
B. General Etiology
1. Gram-positive organisms, many from the skin surface
a. S. aureus
b. S. pyogenes (-hemolytic Streptococcus)
c. Coagulase-negative Staphylococcus (CNS)
d. Corynebacterium spp. (diphtheroids)
2. Gram-negative organisms are not as common in community-acquired infections, but incidence
increases with nosocomial exposure.
a. Pseudomonas aeruginosa
b. Escherichia coli
c. Acinetobacter
3. Yeast (Candida spp.)
4. Likely etiology may vary on the basis of SSTI type.
C. Impetigo
1. Superficial skin infection with discrete purulent lesions
2. Primarily seen in children 25 years of age, but can be seen in older children and adults
3. Most common in hot, humid climates
4. Readily spread with close contact, especially in schools and day care centers
5. Most common organisms
a. S. pyogenes
b. S. aureus
6. Commonly infected sites are exposed areas of the body.
a. Face
b. Extremities
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a. Lesions can be bullous or nonbullous; they initially appear as superficial vesicles and rapidly
enlarge to bullae or pus-filled blisters that readily rupture to produce characteristic golden-yellow
crusts.
b. Systemic signs of infection are minimal.
c. Regional lymph nodes may be enlarged.
8. Diagnosis
a. Cultures of vesicles or bullae should preferably be from crusted lesions and non-open draining
pustules. Open pustules may be colonized with skin flora.
b. A complete blood cell count may show leukocytosis.
9. Treatment
a. May be self-limiting, but antimicrobial treatment is preferred to prevent new lesions, alleviate
symptoms, and prevent complications
b. Oral antimicrobialsConsider erythromycin resistance.
c. Mupirocin ointment three times/day can be used in patients with a limited number of lesions or
involvement of a small surface area.
d. Antimicrobial treatment should be for 710 days.
Table 2.
Impetigo Treatment
Dicloxacillin
Cephalexin
Erythromycin
Clindamycin
Adults
250 mg orally four times/day
300400 mg orally three
875/125 mg orally two times/day
Children
12 mg/kg/day orally divided in four doses
1020 mg/kg/day orally divided in three doses
25 mg/kg/day (amoxicillin component) orally
divided in two doses
D. Folliculitis, Furuncles, and Carbuncles

1. Folliculitis is a superficial inflammation of the hair follicle caused by injury, chemical irritation, or
infection.
2. Furuncles (abscess or boil) and carbuncles occur when folliculitis extends from the hair shaft to
deeper tissues.
3. Etiology
a. Usually caused by S. aureusCA-MRSA outbreaks have been known to occur.
b. Outbreaks of P. aeruginosa infections are associated with inadequately chlorinated pools, hot
tubs, and so forth.
a. Folliculitis: Pruritic, erythematous papules within 48 hours of exposure to organismsSystemic
symptoms are rare, but they have been reported with P. aeruginosa.
b. Furuncles: Usually occur in areas of friction or perspiration
i. Lesion is usually a firm, tender, red nodule that becomes more painful and may drain pus.
ii. CA-MRSA can appear as spider bites, and it has a necrotic center.
c. Carbuncles: Broad, swollen, erythematous, deep, and painful masses, usually on the back of the
neck
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i. Patients with diabetes especially susceptible

ii. Commonly associated with constitutional symptoms such as fever and chills
iii. Bacteremia and spread are a risk.
5. Treatment
a. Folliculitis
i. Antimicrobial treatment usually unnecessary for smaller boils
ii. Warm saline compresses to promote drainage
b. Furuncles and carbuncles
i. Incision and drainage may be required, especially for carbuncles.
ii. Dicloxacillin (covers methicillin-sensitive S. aureus [MSSA] and S. pyogenes)
(a) Adults: 250500 mg orally every 6 hours
(b) Pediatrics: 2550 mg/kg orally divided into four doses
iii. Cephalexin (covers MSSA and S. pyogenes)
(b) Pediatrics: 2550 mg/kg orally divided into four doses
iv. Clindamycin (covers MSSA, some CA-MRSA, and S. pyogenes)
(b) Pediatrics: 1030 mg/kg/day orally divided into three or four doses
(c) Is an oral option for CA-MRSA, but is cross-resistant with erythromycin
v. Trimethoprim/sulfamethoxazole (covers MSSA and CA-MRSA, but not S. pyogenes) (a)
Adults: 1 or 2 double-strength tablets two times/day
(b) Pediatrics: 812 mg/kg (based on trimethoprim component) orally divided into two doses
(c) Is an oral option for CA-MRSA
(d) Because of trimethoprim/sulfamethoxazoles poor activity against Streptococcus
organisms, in patients for whom it is unknown whether there is a staphylococcal or
streptococcal infection, would recommend adding a cephalosporin or clindamycin to the
regimen until a definitive organism is found
vi. Severe CA-MRSA may require intravenous antibiotics with good MRSA coverage such as:
(a) Vancomycin
(b) Linezolid (intravenous and oral formulations available)
(c) Daptomycin
(d) Telavancin
(e) Tigecycline
c. Antimicrobial treatment should be for 710 days.
E. Cellulitis
1. An acute, diffuse, quickly spread skin infection that initially affects the epidermis and dermis and can
spread readily to the deeper tissues
2. Ability to spread through the lymphatic tissue to the bloodstream
3. Etiology
a. Most common pathogens
i. S. aureus (MSSA, MRSA, and CA-MRSA)
ii. S. pyogenes
b. Other pathogens
i. Gram-negative bacilli
ii. Anaerobes
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iii. Variety of gram-positive cocci

a. Usually proceeded by a trauma, wound, abrasion, ulcer, surgery, and so forth
b. Patients may have generalized symptoms of fever, chills, or malaise.
c. Infected area is warm and painful and is characterized by erythema and edemaInflammation
generally is present with little or no necrosis or suppuration.
d. Lesions are non-elevated with poorly defined margins.
e. Tender lymphadenopathy may be present.
5. Diagnosis
a. Usually made by clinical appearance
b. Cultures should be collected when possible.
c. A complete blood cell count usually shows leukocytosis.
d. Blood cultures may be positive in as many as 30% of cases.
6. Treatment
a. Directed against the causative pathogen
i. Empiric or directed therapy
ii. See treatment options for furuncles and carbuncles.
iii. Incision and drainage and intravenous antibiotics may be necessary if complicated cellulitis.
iv. If lesions or erythematous areas are rapidly spreading, if there is a pronounced systemic
response to infection, and/or if there are significant comorbidities (neutropenia, cardiac or
renal failure, trauma), inpatient intravenous therapy may be warranted.
b. Antimicrobial treatment should last 710 days.
F. Erysipelas
1. Infection of the upper dermis and superficial lymphatics
a. Clinically, looks very similar to cellulitis
b. Differs from cellulitis, which affects the deeper dermis and subcutaneous fat
2. More common among infants, young children, and older adults
3. EtiologyAlmost always -hemolytic Streptococcus (S. pyogenes)
a. Very bright red lesion with edema and possible lymphatic streaking
b. Unlike cellulitis, the erysipelas lesion is raised with clearly demarcated margins.
c. Patients usually have fever or flulike symptoms.
5. DiagnosisMay be able to culture by aspirating from the edge of the lesion
6. Treatment
a. Treatment is for 710 days.
b. Penicillin is the treatment of choice because of the exquisite susceptibility of S. pyogenes to
penicillin (intramuscularly or orally).
i. Adult
(a) Oral: Penicillin VK 250500 mg orally every 6 hours
(b) Intramuscular: Procaine penicillin G 600,000 units intramuscularly every 12 hours
ii. Pediatric less than 30 kg Oral: Penicillin VK 2550 mg/kg orally in three or four divided
doses
c. Clindamycin or erythromycin can be used for penicillin-allergic patients. Practitioners must be
aware of the resistance of S. pyogenes to macrolides.
d. Antimicrobial treatment should be for 710 days.
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G. Diabetic Foot Infections

1. One of the most common complications of diabetes
a. Cost for treating a patient can be up to $18,000 per year.
b. Fifty percent of nontraumatic low-extremity amputations in the United States are complications
from diabetic foot infections.
2. Etiology
a. Usually polymicrobial with an average of two to six isolates per culture
b. Includes gram-negative, gram-positive, and anaerobic organisms
c. Staphylococci (CNS, MSSA, MRSA) and streptococci are the most common.
d. Up to 50% can be caused by gram-negative bacilli.
i. E. coli
ii. Klebsiella spp.
iii. Proteus spp.
iv. P. aeruginosa
e. Anaerobes
i. Bacteroides fragilis
ii. Peptostreptococcus spp.
3. PathophysiologyThree factors that lead to high risk of infections:
a. Peripheral neuropathy
b. Ischemia caused by atherosclerosis
c. Diabetic-associated immunologic defects
4. Clinical presentation and diagnosis
a. Infections can be more extensive than they initially appear.
b. Usual clinical signs of pain may be absent because of neuropathy.
c. Fever may be present.
d. Foul-smelling infection may be indicative of anaerobic infections.
e. Diagnosis should include cultures and sensitivities for both aerobic and anaerobic organisms.
f. Radiologic studies may be warranted to evaluate for osteomyelitis.
5. Treatment
a. Usually includes wound care and antimicrobial therapy
b. Goal is to preserve limb and limb function.
c. Wounds must be kept clean and dressings changed often.
d. Tight glycemic control is imperative for adequate wound healing.
e. Most mild (not rapidly spreading or limited systemic response) infections can be treated with
outpatient oral antimicrobial therapy and wound care.
f. Antimicrobials
i. Amoxicillin/clavulanate 875 mg orally two times/day, limited coverage against gram
negatives
ii. Clindamycin 300600 mg orally three times/day does not cover gram-negative organisms.
iii. Fluoroquinolones (levofloxacin 500750 mg orally daily, ciprofloxacin 500 mg orally daily,
or moxifloxacin 400 mg orally daily), good gram-negative coverage
(a) Anaerobic coverage may be added if anaerobic infection is present or highly suspected;
although levofloxacin and moxifloxacin have some coverage against anaerobic
infections, additional therapy may be warranted in true anaerobic infections.
(b) Metronidazole 500 mg orally three times/day or clindamycin 300600 mg orally three
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times/day
g. Treatment is usually 710 days, but it may go up to 2 weeks or longer depending on the response
to the infection.
V. COLLATERAL DAMAGE
A. Overuse or inappropriate use of antimicrobial therapy can lead to the selection of drug-resistant
organisms or unwanted colonization or infection with Clostridium difficile diarrhea or multidrug-resistant
organisms.
1. Broad-spectrum antibiotics and resistance
a. Broad-spectrum antimicrobials are convenient for a one-size-fits-all approach to the treatment
of infections, especially if the agent has good efficacy and convenient dosing.
b. Several studies have shown a parallel increase in resistance with increased use of
fluoroquinolones and third-generation cephalosporins.
i. Third-generation cephalosporin-associated resistance
(a) Vancomycin-resistant enterococci
(b) Extended-spectrum -lactamaseproducing E. coli and Klebsiella spp.
ii. Fluoroquinolone use and increased resistance
(a) MRSA
(b) Fluoroquinolone-resistant gram-negative bacilli such as E. coli and P. aeruginosa
iii. Fluoroquinolones are the most prescribed antimicrobials for adults in ambulatory care
settings and emergency departments.
(a) A study in a single institution showed that 50% of levofloxacin prescribing for CAP in
an emergency department was inappropriate on the basis of practice guidelines.
(b) Fluoroquinolone-resistant E. coli has been seen in populations of cancer patients with
previous exposure to levofloxacin.
2. C. difficile diarrhea
a. Mild to severe diarrhea caused by overgrowth in the large bowel of the anaerobic gram-positive
spore-forming toxin A and Bproducing bacillus
b. Risk factors
i. Broad-spectrum antimicrobial therapy
ii. Prolonged antimicrobial therapy
iii. Age older than 65 years
iv. Comorbidities
v. Inflammatory bowel disease
vi. Malignancy
c. Treatment
i. If possible, remove the offending agent.
ii. Metronidazole 500 mg intravenously or orally three times/day for 10 days
iii. Vancomycin 250 mg ORALLY four times/day for 10 days
B. Antimicrobial Stewardship
1. Key to combating and preventing antimicrobial resistance
2. Emphasis of most stewardship programs. Examples come from institutional practices; however,
antimicrobials are mainly prescribed in outpatient settings.
3. Appropriate antimicrobial prescribing is imperative.
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a.
b.
c.
d.
Avoid the prescribing/use of antibiotics when they are not warranted (viral infections).
Avoid the prolonged use of antimicrobials.
Use practice guidelines and/or protocols when feasible.
Educating practitioners on the risks of antimicrobial resistance and appropriate antimicrobial
prescribing
VI. ROUTINE IMMUNIZATIONS IN INFANTS AND CHILDREN

To review this information, please see the Appendix for the CDC Recommended Immunization Schedule(s) or go to
www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-11x17-fold-pr.pdf.
VII. ANTIMICROBIAL COST

(given in U.S. dollars, but should still give you a relative sense of cost for comparison)
Table 3.
Drug
Dose/Length
Unit Cost
($)
Community-Acquired Pneumonia
Azithromycin
500 mg once, 250 mg/day 4
days
7.78
Clarithromycin
Doxycycline
Levofloxacin
Moxifloxacin
Amoxicillin
500 mg two times/day 7 days

750 mg/day 7 days
400 mg/day 7 days
1 g three times/day 7 days
2 g/125 mg two times/day 7 days
Influenza
Rimantadine
Oseltamivir
Zanamivir

2 inhalations (5 mg/inhalation) two
times/day 5 days
Upper Respiratory Tract Infections

Amoxicillin
500 mg three times/day 10 days
1 g three times/day 10 days
Cost
Total
Treatment
($)
Manufacturer
46.70
Teva
4.52
0.58
30.23
16.35
0.37 (500mg capsule)
63.28
8.12
211.61
114.45
15.54
Ranbaxy
Teva
Ortho-McNeil
Schering
Teva
4.14
(1-g tablet)
115.92
Glaxo
25.62
97.60
70.80
Caraco
Roche
Glaxo
1.83
9.76
70.80
(Diskhaler)
0.37
11.1022.20
Teva
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Drug
Dose/Length
Unit Cost
($)
Cost
Total
Treatment
($)
Manufacturer
500 mg/125 mg three times/day 10

days
2 g/125 mg three times/day 10 days
3.79
113.70
Sandoz
4.14
124.23
Glaxo
Cefprozil
Cefdinir
Trimethoprim/
sulfamethoxazole

600 mg/day 10 days
160/800 mg two times/day 10 days
8.92
5.12
1.44
178.40
51.12
28.80
Greenstone
Teva
Sandoz
Azithromycin
500 mg once on day 1, followed by

250 mg/day on days 25
7.78
46.70
Teva
Clarithromycin
250500 mg two times/day 10

days
4.32
86.4172.8
Clindamycin
150450 mg every 6 hours 10

days
1.19
47.60
142.80
Teva
26.91
16.35
0.38
269
163.50
7.60
Ortho-McNeil
Schering
Greenstone
0.66
26.40
Sandoz
Levofloxacin
500 mg/day 10 days
Moxifloxacin
400 mg/day 10 days
Penicillin VK
Skin and Soft Tissue Infections
Dicloxacillin
250 mg orally four times/day 10
days
Ranbaxy
Cephalexin
250 mg orally four times/day 10

days
0.73
29.20
Teva
Clindamycin
300400 mg orally three times/day

10 days
3.72
111.60
Aurobindo
875/125 mg orally two times/day

10 days
5.01
100.20
Ranbaxy
Trimethoprim/
sulfamethoxazole
1 double-strength tablet two times/day

10 days
1.44
28.80
Sandoz
Linezolid
600 mg orally two times/day 10

days
600 mg intravenously two times/day
10 days
76.70
1534
Pfizer
120.11 (600mg/300 mL)
2402.20
Pfizer
1785.70
for 70-kg
person
Cubist
155
Hospira
Daptomycin
4 mg/kg intravenously daily

10 days
Vancomycin
1 g intravenously two/times/day
10 days
255.10 (500mg vial)

7.75
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REFERENCES
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1. Mandell LA, Wunderink RG, Anzueto A, et al.
Infectious Diseases Society of
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7.
8.
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1. Stevens DL, Bisno AL, Chambers HF, et
al. Practice guidelines for the diagnosis
and management of skin and soft-tissue
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2. Lipsky BA, Berendt AR, Deery HG, et al.
Diagnosis and treatment of diabetic foot
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3. Bisno AL, Stevens DL. Streptococcal
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1. Wong-Beringer A, Nguyen LH, Lee M, et
al. An antimicrobial stewardship program
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of quinolone exposure in cancer patients. Cancer
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Influenza
1. Harper SA, Bradley JS, Englund JA, et al.
Seasonal influenza in adults and children
diagnosis, treatment, chemoprophylaxis, and
institutional outbreak management: clinical
practice guidelines of the Infectious Diseases
Society of America. Clin Infect Dis
2009;48:1003-32.
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1. Anon JB, Jacobs MR, Poole MD, et al.
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bacterial rhinosinusitis. Otolaryngol Head Neck
Surg 2004;130:1-45.
2. Gonzales R, Bartlett JG, Besser RE, et al.
Principles of appropriate antibiotic use for
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3. Ryan MW. Evaluation and management of the
patient with sinus. Med Clin North Am
2010;94:881-90.
4. Costelloe C, Metcalfe C, Lovering A, et al.
Effect of antibiotic prescribing in primary care
on antimicrobial resistance in individual patients:
systematic review and meta-analysis. BMJ
2010;340:c2096.
5. Bisno AL, Gerber MA, Gwaltney JM, et al.
Practice guidelines for the diagnosis and

management of group A streptococcal
pharyngitis. Clin Infect Dis 2002;35:113-25.
Chan TV. The patient with sore throat. Med Clin
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IDSA Clinical Practice Guideline for Acute
Bacterial Rhinosinusitis in Adults and Children.
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Practice Guideline for the Diagnosis and
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5.
Dellit TH, Owens RC, McGowan JE Jr, et

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APPENDIX
FIGURE
1. Recommended
schedule
persons
aged
through
18start
years
(for those
who fall
oropportunity
start late, as
see the
These
recommendations
must beimmunization
read with the footnotes
that for
follow.
For those
who0fall
behind or
late,2013
provide catch-up
vaccination
at behind
the earliest
catch-up
[Figure
2]) 1. To determine minimum intervals between doses, see the catch-up schedule (Figure 2). School entry and adolescent vaccine age
indicated
by schedule
the green bars
in Figure
These are
recommendations
must be read with the footnotes that follow. For those who fall behind or start late, provide catch-up vaccination at the earliest
groups
in bold.
opportunity as indicated by the green bars in Figure 1. To determine minimum intervals between doses, see the catch-up schedule (Figure 2). School entry and
adolescent vaccine age groups are in bold.
Vaccines
Birth
Hepatitis B1 (HepB)
1st
dose
1
mo
2
mos
4
mos
6
mos
2nd
dose
9
mos
12
mos
15
mos
18
mos
19-23
mos
2-3
yrs
4-6
yrs
7-10
yrs
11-12
yrs
13-15
yrs
16-18
yrs
3rd
dose
Rotavirus2 (RV)
RV-1 (2-dose series); RV-5
(3-dose series)
1st
dose
2nd
dose
See
footnote
2
Diphtheria, tetanus, & acellular

pertussis3
(DTaP: <7 yrs)
1st
dose
2nd
dose
3rd
dose
4th
dose
5th
dose
Tetanus, diphtheria, & acellular

pertussis4
(Tdap: 7 yrs)
(Tdap)
Haemophilus influenzae
type b5 (Hib)
1st
dose
2nd
dose
See
footnote
5
3rd or 4th
dose
see footnote 5
Pneumococcal conjugate6a,c
(PCV13)
1st
dose
2nd
dose
3rd
dose
4th
dose
1st
dose
2nd
dose
Pneumococcal
polysaccharide6b,c (PPSV23)
Inactivated poliovirus7 (IPV)
(<18years)
Influenza8 (IIV; LAIV)
2 doses for some : see
footnote 8
3rd
dose
4th
dose
Annual vaccination (IIV only)
Annual vaccination (IIV or LAIV)
Measles, mumps, rubella9

(MMR)
1st
dose
2nd
dose
Varicella10 (VAR)
1st
dose
2nd
dose
2 dose series
see footnote 11
Hepatitis A11 (HepA)

Human papillomavirus12
(HPV2: females only; HPV4:
males and females)
(3 dose
series)
Meningococcal13 (Hib-MenCY
6 wks; MCV4-D9 mos;
MCV4-CRM 2 yrs.)
Range of recommended
ages for all children
1st
dose
see footnote 13
ages for catch-up
immunization
ages for certain high-risk
groups
ages during which catchup is encouraged and for
certain high-risk groups
booster
Not routinely
recommended
This schedule includes recommendations in effect as of January 1, 2013. Any dose not administered at the recommended age should be administered at a subsequent visit,
when indicated and feasible. The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. Vaccination providers
should consult the relevant Advisory Committee on Immunization Practices (ACIP) statement for detailed recommendations, available online at http://www.cdc.gov/
vaccines/pubs/acip-list.htm. Clinically significant adverse events that follow vaccination should be reported to the Vaccine Adverse Event Reporting System (VAERS) online
(http://www.vaers.hhs.gov) or by telephone (800-822-7967). Suspected cases of vaccine-preventable diseases should be reported to the state or local health department.
Additional information, including precautions and contraindications for vaccination, is available from CDC online (http://www.cdc.gov/vaccines) or by telephone
(800-CDC-INFO [800-232-4636]).
This schedule is approved by the Advisory Committee on Immunization Practices (http://www.cdc.gov/vaccines/acip/index.html), the American Academy of Pediatrics (http://
www.aap.org), the American Academy of Family Physicians (http://www.aafp.org), and the American College of Obstetricians and Gynecologists (http://www.acog.org).
___________________________________________________________________________________________________________________________________________________________________________________________________________________________________
134

_________________________________________________________________________________________________________________________________________________________________________________________________________________________________
FIGURE 2. Catch-up immunization schedule for persons aged 4 months through 18 years who start late or who are more than 1 month behind
United States, 2013
Thefigure
figurebelow
belowprovides
provides
catch-up
schedules
minimum
intervals
between
for children
whose vaccinations
have
beenAdelayed.
A vaccine
does
The
catch-up
schedules
andand
minimum
intervals
between
doses doses
for children
whose vaccinations
have been
delayed.
vaccine series
does series
not need
to
notrestarted,
need to regardless
be restarted,
regardless
the
time that
has elapsed
between
doses.
Use the section
appropriate
for the
childs
age.inAlways
use this
table
in conjuncbe
of the
time thatofhas
elapsed
between
doses. Use
the section
appropriate
for the childs
age. Always
use
this table
conjunction
with
Figure
1 and the
tion
with
Figure
1
and
the
footnotes
that
follow.
footnotes that follow.
Persons aged 4 months through 6 years

Minimum
Age for
Dose 1
Vaccine
Minimum Interval Between Doses

Dose
1 to dose 2
Dose
2 to dose 3
Dose
3 to dose 4
Dose
4 to dose 5
6 months3
Hepatitis B1
Birth
4 weeks
8 weeks
and at least 16 weeks after first dose;
minimum age for the final dose is 24 weeks
Rotavirus2
6 weeks
4 weeks
4 weeks2
Diphtheria, tetanus,
pertussis3
6 weeks
4 weeks
4 weeks
6 months
6 weeks
4 weeks
if first dose administered at younger than
age 12 months
8 weeks (as final dose)
if first dose administered at age 1214 months
No further doses needed
if first dose administered at age 15 months
or older
4 weeks5
if current age is younger than 12 months
8 weeks (as final dose)5
if current age is 12 months or older andfirst
dose administered at younger than age 12
months and second dose administered at
younger than 15 months
if previous dose administered at age 15 months
or older
8 weeks (as final

dose)
This dose only
necessary for
children aged 12
through 59 months
who received
3 doses before age
12 months
Pneumococcal6
6 weeks
4 weeks
age 12 months
8 weeks (as final dose for healthy children)
if first dose administered at age 12 months or
older or current age 24 through 59 months
for healthy children if first dose administered at
age 24 months or older
4 weeks
if current age is younger than 12 months
8 weeks (as final dose for healthy children)
if current age is 12 months or older
for healthy children if previous dose
administered at
age 24 months or older
8 weeks (as final

dose)
This dose only
necessary for
children aged 12
through 59 months
who received
3 doses before age
12 months or for
children at high
risk who received
3 doses at any age
Inactivated poliovirus7
6 weeks
4 weeks
4 weeks
6 months7
minimum age 4
years for final dose
6 weeks
8 weeks13
see footnote 13
see footnote 13
Measles, mumps, rubella
12 months
4 weeks
Varicella10
12 months
3 months
Hepatitis A11
12 months
6 months
type b5
Meningococcal13
9
Persons aged 7 through 18 years

Tetanus, diphtheria; tetanus, diphtheria, pertussis4
7 years
Human papillomavirus12
9 years
4 weeks
age 12 months
6 months
if first dose administered at 12 months
or older
4 weeks
Routine dosing intervals are recommended12
Hepatitis A
12 months
6 months
Hepatitis B
Birth
4 weeks
8 weeks
(and at least 16 weeks after first dose)
Inactivated poliovirus7
6 weeks
4 weeks
4 weeks7
Meningococcal13
6 weeks
8 weeks13
Measles, mumps, rubella9
12 months
4 weeks
Varicella10
12 months
3 months
if person is younger than age 13 years
4 weeks
if person is aged 13 years or older
11
6 months
if first dose
administered at
younger than
age 12 months
6 months7
___________________________________________________________________________________________________________________________________________________________________________________________________________________________________
135

_________________________________________________________________________________________________________________________________________________________________________________________________________________________________
FIGURE 1. Recommended adult immunization schedule, by vaccine and age group1

These recommendations must be read with the footnotes that follow.
VACCINE
19-21 years
AGE GROUP
22-26 years
27-49 years
Influenza 2,*
50-59 years
60-64 years
65 years
1 dose annually
Tetanus, diphtheria, pertussis (Td/Tdap) 3,*
Substitute 1-time dose of Tdap for Td booster; then boost with Td every 10 yrs
Varicella 4,*
2 doses
Human papillomavirus (HPV) Female 5,*
3 doses
Human papillomavirus (HPV) Male 5,*
3 doses
Zoster 6
1 dose
Measles, mumps, rubella (MMR) 7,*
1 or 2 doses
Pneumococcal polysaccharide (PPSV23) 8,9

Pneumococcal 13-valent conjugate (PCV13)
Meningococcal 11,*
1 or 2 doses
10
1 dose
1 dose
1 or more doses
Hepatitis A 12,*
2 doses
Hepatitis B 13,*
3 doses
*Covered by the Vaccine Injury Compensation Program

For all persons in this category who
meet the age requirements and who lack
documentation of vaccination or have no
evidence of previous infection;
zoster vaccine recommended regardless
of prior episode of zoster
Report all clinically significant postvaccination reactions to the Vaccine Adverse Event Reporting System (VAERS). Reporting forms and instructions on
filing a VAERS report are available at www.vaers.hhs.gov or by telephone, 800-822-7967.
Information on how to file a Vaccine Injury Compensation Program claim is available at www.hrsa.gov/vaccinecompensation or by telephone,
800-338-2382. To file a claim for vaccine injury, contact the U.S. Court of Federal Claims, 717 Madison Place, N.W., Washington, D.C. 20005; telephone,
202-357-6400.
Additional information about the vaccines in this schedule, extent of available data, and contraindications for vaccination is also available at www.cdc.
gov/vaccines or from the CDC-INFO Contact Center at 800-CDC-INFO (800-232-4636) in English and Spanish, 8:00 a.m. - 8:00 p.m. Eastern Time, Monday
Recommended if some other risk factor
- Friday, excluding holidays.
is present (e.g., on the basis of medical,
Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human
occupational, lifestyle, or other indication) Services.
No recommendation
The recommendations in this schedule were approved by the Centers for Disease Control and Preventions (CDC) Advisory Committee on
Immunization Practices (ACIP), the American Academy of Family Physicians (AAFP), the American College of Physicians (ACP), American
College of Obstetricians and Gynecologists (ACOG) and American College of Nurse-Midwives (ACNM).
FIGURE 2. Recommended vaccinations indicated for adults based on medical and other indications1
Asplenia (including
HIV infection
ImmunoHeart disease, elective splenectomy
CD4+ T lymphocyte
compromising
4,6,7,10,14,15
and persistent
chronic
count
conditions
Men who
complement
(excluding human
have sex lung disease,
Chronic
component
chronic
immunodeficiency < 200 200
with men
liver
4,6,7,10,15
10,14
deficiencies)
alcoholism
cells/L cells/L
(MSM)
disease
INDICATION Pregnancy virus [HIV])
VACCINE
Influenza 2,*
1 dose IIV annually
Tetanus, diphtheria, pertussis (Td/Tdap) 3,*

Varicella 4,*
1 dose Tdap each

pregnancy
1 dose IIV or LAIV

annually
Kidney failure,
end-stage renal
disease, receipt
Healthcare
of hemodialysis Diabetes personnel
1 dose IIV annually
1 dose IIV or LAIV

annually
Substitute 1-time dose of Tdap for Td booster; then boost with Td every 10 yrs
Contraindicated
Human papillomavirus (HPV) Female 5,*

Human papillomavirus (HPV) Male 5,*
2 doses
3 doses through age 26 yrs
Zoster 6
Contraindicated
Measles, mumps, rubella (MMR) 7,*
Contraindicated

1 dose
1 or 2 doses
Pneumococcal polysaccharide (PPSV23) 8,9
1 or 2 doses
Pneumococcal 13-valent conjugate (PCV13) 10

Meningococcal 11,*
1 dose
1 or more doses
Hepatitis A 12,*
Hepatitis B 13,*
2 doses
3 doses
*Covered by the Vaccine Injury Compensation Program

For all persons in this category who meet the age requirements and who lack
documentation of vaccination or have no evidence of previous infection;
zoster vaccine recommended regardless of prior episode of zoster
Recommended if some other risk factor is present (e.g., on the basis of medical,
occupational, lifestyle, or other indications)
No recommendation
These schedules indicate the recommended age groups and medical indications for which administration
of currently licensed vaccines is commonly indicated for adults ages 19 years and older, as of January 1,
2013. For all vaccines being recommended on the Adult Immunization Schedule: a vaccine series does
not need to be restarted, regardless of the time that has elapsed between doses. Licensed combination
vaccines may be used whenever any components of the combination are indicated and when the
vaccines other components are not contraindicated. For detailed recommendations on all vaccines,
including those used primarily for travelers or that are issued during the year, consult the manufacturers
package inserts and the complete statements from the Advisory Committee on Immunization
Practices (www.cdc.gov/vaccines/pubs/acip-list.htm). Use of trade names and commercial sources is
for identification only and does not imply endorsement by the U.S. Department of Health and Human
Services.
___________________________________________________________________________________________________________________________________________________________________________________________________________________________________
136

_________________________________________________________________________________________________________________________________________________________________________________________________________________________________
TABLE. Contraindications and precautions to commonly used vaccines in adults1*

Vaccine
Contraindications
Precautions
Influenza, inactivated vaccine (IIV)
Severe allergic reaction (e.g., anaphylaxis) after

previous dose of any influenza vaccine or to a
vaccine component, including egg protein.
Moderate or severe acute illness with or without fever.

History of Guillain-Barr Syndrome (GBS) within 6 weeks of
previous influenza vaccination.
Persons who experience only hives with exposure to eggs should
receive IIV with additional safety precautions.2
Influenza, live attenuated (LAIV)3

previous dose of any influenza vaccine or to a
vaccine component, including egg protein.
Conditions for which the Advisory Committee
on Immunization Practices (ACIP) recommends
against use, but which are not contraindications
in vaccine package insert: immune suppression,
certain chronic medical conditions such as
asthma, diabetes, heart or kidney disease. and
pregnancy.4

History of GBS within 6 weeks of previous influenza vaccination.
Receipt of specific antivirals (i.e., amantadine, rimantadine,
zanamivir, or oseltamivir) 48 hours before vaccination. Avoid use of
these antiviral drugs for 14 days after vaccination.
Tetanus, diphtheria, pertussis (Tdap);

tetanus, diphtheria (Td)
Severe allergic reaction (e.g., anaphylaxis) after a

previous dose or to a vaccine component.
For pertussis-containing vaccines:
encephalopathy (e.g., coma, decreased level
of consciousness, or prolonged seizures) not
attributable to another identifiable cause
within 7 days of administration of a previous
dose of Tdap or diphtheria and tetanus toxoids
and pertussis (DTP) or diphtheria and tetanus
toxoids and acellular pertussis (DTaP) vaccine.

GBS within 6 weeks after a previous dose of tetanus toxoid
containing vaccine.
History of arthus-type hypersensitivity reactions after a previous
dose of tetanus or diptheria toxoidcontaining vaccine; defer
vaccination until at least 10 years have elapsed since the last
tetanus toxoid-containing vaccine.
For pertussis-containing vaccines: progressive or unstable
neurologic disorder, uncontrolled seizures, or progressive
encephalopathy until a treatment regimen has been established
and the condition has stabilized.
Varicella2

Known severe immunodeficiency (e.g., from
hematologic and solid tumors, receipt of
chemotherapy, congenital immunodeficiency,
or long-term immunosuppressive therapy5
or patients with human immunodeficiency
virus (HIV) infection who are severely
immunocompromised).
Pregnancy.
Recent (within 11 months) receipt of antibody-containing blood

product (specific interval depends on product).6,7
Receipt of specific antivirals (i.e., acyclovir, famciclovir, or
valacyclovir) 24 hours before vaccination; avoid use of these
antiviral drugs for 14 days after vaccination.
Human papillomavirus (HPV)


Pregnancy.
Zoster
Severe allergic reaction (e.g., anaphylaxis) to a

vaccine component.
Known severe immunodeficiency (e.g.,
from hematologic and solid tumors,
receipt of chemotherapy, or long-term
immunosuppressive therapy5 or patients
with HIV infection who are severely
immunocompromised).
Pregnancy.

Receipt of specific antivirals (i.e., acyclovir, famciclovir, or
valacyclovir) 24 hours before vaccination; avoid use of these
antiviral drugs for 14 days after vaccination.
Measles, mumps, rubella (MMR)3

Known severe immunodeficiency (e.g., from
hematologic and solid tumors, receipt of
chemotherapy, congenital immunodeficiency,
or long-term immunosuppressive therapy5 or
patients with HIV infection who are severely
immunocompromised).
Pregnancy.

Recent (within 11 months) receipt of antibody-containing blood
product (specific interval depends on product).6,7
History of thrombocytopenia or thrombocytopenic purpura.
Need for tuberculin skin testing.8
___________________________________________________________________________________________________________________________________________________________________________________________________________________________________
137

_________________________________________________________________________________________________________________________________________________________________________________________________________________________________
TABLE. (Continued) Contraindications and precautions to commonly used vaccines in adults1*
Vaccine
Contraindications
Precautions
Pneumococcal polysaccharide (PPSV)

Pneumococcal conjugate (PCV13)

a previous dose or to a vaccine component,
including to any vaccine containing diphtheria
toxoid.
Meningococcal, conjugate, (MCV4);

meningococcal, polysaccharide (MPSV4)

Hepatitis A (HepA)

Hepatitis B (HepB)

1. Vaccine package inserts and the full ACIP recommendations for these vaccines should be consulted for additional information on vaccine-related contraindications
and precautions and for more information on vaccine excipients. Events or conditions listed as precautions should be reviewed carefully. Benefits of and risks for
administering a specific vaccine to a person under these circumstances should be considered. If the risk from the vaccine is believed to outweigh the benefit, the
vaccine should not be administered. If the benefit of vaccination is believed to outweigh the risk, the vaccine should be administered. A contraindication is a
condition in a recipient that increases the chance of a serious adverse reaction. Therefore, a vaccine should not be administered when a contraindication is present.
2. CDC. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP) United States, 201213
influenza season. MMWR 2012;61:613-8.
3. LAIV, MMR, and varicella vaccines can be administered on the same day. If not administered on the same day, these live vaccines should be separated by at least
28 days.
4. For a complete list of conditions that CDC considers to be reasons to avoid getting LAIV, see CDC. Prevention and control of influenza with vaccines: recommendations
of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR 2010;59(No. RR-8). Available at http://www.cdc.gov/vaccines/pubs/acip-list.htm.
5. Immunosuppressive steroid dose is considered to be 2 or more weeks of daily receipt of 20 mg prednisone or the equivalent. Vaccination should be deferred for
at least 1 month after discontinuation of such therapy. Providers should consult ACIP recommendations for complete information on the use of specific live vaccines
among persons on immune-suppressing medications or with immune suppression because of other reasons.
6. Vaccine should be deferred for the appropriate interval if replacement immune globulin products are being administered.
7. See CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011;60(No. RR-2).
Available at http://www.cdc.gov/vaccines/pubs/acip-list.htm.
8. Measles vaccination might suppress tuberculin reactivity temporarily. Measles-containing vaccine may be administered on the same day as tuberculin skin testing.
If testing cannot be performed until after the day of MMR vaccination, the test should be postponed for at least 4 weeks after the vaccination. If an urgent need
exists to skin test, do so with the understanding that reactivity might be reduced by the vaccine.
* Adapted from CDC. Table 6. Contraindications and precautions to commonly used vaccines. General recommendations on immunization: recommendations of the
Advisory Committee on Immunization Practices. MMWR 2011;60(No. RR-2):4041 and from Atkinson W, Wolfe S, Hamborsky J, eds. Appendix A. Epidemiology and
prevention of vaccine preventable diseases. 12th ed. Washington, DC: Public Health Foundation, 2011. Available at http://www.cdc.gov/vaccines/pubs/pinkbook/
index.html.
Regarding latex allergy. Consult the package insert for any vaccine administered.
___________________________________________________________________________________________________________________________________________________________________________________________________________________________________
138
INFECTIOUS DISEASES IN THE

ACUTE CARE SETTING
139

_________________________________________________________________________________________________________________________________________________________________________________________________________________________________
1. Describe the appropriate treatment of patients with pneumonia, urinary tract infections (UTIs),
infective endocarditis, Clostridium difficile infection, and sepsis in the acute care setting.
2. Identify appropriate preventive therapy for pneumonia, UTIs, infective endocarditis, and C. difficile
infection in the acute care setting.
I. PNEUMONIA
A. Introduction
1. Pneumonia is the most common cause of death attributable to infectious diseases (very high
rates in the elderly) and the seventh most common cause of death in the United States.
2. Hospital-acquired pneumonia is the second most common nosocomial infection (0.6%1.1%
of all hospitalized patients)There is an increased incidence of patients both in the intensive
care unit recovering from thoracic or upper abdominal surgery and in the elderly.
3. Mortality rates
a. Community-acquired pneumonia without hospitalization: Less than 1%
b. Community-acquired pneumonia with hospitalization: About 14%
c. Nosocomial: About 33%50%
B. Community-Acquired Pneumonia
1. Definition: Acute infection of the pulmonary parenchyma, accompanied by the presence of an
acute infiltrate consistent with pneumonia on chest radiograph or auscultatory findings.
Patients must also NOT have any of the following characteristics: hospitalization 2 days or
more in the past 90 days; residence in a long-term care facility; receipt of intravenous
antibiotic therapy, chemotherapy, or wound care in the past 30 days; or attendance at a
hospital or hemodialysis clinic.
2. Symptoms of community-acquired pneumonia are listed below (must have any two). Elderly
patients often have fewer and less severe findings (mental status changes are common).
a. Fever or hypothermia
b. Rigors
c. Sweats
d. New cough with or without sputum (90%)
e. Chest discomfort (50%)
f. Onset of dyspnea (66%)
g. Fatigue, myalgias, abdominal pain, anorexia, and headache
3. Predictors of a complicated course of community-acquired pneumonia are listed below.
Hospitalization should be based on severity-of-illness scores (e.g., CURB-65, PSI
[pneumonia severity index]).
a. Age older than 65 years
b. Comorbid illness (diabetes mellitus, congestive heart failure, lung disease, renal failure,
liver disease)
c. High temperature: More than 38C (101F)
d. Bacteremia
e. Altered mental status
___________________________________________________________________________________________________________________________________________________________________________________________________________________________________
140

_________________________________________________________________________________________________________________________________________________________________________________________________________________________________
f. Immunosuppression (e.g., steroid use, cancer)

g. High-risk etiology (Staphylococcus aureus, Legionella, gram-negative bacilli, anaerobic
aspiration)
h. Multilobe involvement or pleural effusions
C. Hospital-Acquired Pneumonia
1. Hospital-acquired pneumoniaPneumonia that occurs 48 hours or more after admission and
is not incubating at the time of admission
2. Ventilator-associated pneumoniaPneumonia that arises more than 4872 hours after
endotracheal intubation
3. Health careassociated pneumoniaPneumonia developing in a patient who was hospitalized
in an acute care hospital for 2 or more days within 90 days of the infection; resided in a
nursing home or long-term care facility; received intravenous antibiotic therapy,
chemotherapy, or wound care within the last 30 days of the current infection; or attended a
hospital or hemodialysis clinic. Risk factors for hospital-acquired pneumonia:
a. Intubation and mechanical ventilation
b. Supine patient position
c. Enteral feeding
d. Oropharyngeal colonization
e. Stress bleeding prophylaxis
f. Blood transfusion
g. Hyperglycemia
h. Immunosuppression/corticosteroids
i. Surgical procedures: Thoracoabdominal, upper abdominal, thoracic
j. Immobilization
k. Nasogastric tubes
l. Prior antibiotic therapy
m. Admission to the intensive care unit
n. Elderly
o. Underlying chronic lung disease
D. Microbiology
Table 1. Incidence of Pneumonia by Organism
Community Acquired (%)
Unidentifiable
Mycoplasma pneumoniae
Streptococcus pneumoniae
Chlamydophila pneumoniae
Legionella pneumophila
Viruses
4060
1337
920
310
117
0.713
Common
Others:
Uncommon
Hospital Acquired (%)

Unidentifiable
Staphylococcus aureus
Pseudomonas aeruginosa
Enterobacter spp.
Klebsiella pneumoniae
Candida
Acinetobacter spp.
Serratia marcescens
50
10
8
5
4
3
2
2
___________________________________________________________________________________________________________________________________________________________________________________________________________________________________
141

_________________________________________________________________________________________________________________________________________________________________________________________________________________________________
Table 1. Incidence of Pneumonia by Organism

Hospital Acquired (%)

2
1
S. aureus
Moraxella catarrhalis
Pneumocystis pneumonia
Anaerobes
Gram-negative bacilli (e.g., K. pneumoniae)
Escherichia coli
S. pneumoniae
Specific populations in community-acquired

pneumonia:
Alcoholics: S. pneumoniae, oral anaerobes, gramnegative bacilli (i.e., Klebsiella)
Nursing home: S. pneumoniae, H. influenzae, gramnegative bacilli, S. aureus
COPD: S. pneumoniae, H. influenzae, M. catarrhalis
Postinfluenza: H. influenzae, S. aureus, S. pneumoniae
Exposure to water: Legionella
Poor oral hygiene: Oral anaerobes
HIV infection: Pneumocystis jiroveci, S. pneumoniae,
M. pneumoniae, Mycobacterium
Issues in hospital-acquired pneumonia:

P. aeruginosa is transmitted by health care workers
hands or respiratory equipment
S. aureus is transmitted by health care workers hands
Enterobacteriaceae endogenously colonize hospitalized
patients airways (healthy people seldom have gramnegative upper airway colonization)
Stress changes respiratory epithelial cells so that gramnegative organisms can adhere
Up to 70% of patients in the intensive care unit have
gram-negative upper airway colonization, and 25% of
them will become infected through aspiration
COPD = chronic obstructive pulmonary disease; HIV = human immunodeficiency virus.
E. Therapy
1. Community-acquired pneumonia (duration, at least 5 days)
a. Empiric treatment of nonhospitalized patients
i. Previously healthy and no antibiotic therapy in the past 3 months
(a) Macrolide (macrolide: clarithromycin or azithromycin if Haemophilus influenzae
is suspected)
(b) Doxycycline
ii. Comorbidities (chronic obstructive pulmonary disease, diabetes mellitus, chronic
renal or liver failure, congestive heart failure, malignancy, asplenia, or
immunosuppression) OR recent antibiotic therapy (within the past 3 months)
(a) Respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg])
(b) Macrolide (or doxycycline) with high-dose amoxicillin (1 g 3 times/day) or
amoxicillin/clavulanate (2 g 2 times/day) or a cephalosporin (ceftriaxone,
cefuroxime, or cefpodoxime)
b. Empiric treatment of hospitalized patients with moderately severe pneumonia
i. Respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg])
ii. Ampicillin, ceftriaxone, or cefotaxime (ertapenem in select patients) plus a macrolide
(or doxycycline)
c. Empiric treatment of hospitalized patients with severe pneumonia requiring intensive care
unit treatment: Ampicillin/sulbactam, ceftriaxone, or cefotaxime plus either a respiratory
fluoroquinolone or azithromycin (may need to add other antibiotics if Pseudomonas
aeruginosa or methicillin-resistant S. aureus [MRSA] is suspected)
___________________________________________________________________________________________________________________________________________________________________________________________________________________________________
142

_________________________________________________________________________________________________________________________________________________________________________________________________________________________________
d. Treatment durationAt least 5 days, with 4872 hours afebrile and no more than one
sign of clinical instability (elevated temperature, heart rate, or respiratory rate; decreased
systolic blood pressure; or arterial oxygen saturation) before therapy discontinuation
2. Hospital-acquired pneumonia
a. Early onset (less than 5 days) and no risk factors for multidrug-resistant (MDR)*
organisms. Common organisms include Streptococcus pneumoniae, H. influenzae,
methicillin-sensitive S. aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter
spp., and Proteus spp.
i. Third-generation cephalosporin (cefotaxime or ceftriaxone)
ii. Fluoroquinolone (levofloxacin, moxifloxacin, ciprofloxacin)
iii. Ampicillin/sulbactam
iv. Ertapenem
b. Late onset (5 days or longer) or risk factors for MDR organisms. Common organisms
include those previously listed for early onset plus P. aeruginosa, K. pneumoniae
(extended-spectrum -lactamase positive), Acinetobacter spp., MRSA, and Legionella
pneumophila.
i. Ceftazidime or cefepime plus aminoglycoside or fluoroquinolone (cipro-, levo-)
ii. Imipenem, meropenem, or doripenem plus aminoglycoside or fluoroquinolone
(ciprofloxacin, levofloxacin)
iii. Piperacillin/tazobactam plus aminoglycoside or fluoroquinolone (ciprofloxacin,
levofloxacin)
iv. Vancomycin or linezolid should be used only if MRSA risk factors (e.g., history of
MRSA infection/colonization, recent hospitalization or antibiotic use, presence of
invasive health care devices) are present or there is a high incidence locally (greater
than 10%15%).
c. Treatment durationEfforts should be made to decrease therapy duration to as short as 7
or 8 days (14 days for pneumonia secondary to P. aeruginosa).
i. Antibiotic therapy within the past 90 days
ii. Hospitalization for 5 days or more
iii. High resistance in community or hospital unit
iv. Risk factors for health careassociated pneumonia
v. Immunosuppressive disease and/or therapy
*Risk factors for MDR organisms
F. Influenza
1. Characteristics of influenza infection
a. Epidemic with significant mortality
b. Epidemics begin abruptly and peak in 23 weeks; resolve in 56 weeks
c. Occurs almost exclusively in the winter months (December to April)
d. Average overall attack rates of 10%20%
e. Mortality greatest in those older than 65 years (especially with heart and lung disease):
More than 80% of deaths caused by influenza are from this age group (20,000 deaths per
year in the United States)
2. Is it a cold or the flu?
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Table 2. Differentiating the Symptoms of Cold and Influenza

Signs and Symptoms
Influenza
Cold
Onset
Sudden
Gradual
Temperature
Characteristic, high (> 101F [38C]) of 34 days duration
Occasional
Cough
Dry; can become severe
Hacking
Headache
Prominent
Occasional
Myalgia (muscle aches/pains)
Usual; often severe
Slight
Tiredness and weakness
Can last up to 23 weeks
Very mild
Extreme exhaustion
Early and prominent
Never
Chest discomfort
Common
Mild to moderate
Stuffy nose
Sometimes
Common
Sneezing
Sometimes
Usual
Sore throat
Sometimes
Common
3. Pathophysiology
a. Type A
i. Influenza further grouped by variations in hemagglutinin and neuraminidase (e.g.,
H1N1, H1N2)
ii. Changes through antigenic drift or shift
(a) Annual, gradual change caused by mutations, substitutions, and deletions, in
response to the development of human antibodies
(b) Less common dramatic change leading to pandemics
iii. Causes epidemics every 13 years
b. Type B
i. Type B influenza carries one form of hemagglutinin and one form of neuraminidase,
both of which are less likely to mutate than the hemagglutinin and neuraminidase of
type A influenza.
ii. Changes through antigenic drift (minor mutations from year to year); when enough
drifts occur, an epidemic is likely
iii. Causes epidemics every 5 years
4. Prevention
a. Amantadine, rimantadine
i. Prevents about 50% of infections and 70%90% of illnesses (similar to the influenza
vaccine)
ii. Dose/recommendations: short term (57 weeks or the duration of the epidemic);
prophylaxis during a presumed outbreak of influenza A in patients who cannot
receive vaccine (or 2 weeks only if the vaccine is given at the same time)
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iii. Not recommended unless testing shows increased susceptibility

b. Neuraminidase inhibitors
i. Oseltamivir (Tamiflu)
(a) Oseltamivir administered 75150 mg/day orally for 6 weeks during peak
influenza season showed 74% protective efficacy.
(b) Begin oseltamivir 75 mg/day orally for at least 7 days within 2 days of close
contact with an infected individual.
ii. Zanamivir (Relenza): Zanamivir 10 mg/day through inhalation for 4 weeks during
peak influenza season showed 67% protective efficacy.
5. Therapy
a. Treat only if patient has severe symptoms (clinical deterioration or lower respiratory tract
infection) or is at higher risk of complicationsUse only the neuraminidase inhibitors.
b. Amantadine (Symmetrel); rimantadine (Flumadine)
i. Inhibits viral uncoating and release of viral nucleic acid by inhibiting M2 protein
(a) Effective only against influenza A virus
(b) Decreases the duration of signs and symptoms by 1 day
ii. Adverse effects
(a) Central nervous system
(b) Gastrointestinal (GI) systemNausea, vomiting, diarrhea
(c) Peripheral edema
(d) Orthostatic hypotension
iii. Dose
(a) 100 mg orally two times/day
(b) Elderly patients should not receive more than 100 mg/day.
(c) Adjust for renal disease (amantadine > rimantadine).
(d) Therapy duration is 37 days.
(e) Initiate treatment within 12 days of symptoms.
(f) Not recommended unless testing shows increased susceptibility
c. Oseltamivir (Tamiflu)
i. Inhibits neuraminidase; symptoms disappear 11.5 days sooner
ii. Adverse effects: GI (nausea and vomiting)
iii. Dose
(a) A total of 75 mg orally two times/day for 5 days; decrease dose to 75 mg/day
orally in patients with a creatinine clearance less than 30 mL/minute
(b) Initiate within 48 hours of symptom onset.
d. Zanamivir (Relenza)
i. Inhibits neuraminidase; symptoms disappear 11.5 days sooner
ii. Adverse effects: Bronchospasm, cough
iii. Dose
(a) Two inhalations (5 mg/inhalation) two times/day for 5 days
(b) Initiate within 48 hours of symptom onset.
G. Pneumonia Immunizations
1. Pneumococcal vaccine
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i.
Pneumococcal vaccine contains 23 purified capsular polysaccharide antigens of S.

pneumoniae.
ii. The 23 capsular types account for 85%90% of invasive S. pneumoniae infection.
iii. All six serotypes that commonly cause drug-resistant S. pneumoniae infection are in
the vaccine.
iv. Antibody levels remain elevated for at least 5 years.
b. Recommendations (Table 3)
Table 3. Pneumococcal Vaccine Recommendations
Vaccination-Recommended Group
Revaccination
Immunocompetent People
-
People 65 years
Second dose of vaccine if patient

received vaccine 5 years previously
and was < 65 years at the time of
vaccination
People 264 years old with chronic cardiovascular disease,

chronic pulmonary disease, diabetes mellitus, alcoholism,
chronic liver disease, or CSF leaks; adult asthmatics or adult
smokers
Not recommended
People 264 years old with functional or anatomic asplenia
Single revaccination recommended

after 5 years (for anyone 2 years)
People 264 years old living in special environments or social

settings
Not recommended
Single revaccination recommended

after 5 years (for anyone 2 years)
Immunocompromised People
-
Immunocompromised people 2 years, including those with

HIV infection, leukemia, lymphoma, Hodgkin disease, multiple
myeloma, generalized malignancy, chronic renal failure, or
nephrotic syndrome; those receiving immunosuppressive
chemotherapy (including corticosteroids); and those who have
received an organ or bone marrow transplant
CSF = cerebrospinal fluid; HIV = human immunodeficiency virus.
2. Influenza vaccine
a. Characteristics
i. Each years vaccine contains two strains of type A and one strain of type B
Selected by worldwide surveillance and antigenic characterization
ii. Prevents illness in 70%90% of healthy people younger than 65 years
iii. Prevents illness in 53%, hospitalization in 50%, and death in 68% of the elderly
iv. Administer yearly in September or October.
b. Recommendations
i. Everyone older than 6 months should receive the vaccine annually.
ii. Patients with HIV (human immunodeficiency virus)
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(a) No risk to the patient and should be given to anyone receiving antiretrovirals
(b) Studies show a decreased antibody response (less than 60% have adequate
response).
(c) Intranasal live-attenuated vaccine (FluMist)
(1) Indicated for people 249 years of age without underlying illnesses (including
health care workers)
(2) Use of inactivated vaccine is preferred for vaccinating household members,
health care workers, and others who have close contact with
immunosuppressed people.
II. URINARY TRACT INFECTIONS
A. Introduction
1. Most common bacterial infection in humans: 7 million office visits per year; 1 million
hospitalizations
2. Many women (15%20%) will have a urinary tract infection (UTI) during their lifetime.
3. From age 1 to 50, UTIs predominantly occur in women; after age 50, men are affected
because of prostate problems.
B. Microbiology
Table 4. Incidence of Urinary Tract Infections by Organism
Escherichia coli
Staphylococcus
saprophyticus
Proteus mirabilis
Klebsiella pneumoniae
Enterococcus
Nosocomial (%)
73
13
5
4
2
E. coli
Pseudomonas aeruginosa
Other gram-negative bacilli
K. pneumoniae
S. aureus
P. mirabilis
Enterococcus
Fungal
31
10
10
9
6
5
2
14
C. Predisposing Factors
1. Age
2. Female sex
3. Diabetes mellitus
4. Pregnancy
5. Immunosuppression
6. Urinary tract instrumentation
7. Urinary tract obstruction
8. Renal disease; renal transplantation
9. Neurologic dysfunction
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D. Clinical Presentation
1. Lower UTICystitis (elderly patients may have only nonspecific symptoms, such as mental
status changes, abdominal pain, and decreased eating or drinking)
a. Dysuria
b. Frequent urination
c. Urgency
d. Occasionally, gross hematuria
e. Occasionally, foul-smelling urine
2. Upper UTIPyelonephritis (elderly patients may have only nonspecific symptoms, such as
mental status changes, abdominal pain, and decreased eating or drinking)
a. Frequency, dysuria, hematuria
b. Suprapubic pain
c. Costovertebral angle tendernessFlank pain d. Fever, chills
e. Increased white blood cell (count) (WBC)
f. Nausea, vomiting
3. Factors associated with or used to define complicated UTI
a. Male sex
b. Hospital acquired
c. Pregnancy
d. Anatomic abnormality of the urinary tract
e. Childhood UTIs
f. Recent antimicrobial use
g. Diabetes mellitus
h. Indwelling urinary catheter
i. Recent urinary tract instrumentation
j. Immunosuppression
4. Recurrent cystitis
a. Relapse: Infection with the same organism within 14 days of discontinuing antibiotics for
the preceding UTI
b. Reinfection: Infection with a completely different organismMost common cause of
recurrent cystitis
E. Diagnosis: Urinalysis (blood cultures will be positive in 20% of patients with upper UTIs)
1. Pyuria (WBC greater than 510 x 103 cells/mm3)
2. Bacteriuria (greater than 102 CFU [colony-forming units]/mL is diagnostic)
3. Red blood cells
4. Cloudiness
5. Nitrite positive
6. Leukocyte esterase positive
7. Casts (if pyelonephritis)
F. Therapy
1. Uncomplicated cystitis
a. Three-day treatment regimen (vs. 510 days: equal in symptomatic but not in
bacteriologic cure)
i. Trimethoprim/sulfamethoxazole (TMP/SMZ)
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2.
3.
4.
5.
ii. TMP
iii. Fluoroquinolone
b. Alternatives
i. Nitrofurantoin (7-day course)
ii. Fosfomycin (single dose)
c. Single-dose therapy
i. Improved adherence; fewer adverse effects; cheaper
ii. Reduced cure rates compared with a 3- or 7-day regimen
iii. Inappropriate for patients with occult upper tract involvement
iv. First-line antibiotics as listed earlier
Pregnancy (pregnant women should be screened for bacteriuria and treated, even if
asymptomatic)
a. Seven-day treatment regimen
i. Amoxicillin
ii. Nitrofurantoin
iii. Cephalexin
iv. TMP/SMZ
b. Antibiotics to avoid
i. Fluoroquinolones
ii. Tetracyclines
iii. Aminoglycosides
iv. TMP/SMZ (often used but avoidance recommended, especially during the late third
trimester)
Recurrent cystitis
a. Relapse
i. Assess for pharmacologic reason for treatment failure.
ii. Longer treatment (for 26 weeks, depending on length of initial course)
b. Reinfection (reassess need for continuous prophylactic antibiotics every 612 months)
i. If patient has two or fewer UTIs in 1 year, use patient-initiated therapy for
symptomatic episodes (3-day treatment regimens).
ii. If patient has three or more UTIs in 1 year and they are temporally related to sexual
activity, use post-intercourse prophylaxis with TMP/SMZ single strength, cephalexin
250 mg, or nitrofurantoin 50100 mg.
iii. If patient has three or more UTIs in 1 year that are unrelated to sexual activity, use
daily or three times/week prophylaxis with trimethoprim 100 mg, TMP/SMZ single
strength, cephalexin 250 mg, norfloxacin 200 mg, or nitrofurantoin 50100 mg.
Uncomplicated pyelonephritis
a. Outpatient therapy (if patient is not immunocompromised or does not have nausea and
vomiting)
i. TMP/SMZ
ii. Fluoroquinolone
b. Therapy duration: 514 days (5 days with levofloxacin, 14 days with TMP/SMZ)
Complicated UTIs
a. Inpatient therapy
i. Fluoroquinolone
ii. Aminoglycoside
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iii. Extended-spectrum -lactam

b. Therapy duration: 514 days (5 days with levofloxacin)
6. Catheter-related UTIs
a. Short-term indwelling catheters
i. About 5% of patients will develop a UTI for each day of catheterization; by 30 days,
75%95% of patients with an indwelling catheter will have bacteriuria.
ii. Preventive antimicrobial therapy is not recommendedIt only increases the chance
of selecting out resistant organisms.
iii. Asymptomatic patients with bacteriuria should not be treated.
iv. Symptomatic patients with bacteriuria should be treated with 710 days of antibiotics
and catheter removal; a shorter course of therapy (57 days) should be used if the
catheter cannot be removed.
v. The most common organisms are E. coli (21.4%), Candida spp. (21.0%),
Enterococcus spp. (14.9%), P. aeruginosa (10.0%), Klebsiella pneumoniae (7.7%),
and Enterobacter spp. (4.1%).
b. Long-term indwelling catheters
i. Virtually all patients will be bacteriuric with two to five organisms.
ii. Asymptomatic patients should not be treated.
iii. Symptomatic patients should be treated for a short period (7 days) to prevent
resistance, and catheter replacement may be indicated.
7. Prostatitis and epididymitis
a. Acute bacterial prostatitis
i. Primarily gram-negative organisms
ii. Therapy duration, 4 weeks
(a) TMP/SMZ
(b) Cephalosporins
(c) Fluoroquinolones
b. Chronic bacterial prostatitis
i. Difficult to treat
ii. Therapy duration, 14 months
(a) TMP/SMZ
(b) Fluoroquinolones
8. Epididymitis
a. Older than 35 years; most likely caused by enteric organisms
i. Therapy duration: 10 days to 4 weeks
ii. Antibiotics: TMP/SMZ or fluoroquinolones
b. Younger than 35 years; most likely gonococcal or chlamydial infection
i. Therapy duration: 10 days
ii. Antibiotics: Ceftriaxone 250 mg intramuscularly once plus doxycycline 100 mg two
times/day
III. ENDOCARDITIS
A. Introduction
1. Infection of the heart valves or other endocardial tissue
2. Platelet-fibrin complex becomes infected with microorganismsVegetation
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3. Main risk factors include mitral valve prolapse, prosthetic valves, and intravenous drug
abuse.
4. Three or four cases per 100,000 population per year
B. Presentation/Clinical Findings
a. Fever: Low grade and remittent
b. Cutaneous manifestations (50% of patients): Petechiae (including conjunctival), Janeway
lesions, splinter hemorrhage
c. Cardiac murmur (90% of patients)
d. Arthralgias, myalgias, low back pain, arthritis
e. Fatigue, anorexia, weight loss, night sweats
2. Laboratory findings
a. Anemia: Normochromic, normocytic
b. Leukocytosis
c. Elevated erythrocyte sedimentation rate and C-reactive protein d. Positive blood culture
in 78%95% of patients
3. Complications
a. Congestive heart failure: 38%60% of patients
b. Emboli: 22%43% of patients
c. Mycotic aneurysm: 5%10% of patients
C. Microbiology
1. Three to five blood cultures of at least 10 mL each should be drawn during the first 2448
hours.
2. Empiric therapy should be initiated only in acutely ill patients. In these patients, three blood
samples should be drawn during a 15- to 20-minute period before initiating antibiotics.
Table 5. Incidence of Microorganisms in Endocarditis
Organism
Incidence (%)
Streptococcus
50
S. aureus
25
Enterococcus
Coagulase-negative Staphylococcus
Gram-negative bacilli
Candida albicans
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D. Treatment
Table 6. Treatment Recommendation for Endocarditis
Length of Therapy (weeks)
Organism
Recommended Therapy
Native Valve
Prosthetic Valve
6a
Ceftriaxone
Ceftriaxone + gentamicin
6a
Vancomycin
Penicillin G + gentamicin
4b
Ceftriaxone + gentamicin
4b
Vancomycin
Oxacillin or nafcillin
- Gentamicin for 35 days
- Plus rifampin in prosthetic valves
6b
Cefazolin
- Gentamicin for 35 days
6b
Vancomycin (only if severe PCN allergy)

6b
Staphylococcus
methicillin resistant
Vancomycin
6b
Enterococcus
Penicillin G or ampicillin + gentamicin or

streptomycin
46
Vancomycin + gentamicin or streptomycin
Enterococcus
penicillin resistant
Ampicillin/sulbactam or vancomycin +
gentamicin
Enterococcus faecium
penicillin, aminoglycoside,
and vancomycin resistant
Linezolid
Quinupristin/dalfopristin
Enterococcus faecalis
penicillin, aminoglycoside,
and vancomycin resistant
Imipenem/cilastatin + ampicillin
Ceftriaxone + ampicillin
HACEK group
Ceftriaxone
Ampicillin/sulbactam
Fluoroquinolone (cipro-, levo-, gati-, moxi-)
Streptococcus viridans
Penicillin G
(with penicillin MIC 0.12
Penicillin G + gentamicin
mcg/mL)
S. viridans (with penicillin

MIC > 0.12 mcg/mL)
Staphylococcus
methicillin sensitive
Gentamicin can be added for 2 weeks if creatinine clearance is greater than 30 mL/minute.
Gentamicin for 2 weeks.
HACEK = [Haemophilus, Actinobacillus Cardiobacterium, Eikenella, Kingella]; MIC = minimum inhibitory concentration; PCN
= penicillin.
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E. Prophylaxis
Table 7. Endocarditis Prophylaxis
Conditions in Which Prophylaxis Is Necessary
Dental Procedures That Require Prophylaxis
- Prosthetic cardiac valves including bioprosthetic and

homograft valves
- Previous bacterial endocarditis
- Congenital heart disease
- Unrepaired cyanotic congenital heart disease
- Completely repaired congenital heart defect with prosthetic
material or device during the first 6 months after the
procedure
- Repaired congenital heart disease with residual defects
adjacent to or at the site of a prosthetic patch or device
- Cardiac transplant recipients who develop cardiac
valvulopathy
- Any dental procedure that involves the gingival

tissues or periapical region of a tooth and for
procedures that perforate the oral mucosa
Other Procedures That Require Prophylaxis
Respiratory tract
- Tonsillectomy and/or adenoidectomy
- Surgical operations that involve an incision or
biopsy of the respiratory mucosa
F. Recommended Prophylaxis for Dental or Respiratory Tract Procedures

Table 8. Prophylaxis for Dental or Respiratory Tract Procedures
Situation
Agent
Regimen
Standard general
prophylaxis
Amoxicillin
Adults: 2 g; children: 50 mg/kg 1 hour before procedure
Unable to take oral

medications
Ampicillin
Adults: 2 g IM/IV; children: 50 mg/kg IM/IV within 30 minutes

before procedure
Cefazolin or
ceftriaxone

before procedure
Clindamycin
Adults: 600 mg; children: 20 mg/kg 1 hour before procedure
Cephalexin
Adults: 2 g; children: 50 mg/kg 1 hour before procedure
Azithromycin or
clarithromycin
Adults: 500 mg; children: 15 mg/kg 1 hour before procedure
Allergic to penicillin
Allergic to penicillin and Clindamycin

unable to take oral
medications
Cefazolin or
ceftriaxone
Adults: 600 mg; children: 20 mg/kg IV within 30 minutes

before procedure
before procedure
IM = intramuscularly; IV = intravenously.
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IV. CLOSTRIDIUM DIFFICILE INFECTION

A. Introduction
1. C. difficile is transmitted by the fecal-oral route.
2. Overgrowth in the GI tract occurs after antibiotic therapy.
3. Risk factors: Hospital stays, medical comorbidities, extremes of age, immunodeficiency
states, advancing age, use of broad-spectrum antibiotics for extended periods
4. Production of endotoxins A and B causes pathogenesis.
5. Symptoms: Watery diarrhea, abdominal pain, leukocytosis, GI tract complications
6. New strain (BI/NAP1) produces more enterotoxin, produces binary toxin, has increased
sporulation capacity, and is resistant to fluoroquinolones. Increased risk of metronidazole
failure, morbidity, and mortality
B. Therapy
1. Determining severity of infection (based on IDSA [Infectious Diseases Society of America]
guidelines)
a. Initial episode, mild or moderate = WBC 15,000/mm3 or lower and a serum creatinine
level of less than 1.5 times the premorbid level
b. Initial episode, severe = WBC 15,000/mm3 or higher or a serum creatinine level of 1.5
times or greater than the premorbid level
c. Initial episode, severe complicated = hypotension or shock, ileus, megacolon
2. Initial episode mild-moderate: Metronidazole 500 mg orally or intravenously three times/day
for 1014 days
3. Initial episode, severe: Vancomycin 125 mg orally four times/day for 1014 days
4. Initial episode, severe complicated: Vancomycin 500 mg four times/day by mouth or
nasogastric tube plus metronidazole 500 mg intravenously three times/day
5. First recurrence: Treat the same as for initial episode.
6. Second recurrence: Vancomycin in a tapered and/or pulsed regimen
7. Fidaxomicin (Dificid) 200-mg tablet orally twice daily for 10 days
a. FDA (U.S. Food and Drug Administration) label approved for patients 18 years or older
b. Not systemically absorbed, few adverse effects (nausea, vomiting, abdominal pain)
c. Activity fairly specific for Clostridium, fewer effects on normal gut flora
d. Significantly reduced incidence of recurrent infections compared with vancomycin
e. Very expensive
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REFERENCES
Pneumonia
1. Mandell LA, Wunderink RG, Anzueto A, et al.
Infectious Diseases Society of
America/American Thoracic Society consensus
guidelines on the management of communityacquired pneumonia in adults. Clin Infect Dis
2007;44(suppl 2):S27-S72.
2. American Thoracic Society; Infectious Diseases
Society of America. Guidelines for the
management of adults with hospital-acquired,
ventilator-associated, and healthcare-associated
pneumonia. Am J Respir Crit Care Med
2005;171:388-416.
Endocarditis
1. Wilson W, Taubert KA, Gewitz M, et al.
Prevention of infective endocarditis. Guidelines
from the American Heart Association.
Circulation 2007;115:1656-8.
2. Baddour L, Wilson WR, Bayer AS, et al.
Infective endocarditis: diagnosis, antimicrobial
therapy, and management of complications. A
statement for healthcare professionals from the
Committee on Rheumatic Fever, Endocarditis,
and Kawasaki Disease, Council on
Cardiovascular Disease in the Young, and the
Councils on Clinical Cardiology, Stroke, and
Cardiovascular Surgery and Anesthesia,
American Heart Association. Circulation
2005;111:e394-e433.
Urinary Tract Infections

1. Warren JW, Abrutyn E, Hebel JR, et al.
Guidelines for antimicrobial treatment of
uncomplicated acute bacterial cystitis and acute
pyelonephritis in women. Clin Infect Dis
1999;29:745-58.
2. Treatment of urinary tract infections in
nonpregnant women. ACOG Practice Bulletin
91. American College of Obstetricians and
Gynecologists. Obstet Gynecol 2008;111:78594.
Gastrointestinal Infections
1. Clinical practice guidelines for Clostridium
difficile infection in adults: 2010 update by the
Society for Healthcare Epidemiology of America
(SHEA) and the Infectious Diseases Society of
America (IDSA). Infect Control Hosp Epidemiol
2010;31:431-55.
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GASTROENTEROLOGY
156
Gastroenterology
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1. Review and apply national guideline treatment strategies to the following gastrointestinal (GI) disorders: gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), viral hepatitis, chronic
liver disease, and prevention of stress-related mucosal disease (SRMD).
2. Recommend appropriate pharmacologic and nonpharmacologic interventions for the management of
GERD.
3. Differentiate between clinical signs, symptoms, risk factors, and treatment of both Helicobacter pylori and nonsteroidal anti-inflammatory drugassociated PUD.
4. Discuss the role of pharmacologic intervention inprevention of SRMD.
5. identify the common manifestations of chronic liver disease and their treatment.
6. Review the treatment and prevention of both acute and chronic viral hepatitis.
7. Recognize pertinent information for educating patients and prescribers regarding the appropriate use
of pharmacologic agents for various GI disorders.
8. Recommend appropriate pharmacologic and nonpharmacologic interventions for diarrhea and constipation.
9. Understand commonly encountered statistical tests and concepts using GI disorders as examples.
I. GASTROESOPHAGEAL REFLUX DISEASE (GERD)

A. Definition
1. A condition which develops when reflux of stomach contents causes troublesome symptoms
and/or complications. This newer definition is based on the Montreal classification (Am J
Gastroenterol 2006;101:190020) and is used as the basis for the recent American
Gastroenterological Association (AGA) guidelines (Gastroenterology 2008;135:138391).
a. Strength of guideline evidence is rated grade A, B, C, D, or insufficient, and quality is
rated good, fair, or poor.
b. Nonerosive reflux disease is not included as a classification in these new guidelines.
2. Definition subdivides GERD into the following categories:
a. Esophageal syndromes
i. Symptomatic syndromes
(a) Typical reflux syndrome
(b) Reflux chest pain syndrome (presents similarly to cardiac chest pain)
ii. Syndromes with esophageal injury
(a) Reflux esophagitis
(b) Reflux stricture
(c) Barrett esophagus
(d) Adenocarcinoma
b. Extraesophageal syndromes
i. Established association
(a) Reflux cough
(b) Reflux laryngitis
(c) Reflux asthma
(d) Reflux dental erosions
ii. Proposed association
(a) Sinusitis
(b) Pulmonary fibrosis
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(c) Pharyngitis
(d) Recurrent otitis media
3. Symptoms
a. Patients ultimately decide how troublesome symptoms are on the basis of their
interference with normal daily activities or well-being.
b. Typical symptoms: Heartburn (pyrosis), regurgitation, acidic taste in the mouth
c. Extraesophageal symptoms (formerly referred to as atypical): Chronic cough, asthma-like
symptoms, recurrent sore throat, laryngitis/hoarseness, dental enamel loss, and
noncardiac chest pain; sinusitis/pneumonia/bronchitis/otitis media are less common
atypical symptoms
d. Alarm symptoms: Dysphagia (troublesome dysphagia is the preferred term in the new
guidelines), odynophagia, bleeding, weight loss, choking, chest pain, and epigastric mass.
These symptoms warrant immediate referral for more invasive testing.
e. Aggravating factors: Recumbency (gravity), increased intra-abdominal pressure, reduced
gastric motility, decreased lower esophageal sphincter (LES) tone, and direct mucosal
irritation
f. Long-term complications: Esophageal erosion, strictures/obstruction, Barrett esophagus,
and reduction in patients quality of life (Aliment Pharmacol Ther 2003;18:76776)
B. Diagnosis
1. Symptoms
a. Patient description of classic GERD symptoms, such as pyrosis, is often enough to
consider it an initial diagnosis; invasive testing is therefore not indicated in
uncomplicated cases.
b. The AGA guidelines state that it is reasonable to assume a diagnosis of GERD in patients
who respond to initial acid-suppressive therapy, particularly proton pump inhibitors
(PPIs).
c. Symptoms do not predict the degree of esophagitis or complications secondary to GERD,
if present.
d. Patients presenting with extraesophageal symptoms should be assessed on a case-by-case
basis to consider the need for referral or alternative/invasive testing.
e. Cardiac etiologies (ischemic) should be considered and explored before arriving at a
diagnosis of reflux chest pain syndrome.
2. Endoscopy. (See guidelines on endoscopy in GERD. Gastroenterology 2006;131:131536.)
a. Considered the technique of choice to identify Barrett esophagus (with biopsy) or
complications of GERD; findings of typical symptoms in association with endoscopic
mucosal changes are about 97% specific for the diagnosis of GERD; however, most
patients with typical/atypical symptoms will have normal-appearing esophageal mucosa
on endoscopy. Biopsies should be performed in areas of suspected metaplasia, dysplasia,
or malignancy.
b. Used in patients older than 45 years, those presenting with alarm symptoms (particularly
troublesome dysphagia), and those refractory to initial treatment, as well as in those with
a preoperative assessment or possibly when extraesophageal symptoms are present (grade
B)
c. Routine endoscopy to assess disease progression is not recommended (grade D).
d. Routine screening for Barrett esophagus in patients 50 years or older with more than
510 years of Heartburn is not recommended (evidence grade: insufficient).
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3. Manometry
a. Used to evaluate peristaltic function of the esophagus in patients with normal endoscopic
findings
b. Should be used before pH testing to rule out esophageal motility disorders and to help
localize the LES for subsequent pH testing (grade B)
4. pH testing. (See review in Aliment Pharmacol Ther 2005;22(suppl 3):29)
a. The main outcome measure of esophageal pH monitoring is the percentage of time the
pH value is less than 4 in a 24-hour period.
b. Ambulatory pH testing is useful in the following clinical situations:
i. Patients with no mucosal changes on endoscopy and normal manometry who have
continued symptoms (both typical and atypical) (grade B)
ii. Patients who are refractory to therapeutic doses of appropriate pharmacologic agents
iii. Monitoring of reflux control in patients with continued symptoms on drug therapy
c. Sensitivity/specificity of 96% reported
d. The PPIs should be withheld for 7 days before pH testing, if possible, for the most
accurate results.
5. Role of H. pylori testing and eradication is controversial in patients presenting with GERD
symptoms; should be assessed on the basis of patient presentation and risk factors for gastric
cancer. A 4-week trial of a twice-daily PPI can be considered for patients thought to have
reflux chest pain syndrome before manometry or pH testing (grade A). Reported sensitivity
and specificity of a short course of PPIs are 80% and 74% for diagnosing reflux chest pain
syndrome.
C. Treatment Strategies for GERD
1. Nonpharmacologic interventions/lifestyle modifications are unlikely to control symptoms in
most patients. The AGA guidelines cite insufficient evidence to advocate lifestyle
modifications for all patients; rather, they advocate use in targeted populations. Thus, the
following lifestyle modifications should be implemented only for the patient populations
specified.
a. Dietary modifications in patients whose symptoms are associated with certain foods or
drinks
i. Avoid aggravating foods/beverages; some may reduce LES pressure (alcohol,
caffeine, chocolate, citrus juices, garlic, onions, peppermint/spearmint) or cause
direct irritation (spicy foods, tomato juice, coffee).
ii. Reduce fat intake (high-fat meals slow gastric emptying) and portion size.
iii. Avoid eating 23 hours before bedtime.
iv. Remain upright after meals.
b. Weight loss for overweight or obese patients (grade B)
c. Reduce/discontinue nicotine use in patients who use tobacco products (affects LES).
d. Elevate the head of the bed (68 in.) if reflux is associated with recumbency (grade B).
e. Avoid tight-fitting clothing (decreases intra-abdominal pressure).
f. Avoid medications that may reduce LES pressure, delay gastric emptying, or cause direct
irritation: -Adrenergic antagonists, anticholinergics, benzodiazepines, calcium channel
blockers, estrogen, nitrates, opiates, tricyclic antidepressants, theophylline, NSAIDs, and
aspirin.
2. Pharmacologic therapies
a. initial treatment will depend on severity, frequency, and duration of symptoms.
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i.
Step-down treatment: Starting with maximal therapy, such as therapeutic doses of

PPIs, is always appropriate as a first-line strategy in patients with documented
esophageal erosion. Advantages: Rapid symptom relief, avoidance of
over-investigation. Disadvantages: Potential overtreatment, higher drug cost,
increased potential of adverse effects
ii. Step-up treatment: Starting with lower-dose OTC products. Advantages: Avoids
overtreatment, has lower initial drug cost. Disadvantages: Potential undertreatment
(partial symptom relief), may take longer for symptom control, may lead to
over-investigation
b. AGA guideline recommendations (Gastroenterology 2008;135:138391)
i. Empiric drug therapy is appropriate for patients with uncomplicated heartburn.
ii. Use of antisecretory drugs for patients with esophageal GERD symptoms, with or
without esophagitis, is strongly recommended (grade A).
iii. PPIs are more effective than histamine-2 receptor antagonists (H2RAs), which are, in
turn, better than placebo for patients with esophageal GERD symptoms.
iv. All PPIs are similar in efficacy when used for patients with esophageal GERD
symptoms. Selection of drugs is based on adverse effects, onset of action, and
prescription plan coverage. For instance, changing to an alternative PPI or lowering
the dose if a patient experiences adverse effects is a reasonable approach.
v. Data are weak to support using PPIs or H2RAs above standard doses. However,
twice-daily dosing of PPIs is appropriate in patients who continue to have symptoms
on once-daily PPI therapy (grade B).
vi. Rapid-acting drugs should be used for patients who wish to take the drug in response
to symptoms. Antacids are the fastest-acting agents available and may be combined
with both PPIs and H2RAs. The PPIs and H2RAs are more effective at preventing
heartburn.
vii. Maintenance therapy is appropriate for patients with esophagitis in whom PPIs have
been effective (grade A). Titration to the lowest effective dose is recommended.
Most patients with nonerosive disease will continue on maintenance therapy if
they initially respond, but it may not be possible to down-titrate them to on-demand
therapy. On-demand therapy is not appropriate for patients with erosive esophagitis.
viii. Dosing PPIs less than once daily as maintenance therapy is ineffective for patients
who initially had erosive esophagitis (grade D).
ix. No evidence of improved efficacy by adding a bedtime dose of H2RA to twice-daily
PPI therapy (evidence grade: insufficient)
x. Data are weak to support the use of PPIs in patients with extraesophageal symptoms.
c. AGA guideline recommendations for the management of extraesophageal symptoms
i. The presence of extraesophageal GERD syndromes in the absence of esophageal
GERD syndromes is rare. Chronic cough, laryngitis, and asthma all have definite
associations with GERD.
ii. Evidence is fair for the use of once- or twice-daily PPI therapy in patients with an
extraesophageal syndrome and a concomitant esophageal GERD syndrome (grade
B). A 2-month trial of twice-daily PPI therapy would be an appropriate therapy for
these patients.
iii. Evidence is for the use of once- or twice-daily PPI therapy in patients with an
extraesophageal syndrome in the absence of an esophageal GERD syndrome (grade
D).
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iv. Evidence is insufficient to recommend once- or twice-daily PPI therapy for patients
with suspected reflux cough syndrome.
d. Pharmacologic agents
i. Calcium-, aluminum-, and magnesium-based products are available OTC in a wide
variety of formulations (capsules, tablets, chewable tablets, and suspensions).
(a) Neutralizing acid and raising intragastric pH results in decreased activation of
pepsinogen and increased LES pressure; rapid onset of action but short duration,
necessitating frequent dosing
(b) Some products (Gaviscon) contain the anti-refluxant alginic acid, which forms a
viscous layer on top of gastric contents to act as a barrier to reflux (variable added
efficacy).
(c) Used as first-line therapy for intermittent (less than 2 times/week) symptoms or as
breakthrough therapy for those on PPI/H2RA therapy; not appropriate for healing
established esophageal erosions
(d) Adverse reactions: Constipation (aluminum), diarrhea (magnesium), accumulation
of aluminum/magnesium in renal disease with repeated dosing
(e) Drug interactions: Chelation (fluoroquinolones, tetracyclines), reduced absorption
because of increases in pH (ketoconazole, itraconazole, iron, atazanavir,
delavirdine, indinavir, nelfinavir) or increases in absorption leading to potential
toxicity (raltegravir, saquinavir)
ii. Histamine-2 receptor antagonists
(a) Reversibly inhibit histamine-2 receptors on the parietal cell
(b) All agents available as prescription and OTC products; a variety of formulations
available; generics exist for all prescription products
Table 1. Histamine2-Receptor Antagonists
Agent
Oral OTC Formulations
Oral Prescription Formulations
Ranitidine (Zantac)
75-mg tablet (Zantac 75)

150-mg tablet (Zantac 150)
150-mg tablets/EFFERdose tablets/granules

300-mg tablet
15 mg/mL of syrup
Cimetidine (Tagamet)
200-mg tablet (Tagamet-HB)
300-, 400-, 800-mg tablets

300 mg/5 mL of solution
Nizatidine (Axid)
75-mg tablet (Axid AR)
150-mg/300-mg capsules
15 mg/mL of solution
Famotidine (Pepcid)
10-mg tablets, gelatin capsules,

20-mg/40-mg tablets
chewable tablets (Pepcid AC)
20-mg/40-mg rapidly disintegrating tablet
20-mg tablets
40-mg/5-mL suspension
10 mg + 800 mg of calcium
carbonate + 165 mg of magnesium
hydroxide chewable tablets
Pepcid Complete
OTC = over the counter.
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(c) OTC H2RA products may be used for on-demand therapy for intermittent
mild-moderate GERD symptoms; preventive dosing before meals or exercise is
also possible for all agents. Higher prescription doses are often required for more
severe symptoms or for maintenance dosing. Prolonged use may result in the
development of tolerance and reduced efficacy (tachyphylaxis).
(d) Therapy with H2RAs is less efficacious than therapy with PPIs in healing erosive
esophagitis.
(e) Adverse effects: Most are well tolerated. Central nervous system (CNS) effects
such as headache, dizziness, fatigue, somnolence, and confusion are the most
common. Elderly patients and those with reduced renal function are more at risk.
Prolonged cimetidine use is associated with the rare development of
gynecomastia.
(f) Drug interactions: May affect the absorption of drugs dependent on lower gastric
pH, such as ketoconazole, itraconazole, iron, atazanavir, delavirdine, indinavir,
and nelfinavir, or increases in absorption leading to potential toxicity (raltegravir,
saquinavir). Cimetidine also inhibits cytochrome P450 (CYP) enzymes 1A2,
2C9, 2D6, and 3A4. Warfarin, theophylline, and other agents metabolized by
these enzymes may be affected. Cimetidine may also compete with medications
and creatinine for tubular secretion in the kidney.
iii. Proton pump inhibitors
(a) irreversibly inhibit the final step in gastric acid secretion; greater degree of acid
suppression achieved and typically longer duration of action than H2RAs
(b) Most effective agents for short- and long-term management of GERD, as well as
for management of erosive disease (Aliment Pharmacol Ther 2003;18:55968)
(c) Most costly agents: Omeprazole and lansoprazole now available as a generic
prescription-strength product and OTC. The OTC products are considered safe
and effective for intermittent short-term (2 weeks) use in patients with typical
heartburn symptoms. Long-term use of OTC products should be discussed with
prescriber to prevent loss of follow-up or to assess for potential undertreatment
(Digestion 2009;80:22634). Pantoprazole and esomeprazole are available in
intravenous formulations.
(d) Most effective when taken orally before meals; for divided dosing, give evening
dose before evening meal instead of at bedtime.
Table 2. Proton Pump Inhibitors
Product
Dosage Forms
Esomeprazole (Nexium)
Delayed-release capsule (20 mg/40 mg)

IV solution (20- and 40-mg vials)
Delayed-release oral suspension (10-, 20-, 40-mg packets)
Omeprazole (Prilosec)
Prilosec OTC
Zegerid
Zegerid OTC
Delayed-release capsule (10 mg/20 mg/40 mg)

Delayed-release 20-mg tablet (magnesium salt)
Immediate-release powder for oral suspension (20- and 40-mg packets); sodium
bicarbonate buffer = 460 mg of Na+/dose (two 20-mg packets are not equivalent to
one 40-mg packet)
Zegerid OTC 20 mg immediate-release capsules with sodium bicarbonate (1100
mg/capsule)
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Table 2. Proton Pump Inhibitors

Product
Dosage Forms
Lansoprazole (Prevacid)
Prevacid 24HR 15-mg delayed-release capsule
Lansoprazole (Prevacid 24HR) Delayed-release capsule (15 mg/30 mg)
Delayed-release oral suspension (15 mg/30 mg)
Delayed-release orally disintegrating tablet (15 mg/30 mg)
IV solution (30 mg/vial)
Rabeprazole (AcipHex)
Delayed-release enteric-coated tablet (20 mg/40 mg)
Pantoprazole (Protonix)
Delayed-release tablet (20 mg/40 mg)

IV solution (40 mg/vial)
Dexlansoprazole (Dexilant)
Delayed-release capsule (30 mg/60 mg)
IV = intravenous; Na = sodium; OTC = over the counter.
(e) Alternative administration

Table 3. Alternative Administration Techniques for Proton Pump Inhibitors
Product
Alternative Administration Technique
Omeprazole (Prilosec)
Esomeprazole (Nexium)
Zegerid
Open capsules; mix with applesauce/juice

Simplified omeprazole suspension; contents dissolved in bicarbonate (NG/OG)
Open esomeprazole capsules and mix with 60 mL of water by NG tube or dissolve
oral suspension in 15 mL of water and administer by NG tube; IV bolus or
continuous infusion
Zegerid mix packet with 20 mL of water in syringe (NG)
Lansoprazole (Prevacid)
Open capsules; mix with applesauce, ENSURE, cottage cheese, pudding, yogurt, or
strained pears or 60 mL of tomato/orange/apple juice
Open capsules + 40 mL of apple juice (NG/OG)
Simplified lansoprazole suspension; contents dissolved in bicarbonate (NG/OG)
DO NOT use oral suspension for NG/OG; mix packet with 30 mL of water and
swallow
Orally disintegrating tablet by oral syringe: Use 4 mL for 15 mg or 10 mL for 30 mg
Orally disintegrating tablet by NG tube (> 8 French): Same preparation as for oral
syringe
IV (bolus or continuous infusion)
Rabeprazole (AcipHex)
DO NOT CRUSH
Pantoprazole (Protonix)
DO NOT CRUSH
IV (bolus or continuous infusion)
Pantoprazole suspension (bicarbonate)
(Am J Health Syst Pharm 2003;60:13249)
Dexlansoprazole (Dexilant) Open capsules and sprinkle on applesauce

IV = intravenous; NG = nasogastric; OG = orogastric.
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(f) Adverse reactions: Overall, well tolerated; possible adverse effects include
headache, dizziness, nausea, diarrhea, and constipation. Long-term use is not
associated with significant increases in endocrine neoplasia or symptomatic
vitamin B12 deficiency.
(1) A cohort study of 364,683 users of both PPIs and H2RAs found an elevated
risk of community-acquired pneumonia with these agents. The adjusted
relative risk of pneumonia was 1.89 (95% confidence interval [CI],
1.362.62) with PPI use and 1.63 (95% CI, 1.072.48) for H2RA use.
Patients at risk of community-acquired pneumonia include the
immunocompromised, the elderly, children, and those with asthma or chronic
obstructive pulmonary disease. Acid suppression should be used for these
patients only if necessary and only at the lowest possible dose (JAMA
2004;292:195560).
(2) A recent large prospective cohort study of hospitalized patients revealed an
increased risk of hospital-acquired pneumonia in nonventilated patients who
were prescribed PPIs (OR = 1.3; 95% CI, 1.11.4) (JAMA
2009;301:21208).
(3) Another recent study revealed a higher incidence of fracture in patients
receiving higher doses of PPIs for longer durations (OR = 1.44; 95% CI,
1.31.59) (JAMA 2006;296:294753). This may be attributable to reductions
in the absorption of calcium in patients receiving potent acid suppression or,
possibly, interference with osteoclast function.
(4) New U.S. Food and Drug Administration (FDA) labeling for PPIs as of May
2010 stating that PPIs may increase the risk of hip and spine fracture
(www.fda.gov/
Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvider
s/ ucm213206.htm#SafetyAnnouncement). The 2008 AGA guidelines cite
insufficient evidence to recommend bone density screening or calcium
supplementation because of PPI use. Screening for osteoporosis in
populations at risk, such as the elderly, is recommended regardless of PPI
use.
(5) Studies have revealed an association of overgrowth of Clostridium difficile in
patients receiving PPIs, particularly in the hospital setting. Odds ratios were
reported as 2.1 (95% CI, 1.332.25) (J Hosp Infect 2003;54:2435, CMAJ
2004;171:338).
(6) FDA warning in 2011 regarding risk of hypomagnesemia is patients
receiving PPIs (www.fda.gov/Drugs/DrugSafety/ucm245011.htm)
(A) Most often associated with use greater than 1 year
(B) May lead to tetany, arrhythmias, or seizures
(C) May require discontinuation of PPIs and/or magnesium supplementation
(D) Consider checking a baseline serum magnesium concentration in patients
receiving diuretics or digoxin or requiring long-term PPI use.
(g) Drug interactions: Drugs with pH-dependent absorption (e.g., ketoconazole,
itraconazole, protease inhibitors); omeprazole inhibits the metabolism of
diazepam through CYP2C19. Recent data suggest a reduced effectiveness of
clopidogrel through CYP2C19-mediated inhibition of conversion to active
metabolite by omeprazole and esomeprazole.
(1) Recommendations are to avoid omeprazole, esomeprazole, and cimetidine
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(CYP effects, also) in patients receiving clopidogrel. See FDA letter at

www.fda.gov/
Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts
/ ucm190848.htm.
(2) New guidelines (JACC 2010;56:116) on PPI/clopidogrel interaction
Conclude that the magnitude of interaction is generally less than a hazard
ratio or odds ratio of 2. Findings from studies are inconsistent, with most
Citing omeprazole as the most implicated. Although PPIs should be used in
patients at high risk of GI bleeding, H2RAs, although less effective, could
possibly be used in patients at low risk of bleeding or those whose symptoms
Are not severe enough to warrant PPI therapy. Cimetidine should be avoided.
iv. Promotility agents
(a) Guidelines recommend against the use of metoclopramide as adjunctive therapy
or monotherapy in patients with both esophageal and extraesophageal symptoms
because the risk of adverse effects (extrapyramidal symptoms [EPS]) or tardive
dyskinesia) outweighs the benefit (grade D).
(b) Work through cholinergic mechanisms to facilitate increased gastric emptying.
(c) Metoclopramide: Dopamine antagonist; needs to be dosed several times a day;
associated with many adverse effects such as dizziness, fatigue, somnolence,
drowsiness, EPS, and hyperprolactinemia. New 5- and 10-mg ODT formulations
(metoclopramide [Metozolv ODT]) are now available. Indications for GERD and
diabetic gastroparesis
(d) Bethanechol: Cholinergic agonist; poorly tolerated because of adverse effects
such as diarrhea, blurred vision, and abdominal cramping; may also increase
gastric acid production
(e) Cisapride: Available only on a restricted basis for patients whose other therapies
have failed; cisapride was withdrawn from the market initially because of cardiac
arrhythmia (torsades de pointes) when used in combination with drugs inhibiting
CYP3A4
v. Surgical therapy
(a) PPI therapy should be tried before surgical intervention because of better safety
(grade A).
(b) Antireflux surgery such as fundoplication remains a viable option for
maintenance therapy of GERD; typically used in patients unresponsive to or
intolerant of medical therapy (grade A)
(c) A study showed increases in cardiovascular (CV) mortality in a veteran
population treated with antireflux surgery versus medical therapy as a long-term
treatment option (JAMA 2001;285:23318). However, although patients had
fewer GERD symptoms after surgery, most were unable to discontinue medical
therapy completely.
(d) Antireflux surgery can be considered for patients with extraesophageal GERD
syndromes if symptoms persist despite PPI therapy (grade C).
(e) Antireflux surgery is not recommended for patients who are well controlled on
medical therapy or for prevention of Barrett esophagus (grade D).
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II. PEPTIC ULCER DISEASE

A. Classification of PUD
1. Duodenal ulcer
a. Common causes: H. pylori infection (95%), NSAIDs, low-dose aspirin
b. Uncommon causes: Zollinger-Ellison syndrome, hypercalcemia, granulomatous diseases,
neoplasia, infections (cytomegalovirus, herpes simplex, tuberculosis), ectopic pancreatic
tissue
c. Clinical signs/symptoms: Epigastric pain, possibly worse at night; often, pain occurs 13
hours after a meal and may be relieved by eating. Pain may also be episodic. Associated
symptoms may include heartburn, belching, a bloated feeling, nausea, and anorexia.
2. Gastric ulcer:
a. Common causes: NSAIDs, H. pylori infection
b. Uncommon causes: Crohn disease (CD), infections (cytomegalovirus, herpes simplex)
c. Clinical signs/symptoms: Epigastric pain, which is often made worse by eating; associated
symptoms may include heartburn, belching, a bloated feeling, nausea, and anorexia
3. Complications of PUD
a. Bleeding
b. Gastric outlet obstruction
c. Perforation
4. Patients at risk of NSAID-induced GI toxicity (Am J Gastroenterol 2009;104:72838)
Table 4. Risk Factors for NSAID-Induced GI Complications
Category
Risk Factors
High risk
1. History of complicated ulcer

2. Several (> 2) risk factors
3. Concomitant use of corticosteroids, anticoagulants, or antiplatelet drugs
Moderate risk
(1 or 2 risk factors)
1. Age > 65 years

2. High-dose NSAID therapy
3. History of uncomplicated ulcer
4. Concurrent use of aspirin (including low dose), corticosteroids, or anticoagulants
Low risk
No risk factors
GI = gastrointestinal; NSAID = nonsteroidal anti-inflammatory drug.
a. Some NSAIDs (e.g., ibuprofen, diclofenac, nabumetone) are intrinsically less toxic to the
GI tract than naproxen, which is considered moderate risk. Other agents, such as piroxicam
or ketorolac, are considered high-risk drugs.
b. Duration of NSAID use (higher risk in first 3 months). Presence of chronic debilitating
disorders such rheumatoid arthritis or CV disease may also contribute to the increased GI
toxicity of NSAIDs, but these are not generally considered independent risk factors.
c. H. pylori infection is thought to confer additive risk of GI toxicity in NSAID users.
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5. Diagnosis
a. Symptom presentation
b. Testing for H. pylori infection: Practitioners must be willing to treat if testing is positive
because H. pylori is a known carcinogen.
i. Testing is indicated for patients with active ulcer disease, history of PUD, or gastric
mucosaassociated lymphoid tissue lymphoma.
ii. The test-and-treat strategy for identifying H. pyloripositive patients is also
acceptable for patients with unevaluated dyspepsia who have no alarm symptoms and
are younger than 55 years (Am J Gastroenterol 2007;102:180825).
c. Diagnostic tests for H. pylori infection (Aliment Pharmacol Ther 2003;16(suppl
1):1623)
i. invasive (endoscopic)
(a) Histology: 90%95% sensitive, 98%99% specific, subject to sampling error
(b) Rapid urease tests (CLOtest, Hpfast, and PyloriTek): Detect the presence of
ammonia (NH3) on a sample generated by H. pylori urease activity; 80%95%
sensitive, 95%100% specific. False negatives may result from a partly treated
infection, GI bleeding, achlorhydria, or use of PPIs, H2RAs, or bismuth. Patients
should discontinue antisecretory agents for at least 1 week before test is
performed.
(c) Culture: Costly, time-consuming, and technically difficult, although 100%
specific
ii. Noninvasive
(a) Serologic tests (QuickVue H. pylori gII, FlexSure HP): Detect immunoglobulin
(Ig)G to H. pylori in the serum by ELISA (enzyme-linked immunosorbent assay);
85% sensitive, 79% specific. Cannot distinguish between active infection and
past exposure. Because antibodies persist for long periods after eradication,
cannot use to test for eradication after treatment. Newly available tests will detect
the presence of CagA or VacA antibodies.
(b) Urea breath test (BreathTek UBT, PYtest): Detects the exhalation of radioactive
CO2 after the ingestion of 13C- or 14C-radiolabeled urea. H. pylori hydrolysis of
the radiolabeled urea results in CO production; 97% sensitive, 95% specific.
Used to make a diagnosis and to test for eradication. Recent use of antibiotics or
PPIs may result in false negatives in up to 40% of patients. Patients should
discontinue antisecretory agents or antibiotics at least 2 weeks before UBT
testing or wait 4 weeks after treatment has ended before having the UBT
performed.
(c) Stool antigen tests (Premier Platinum HpSA, ImmunoCard STAT! HpSA):
Polyclonal or monoclonal antibody tests that detect the presence of H. pylori in
the stool; 88%92% sensitive, 87% specific. Can be used to make a diagnosis
and confirm eradication. Recent use of bismuth, antibiotics, or PPIs may also
result in false negatives. Patients should discontinue antisecretory agents or
antibiotics at least 2 weeks before UBT testing or wait 4 weeks after treatment
has ended before having the UBT performed.
6. Treatment of H. pyloriassociated ulcers (Am J Gastroenterol 2007;102:180825)
a. General recommendations, based on the American College of Gastroenterology (ACG)
guidelines, are to include an antisecretory agent (preferably a PPI) plus at least two
antibiotics (clarithromycin and amoxicillin or metronidazole) in the eradication regimen.
H. pylori eradication has been shown to have a relative risk reduction of 54% for
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b.
c.
d.
e.
f.
g.
duodenal ulcer recurrence and a 38% relative risk reduction for gastric ulcer recurrence
(Cochrane Database Syst Rev 2006;2:CD003840).
Therapy duration is 714 days, depending on the regimen chosen. The ACG guidelines
state that 14 days is preferred. Most regimens last for 10 days.
Follow-up testing for eradication should be performed in patients with a history of ulcer
complication, gastric mucosaassociated lymphoid tissue lymphoma, early gastric cancer,
or recurrence of symptoms.
UBTs or stool antigen tests are preferred for confirming eradication (should wait at least
4 weeks after treatment for both).
Quadruple-based therapy with bismuth subsalicylate, metronidazole, tetracycline, and a
PPI can be used for 14 days as initial therapy if triple-based therapy fails or if the patient
has an intolerance of or allergy to components of the triple-drug therapy. Use of Pylera, a
quadruple-based therapy formulated with tetracycline, bismuth, and metronidazole in 1
capsule, received FDA label approval in 2007. This product contains bismuth subcitrate
salt rather than subsalicylate salt.
Sequential therapy is a relatively new type of treatment in which a PPI and amoxicillin
are given first for the first 5 days, followed by a PPI, clarithromycin, and tinidazole for an
additional 5 days. This therapy requires further validation before widespread use will be
accepted.
A bismuth-based quadruple therapy for 14 days or a levofloxacin-based triple therapy for
10 days can be used in patients who have not responded to initial regimens as salvage
therapy.
a,b
Table 5. H. pylori Treatment Regimens
Duration
(days)
Efficacy
(%)c
Lansoprazole 30 mg BID + amoxicillin 1000 mg BID + clarithromycin 500 mg BID
1014
8186
Esomeprazole 40 mg once daily + amoxicillin 1000 mg BID + clarithromycin 500 mg BID
1014
7085
Omeprazole 20 mg BID + amoxicillin 1000 mg BID + clarithromycin 500 mg BID
1014
7085
Rabeprazole 20 mg PO BID + amoxicillin 1000 mg BID + clarithromycin 500 mg BID
7085
Bismuth subsalicylate 525 mg QID + metronidazole 500 mg TID + tetracycline 500 mg

QID + PPI BID
14
7590
Bismuth subcitrate 420 mg + tetracycline 375 mg + metronidazole 375 mgd + PPI BID
10
8592
10 (5 each
treatment)
> 90
Regimen
Sequential therapy
PPI + amoxicillin 1 g BID for 5 days; then PPI, clarithromycin 500 mg BID + tinidazole
500 mg BID for 5 days
a
Pantoprazole 40 mg BID or dexlansoprazole does not have an FDA-approved indication for H. pylori eradication; however, it
could be substituted in any of the 10- to 14-day regimens.
b
Metronidazole 500 mg BID can be substituted for amoxicillin or clarithromycin in patients with penicillin or macrolide allergy
for the triple-drug regimens. Treat for 14 days in this instance.
c
Rates are based on intention to treat.
d
Triple-capsule formulation.
BID = 2 times/day; FDA = U.S. Food and Drug Administration; PO = orally; PPI = proton pump inhibitor; QID = 4 times/day;
TID = 3 times/day.
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7. Primary prevention of NSAID-induced ulcers (ACG guidelines. Am J Gastroenterol

2009;104:72838)
a. implement risk factor modification.
b. Test and treat for H. pylori if patient is beginning long-term NSAID therapy.
c. Determine level of GI-related risk (low, medium, high) using Table 4.
d. Based on association of increased risk of CV events with NSAID use, patients CV risk
should be determined as well. The ACG guidelines define those at high CV risk as
patients who require low-dose aspirin for prevention of cardiac events. Naproxen is the
only NSAID that does not appear to increase the risk of CV events; therefore, its use is
preferred in patients with CV risk factors (Am J Gastroenterol 2009;104:72838).
Table 6. Preventive Strategies Based on Risk of NSAID-Related GI Complications and CV Risk
If low CV risk and:
Low GI riska NSAID (lowest dose of least ulcerogenic agent)
Moderate GI riskb NSAID + PPI or misoprostol
High GI riskc COX-2 inhibitor + PPI or misoprostol
If high CV risk (requirement for low-dose aspirin) and:
Low GI riska Naproxen + PPI or misoprostol
Moderate GI riskb Naproxen + PPI or misoprostol
High GI riskc Avoid NSAIDs or COX-2 inhibitors
a
No risk factors.
1 or 2 risk factors present.
c
Positive history of ulcer complication or several (more than 2) risk factors or use of steroids and anticoagulants.COX-2 =
cyclooxygenase-2; CV = cardiovascular; GI = gastrointestinal; NSAID = nonsteroidal anti-inflammatory drug; PPI = proton
pump inhibitor.
b
e. Misoprostol (Cytotec) should be given at full doses (800 mcg/day in divided doses);
however, this therapy is poorly tolerated because of excessive nausea, vomiting, diarrhea,
and abdominal cramping.
f. Concomitant use of antiplatelet agents and NSAIDs: Recent guidelines from a consensus
cardiology and GI group (ACCF [American College of Cardiology
Foundation]/ACG/AHA [American Heart Association]) (Circulation 2008;118:1894-909)
i. Need for antiplatelet therapy should first be evaluated.
ii. If antiplatelet therapy is deemed necessary, then assess for the presence of GI risk
factors (see Table 4 above). These guidelines also cite dyspepsia or GERD symptoms
as risk factors.
iii. Test and treat for H. pylori in patients with a history of a nonbleeding ulcer and in
those with a history of an ulcer-related complication. Eradicating H. pylori before
beginning long-term antiplatelet therapy is optimal.
iv. PPIs are the preferred gastroprotective agents for both the treatment and prevention
of aspirin- and NSAID-associated GI injury.
v. Gastroprotective therapy should be prescribed for patients with GI risk factors who
require the use of any NSAID (including OTC and cyclooxygenase-2 [COX-2]
inhibitors) in conjunction with cardiac-dose aspirin.
vi. Gastroprotective therapy should be prescribed for patients with GI risk factors who
require preventive doses of aspirin. Aspirin doses greater than 81 mg/day should not
be used in patients with GI risk factors during the long-term phase of aspirin therapy.
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vii. PPIs should be prescribed for patients receiving concomitant aspirin and
anticoagulant therapy (unfractionated heparin, low-molecular-weight heparin, and
warfarin).
viii. A target INR of 2.02.5 should be used in patients for whom warfarin is added to
concomitant aspirin and clopidogrel therapy. The combination of both aspirin and
clopidogrel with warfarin should only be used when benefit outweighs risk.
ix. Clopidogrel is not recommended as a substitute for patients with recurrent ulcer
bleeding. Aspirin plus a PPI is superior to clopidogrel.
x. The health care provider who decides to discontinue aspirin therapy in patients with
short-term bleeding episodes should weigh the risks of subsequent GI or cardiac
events.
xi. For patients receiving dual antiplatelet therapy (aspirin plus clopidogrel) who require
elective endoscopy (particularly colonoscopy and polypectomy), consider deferring if
patient is at high risk of cardiac events. Elective endoscopy should be deferred for 1
year after the placement of drug-eluting stents.
8. Treatment/secondary prevention of NSAID-induced ulcers (Am J Gastroenterol
1998;93:203746, Aliment Pharmacol Ther 2004;19:197208)
a. Risk factor modification
b. Discontinue/lower dose of NSAID if possible. Ulcers will heal with appropriate
treatment, but it may take longer with continued NSAID use.
c. Test for H. pylori and treat if present.
d. Drug therapy
i. PPIs: Drugs of choice for healing and secondary prevention of NSAID-induced
ulcers (N Engl J Med 1998;338:71926, N Engl J Med 1998;338:72734). New
combination product Vimovo contains esomeprazole with naproxen in the same
tablet (375 mg/20 mg or 500 mg/20 mg).
ii. Misoprostol: Appears to be as effective as PPIs for healing/secondary prevention (N
Engl J Med 1998;338:72734); however, it necessitates several doses per day and is
poorly tolerated because of the high incidence of diarrhea and abdominal pain
iii. Cyclooxygenase inhibitors: Celecoxib was shown to have rates of ulcer recurrence
and bleeding comparable with a diclofenac and omeprazole combination; use of
celecoxib may be limited by its recent association with CV effects (N Engl J Med
2002;347:210411). Use of celecoxib is uncertain in combination with low-dose
aspirin for secondary prevention of GI events.
iv. Combination of a COX-2 inhibitor and a PPI is not well studied but may be
considered in high-risk patients such as the elderly, especially if they are receiving
aspirin plus steroids or warfarin or have a history of a recent complicated GI event
and require continued NSAID or aspirin use.
v. The H2RAs: Inferior to misoprostol and PPIs in healing and preventing recurrence
vi. Clopidogrel is not recommended as a substitute in patients with recurrent ulcer
bleeding. Aspirin plus a PPI is superior to clopidogrel (Circulation
2008;118:1894909).
e. CV safety of COX-2 inhibitors and NSAIDs
i. The main theory underlying the development of excess thrombotic events with
COX-2 inhibitor use is that by reducing COX-2mediated prostacyclin production,
the prothrombic prostaglandin thromboxane A2 continues to be produced by COX-1,
leading to the development of a prothrombic state. The degree of development of
these events does not appear to be equal across the class of COX-2 inhibitors.
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ii. Guidelines for appropriate use and safety of NSAIDs, aspirin, and COX-2 inhibitors
have been published by both the AHA (Circulation 2007;115:163442) and a
multidisciplinary clinical group (Clin Gastroenterol Hepatol 2006;4:10829).
iii. Celecoxib was not associated with increases in CV events until the APC (Adenoma
Prevention with Celecoxib) trial for cancer prevention was terminated in December
2004. Daily doses of 400 and 800 mg of celecoxib conferred a 2.5- and 3.4-fold
higher risk of fatal and nonfatal myocardial infarction, which suggests a dose-related
response for this toxicity (N Engl J Med 2005;352:107180).
iv. A stepped approach is recommended for patients with CV disease or risk factors for
ischemic heart disease who require analgesic treatment of musculoskeletal symptoms
based on recommendations from the AHA (Circulation 2007;115:163442).
(a) Consider using acetaminophen, aspirin, tramadol, or short-term narcotics first.
(b) Nonacetylated salicylates can be considered next.
(c) NonCOX-2-selective NSAIDS can be used next, followed by NSAIDs with
some COX-2 activity. Use the lowest dose possible to control symptoms.
(d) The COX-2 inhibitors should be reserved as last line. In patients at increased risk
of thromboembolic events, coadministration with aspirin and a PPI may be
considered.
(e) Routinely monitor BP, renal function, and signs of edema or GI bleeding.
v. Methods to reduce CV risk such as tobacco cessation, BP and lipid control, and
glucose control are recommended for NSAID users but have not been proved to
reduce NSAID-associated CV risk. In patients for whom the risk of GI bleeding
outweighs the CV risk, lower-risk NSAIDs such as ibuprofen, etodolac, diclofenac,
or celecoxib should be used. In patients for whom the CV risk outweighs the risk of
GI bleeding, COX-2 inhibitors should be avoided. Limit the dose and therapy
duration if possible (Clin Gastroenterol Hepatol 2006;4:10829).
vi. An FDA article also reviews the effects of ibuprofen on the attenuation of aspirins
antiplatelet effects (www.fda.gov/cder/drug/infopage/ibuprofen/science_ paper.htm).
The AHA (Circulation 2007;115:163442) recommends that ibuprofen be taken at
least 30 minutes after or 8 hours before the ingestion of immediate-release low-dose
aspirin to prevent this interaction.
III. UPPER GI BLEEDING

A. Background: Prevalence is 170 cases/100,000 adults; associated annual costs are about $750
million, and mortality is 6%10%.
B. Causes of Upper GI Bleeding
1. Peptic ulcer disease (40%70%)
a. NSAIDs and low-dose aspirin use
b. H. pylori
2. Esophagitis
3. Erosive disease
4. Esophageal varices
5. Mallory-Weiss tear
6. Neoplasm
7. Stress ulcers (critically ill patients)
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C. Clinical Symptoms and Presentation

1. Hematemesis or coffee-ground emesis
2. Hematochezia
3. Nausea, vomiting
4. Melena
5. Shock (tachycardia, clammy skin)
6. Hypotension
7. Associated organ dysfunction (renal/hepatic/cardiac/cerebral hypoperfusion)
Table 7. Clinical Predictors of Death Associated with Nonvariceal UGIB (Ann Intern Med 2003;139:84357)
Advanced age (> 75 years highest risk)
Shock/hypotension
> 1 comorbid condition
Continued bleeding/rebleeding
Blood in gastric aspirate
Hematemesis
Red blood on rectal examination

Elevated serum urea
Serum creatinine > 150 micromoles/L (1.7 mg/dL)
Elevated aminotransferases
Sepsis
Onset of bleeding during hospitalization for other causes
UGIB = upper gastrointestinal bleeding.
D. Predictors of Persistent or Recurrent Upper GI Bleeding

Table 8. Predictors of Persistent or Recurrent Upper GI Bleeding
Age > 65 years
Shock (systolic blood pressure < 100 mm Hg)
Comorbid illness
Erratic mental status
Ongoing bleeding
Red blood on rectal examination
Melena
Blood in gastric aspirate
Hematemesis
Initial hemoglobin < 10 g/dL or hematocrit < 30%

Coagulopathy
Endoscopic findings:
Active bleeding on endoscopy
Presence of high-risk stigmata
Adherent clot
Ulcer size 2 cm
Gastric or duodenal ulcer
Location of ulcer on superior or posterior wall
GI = gastrointestinal.
E. Prophylaxis of SRMD in Critically Ill Patients

1. Stress-related injury: Superficial diffuse upper GI ulceration
2. Stress ulcer: Deeper mucosal ulceration; may lead to bleeding and hemodynamic compromise
3. Contributing factors to the development of SRMD
a. Hypoperfusion of the GI tract
b. Altered susceptibility to gastric acid
c. Loss of defense mechanisms: Mucous/bicarbonate layer, prostaglandins, cellular renewal
d. Alterations in gastric motility; may affect absorption of drugs
4. Pharmacologic prevention
a. Not routinely recommended in nonintensive care unit settings
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b. Recommended in patients in an intensive care unit setting with the following risk factors:
Table 9. Risk Factors for Initiation of Prophylaxis of SRMD
Mechanical ventilation > 48 hoursa
Coagulopathy (platelet count < 50,000/mm3, INR > 1.5)a
Thermal injury (> 35% BSA)
Severe head or spinal cord injury
GI bleeding/ulceration within last year
Multiple trauma (injury severity score > 16)
Perioperative transplant period
Low intragastric pH
Major surgery (lasting > 4 hours)
Acute lung injury
Two or more of the following:

Sepsis syndrome
ICU stay > 1 week
Occult bleeding 6 days
High-dose corticosteroids (250 mg of
hydrocortisone equivalent)
Hepatic failure
Acute renal insufficiency
Hypotension
Anticoagulation
Independent risk factors.

BSA = body surface area; GI = gastrointestinal; ICU = intensive care unit; INR = international normalized ratio.
5. Preventive treatment options (Am J Health Syst Pharm 1999;56:34779)

a. Antacids: Effectively raise pH and prevent bleeding; require several oral doses per day or
Administration by NG tube; possibility of diarrhea, constipation, and electrolyte
abnormalities
b. Sucralfate:
i. Works by providing a direct mucosal barrier; also modulates pepsin, mucus activity,
bicarbonate secretion, and tissue growth repair
ii. Use has fallen out of favor. Requires many oral doses or administration by NG tube.
May lead to aluminum accumulation and constipation. No effect on platelet count
and is associated with lower rates of pneumonia development. Possibility of binding
to other drugs in GI tract
iii. General efficacy regarding bleeding considered similar to that of H2RAs (some data
suggest inferiority to H2RAs; N Engl J Med 1998;338:7917)
c. Histamine-2 receptor antagonists
i. Reduce gastric acid secretion by inhibiting histamine stimulation of the parietal cell;
may be associated with the development of tolerance/tachyphylaxis with continued
use
ii. Considered efficacious in the prevention of clinically significant bleeding; oral,
intravenous intermittent dosing, and continuous infusion are all possible options;
high-dose intravenous (ranitidine, cimetidine, or famotidine) use can be considered
first-line therapy. Cimetidine is the only H2RA that is FDA approved for the
prevention of SRMD.
iii. Associated with CNS adverse effects as well as the rare development of
thrombocytopenia; require adjustment for renal dysfunction
d. Proton pump inhibitors
i. The ASHP (American Society of Health-System Pharmacists) guidelines include
minimal recommendations for PPI use because of the lack of data at that time;
however, PPIs are commonly used for the prevention of SRMD.
ii. Recent meta-analysis suggests that PPIs are similar in safety and efficacy to H2RAs
(Crit Care Med 2010;38:1197205).
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iii. Oral or intravenous routes may be used. Alternative formulations exist for patients
with difficulty swallowing or with feeding tubes (see section on GERD).
iv. Oral PPIs are also as efficacious as intravenous PPI therapy for maintaining
equivalent pH (Am J Gastroenterol 2001;96:205865, Aliment Pharmacol Ther
1998;12:102732, Aliment Pharmacol Ther 2001;15:180717, Aliment Pharmacol
Ther 2003;18:70511).
v. Intravenous PPI therapy is generally considered equivalent to high-dose intravenous
H2RA therapy.
vi. Recent associations with C. difficile infections in hospitalized patients
V. COMPLICATIONS OF LIVER DISEASE

a
Table 10. Child-Pugh Classification of the Severity of Cirrhosis (Br J Surg 1973;60:6469)
Variable
Score
1 point
2 points
3 points
Encephalopathy
Absent
Mild-moderate
Severe to coma
Ascites
Absent
Slight
Moderate
Bilirubin (mg/dL)
<2
23
>3
Albumin (g/L)
> 3.5
2.83.5
< 2.8
Prothrombin time
(seconds above normal)
14
46
>6
Class A = total score of 5 or 6; class B = total score of 79; class C = total score more than 10.
Table 11. Model for End-Stage Liver Disease (MELD) (Hepatology 2007;45:797805)
Version
Calculation
Comment
Original
9.57 ln(creatinine) + 3.78 ln(total

bilirubin) + 11.2 ln(INR) + 6.43
Score ranges from 6 to 40

Higher number indicates more severe disease
Used to predict mortality and prioritize patients for liver
transplantation
MELD-Na
MELD Na [0.025 MELD

(140 Na)] + 140
Incorporates sodium
May better discriminate risk of death
UNOS
modification
Original MELD equation with limits

set on laboratory values that are
entered
Lower end of laboratory values for SCr, bilirubin, and

INR are set at 1 with a maximum of 4
If two or more dialysis treatments within the prior week
or 24 hours of CVVHD within the prior week, SCr
concentration automatically set to 4.0 mg/dL
MELD Score Calculators. Available at www.mayoclinic.org/meld/mayomodel5.html.

CVVHD = continuous venovenous hemodialysis; INR = international normalized ratio; Na = nationwide; SCr = serum
creatinine; UNOS = United Network for Organ Sharing.
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A. Ascites
1. Definition: Free fluid in the abdominal cavity secondary to increased resistance within the
liver (forces lymphatic drainage into the abdominal cavity) and reduced osmotic pressure
within the bloodstream (hypoalbuminemia); develops at a 5-year cumulative rate of 30% in
compensated liver disease
2. Clinical features: Protuberant abdomen, shifting dullness, fluid wave, bulging flanks,
abdominal pain
3. Diagnosis
a. Clinical features
b. Abdominal ultrasonography
c. Paracentesis. Can use serum ascites albumin gradient, calculated by subtracting the
ascites albumin concentration from the serum albumin concentration; a value greater than
1.1 indicates ascites secondary to portal hypertension
4. Treatment (Hepatology 2009;49:2087107)
a. Attainment of negative sodium balance
i. Dietary sodium restriction (less than 2000 mg/day), fluid restriction to less than 1.5
L/day if serum sodium is less than 120125 mmol/L
ii. Goal is excretion greater than 78 mmol/day of sodium. A random spot urine
sodium concentration greater than the potassium concentration (ratio greater than 1)
correlates with a 24-hour sodium excretion of greater than 78 mmol/day with 90%
accuracy.
iii. Diuretics
(a) Patients with minimal fluid overload may be treated with spironolactone alone
(doses up to 400 mg/day); however, a combination of furosemide and
spironolactone is preferable as initial therapy in most patients.
(b) When used in combination, a ratio of 40 mg of furosemide to every 100 mg of
spironolactone is an appropriate starting regimen. Amiloride 1040 mg/day may
be substituted for spironolactone in patients who develop tender gynecomastia.
(c) If tense ascites is present, may use large-volume paracentesis. Administer
albumin at a dose of 68 g/L of ascitic fluid removed (if more than 5 L is
removed at one time).
iv. No upper limit of weight loss if massive edema is present, 0.5 kg/day in patients
without edema
v. The goal is to achieve 78 mmol or more urinary sodium excretions per day with
diuretics.
vi. Monitor for electrolyte imbalances, renal impairment, and gynecomastia
(spironolactone).
b. Discontinue drugs associated with sodium/water retention such as NSAIDs
B. Hepatic Encephalopathy
1. Definition: Disturbance in CNS function secondary to hepatic insufficiency, resulting in a
broad range of neuropsychiatric manifestations
a. Thought to be secondary to the accumulation of nitrogenous substances (mainly NH3)
arising from the gut; overall, NH serum concentrations do not correlate well with mental
status
b. Other theories are related to the activation of -aminobutyric acid receptors by
endogenous benzodiazepine-like substances, possible zinc deficiency, or altered cerebral
metabolism.
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2. Clinical features
a. May result in acute encephalopathy with altered mental status and progress to coma if
untreated; asterixis (hand flap) is a classic physical finding
b. May be precipitated by various factors including constipation, GI bleeding, infection,
hypokalemia, dehydration, hypotension, and CNS-active drugs
(benzodiazepines/narcotics)
3. Treatment (Am J Gastroenterol 2001;96:196876)
a. Assess need for airway support and remove possible precipitating factors.
b. Main treatments targeted at reducing the nitrogen load in the gut
c. Lactulose
i. Nonabsorbable disaccharide: Metabolized by colonic bacteria to acetic and lactic
acid; NH3 present in the GI lumen is reduced to ammonium ion (NH4+) through the
reduction in pH (ammonia trapping) and is therefore unable to diffuse back into the
bloodstream. Lactulose may also alter bacterial metabolism, resulting in increased
uptake of NH3.
ii. Dose: 45 mL orally every 12 hours until the patient has a loose bowel movement;
then titrate to two or three loose bowel movements a day (typically, a 15- to 45-mL
dose 2 or 3 times/day); may also administer as an enema (300 mL plus 700 mL of
water retained for 1 Hour). Powder formulation (KRISTALOSE) in 10- and 20-g
packets that may be dissolved in 4 oz of water (10 g = 15 mL of traditional lactulose).
This formulation is more palatable than the traditional syrup.
iii. May be continued over the long term for the prevention of recurrent encephalopathy
iv. Flatulence, diarrhea, and abdominal cramping are common adverse effects.
d. Antibiotics
i. Targeted at reducing the number of intraluminal urease-producing bacteria that may
be associated with excess NH3 production
ii. Neomycin (36 g/day in three or four divided doses 12 weeks; then 12 g/day
maintenance) or metronidazole (250 mg orally 2 times/day) may be used; neomycin
is considered as effective as lactulose.
iii. From 1% to 3% of neomycin is absorbed, so use caution with long-term use in
patients.
Having renal insufficiency; long-term metronidazole use may result in
peripheral neuropathy.
iv. Rifaximin is as effective as lactulose and other nonabsorbable antibiotics and may be
better tolerated. Approved dose for reduction in overt encephalopathy in patients 18
years and older is 550 mg 2 times/day. Drug cost may be greater, but this may be
offset by fewer hospitalizations and shorter lengths of stay. Previous studies in the
short-term setting have used 400 mg 3 times/day (Pharmacotherapy
2008;28:101932).
e. Other possible treatments
i. Benzodiazepine antagonists such as flumazenil may be used in cases of suspected
benzodiazepine overdose.
ii. Zinc supplementation should used in patients with documented zinc deficiency.
C. Gastroesophageal Varices (Am J Gastroenterol 2009;104:180229)
1. Background
a. Resistance to blood flow within the liver secondary to cirrhosis results in the
development of portal hypertension. Collateral blood vessels (such as esophageal varices)
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are formed because of this increased resistance to blood flow.

b. variceal hemorrhage may occur in around 25%35% of patients with cirrhosis and
varices; mortality rates are as high as 30%50% per bleed; recurrence rates are as high as
70% within the first 6 months after an initial bleed.
2. Management of acute variceal bleeding
a. Fluid resuscitation and hemodynamic stabilization. Maintain hemoglobin concentration
of About 8 g/dL. Administration of fresh frozen plasma or platelet may be considered for
patients with considerable coagulopathy.
b. Endoscopy to assess the extent of disease with potential intervention
i. Sclerotherapy: Effective in discontinuing bleeding in 80%90% of patients; may be
associated with complications such as perforation, ulceration, stricture, and
bacteremia; possible sclerosing agents include ethanolamine and sodium tetradecyl
sulfate
ii. Endoscopic variceal band ligation may be used as an alternative to sclerotherapy;
fewer complications
c. Medical management of acute variceal bleeding
i. Should be instituted after fluid resuscitation (before endoscopy, if possible)
ii. Most therapies are targeted at reducing splanchnic blood flow and portal pressure;
combination of endoscopic and vasoactive therapies most effective
iii. Vasopressin: 0.20.4 unit/minute plus nitroglycerin 40400 mcg/minute for 35 days
(a) Vasopressin use results in splanchnic vasoconstriction; used less often secondary
to need for both drugs and coronary vasoconstriction/hypertension with
vasopressin (nitroglycerin attenuates these effects to some extent)
(b) More adverse effects than octreotide, so overall, less preferable
iv. Octreotide or somatostatin
(a) Works possibly by preventing postprandial hyperemia, by reducing portal
pressure (by reduced splanchnic blood flow) through inhibitory effects on
vasoactive peptides such as glucagon, or by a local vasoconstrictor effect
(b) Preferred agents in combination with endoscopic interventions because of more
favorable adverse effect profiles; main adverse effects include hyperglycemia
and abdominal cramping (Digestion 1999;60(suppl 2):3141)
(c) Dosing
(1) Octreotide: 50-mcg intravenous bolus; then 50 mcg/hour intravenously for
35 days
(2) Somatostatin: 250-mcg intravenous bolus; then 250500 mcg/hour
intravenously for 35 days
v. Nondrug measures to control bleeding
(a) Typically used for medically unresponsive bleeding
(b) Minnesota or Blakemore tube: Balloon compression applied directly to bleeding
varices
(c) Transjugular intrahepatic portosystemic shunt: Results in shunting of blood from
the portal circulation; however, may be associated with complications such as
bleeding and infection
(d) Surgery
vi. Antibiotic therapy
(a) The use of oral or intravenous prophylactic antibiotics in patients with cirrhosis
with variceal bleeding has been shown to reduce short-term mortality; they
should be prescribed (Hepatology 1999;29:165561).
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(b) Typical regimens include a fluoroquinolone (norfloxacin or ciprofloxacin) orally

for 7 days. Intravenous therapy (ciprofloxacin) can be used if the oral route of
administration is not an option. Ceftriaxone 1 g/day intravenously may be used if
high rates of fluoroquinolone resistance are present.
d. Prevention of variceal bleeding
i. Primary prophylaxis
(a) A screening EGD (esophagogastroduodenoscopy) is recommended to evaluate
for esophageal and gastric varices when the diagnosis of cirrhosis is made.
(b) Pharmacologic therapy is not recommended to prevent the development of
varices in patients with cirrhosis who have not yet developed varices.
(c) Patients with small varices and no history of bleeding, but meeting the criteria for
increased risk of bleeding (Child-Pugh class B or C, red wale marks on varices),
should receive preventive drug therapy with nonselective -blockers.
(d) Nonselective -blockers can be considered; however, the long-term benefit is
unclear in patients who have small varices and no history of bleeding but who
DO NOT meet the criteria for increased risk of bleeding.
(e) Nonselective -blockers are indicated in all patients with medium/large varices
and no history of bleeding. An endoscopic variceal ligation (EVL) can be used if
nonselective -blockers are contraindicated.
(f) Mechanism of nonselective -blockers: Blockade of -receptors reduces cardiac
output, whereas blockade of -receptors prevents splanchnic vasodilation;
unopposed 1-mediated constriction of the splanchnic circulation also leads to
reductions in portal pressure.
(g) Therapy should aim for an HR of 5560 beats/minute or a 25% reduction from
baseline.
(h) Nonselective -blockers are associated with a significant reduction in the
incidence of first bleed (OR = 0.54; 95% CI, 0.390.74), with a trend toward
reduced mortality (Ann Intern Med 1992;117:5970).
(i) Long-acting nitrates (isosorbide mono- or dinitrate) should not be used for
primary prophylaxis. These agents are believed to decrease intrahepatic
resistance and are considered as effective as propranolol; however, there is an
increased incidence of mortality in some studies when used as monotherapy.
(j) Shunt surgery or endoscopic sclerotherapy should not be used for primary
prophylaxis.
ii. Secondary prophylaxis
(a) All patients with a history of variceal bleeding should receive secondary
prophylaxis to prevent recurrent bleeding.
(b) A combination of endoscopic variceal band ligation and nonselective -blockers
is considered the most effective regimen.
(c) Nonselective -blockers are associated with a 20% reduction in the incidence of
variceal rebleeding (p<0.001; 11%28%); reductions in mortality are minimal
and inconsistent among trials (Hepatology 1997;25:6370); most studies are of
patients with Child-Pugh class A or B cirrhosis; class C patients may be unable to
tolerate -blockers.
(d) Combining nonselective -blockers with nitrates leads to slightly better
reductions in rebleeding rates; however, no added mortality benefit is observed,
and there is a higher incidence of adverse effects with the combination.
(e) Sclerotherapy is no longer recommended for secondary prophylaxis because
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EVL is better with fewer complications.

(f) The transjugular intrahepatic portosystemic shunt is very effective in preventing
recurrent bleeding; however, it is associated with a 30%40% incidence of
encephalopathy; reserve for medically unresponsive patients.
(g) Contraindications to nonselective -blockers: Asthma, insulin-dependent diabetes
with frequent hypoglycemia, peripheral vascular disease
(h) Adverse effects of nonselective -blockers: Light-headedness, fatigue, shortness
of breath, sexual dysfunction, bradycardia
(i) Adverse effects of EVL: Transient dysphagia, chest discomfort
D. Spontaneous Bacterial Peritonitis (SBP) (Hepatology 2009;49:2087107)
1. Background
a. Definition: Infection of previously sterile ascitic fluid without an apparent
intra-abdominal source. SBP is considered a primary peritonitis as opposed to secondary.
b. May be present in 10%30% of hospitalized patients with cirrhosis and ascites
c. Associated with 20%40% of in-hospital mortality; poor prognosis after recovery, with
2-year survival after initial episode reported as about 30%
2. Pathophysiology
a. Principal theory is seeding of the ascitic fluid from an episode of bacteremia.
b. Because the bacteria usually present are enteric pathogens, they may enter the blood
because of increases in gut permeability secondary to portal hypertension, suppression of
hepatic reticuloendothelial cells, or translocation of the gut wall and dissemination
through the mesenteric lymph system.
c. Reduced opsonic activity of the ascitic fluid and alterations in neutrophil function may
also be contributing factors.
d. Enteric gram-negative pathogens are most commonly involved, and more than 90% of
cases involve a single bacterial species.
Table 12. Most Commonly Isolated Bacteria Responsible for Spontaneous Bacterial Peritonitis
Gram-negative Bacilli (50%)
Gram-positive Bacilli (17%)
Escherichia coli 37%
Streptococcus pneumoniae 10%
Klebsiella spp. 6%
Other streptococci 6%
Other 7%
Staphylococcus aureus 1%
3. Clinical and laboratory features

a. Clinical presentation may be variable, but common symptoms include fever, abdominal
pain, nausea, vomiting, diarrhea, rebound tenderness, and exacerbation of
encephalopathy; about 33% of patients may present with renal failure, which is
associated with significant increases in mortality. Although GI bleeding and septic
shock/hypotension occur, they are rare.
b. Laboratory
i. May see systemic leucocytosis or increases in SCr
ii. Abdominal paracentesis must be performed:
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(a) The presence of more than 250 polymorphonuclear cells/mm3 is diagnostic for SBP.
(b) Lactate dehydrogenase, glucose, and protein values may help distinguish it from
secondary peritonitis.
iii. Blood cultures positive in 50%70% of cases; ascitic fluid cultures positive in 67%
of cases
iv. Gram stain of ascitic fluid is typically low yield.
4. Treatment of acute SBP (Hepatology 2009;49:2087107)
a. Because of the high associated mortality, treatment should be initiated promptly in
patients with clinical and laboratory features consistent with SBP.
b. Up to 86% of ascetic fluid cultures may be negative if one dose of an antibiotic is given
before cultures are drawn.
c. Predictors of poor outcomes include bilirubin more than 8 mg/dL, albumin less than 2.5
g/dL, creatinine more than 2.1 mg/dL, hepatic encephalopathy, hepatorenal syndrome,
and upper GI bleeding.
d. Antibiotic therapy plus albumin if patient meets criteria for use (see below)
i. Empiric therapy targeting enteric gram-negative organisms should be instituted.
ii. Third-generation cephalosporins have been studied the most and are considered first
line: Cefotaxime (2 g every 812 hours) or ceftriaxone (2 g/day intravenously)
iii. Other agents such as fluoroquinolones may be used.
iv. Avoid aminoglycosides because of the high risk of renal failure in patients with
cirrhosis and SBP.
v. Treatment duration: 510 days; most studies suggest that a 5-day treatment period is
as effective as a 10-day period
e. Albumin
i. Rationale: The hemodynamics of patients with cirrhosis reflect a state of
intravascular hypovolemia and organ hypoperfusion; SBP is thought to enhance this
effect, resulting in progressive renal hypoperfusion and precipitation of renal failure
or hepatorenal syndrome.
ii. The regimen most commonly used is based on one study (N Engl J Med
1999;341:4039).
(a) Albumin dosing: 1.5 g/kg on admission; 1 g/kg on hospital day 3
(b) In addition, should give antibiotic treatment; cefotaxime was used in this study
(c) The incidence of renal failure was reduced to 10% versus 33% for placebo
(p=0.002).
(d) In-hospital mortality was 10% for albumin versus 29% for placebo (p=0.01).
(e) 30-day mortality was reduced to 21% with albumin versus 41% for placebo
(p=0.03).
(f) Recent guidelines suggest using this albumin regimen with antibiotics if SCr is
more than 1 mg/dL, BUN more than 40 mg/dL, or total bilirubin more than 4
mg/dL (Hepatology 2009;49:2087107).
5. Prevention (Hepatology 2009;49:2087107)
a. Prophylactic oral antibiotics are used to prevent SBP in high-risk patients to reduce the
number of enteric organisms in the GI tract (GI decontamination), with the hope of
reducing the chance of bacterial translocation.
b. Antibiotic regimens are similar for both primary and secondary prevention:
i. Fluoroquinolones: Norfloxacin or ciprofloxacin
ii. Trimethoprim/sulfamethoxazole 1 double-strength tablet 5 times/week (Monday
through Friday)
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c. Primary prevention
i. For acute upper GI bleeding (7-day course during hospitalization only), give
ceftriaxone or norfloxacin 400 mg 2 times/day.
ii. May also consider for indefinite use in patients without GI bleeding if ascitic fluid
protein concentration is less than 1.5 g/dL and at least one of the following is present:
SCr more than 1.2 mg/dL, BUN more than 25 mg/dL, sodium less than 130 mg/dL,
or Child-Pugh score more than 9 with bilirubin more than 3 mg/dL
iii. Use norfloxacin 400 mg once daily or trimethoprim/sulfamethoxazole.
d. Secondary prevention
i. All patients recovering from an initial episode of SBP should be treated with oral
prophylactic antibiotics (norfloxacin or trimethoprim/sulfamethoxazole) indefinitely.
ii. Consider patient for liver transplantation because 2-year survival is 25%30% after
recovery.
E. Alcoholic Liver Disease
1. Subset of chronic liver disease. Patients may develop steatosis and eventually progress to
cirrhosis. About 10%35% of patients may develop severe alcoholic hepatitis.
2. Prognosis of alcoholic hepatitis may be initially evaluated by the Maddrey discriminant
function (MDF) score, calculated as 4.6 (patients PT control PT) + total bilirubin (mg/dL),
where PT is prothrombin time. Patients with a score greater than 32 are believed to have a
poor prognosis.
a. Patients with an MDF greater than 32, with or without encephalopathy, should be
considered for a 4-week course of prednisolone 40 mg/day, followed by a 2-week taper.
This may lead to a 30% decrease in the risk ratio of short-term death.
b. Patients with an MDF greater than 32 can be considered for treatment with pentoxifylline
400 mg 3 times/day, especially if there are contraindications to corticosteroids. This has
shown 40% lower hospital mortality compared with placebo.
3. Long-term treatment of alcoholic liver disease with propylthiouracil or colchicine is not
recommended.
VI. VIRAL HEPATITIS

A. For all hepatitis virus infections, acute hepatitis is defined as infection for less than 6 months,
whereas chronic infection is infection for greater than 6 months.
B. Hepatitis A Virus
1. Background
a. An RNA virus that is associated with the development of self-limited hepatitis
b. Transmission occurs mainly through the fecal-oral route.
i. Areas of poor sanitation; also associated flooding, leading to increased spread
ii. Foodborne: Shellfish, water, milk, vegetables
iii. Person-to-person contact: Sexual, day care, intravenous drug use, household,
restaurant workers
c. After exposure, incubation for 1450 days takes place; patients may show general,
nonspecific symptoms such as nausea, vomiting, diarrhea, myalgia, fever, abdominal
pain, and jaundice.
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d. Most patients have self-limited disease lasting less than 2 months; death of the hepatocyte
results in elimination of the virus.
e. Hepatitis A virus is associated with very low mortality (less than 1%) and is not
associated with the development of chronic hepatitis. Fulminant hepatitis may occur in
some instances.
2. Diagnosis
a. Clinical signs/symptoms such as nausea, abdominal pain, jaundice, fever, malaise, or
anorexia. Some patients may have mild asymptomatic disease.
b. Recent possible exposures
c. Laboratory data
i. igM antibody to HAV (anti-HAV): Detectable in the serum 510 days before the
onset of symptoms; once the infection clears, the IgM antibody is replaced by IgG
antibodies during a 2- to 6-month period; these antibodies confer lifelong protective
immunity against subsequent infection
ii. Elevation of aminotransferases
d. Management of acute HAV infection is mainly supportive; avoid hepatotoxic
medications such as acetaminophen.
3. Preexposure prophylaxis
a. Active (vaccination) or passive (immune globulin) prophylaxis can be used.
b. Havrix (GlaxoSmithKline) and Vaqta (Merck) are the two available HAV vaccines;
Twinrix is a combination HAV and HBV product (GlaxoSmithKline).
c. Populations requiring preexposure prophylaxis with HAV vaccine:
i. All children older than 1 year
ii. Children living in areas where hepatitis rates are above twice the national average
iii. People working in or traveling to countries with high or intermediate endemicity
(may take up to 4 weeks for full protection)
iv. Men who have sex with men
v. illegal drug users
vi. Those with occupational risk of exposure (exposure to sewage)
vii. Patients with chronic liver disease
viii. Patients with clotting factor disorders
ix. Optional: Food handlers, workers in institutions
d. Populations requiring preexposure prophylaxis with HAV immune globulin
ii. Children younger than 1 year (vaccine not approved for this age group)
iii. Doses: 0.02 mL/kg intramuscularly (3 months coverage or more); 0.06 mL/kg
intramuscularly (35 months coverage); repeat every 5 months if travel or exposure
is prolonged
4. Postexposure prophylaxis
a. immune globulin can be given at a dose of 0.02 mL/kg intramuscularly within 2 weeks of
exposure. Hepatitis A vaccine may also be used. Efficacy approaches that of immune
globulin, but it is recommended only in patients 12 months to 40 years of age.
b. Offer to those not previously vaccinated in the following situations:
i. Close personal contact with a documented infected person
ii. Staff or attendees of day care centers if one or more cases are recognized in children
or employees or if cases are recognized in two or more households of attendees
iii. Common sources of exposure:
(a) If a food handler receives a diagnosis of HAV, vaccine or immune globulin
should be administered to other food handlers at the same establishment.
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Administering HAV vaccine or immune globulin to patrons typically is not

indicated but may be considered if:
(1) The food handler, who was likely infectious, directly handled uncooked or
cooked food and had diarrhea or poor hygienic practices.
(2) Patrons can be identified and treated in 2 weeks or less after exposure.
(b) In settings where repeated exposures to HAV may have occurred, stronger
consideration of HAV vaccine or immune globulin use could be warranted. In a
common-source outbreak, postexposure prophylaxis should not be provided to
exposed individuals after cases have begun to occur because the 2-week period
after exposure during which immune globulin or HAV vaccine is known to be
effective will have been exceeded.
C. Hepatitis B Virus (HBV)
1. Background
a. HBV is a DNA virus; there are more than 350 million infected patients worldwide.
b. Transmission routes
i. Parenteral: Intravenous drug abuse, needlestick, transfusion, ear or body piercing
ii. Bodily fluids: Saliva, semen, vaginal fluid
iii. Sexual contact: Heterosexual and homosexual; prostitution
iv. Perinatal: Mother to child at birth
c. Associated with both acute and chronic disease. Natural history of HBV is
age-dependent. Risk of developing chronic infection after an acute infection is 90% in
neonates, 25%30% in children younger than 5 years, and 10% in adults.
d. Chronic infection with HBV increases the risk of developing hepatocellular carcinoma.
e. Diagnosis
i. Clinical signs and symptoms: Nausea, vomiting, diarrhea, myalgia, fever, abdominal
pain, jaundice (30% may have no symptoms)
ii. Serologic diagnosis
iii. Combinations of serologic markers must be reviewed to distinguish acute from
chronic infections.
iv. Eight different HBV genotypes (AH) exist. Routine genotype testing is not endorsed
by the guidelines.
Table 13. HBV Serologies
Serologic Marker
Abbreviation
Comment
Surface antigen
HBsAg
First detectable serum antigen during acute infection;

also present in chronic infection
Core antigen
HBcAg
Present early after cell damage during acute infection; typically unable to
measure this in the serum
E antigen
HbeAg
Denotes ongoing active viral replication
Antisurface
antigen antibody
Anti-HBs
Confers protective immunity; present after recovery from acute infection or

after vaccination
Anticore antigen
antibody (IgG)
Anti-HBc
Appears at onset of symptoms

Denotes prior exposure to HBV
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Table 13. HBV Serologies

Serologic Marker
Abbreviation
Comment
Cannot use to distinguish acute from chronic infection
Anti-E antibody
Anti-HBe
May indicate peak replication has passed
HBV DNA
HBV DNA
Marker of active HBV replication
HBcAg = hepatitis B core antigen; HBeAg = hepatitis B early antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B
virus; IgG = immunoglobulin G.
(a) Most patients will have hepatitis B early antigen (HBeAg)-positive disease.
(b) HBeAg-negative disease: Mutation in the precore or core promoter regions.
These variants are known as precore mutants; these mutations do not allow
monitoring of loss of E antigen as a clinical marker of suppressed replication.
Monitor reduction in HBV DNA in these patients; patients infected with these
variants also tend to have lower serum HBV DNA and more fluctuating liver
function tests.
(c) Centers for Disease Control and Prevention guidelines for screening for HBV
infection (MMWR 2008;57(RR-08):120). The serologic assay for HBV surface
antigen (HBsAg) should be the serologic screening test used for the following
populations. Additional HBVs are needed in combination with the HBsAg for
select populations as listed below.
(1) People born in geographic regions with HBsAg prevalence of more than
2%, regardless of vaccination history
(2) Men who have sex with men; also test for anti-HBc or anti-HBs
(3) Past or current intravenous drug users; also test for anti-HBc or anti-HBs
(4) Individuals receiving cytotoxic chemotherapy or immunosuppressive
therapy related to organ transplantation or rheumatologic or GI disorders. In
addition, test for anti-HBc or anti-HBs.
(5) U.S.-born person not vaccinated as infant whose parents were born in
regions with HBV endemicity more than 8%
(6) People with elevated ALT/AST of unknown etiology
(7) Donors of blood, plasma, organs, tissues, or semen. In addition, test for
anti-HBc and HBV DNA.
(8) Pregnant women (during each pregnancy, preferably in the first trimester)
(9) Infants born to HBsAg-positive mothers
(10) Household, needle-sharing, or sex contacts of individuals known to be
HBsAg positive. In addition, test for anti-HBc or anti-HBs.
(11) Individuals who are the sources of blood or bodily fluid for exposures that
might require postexposure prophylaxis
(12) Individuals who are human immunodeficiency virus (HIV) positive. In
addition, test for anti-HBc or anti-HBs.
v. Clinical definitions
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Table 14. Clinical Definitions of HBV

Chronic HBV Infection
Inactive HBV Carrier State
HBsAg positive > 6 months

Serum HBV DNA 20,000 IU/mL (105 copies/mL),
lower values 200020,000 IU/mL (104105
copies/mL) are often observed in HBeAg-negative
chronic hepatitis B
Persistent/intermittent elevation of AST/ALT
Chronic hepatitis and moderate-severe
necroinflammation on biopsy
HBsAg positive > 6 months

HBeAg negative, anti-HbeAg positive
Serum HBV DNA < 2000 IU/mL (104 copies/mL)
Persistently normal AST/ALT; absence of significant
hepatitis on biopsy
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HBcAg = hepatitis B core antigen; HBeAg = hepatitis B early
antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; LFT = liver function test; ULN = upper limit of normal.
2. Treatment of chronic infection

a. Treatment recommendations (Hepatology 2009;50:136)
i. Patients who are HBeAg positive with elevated ALT concentrations and
compensated liver disease should be observed for 36 months for spontaneous
conversion from HBeAg positive to anti-HBeAg negative before initiating treatment.
Antiviral treatment should be considered in patients whose ALT remains greater than
2 times the ULN and whose HBV DNA is more than 20,000 IU/mL.
ii. Patients who are HBeAg negative with positive anti-HBe as well as normal ALT and
HBV less than 2000 IU/mL should be monitored every 3 months for 1 year and then
every 612 months if they remain in the inactive carrier state.
b. Patients who meet the criteria for chronic infection as outlined previously should be
treated. Choice of initial therapy is based on patient profile, prior treatments, and
contraindications to drug therapy and medication/monitoring costs.
c. Monitoring for efficacy should be based on the following responses:
i. Biochemical: Liver function tests to within the normal range
ii. Virologic: HBV DNA to undetectable concentrations and loss of HBeAg if HBeAg
positive
(a) A primary nonresponse is considered a decrease in HBV DNA less than 2
logs/mL after at least 24 weeks of therapy. Patients NOT meeting these criteria
should receive an alternative treatment.
(b) Response should be assessed by reductions in HBV DNA for HbeAg-negative
patients.
3. Drug therapies
a. interferon alfa/PEG-IFN
i. Cytokine with antiviral, antiproliferative, and immunomodulatory effects
ii. Best predictors of response to treatment are high pretreatment ALT, low-serum HBV
DNA, presence of active inflammation on biopsy, and acquisition of infection
because an adult HBeAg-negative disease responds less favorably to IFN.
iii. Dosing:
(a) Traditional agents: HBeAg positive: Typical dose is 5 MU/day subcutaneously
1624 weeks or 10 MU subcutaneously 3 times/week 1624 weeks; patients
with HBeAg-negative disease should be treated for 12 months.
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(b) PEG -2a (Pegasys): 180 mcg subcutaneously once weekly 48 weeks (duration
is same for HBeAg-negative and HBeAg-positive disease)
iv. In general, response to traditional IFN is poor; 37% loss of HBsAg, 33% loss of
HBeAg with 1224 weeks of treatment; this equates to about 20% better than placebo.
Some trials suggest that PEG-IFN has only slightly better efficacy in HBeAg-positive
disease, with 25% loss of HBV DNA and 30% loss of HBeAg at 48 weeks. Adherence
may be better because of less-frequent dosing.
v. if a response is obtained, it is usually long lasting (more than 48 years).
vi. Treatment with IFN typically results in an increase in ALT 48 weeks into treatment.
This is an expected response; it should not be viewed as an adverse effect of therapy.
Table 15. Available INF Products
Product
IFN Subtype Route of Administration
Dosage Form(s)
-2a
SQ or IM
Single-dose vial (36 MU/mL)

Multidose vial (18 MU/vial)
Prefilled syringe (3, 6, 9 MU/0.5 mL)
Infergen
con-1
SQ
Single-dose vials
9 mcg (0.3 mL), 15 (0.5 mL)
Introna
-2b
SQ or IM
Powder, solution, multidose pen
PEG-Intron
PEG -2b
SQ
Single-dose vials (2 mL) + diluent

50, 80, 120, 150 mcg/0.5 mL
Single-use REDIPEN 50, 80, 120, 150 mcg/0.5 mL
Pegasysa,b
PEG -2a
SQ
Single-dose vial (1 mL)

180 mcg/mL
Prefilled 180 mcg syringes (4/pack)
Roferon A
Preferred for HBV.

FDA approved for HBV.
IM = intramuscular; INF = interferon alfa; PEG = pegylated; SQ = subcutaneous.
vii. Adverse effects

(a) IFN is associated with many serious adverse effects, including bone marrow
suppression (J Clin Gastroenterol 2005;39:S9S13).
(1) Leukopenia: May use filgrastim (granulocyte colony-stimulating factor) for support
(2) Thrombocytopenia: Minimal data with oprelvekin (interleukin-11). Not used
because of many adverse effects including pulmonary hypertension
(b) Predisposition to infections
(c) CNS: Depression, psychosis, anxiety, insomnia, seizures. Adverse CNS effects
occur in 22%31% of patients.
(d) Flulike symptoms (tolerance usually develops after a few weeks)
(e) Anorexia, alopecia, thyroid dysfunction, neuropathy
(f) Exacerbation of underlying autoimmune disorders (i.e., thyroid)
(g) Ischemic/hemorrhagic CV disorders
(h) Serious hypersensitivity and rash formation
(i) Manufacturers give recommendations for dose reductions in patients who develop
bone marrow suppression and depression while on therapy.
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(j) Contraindicated in patients with a history of current psychosis, severe depression,

neutropenia, thrombocytopenia, symptomatic heart disease, decompensated liver
disease, and uncontrolled seizures; also, use caution in patients with autoimmune
disorders
b. Reverse transcriptase inhibitors (RTIs)
i. in general, lamivudine and telbivudine are not preferred as first-line therapies
because of high resistance rates.
ii. All RTIs carry a black box warning for the development of lactic acidosis and severe
hepatomegaly with steatosis. Monitor for worsening liver function tests, and
periodically assess renal function. Female and obese patients are at higher risk.
iii. Lamivudine (Epivir-HBV)
(a) Reduces HBV DNA by 34 logs
(b) Dose: 100 mg/day orally (tablets or solution) for at least 1 year (HBeAg negative
and positive); dose is 150 mg orally 2 times/day for patients with HIV
coinfection; doses require adjustment for reduced renal function
(c) Efficacy: 17%32% loss of HBeAg and 41%72% normalization of ALT at 52
weeks; may be used for IFN failures and in patients with decompensated liver
disease
(d) Toxicity: Well tolerated (headache, nausea, vomiting, fatigue), rare lactic
acidosis
(e) Resistance: Prolonged use is associated with the development of mutations in the
YMDD sequence of the HBV polymerase (20% at 1 year, 70% at 4 years). Risk
factors for lamivudine resistance include elevated pretherapy HBV DNA or ALT,
male sex, increased body mass index, previous exposure to lamivudine or
famciclovir, and inadequate suppression on HBV DNA after 6 months of
treatment.
(f) Therapy discontinuation is often accompanied by rebound liver function test
elevations; viral breakthrough may also be evident during treatment.
iv. Adefovir (Hepsera)
(a) Reduces HBV DNA by 24 logs
(b) Indicated in HBeAg-positive and HBeAg-negative disease, as well as in
decompensated liver disease; also effective in lamivudine-resistant YMDD
mutants and IFN failures
(c) Dose: 10 mg orally every day for at least 1 year in HBeAg-negative and
HBeAg-positive disease
(d) Efficacy: Up to 72% normalization of ALT and 12% loss of HBeAg at 48 weeks
(e) Toxicity: Renal dysfunction (3%), headache, nausea, vomiting, fatigue, rare
lactic acidosis
(f) Therapy discontinuation is often accompanied by rebound liver function test
elevations; viral breakthrough may also be evident during treatment. Resistance
reported as 29% at 5 years
v. Entecavir (Baraclude)
(a) Indicated for HBeAg-negative and HBeAg-positive patients with persistently
elevated AST/ALT or histologically active disease. Effective in
lamivudine-resistant YMDD mutants
(b) Reduces HBV DNA by up to 6.86 logs in HBeAg-positive, naive patients and by
5.2 logs in HBeAg-negative patients or those with lamivudine resistance
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(c) Dose: 0.5 mg orally once daily for individuals older than 16 years and nucleoside
naive; 1 mg orally once daily for patients older than 16 years with HBV viremia
while receiving lamivudine or in lamivudine-resistant HBV
(d) Dose adjustments required for renal impairment
(e) Toxicity: Similar to lamivudine with headache, cough, upper respiratory
infection, abdominal pain; possibly fewer ALT flares. Rare lactic acidosis.
Resistance reported as similar to 1% at 5 years
vi. Telbivudine (Tyzeka)
(a) Indicated for HBeAg-negative and HbeAg-positive patients with persistently
elevated AST/ALT or histologically active disease
(b) Not effective in lamivudine-resistant YMDD mutants
(c) A direct comparison with lamivudine (GLOBE trial) showed greater efficacy in
both HBeAg-negative and HBeAg-positive patients.
(d) Reduces HBV DNA by up to 6.45 logs in HBeAg-positive, naive patients and by
5.2 logs in HBeAg-negative patients
(e) Dose: 600 mg orally once daily. Dose adjustments required for renal impairment
(f) Toxicity: Similar to lamivudine; small incidence of myopathy. Creatine kinase
elevations greater than 7 times the ULN; for telbivudine, 9% versus 3% with
lamivudine in the GLOBE study. Rare lactic acidosis. Resistance reported as
25% at 2 years
vii. Tenofovir (Viread)
(a) Nucleotide analog, formulated as tenofovir disoproxil fumarate indicated for
chronic HBV infection
(b) Effective for lamivudine-resistant HBV
(c) A direct comparison with adefovir for 48 weeks showed greater viral suppression
to less than 400 copies/mL plus histologic improvement for tenofovir compared
with adefovir in HBeAg-positive patients (66% vs. 12%; p<0.001) and
HBeAg-negative patients (71% vs. 49%; p<0.001) (N Engl J Med
2008;359:244255). Dose: 300 mg orally once daily. Dose adjustments required
for renal impairment
(d) Toxicity: Overall, well tolerated. Headache, nausea, and nasopharyngitis most
commonly reported. Potential renal toxicity, so periodic monitoring of SCr
recommended. Potential ALT flares on withdrawal. Rare lactic acidosis
Table 16. Summary of Treatment Recommendations for Chronic HBV Infection in Adults
HBV Population
Preferred Treatment Options
Duration
Comments
HBeAg positive
Entecavir and tenofovir are preferred

oral agents
Use of the other oral reverse
transcriptase inhibitors is possible but
not preferred
Minimum
of 1 year
Preferred if contraindications or
nonresponse to INF
INF
PEG-INF
16 weeks
48 weeks
If contraindication or no response,
use entecavir and tenofovir
Entecavir and tenofovir are preferred
> 1 year
Preferred if contraindications or no
HBeAg negative
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Table 16. Summary of Treatment Recommendations for Chronic HBV Infection in Adults
HBV Population
Preferred Treatment Options
Duration
oral agents
Use of the other oral reverse
transcriptase inhibitors is possible but
not preferred
Development of
resistant HBV
response to INF
1 year
INF
PEG-INF
Lamivudine or telbivudine resistance:
Add adefovir or tenofovir or change to
entecavir
Adefovir resistance: Add lamivudine
Entecavir resistance: Change to
tenofovir
Comments
N/A
If contraindication or nonresponse,
use entecavir and tenofovir
Confirm resistance with genotypic
testing
Reinforce adherence to therapy
HBeAg = hepatitis B early antigen; HBV = hepatitis B virus; INF = interferon alfa; N/A = not applicable; PEG = pegylated.
4. Preventive strategies
a. vaccination (preexposure); indicated in the following groups:
i. All infants born to HBsAg-negative mothers
ii. Adolescents with high-risk behavior (intravenous drug abuse, multiple sex partners)
iii. Workers with possible occupational risk of exposure
iv. Staff and clients at institutions for the developmentally disabled
v. Hemodialysis patients
vi. Patients receiving clotting factor concentrates
vii. Household contacts and sex partners of infected patients
viii. Adoptees from countries where HBV infection is endemic
ix. International travelers (more than 6 months travel in an endemic area, short-term
travel if contact with blood in a medical setting is expected, or sexual contact with
residents in areas of intermediate- to high-endemic disease); series of vaccinations
started 6 months before travel
x. injection drug users
xi. Sexually active homosexual or bisexual men, as well as heterosexual men and
women
xii. Patients seeking treatment of a sexually transmitted disease
xiii. Inmates of long-term correctional facilities
xiv. Patients with chronic HIV infection or chronic liver disease
xv. All other individuals seeking protection from HBV infection
b. Available HBV vaccines (dose schedules vary by age)
i. Dose schedules
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Table 17. Dose Schedules for Hepatitis B Vaccinations

Patient and Age Groups
Recombivax HB
Engerix-B
Dose
(mcg)
Volume
(mL)
Dose
(mcg)
Infants (< 1 year)
0.5
10
Children (110 years)
0.5
10
1115 years
10
N/A
1119 years
0.5
10
0.5
Adults
20 years
10
20
Hemodialysis patients
and other immunocompromised individuals
< 20 years
0.5
10
0.5
> 20 years
40
40
Adolescents
Schedule
Volume Most common schedule is 3

(mL) IM doses at 0, 1, and 6
months
0.5
Variations in schedule may
0.5
occur depending on age and
medical history
N/A
IM = intramuscular; N/A = not applicable.
ii. Obtain titers 12 months after the third dose of the series for health care personnel.
iii. Hepatitis B vaccines are available as combination products with HAV (Twinrix),
DTP/IPV (Pediarix), and Hib (Comvax). Avoid Twinrix in patients with HIV.
c. Postexposure prophylaxis
i. Exposure may result in the need for HBV vaccine and/or immune globulin.
ii. Doses of HBV immune globulin are 0.06 mL/kg intramuscularly and must be given
within 7 days of exposure.
iii. Patient populations requiring postexposure prophylaxis
(a) Perinatal transmission
(1) Children born to HBsAg-positive mothers should receive vaccine plus HBV
immune globulin within 12 hours of birth.
(2) Children born to mothers with unknown HBsAg status (but suspected)
should receive vaccine within 12 hours of birth; testing should be performed
on child, and if positive, HBV immune globulin should be administered
within 1 week.
(3) Infants weighing less than 2 kg at birth whose mothers are documented to be
HBsAg negative should receive the first dose of vaccine 1 month after birth
or at hospital discharge, whichever comes first.
(b) Sexual contact or household contact with an infected person: Should receive
HBV immune globulin plus vaccine series if exposed person is previously
unvaccinated
(c) Sexual contact or household contact with an HBV carrier: Should receive vaccine
series if exposed person was previously unvaccinated
D. Hepatitis C Virus
1. Background
a. RNA virus: Six genotypes (50 subtypes)
i. Genotype 1 (subtypes 1a, 1b, and 1c) accounts for 70%75% of infections in the
United States.
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ii. Genotypes 2 (subtypes 2a, 2b, and 2c) and 3 (3a and 3b) are common in the United
States.
iii. Genotype helps determine therapy duration and likelihood of responding to therapy.
b. Leading cause of liver disease and liver transplantation in the United States; also, a
common cause of hepatocellular carcinoma
c. viral replication occurs in the hepatocyte (virus is not directly cytopathic).
d. Transmission: Mainly bloodborne (transfusion, intravenous drug abuse)
i. High risk: Transfusion, intravenous drug abuse
ii. Low risk:
(a) Snorting cocaine or other drugs
(b) Occupational exposure
(c) Body piercing and acupuncture with unsterilized needle
(d) Tattooing
(e) From pregnant mother to child
(f) Nonsexual household contacts (rare)
(g) Sharing razors and/or toothbrushes
(h) Sexual transmission
e. Associated with acute and chronic infection; after acute infection, most patients
(60%85%) will develop chronic infection
2. Clinical features: About 30% of patients are asymptomatic.
a. Acute infection: Symptoms present 412 weeks after exposure; most patients are
asymptomatic and seldom progress to fulminant disease; those who develop symptoms
have nonspecific findings such as malaise, weakness, anorexia, and jaundice.
b. Chronic infection: Defined as the presence of viral RNA in the serum for 6 months or
more
i. May be associated with the long-term development of end-stage liver disease,
cirrhosis, hepatocellular carcinoma
ii. Progression to complications and end-stage liver disease may be accelerated by
concurrent alcohol use and coinfection with HIV; younger females have slower
progression.
c. Extrahepatic manifestations: Rheumatoid symptoms, glomerulonephritis,
cryoglobulinemia
3. Diagnosis and monitoring
a. Clinical signs/symptoms such as nausea, abdominal pain, jaundice, fever, malaise, or
anorexia. Many patients have asymptomatic disease.
b. Laboratory
i. Serum anti-HCV antibodies: 99% sensitivity/specificity (enzyme immunoassays).
Used as an initial screening for HCV; presence of anti-HCV antibody does not confer
protective immunity from subsequent infection
ii. Serum HCV RNA
(a) Obtain in patients who test positive for anti-HCV antibodies.
(b) Quantitative: Viral load is typically polymerase chain reaction reported in
international units per milliliter; obtain for patients who will receive treatment;
for use in monitoring treatment response. Preferred assays for diagnosis and
monitoring of drug therapy
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(c) Qualitative: Typically, polymerase chain reaction; lower limit of detection is 50 IU/mL
(equivalent to 100 copies/mL) preferred (specificity is about 98%); typically used to
confirm diagnosis in patients who are HCV antibody positive. The American Association
for the Study of Liver Diseases (AASLD) guidelines state that there is no longer a need
for qualitative assays. Quantitative assays are preferred.
Table 18. Definitions and Monitoring of Chronic HCV Treatment Based on HCV RNA
Parameter
Definition
Rapid virologic
response (RVR)
Undetectable HCV RNA at week 4 of treatment
Early virologic
response (EVR)
> 2-log reduction in HCV RNA compared with baseline or undetectable HCV RNA at 12
weeks
End-of-treatment
response (ETR)
Undetectable HCV RNA at the end of a 24- or 48-week course depending on genotype
Sustained virologic
response (SVR)
Undetectable HCV RNA 24 weeks after finishing treatment
Breakthrough
Reappearance of HCV RNA while on treatment
Relapse
Reappearance of HCV RNA after finishing a course of treatment
Nonresponder
Failure to clear HCV RNA from serum after 24 weeks of therapy
Null responder
Failure to decrease HCV RNA by < 2 logs after 24 weeks of therapy
Partial responder
Decrease in HCV RNA by > 2 logs after 24 weeks of therapy but HCV RNA still detectable
HCV = hepatitis C virus.
iii. Liver biopsy: Consider if patient and health care provider wish to obtain information
regarding fibrosis stage or prognostic purposes or to make a decision regarding
treatment. ALT: Nonspecific; may fluctuate with chronic disease (should decrease
with treatment)
iv. Genotyping: Genotype 1 is the most common genotype in the United States; it is also
the least responsive to treatment. Genotypes 2 and 3 are the other most common
genotypes in the United States.
v. Treatment response depends on other factors such as race, age, or coinfection.
4. Treatment
a. Acute HCV infection
i. Patients with acute HCV should be considered for IFN-based therapy, preferably
with PEG-IFN for 1224 weeks. Adding ribavirin may be considered, but it is
unclear whether this improves sustained virologic response (SVR) rates.
ii. Alternatively, treatment may be delayed for 812 weeks to assess for spontaneous
resolution.
iii. Main benefit of treatment is prevention of chronic infection.
b. Chronic infection (Hepatology 2009;49:133564, 2009;39:114771)
i. Therapy goal is to attain an SVR.
ii. Indications for the treatment of patients who are treatment naive
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(a) Age older than 18 years and positive serum HCV RNA
(b) Portal or bridging fibrosis with at least moderate inflammation/necrosis on
biopsy
(c) Compensated liver disease, acceptable hemoglobin (13 g/dL men, 12 g/dL
women) and neutrophils (more than 1500/mm3), SCr less than 1.5 mg/dL
(d) Willingness to be treated and be adherent
(e) No contraindications to therapy
iii. Difficult patient populations that require individualized therapy
(a) Normal ALT (treatment dependent on genotype, degree of fibrosis, symptoms)
(b) Liver biopsy indicating no or mild fibrosis
(c) Advanced liver disease (fibrosis or decompensated cirrhosis)
(d) Recurrence after liver transplantation
(e) Patients younger than 18 years
(f) Coinfection with HIV or HBV
(g) Chronic kidney disease
(h) Users of alcohol or illicit drugs who are willing to participate in substance abuse
treatment programs
(i) Nonresponder or relapser
iv. Contraindications to treatment of chronic HCV
(a) Major uncontrolled depressive disorder
(b) Solid-organ transplantation (renal, heart, lung)
(c) Autoimmune hepatitis or other autoimmune conditions
(d) Untreated thyroid disease
(e) Pregnant or unwilling to adhere to adequate contraception
(f) Severe concurrent medical disease (hypertension, heart failure, coronary heart
disease, poorly controlled diabetes mellitus, chronic obstructive pulmonary
disease)
(g) Age younger than 2 years
(h) Hypersensitivity to IFN or ribavirin
c. Ribavirin in the treatment of HCV infection
i. Oral nucleoside analog
ii. Available as 200-mg tablets (Copegus) or capsules (Rebetol) (generic now available)
iii. Significant adverse effect profile
(a) Hemolytic anemia: May occur in up to 10% of patients (usually within 12
weeks of initiating therapy): may worsen underlying cardiac disease; monitor
complete blood cell count (CBC) at baseline, 2 weeks, 4 weeks, and periodically
thereafter. In patients with no cardiac history, decrease dose to 600 mg/day when
hemoglobin drops to 10 g/dL or less, and discontinue when hemoglobin drops to
8.5 g/dL or less. In patients with a cardiac history, decrease dose to 600 mg/day if
hemoglobin drops more than 2 g/dL in any 4-week period during treatment.
Discontinue if hemoglobin drops to less than 12 g/dL 4 weeks after dose
reduction. May use epoetin or darbepoetin to stimulate red blood cell production,
improve anemia (J Clin Gastroenterol 2005;39:S9S13), and sustain initial
starting dose. Also need to confirm iron studies are normal and within range
during treatment
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(b) Teratogenicity: Category X drug; requires a negative pregnancy test at baseline

and every month up to 6 months after treatment, as well as the use of two forms
of barrier contraception during treatment and for 6 months after treatment.
Applies to women taking the drug and female partners of male patients taking
ribavirin
(c) Contraindicated in patients with creatinine clearance (CrCl) less than 50
mL/minute and underlying hemoglobinopathies
(d) Other possible adverse events include pancreatitis, pulmonary dysfunction
(dyspnea, pulmonary infiltrate, and pneumonitis), insomnia, irritability or
depression (often referred to as riba rage) and pruritus.
d. Protease inhibitors for chronic HVC infection. Role at this time is as add-on therapy to
interferon and ribavirin as first-line therapy for patients with genotype 1.
Table 19. Protease Inhibitors Used in the Treatment of Chronic HVC Infection
Telaprevir (Incivek)
Boceprevir (Victrelis)
FDA-approved
indication
Long-term HCV therapy (genotype 1) in

combination with PEG-IFN and ribavirin in
patients with compensated liver disease
Not studied in Child-Pugh class B or C
Dose and formulation
750 mg orally 3 times/day for at least 12 weeks,

followed by PEG-IFN and ribavirin for 12
weeks if undetectable HCV RNA at weeks 4
and 12
Give doses 79 hours apart; give with meal that
has at least 20 g of fat ingested 20 minutes
prior
375-mg tablets
Take missed doses if within 4 hours
Pregnant women or male partners of pregnant
women (category B, but must be used with
ribavirin, which is category X)
CYP3A4 substrates or inducers
Alfuzosin, rifampin, DHE, St. Johns wort,
atorvastatin, lovastatin, simvastatin,
pimozide, sildenafil, tadalafil, oral triazolam
or midazolam
Several other drug-drug interactions that may
require dose adjustment of interacting drug
(see package insert)
Chronic HCV genotype 1 infection, in

combination with peginterferon alfa
and ribavirin, in adult patients ( 18
years old) with compensated liver
disease, including cirrhosis, who were
previously untreated or who have not
responded to previous interferon and
ribavirin therapy
800 mg orally 3 times/day
Give doses 79 hours apart; give with
meal or light snack
200-mg capsules
Take missed doses if within 2 hours
Contraindications
Adverse effects
Rash (56%), DRESS syndrome, or

Stevens-Johnson syndrome Anemia, pruritus,
nausea
Pregnant women or male partners of

pregnant women (category B, but must
be used with ribavirin, which is
category X) CYP3A4 substrates or
inducers
Alfuzosin, rifampin, DHE, St. Johns
wort, atorvastatin. lovastatin,
simvastatin, pimozide, sildenafil,
tadalafil, oral triazolam, or midazolam
Several other drug-drug interactions
that may require dose adjustment of
interacting drug (see package insert)
Anemia, neutropenia, fatigue, dysgeusia
CYP = cytochrome P450; DHE = dihydroergotamine; DRESS = drug reaction/rash with eosinophilia and systemic symptoms;
HCV = hepatitis C virus.
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e. Recommendations from the AASLD guidelines for the treatment of chronic HCV
infection
i. First-line therapy: PEG-IFN plus ribavirin
ii. Efficacy: 42%46% SVR for genotype 1; 76%82% SVR for genotype 2 or 3
iii. Factors associated with increased response: Genotype other than 1, lower initial HCV
RNA (less than 600,000 IU/mL), minimal fibrosis/inflammation on biopsy, lower
body weight or surface area, and nonAfrican Americans
f. Dosing of HCV treatment regimens
i. Pegylated interferon
(a) Pegasys: 180 mcg/week subcutaneously
(b) PEG-Intron: 11.5 mcg/kg/week subcutaneously
ii. Ribavirin (Rebetol or Copegus 200-mg tablets or capsules); generic products are now
available as well
(a) Genotype 1:
(1) Copegus with Pegasys: 1200 mg/day in two divided doses (more than 75 kg);
1000 mg/day in two divided doses (less than 75 kg/day)
(2) Rebetol with PEG-Intron: 800 mg/day if less than 65 kg, 1000 mg/day if
6580 kg, 1200 mg/day for 81105 kg, 1400 mg/day if more than 105 kg
(b) Genotype 2 or 3: 800 mg/day in two divided doses
iii. Protease inhibitors for genotype 1 (see table above for dosing)
iv. Treatment duration
(a) Genotype 1:
Table 20. Treatment Recommendations for Chronic HCV Genotype 1 Infection
Regimen
PEG-IFN +
ribavirin +
boceprevir
PEG-IFN +
ribavirin +
telaprevir
Patient Group
Previously untreated
Patients with HCV

RNA > 100 IU/mL at
week 12 or detectable
HCV RNA at week 24
Patient group
Treatment naive or
prior relapse
HCV RNA
Week 4
Undetectable
Detectable
HCV RNA
Week 8
Undetectable
Undetectable
Undetectable
Detectable
Undetectable
Undetectable
N/A
N/A
Discontinue all three drugs
Undetectable
Undetectable
Detectable
(1000 IU/mL
or less)
Detectable
(1000 IU/ml
or less)
1. Continue all three drugs for 12 weeks

2. Then treat with PEG-IFN and ribavirin
for an additional 12 weeks (24 weeks
total)
1. Continue all three drugs for 12 weeks
2. Then treat with PEG-IFN and ribavirin
for an additional 36 weeks (48 weeks
total)
Recommendation
Continue all three drugs for 28 weeks total
1. Continue all three drugs for a total of 36
weeks.
2. Then continue PEG-IFN and ribavirin
through week 48
Continue all three drugs for 36 weeks total
1. Continue all three drugs for a total of 36
weeks.
2. Then continue PEG-IFN and ribavirin
through week 48
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Table 20. Treatment Recommendations for Chronic HCV Genotype 1 Infection

Regimen
Patient Group
All patients
Dete ctable HCV RNA
at 24 weeks
HCV RNA
Week 4
1000
IU/mL
N/A
HCV RNA
Week 8
1000
IU/mL
N/A
Recommendation
Discontinue all three drugs at week 12
Discontinue PEG-IFN and ribavirin
HCV = hepatitis C virus; N/A = not applicable; PEG-IFN = pegylated interferon.
(b) Genotypes 2 and 3: Treat for 24 weeks.

v. Re-treatment with PEG-IFN plus ribavirin is not recommended in patients who did
not achieve an SVR after a prior full course of therapy for genotypes 2 and 3.
vi. Re-treatment with PEG-IFN plus ribavirin may be considered for nonresponders or
relapsers with genotypes 2 and 3 previously treated with an unmodified IFN with or
without ribavirin or PEG-IFN monotherapy if they have bridging fibrosis or cirrhosis.
See dosing above for genotype 1 patients who are considered previous partial
responders or relapsers.
g. Prevention of HCV
i. No vaccine or immune globulin available
ii. Risk factor modification
(a) Intravenous drug abuse: Methadone maintenance, syringe exchange
(b) Sexual contact: Appropriate barrier contraception
(c) Avoid blood exposure: Occupational (universal precautions) or other contact,
such as sharing toothbrushes or razors or receiving a tattoo
(d) The HAV and HBV vaccine to prevent further progression of liver disease
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REFERENCES
1. ASHP therapeutic guidelines on stress ulcer
prophylaxis. Am J Health Syst Pharm
1999;56:34779.
Gastroesophageal Reflux Disease

1. American Gastroenterological Association
Institute. Medical position statement on the
management of gastroesophageal reflux
disease. Gastroenterology
2008;135:138391.
2. American Gastroenterological Association
Institute. Technical review on the
management of gastroesophageal reflux
disease. Gastroenterology
2008;135:1392413.
3. Haag S, Andrews JM, Katelaris PH, et al.
Management of reflux symptoms with
over-the-counter proton pump inhibitors:
issues and proposed guidelines. Digestion
2009;80:22634.
Complications of Chronic Liver Disease

1. Garcia-Tsao G, Lim J; Members of the
Veterans Affairs Hepatitis C Resource
Center Program. Management and treatment
of patients with cirrhosis and portal
hypertension: recommendations from the
Department of Veterans Affairs Hepatitis C
Resource Center Program and the National
Hepatitis C. Am J Gastroenterol
2009;104:180229.
2. Runyon BA. Management of adult patients
with ascites due to cirrhosis: an update.
Hepatology 2009;49:2087107.
3. Blei AT, Cordoba J. Hepatic
encephalopathy. Am J Gastroenterol
2001;96:196876.
4 OShea RS, Dasarathy S, McCullough AJ.
Alcoholic liver disease. Am J Gastroenterol
2010;105:1432.
Peptic Ulcer Disease

1. Chey WD, Wong BVY. American College
of Gastroenterology guidelines for the
management of Helicobacter pylori
infection. Am J Gastroenterol
2007;102:180825.
2. Lanza FL, Chan FKL, Quigley EMM, et al.
Guidelines for the prevention of
NSAID-ulcer complications. Am J
Gastroenterol 2009;104:72838.
3. Wilcox CM, Allison J, Benzuly K, et al.
Consensus development conference on the
use of nonsteroidal anti-inflammatory
agents, including cyclooxygenase inhibitors
and aspirin. Clin Gastroenterol Hepatol
2006;4:10829.
4. ACCF/ACG/AHA. 2008 expert consensus
document on reducing the gastrointestinal
risks of antiplatelet therapy and NSAID use.
Circulation 2008;118:1894909.
5. ACCF/ACG/AHA 2010 expert consensus
document on the concomitant use of proton
pump inhibitors and thienopyridines: a
focused update of the ACCF/ACG/AHA
2008 expert consensus document on
reducing the gastrointestinal risks of
antiplatelet therapy and NSAID use. J Am
Coll Cardiol 2010;56:205166.
Upper GI Bleeding and SRMD
Viral Hepatitis
1. Update: prevention of hepatitis A after
exposure to hepatitis A virus and in
international travelers. Updated
recommendations of the Advisory
Committee on Immunization Practices
(ACIP). MMWR 2007;56:10804.
2. Lok A, McMahon BJ. Chronic hepatitis B:
update 2009. Hepatology 2009;50:136.
3. Centers for Disease Control and Prevention.
Updated U.S. Public Health Service
guidelines for the management of
occupational exposures to HBV, HCV, and
HIV and recommendations for postexposure
prophylaxis. MMWR 2001;50(RR-11):152.
A comprehensive immunization strategy to
eliminate transmission of hepatitis B virus
infection in the United States:
(ACIP). Part 1. Immunization of infants,
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7. Ghany MG, Strader DB, Thomas DL, et al.

Diagnosis, management, and treatment of
hepatitis C: an update. Hepatology
2009;49:133564.
8. Ghany MG, Nelson DR, Strader DB, et al.
An update on treatment of genotype 1
chronic hepatitis C virus infection: 2011
practice guideline by the American
Association for the Study of Liver Diseases.
Hepatology 2011;54:143344.
9. 4. Ramkumar D, Rao SSC. Efficacy and
safety of traditional medical therapies for
chronic constipation: systematic review. Am
J Gastroenterol 2005;100:93671.
children, and adolescents. MMWR

2005;54(RR-16):123.
A comprehensive immunization strategy to
eliminate transmission of hepatitis B virus
infection in the United States:
(ACIP). Part II. Immunization of adults.
MMWR 2006;54(RR-16):140.
Recommendations for identification and
public health management of persons with
chronic hepatitis B virus infection. MMWR
2008;57(RR-08):120.
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1. Given a patient with hypertension, outline the optimal pharmacologic management on the
basis of practice guidelines and clinical trial evidence.
2. Identify and determine the appropriate therapeutic goals for a patient with dyslipidemia on
the basis of cardiovascular (CV) risk factors.
3. Develop a pharmacotherapy treatment plan for a patient with dyslipidemia on the basis of
various cholesterol targets as well as CV risk factors.
4. Develop a pharmacotherapy treatment plan for a patient with peripheral arterial disease
(PAD).
5. Demonstrate an understanding of the pathophysiology, prognosis, and economic impact of
PAD.
6. Create an evidence-based drug regimen for a patient with coronary artery disease in both the
presence and absence of stable angina.
7. Distinguish between the different acute coronary syndromes (ACSs), ST-segment elevation
myocardial infarction, nonST-segment elevation myocardial infarction, and unstable angina
by diagnosis as well as treatment.
8. Develop a pharmacotherapy treatment plan for a patient presenting with the various ACSs.
9. Recommend patient-specific pharmacologic management of chronic heart failure, with an
emphasis on mortality-reducing drugs and their target dosages.
10. Develop an appropriate pharmacologic and monitoring plan for a patient with atrial
fibrillation.
11. Discuss indications for warfarin and goal INR for specific patients, and adjust therapy
according to INR, other clinical findings, and/or patient factors.
12. Describe how to design a treatment plan for a patient receiving warfarin who needs to
undergo an invasive procedure.
13. Determine the appropriate immunizations for an adult given his/her age and medical
conditions.
I. Hypertension
A. Background
1. Definition: Hypertension is considered a blood pressure (BP) of 140/90 mm Hg or
higher.
2. Statistics
a. Most common chronic disease in the United States
b. Affects 50 million Americans
c. The normotensive 50-year-old lifetime risk of developing hypertension is 90%.
d. For each 20-mm Hg increase in systolic BP and 10-mm Hg increase in diastolic
BP, there is a 2-fold increased risk of cardiovascular (CV) disease (e.g., stroke,
MI).
e. Only 31% of patients with hypertension have it under adequate control.
3. Etiology
a. Essential hypertension: 90% (no identifiable cause)
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i. Contributed to by obesity
ii. Evaluate sodium (Na) intake.
b. Secondary hypertension
i. Primary aldosteronism
ii. Renal parenchymal disease
iii. Thyroid or parathyroid disease
iv. Medications (e.g., cyclosporine, nonsteroidal anti-inflammatory drugs
[NSAIDs], sympathomimetics)
4. Diagnosis
a. Periodic screening for all individuals older than 21 years
b. Patient should be seated quietly in chair for at least 5 minutes.
c. Use appropriate cuff size (bladder length at least 80% the circumference of the
arm).
d. Take BP at least twice, separated by at least 2 minutes.
e. The average BP on two separate visits is required to diagnose hypertension
accurately.
5. Benefits of lowering BP
a. 40% decrease in stroke
b. 25% decrease in myocardial infarction (MI)
c. 50% decrease in heart failure (HF)
6. Effects of lifestyle modifications on BP
Table 1.
Modification
Recommendation
Weight reduction
Attain/maintain BMI less than 25 kg/m2
(if more than 25 kg/m2)
Approximate
Systolic BP
Reduction
520 mm Hg per 10kg weight loss
Adopt DASH eating

plan (includes
substantial potassium
intake)
Consume a diet rich in fruits, vegetables, and low-fat

dairy products with a reduced content of saturated and
total fat
814 mm Hg
Dietary sodium
restriction
Reduce dietary sodium intake to no more than 2.4 g of

sodium
28 mm Hg
Physical activity
Engage in regular aerobic physical activity such as

49 mm Hg
brisk walking (at least 30 minutes/day most days of the
week)
Moderation of alcohol
consumption
Limit consumption to:

Men: 2 drinks/day
Women: 1 drink/day
24 mm Hg
BMI = body mass index; BP = blood pressure; DASH = Dietary Approaches to Stop Hypertension.
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B. Therapeutic Management
1. Patient classification and management in adults: Primary classification based on
systolic BP
Table 2.
BP Classification
Normal
Systolic BP (mm
Hg)
Diastolic BP (mm Hg)
Lifestyle
Modification
< 120
AND
< 80
Encourage
Prehypertension
120139
OR
8089
Yes
Stage 1 hypertension
140159
OR
9099
Yes
Stage 2 hypertension
160
OR
100
Yes
BP = blood pressure.
2. Select treatment goal.

a. Seventh Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure (JNC 7) goals are less than
140/90 mm Hg for all patients except for those with diabetes and/or significant
chronic kidney disease (defined as estimated glomerular filtration rate less than 60
mL/minute/1.73m2 [about when serum creatinine {SCr} is greater than 1.5 mg/dL
in men or greater than 1.3 mg/dL in women]) OR albuminuria (greater than 300
mg/day or greater than 200 mg alb/g creatinine)], in which the goal is 130/80 mm
Hg.
b. Other treatment goals exist; however, they are controversial and not universally
accepted.
i. American Heart Association 2007 recommendation
ii. International Society on Hypertension in Blacks recommendations
3. Select appropriate therapy
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Figure 1.
NOTE: Strength of recommendation (A, B, and C = good, moderate, and poor evidence to support
recommendation) and quality of evidence [1 = Evidence from more than 1 properly randomized,
controlled trial. 2 = Evidence from at least 1 well-designed clinical trial with randomization, from cohort
or case-controlled analytic studies; or dramatic results from uncontrolled experiments or subgroup
analyses. 3 = Evidence from opinions of respected authorities, based on clinical experience, descriptive
studies, or reports of expert communities] are in brackets.
Modified from Saseen JJ, MacLaughlin EJ. Hypertension. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM, eds. Pharmacotherapy: A Pathophysiological Approach, 8th ed. New York: McGraw-Hill,
2008:chap 19.
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker.
4. Considerations with specific antihypertensive agents

a. -Blockers
i. Caution with asthma, severe chronic obstructive pulmonary disease
(especially higher doses) because of pulmonary -receptor blockade
ii. Increased risk of developing diabetes compared with ACE inhibitor,
angiotensin receptor blocker (ARB), and calcium channel blocker; use caution
in patients at high risk of diabetes mellitus (e.g., family history, obese)
iii. May mask some signs of hypoglycemia in patients with diabetes mellitus
iv. May cause depression
b. Thiazides
i. May worsen gout by increasing serum uric acid
ii. Increased risk of developing diabetes compared with angiotensin-converting
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enzyme (ACE) inhibitors, ARBs, and calcium channel blockers; use caution in
patients at high risk of diabetes mellitus (e.g., family history, obese)
iii. May assist in the management of osteoporosis by preventing urine calcium
loss
c. ACE inhibitors and ARBs
i. Contraindicated in pregnancy
ii. Contraindicated with bilateral renal artery stenosis
iii. Monitor potassium (K) closely, especially if renal insufficiency exists or
another K-sparing drug is in use.
iv. The presence of diabetic nephropathy should influence the choice of an ACE
inhibitor versus an ARB.
d. Aliskiren
i. A direct rennin antagonist
ii. When combined with losartan (100 mg/day) in patients with hypertension,
type 2 diabetes mellitus, and nephropathy (albumin-to-creatinine ratio greater
than 300 mg/g or greater than 200 mg/g), aliskiren showed renoprotective
effects independently of its BP effects (N Engl J Med 2008;358:243346).
iii. Whether this combination is superior to ACE inhibitor/ARB combinations is
unknown.
Table 3.
Type
Nephropathy
Agent
Any level of proteinuria
ACEI
Microalbuminuria
ACEI or ARB
Macroalbuminuria and renal insufficiency (i.e., elevated SCr)
ARB
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; SCr = serum creatinine.
5. Considerations within specific patient populations

a. Patients with ischemic heart disease: Potent vasodilators may cause reflex
tachycardia, thereby increasing myocardial oxygen demand (hydralazine, minoxidil,
and calcium channel blockers with dihydropyridine); can attenuate this by also using
an atrioventricular nodal depressant (non-dihydropyridine calcium-channel blocker
or -blocker)
b. Elderly patients:
i. Caution with antihypertensive agents and orthostatic hypotension
ii. Initiate with low dose and titrate slowly.
c. African American patients: -Blockers and ACE inhibitors are generally less
effective as monotherapy than in white patients; however, combination therapy
with thiazides improves effectiveness, and it should still be used if comorbid
conditions dictate.
d. Pregnant women
i. Methyldopa and hydralazine are recommended if a new therapy is initiated.
ii. Most antihypertensives (except for ACE inhibitors and ARBs) can be safely
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continued in pregnancy.
6. Monitoring
a. Have the patient return in 4 weeks to assess efficacy.
b. May have patient follow up sooner if BP is particularly worrisome
c. If there is an inadequate response from the first agent (and adherence verified)
and no compelling indication exists, initiate therapy with a drug from a different
class.
II. Dyslipidemia
A. Diagnosis
1. Complete fasting lipoprotein profile preferred (i.e., total cholesterol [TC], low-density
lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TG])
2. After 912 hours of fasting (however, with the availability of measuring direct LDL,
fasting not always necessary)
B. ATP (Adult Treatment Panel) III Lipid and Lipoprotein Classification
1. LDL (mg/dL)
Less than 100
Optimal
100129
Near-optimal/above optimal
130159
Borderline high
160189
High
190 or more
Very high
2. HDL (mg/dL)
Less than 40
Low
60 or more
High
3. TC (mg/dL)
Less than 200
Desirable
200239
Borderline high
240 or more
High
4. TG (mg/dL)
Less than 150
Normal
150199
Borderline high
200499
High
500 or more
Very high
Classification National Institutes of Health National Heart, Lung and Blood Institute.
Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III). Available at
www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.
C. Coronary Heart Disease and Risk Equivalents
1. Coronary heart disease (CHD): MI, coronary artery bypass graft, percutaneous
coronary intervention with or without stent, acute coronary syndrome (ACS)
2. Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal
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aortic aneurysm, and symptomatic carotid artery disease)

3. Diabetes mellitus
4. 10-year risk of CHD is more than 20% on the basis of Framingham.
D. Main Positive Risk Factors (exclusive of LDL) That Modify LDL Goals
1. Cigarette smoking
2. Hypertension (BP 140/90 mm Hg or higher or taking an antihypertensive drug)
3. Low HDL (less than 40 mg/dL)
4. Family history of premature CHD
a. CHD in male first-degree relative younger than 55 years
b. CHD in female first-degree relative younger than 65 years
5. Age (men 45 years or older; women 55 years or older)
E. Main Negative Risk Factors (exclusive of LDL) That Modify LDL Goals: High HDL
(more than 60 mg/dL) (subtract 1 from the total number of risk factors)
F. Risk Assessment
1. For patients with several (two or more) risk factors, perform a Framingham 10-year
CHD risk assessment.
2. For patients with zero or one risk factor, a 10-year risk assessment is not required.
3. A 10-year CHD risk assessment is based on Framingham tables.
a. Sex
b. Age
c. Total cholesterol
d. Smoking
e. High-density lipoprotein
f. Systolic BP
G. Three Categories of Risk That Modify LDL Goals
Table 4. Goal LDL According to Risk Category and LDL Concentration to Start
Pharmacotherapy
Risk Categorya
LDL Goal (mg/dL)
LDL to Start Pharmacotherapy (mg/dL)
CHD and CHD risk

equivalents
(10-year risk > 20%)
< 100 (optional < 70)
130; 100 optional ( 100 or < 100)
Several (2+) risk factors

(10-year risk 10%20%)
< 130 (optional < 100) 130 ( 100)
Several (2+) risk factors

(10-year risk < 10%)
< 130
160
0 or 1 risk factor
< 160
190; 160 optional
Risk factors: See item D above. The LDL concentrations in parentheses are from Grundy SM, et al. Implications of recent
clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227
39. Only concentrations that are different from the National Cholesterol Education Panel guidelines are included in parentheses.
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Consider less than 70 for everyone at very high CHD risk or with stable CHD, based on PROVE-IT (N Engl J Med 2004;350)
and TNT (N Engl J Med 2005;352:142535) studies, which were published after the 2004 ATP (Adult Treatment Panel) III
update.
CHD = coronary heart disease; LDL = low-density lipoprotein.
Classification National Institutes of Health National Heart, Lung and Blood Institute. Third Report of the Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Available at
H. Therapeutic Lifestyle Changes

1. Initiate therapeutic lifestyle changes if LDL is above goal.
a. Weight reduction
b. Increased physical activity
c. Therapeutic lifestyle changes in diet
d. Plant stanols/sterols (2 g/day): Soybean and tall pine tree oils
e. Viscous (soluble) fiber (1025 g/day): Oats, barley, pectin, psyllium
f. Nutrient composition of therapeutic lifestyle changes diet
Table 5. Dietary Recommendations
Nutrient
Recommended Intake
Saturated fat
Less than 7% of total calories
Polyunsaturated fat
Up to 10% of total calories
Monounsaturated fat
Up to 20% of total calories
Total fat
25%35% of total calories
Carbohydrate
50%60% of total calories
Fiber
2030 g/day
Protein
About 15% of total calories
Cholesterol
Less than 200 mg/day
Classification National Institutes of Health National Heart, Lung and Blood Institute. Third Report of the Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Available at
I. Management of Low HDL

1. If TG is 500 mg/dL or greater, TG is primary target.
2. If TG is 200499 mg/dL, non-HDL is secondary target of therapy.
3. If TG is less than 200 mg/dL and HDL is low, consider niacin or fibrates; may add to
statins after lowering LDL
4. Niacin is safer in combination with statins than with fibrates (myopathy).
5. Smoking cessation, exercise
J. Management of Very High TG Concentrations (500 mg/dL or more)
1. Therapy goal: Prevent acute pancreatitis.
2. Very low-fat diets (15% or less of caloric intake), reduce or eliminate alcohol
3. TG-lowering drug usually required
4. Fibrate or niacin
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5. Reduce TG before LDL lowering.

6. After TG concentrations are reduced, lower LDL. Achieve LDL goal before treating
non-HDL.
7. Non-HDL cholesterol (HDL-C): Secondary target
a. Non-HDL = VLDL + LDL (VLDL = very LDL)
b. Non-HDL = (TC HDL)
c. Non-HDL: Secondary target of therapy when serum TG is 200 mg/dL or greater
d. Non-HDL goal: LDL goal plus 30 mg/dL
e. Comparison of LDL and non-HDL goals for three risk categories
f. Therapeutic approaches to elevated non-HDL
i. Intensify therapeutic lifestyle changes.
ii. Intensify LDL-lowering drug therapy.
Table 6. Emerging Risk Factors
Emerging Risk Factor and Key Points
Increased by
High-sensitivity C-reactive protein (hs-CRP)

Is a mediator of immune response
Serves as marker of inflammation
May be stronger CHD risk predictor than

LDL-C
Unknown whether there are clinical benefits
from lowering hs-CRP
May be useful in motivating a patient to
adhere to lifestyle modifications (i.e., patient
with unremarkable lipid panel needing
lifestyle modification)
Use selectively (i.e., LDL-C, > 2 risk
factors, and 10-year risk 10%20%; if hsCRP > 1 mg/L, use more intensive
treatment)
A value > 2 mg/dL is a strong predictor of
CHD risk
Inflammation
Smoking
Hormone
replacement
therapy
Fibrinogen
Inflammation
Many factors modulate fibrinogen levels
Smoking
(diabetes, hypertension, inflammation,
obesity, sedentary lifestyle, smoking)
Elevated levels associated with
cardiovascular events
Unknown whether it has causal role or is a
marker of vascular damage
to lowering fibrinogen
Measurement and
Decreased by Interpretation
Weight loss
Physical
activity
Statins
Fibrates
Ezetimibe
Aspirin
Obtain two hs-CRP

measurements
Use lower or average
Patient must be clinically
stable (no infection, recent
hospitalization, recent trauma)
If > 10 mg/L, repeat test;
probably noncardiac cause of
elevation. Chronic
inflammatory diseases (e.g.,
rheumatoid arthritis) will
increase CRP concentrations
Risk level of hs-CRP
Low: < 1.0 mg/L
Intermediate: 1.03.0 mg/L
High: > 3 mg/L
Exercise
Stop
smoking
Niacin
Fibrates
No recommendations at this
time
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Table 6. Emerging Risk Factors

Measurement and
Decreased by Interpretation
Emerging Risk Factor and Key Points
Increased by
Homocysteine
Patients with inborn errors in homocysteine
metabolism have a high risk of venous
thrombosis at early age (< 30 years). Risk
may be partly decreased with high-dose B
vitamins
Mild-moderate elevations may predispose
patients to atherosclerosis
Unknown whether it has causal role or is a
marker of vascular damage
Unknown whether there are cardiovascular
benefits to lowering homocysteine.
Lowering homocysteine with folic acid has
not been associated with cardiovascular risk
reduction
Renal failure
Replacement No recommendations at this
time
of folate,
Hypothyroidis
vitamin B6,
m
vitamin B12
Deficiency of
folate, vitamin Genetics
B6, vitamin
B12
Methotrexate
Genetics
Lp(a)
Inflammation
LDL-like particle controlled mainly by
Genetics
genetics
May be highly thrombogenic
When elevated, may increase the risk of
cardiovascular events in patients with
diabetes, hypertension, LDL-C, HDL-C,
homocysteine, fibrinogen
Unaffected by diet or exercise
to lowering Lp(a)
Optimal role in screening/risk determination
has not been determined
Niacin
Estrogen
Genetics
No recommendations at this
time
HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a).
K. Elevated C-Reactive Protein in Low-Risk Individuals: JUPITER study (Ridker PM, et al. N Engl
J Med 2008;359:2195207)
1. More than 15,000 subjects with no prior coronary artery disease (CAD) or diabetes mellitus,
with normal LDL (less than 130 for inclusion; median, 108), high C-reactive protein (2 mg/L
or greater) (median C-reactive protein, 4.24.3)
2. Rosuvastatin 20 mg versus placebo
3. Trial was terminated early because of significant reduction in CV death and CV events
(hazard ratio = 0.56; 95% confidence interval, 0.460.69)
L. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) Reductase Inhibitors (statins)
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Figure 2.
1. Efficacy
a. Drugs of choice for high LDL and/or CHD or CHD risk
b. When selecting a statin, consider the percentage of LDL reduction needed.
i. (current LDL goal LDL)/current LDL 100
ii. Select an initial dose to achieve an LDL reduction of 30%40% if possible.
c. Reduce LDL 24%60%.
d. Reduce TG 7%40%.
e. Raise HDL 5%15%.
f. Reduce major coronary events.
g. Reduce CHD mortality.
h. Reduce coronary procedures (percutaneous transluminal coronary angioplasty/coronary
artery bypass graft).
i. Reduce stroke.
j. Reduce total mortality.
2. Mechanism of action: Inhibits enzyme responsible for converting HMG-CoA to mevalonate
(rate-limiting step in production of cholesterol)
3. Main adverse effects/monitoring
a. Myopathy (check creatine kinase at baseline and then only if muscle symptoms occur; no
regular monitoring)
b. Increased liver enzymes
c. Liver function tests (LFTs) at baseline, 3 months, and yearly
4. Contraindications
a. Absolute: Severe liver disease (AST/ALT [aspartate aminotransferase/alanine
aminotransferase] more than 3 ULN [upper limits of normal])
b. Relative: Use with certain medications (strong cytochrome P450 [CYP] 3A4 inhibitors).
5. Drug interactions
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a. CYP3A4 substrates: Simvastatin, lovastatin, atorvastatin

i. Avoid, if possible, with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,
erythromycin, clarithromycin, HIV [human immunodeficiency virus] protease
inhibitors, nefazodone, cyclosporine, telithromycin, danazol, amiodarone, verapamil).
ii. Preferable to use pravastatin, rosuvastatin
b. Fibrates: Increased risk of myopathy/rhabdomyolysis when coadministered with statins
i. Risk is greater with gemfibrozil than with fenofibrate.
ii. Niacin: Doses greater than 1 g/day increase the risk of myopathy/rhabdomyolysis
when used concomitantly with statins; risk is lower than with fibrates; statins and
niacin are usually used together; monitor for muscle pain
Table 7. Statin Doses and LDL-Lowering Effect
Drug and Dose
LDL-C Average Reduction (%)
Lovastatin ER (Altocor)
10 mg/day
20 mg/day
40 mg/day
60 mg/day
24
30
36
41
Rosuvastatin (Crestor)
5 mg/day
10 mg/day
20 mg/day
40 mg/day
45
52
55
63
Fluvastatin (Lescol)
20 mg/day
40 mg/day
40 mg twice daily
22
25
36
Atorvastatin (Lipitor)
10 mg/day
20 mg/day
40 mg/day
80 mg/day
39
43
50
60
Lovastatin (Mevacor)
10 mg/day
20 mg/day
40 mg/day
40 mg twice daily
21
27
31
42
Simvastatin (Zocor)
5 mg/day
10 mg/day
20 mg/day
40 mg/day
80 mg/day
26
30
38
41
47
Pitavastatin (Livalo)
1 mg/day
2 mg/day
4 mg/day
32
36
43
Pravastatin (Pravachol)
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Table 7. Statin Doses and LDL-Lowering Effect

Drug and Dose
LDL-C Average Reduction (%)
10 mg/day
20 mg/day
40 mg/day
80 mg/day
22
32
34
37
Note: For any doubling of statin dose, the LDL-C will only decrease by an additional 6%.
ER = extended release; LDL-C = low-density lipoprotein cholesterol.
M. Bile Acid Sequestrants

1. Principal actions
a. Reduce LDL 15%26%.
b. Raise HDL 3%6%.
c. May increase TG concentrations
d. Reduce major coronary events.
e. Reduce CHD mortality.
2. Mechanism of action: Bind to bile acids to disrupt enterohepatic recirculation of bile acids.
Liver is stimulated to convert hepatocellular cholesterol to bile acids.
3. Adverse effects: Gastrointestinal (GI) distress/constipation
4. Decreased absorption of other drugs: Warfarin, -blockers, and thiazides, so administer drugs
12 hours before or 4 hours after bile acid
5. Contraindications: Dysbetalipoproteinemia, increased TG concentrations (especially greater
than 400 mg/dL)
Table 8. Bile Acid Sequestrants
Drug
Brand
Dose Range (g)
Cholestyramine
Questran
416
Colestipol
Colestid
520
Colesevelam
Welchol
2.63.8
Table 9. Dose-Dependent Effects of BAS on LDL-C Concentrations

Colestipol
Cholestyramine
Dose (g)
% LDL-C Reduction
12
10
20
15
24
48
812
13
1216
17
1620
21
2024
28
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Table 9. Dose-Dependent Effects of BAS on LDL-C Concentrations
Colesevelam
Dose (g)
% LDL-C Reduction
3.8
15
4.5
18
BAS = bile acid sequestrant; LDL-C = low-density lipoprotein cholesterol.
N. Niacin
1. Main actions
a. Lowers LDL 15%26%
b. Lowers TG 20%50%
c. Raises HDL 15%26%
d. Reduces major coronary events
e. Possibly reduces total mortality
f. Lowers lipoprotein(a)
2. Mechanism of action: Inhibits mobilization of free fatty acids from peripheral adipose tissue
to the liver, so reduces VLDL synthesis (LDL and TG)
3. Adverse effects: Flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity;
monitor LFTs at baseline, every 612 weeks, and then yearly
4. Sustained release appears to be more hepatotoxic than other preparations (e.g., over-thecounter drugs). Available as Slo-Niacin or 2 times/day generic niacin over the counter. Use
of these products should be avoided
5. Extended release and sustained release are less likely to cause flushing.
6. Contraindications: Liver disease, severe gout, active peptic ulcer
7. Flushing can be minimized by taking ASA 30 minutes before niacin, taking at bedtime with
food, and avoiding hot beverages, spicy foods, and hot showers around the time of
administration.
Table 10. Niacin Formulations
Drug Form
Brand Name
Dose Range (g)
Immediate release
Niacin
1.53
Extended release
Niaspan
12
Sustained release
Slo-Niacin
12
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Table 11. Dose-Dependent Effects of Extended-Release Niacin (Niaspan) on Lipid Parameters

TC (%)
LDL-C (%)
TG (%)
HDL-C (%)
Niaspan 500 mg
+10
Niaspan 1000 mg
+15
Niaspan 1500 mg
11
14
28
+22
Niaspan 2000 mg
12
17
35
+26
HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; TG =
triglycerides.
O. Fibrates
1. Main actions
a. Lower LDL 5%20% (with normal TG)
b. May raise LDL to 45% (with very high TG)
c. Lower TG 30%55%
d. Raise HDL 18%22%
e. Reduce progression of coronary lesions
f. Reduce major coronary events
2. Mechanism of action: Reduce rate of lipogenesis in the liver
3. Adverse effects: Dyspepsia, gallstones, myopathy, increased hepatic transaminases; monitor
LFTs every 3 months during first year and then periodically
4. Contraindications: Severe renal or hepatic disease
Table 12. Fibrate Formulations and Dosing
Druga
Brand Name
Dose
Gemfibrozil
Lopid
600 mg 2 times/day
Fenofibrate
TriCor
48145 mg/day without regard to meals
Fenofibrate
Lofibra micronized
67200 mg/day with meals
Fenofibrate
Lofibra
Fenofibrate
Antara
Fenofibrate
Fenoglide
Fenofibrate
Lipofen
Fenofibrate
Triglide
Fenofibric acid
Trilipix
The fenofibrate formulations are not interchangeable.
P. Ezetimibe (Zetia) 10 mg/day

1. Efficacy
a. Lowers LDL 18%20%
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2.
3.
4.
5.
6.
7.
b. May raise HDL 1%5%

c. Lowers TG 7%17%
Mechanism of action: Inhibition of cholesterol absorption
Adverse effects: Headache, rash; no monitoring necessary, except LFTs when coadministered
with statins
Adjunctive therapy to statin
No outcomes data
In patients with familial hypercholesterolemia, combined therapy with ezetimibe and
simvastatin did not result in significant changes in intima-media thickness compared with
simvastatin alone, despite decreases in concentrations of LDL and C-reactive protein
(Kastelein JJP, et al. N Engl J Med 2008;358:143143).
Possible increased cancer risk; but evidence is conflicting
Table 13. Effect of Ezetimibe on Lipid Parameters

TC (%)
LDL-C (%)
TG (%)
HDL-C (%)
Ezetimibea alone
12
18
+1
Ezetimibea,b + HMG-CoA
17
25
14
+3
Ezetimibe + fenofibrate 160 mg
22
20
44
+19
Mean percent change from baseline.

Represents mean of all statins.
HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; TG =
triglycerides.
Q. Omega-3 Acid Ethyl Esters (Lovaza)

1. Efficacy
a. Lowers TG 26%45%
b. May raise LDL to 45% when TG concentrations are very high
c. Raises HDL 11%14%
2. Mechanism of action: Unknown. Possible inhibition of acyl CoA:1,2 diacylglycerol
acyltransferase, increase in hepatic -oxidation, or reduction in TG hepatic synthesis
3. Adverse effects: GI (e.g., burping, taste perversion, dyspepsia); at more than 3 g/day:
Inhibition of platelet aggregation, bleeding
4. Dose: 4 g/day as a single daily dose or in two divided doses
III. Peripheral Arterial Disease

A. Definition
1. Peripheral arterial disease (PAD) is a generic term that encompasses vascular insufficiencies
caused by noncoronary arteries secondary to atherosclerotic occlusions. The arteries affected
supply bloodflow to the brain, visceral organs, and limbs.
a. FunctionalCaused by spasm of the vessels. Ex. Raynaud disease
b. OrganicCaused by structural changes in blood vessels. Ex. Fatty buildup in the arteries
2. In North America and Europe, around 27 million people are affected by the disease. About
10.5 million people are symptomatic, and 16.5 million are asymptomatic. The incidence
increases with age, with about 20% of patients older than 70 years affected.
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B. SymptomsMay be initially asymptomatic and then progress to intermittent claudication and

possibly to critical leg ischemia
1. Leg or hip pain during walking
2. Cold legs and feet
3. Changes in skin color
4. Pain that is reduced upon resting
5. Numbness or tingling
C. Diagnosis
1. Ankle brachial index (ABI): BP is measured in the arms and ankles using a regular BP cuff
and a Doppler. The two pressures are then compared, and a determination is made on the
adequacy of bloodflow. The specific index or reference number is determined by dividing the
ankle systolic pressure by the arm systolic pressure.
a. May be done with or without a treadmill
b. Calculation of ABI
i. Right ABI = Higher right ankle pressure/higher brachial pressure
ii. Left ABI = Higher left ankle pressure/higher brachial pressure
Table 14. ABI Interpretation
Level
Interpretation
11.29
Normal resting ABI
0.910.99
Borderline
0.410.9
Mild to moderate
00.4
Severe
ABI = ankle brachial index.
2. Pulse volume recordingUsed to establish initial lower extremity diagnosis (localization and
severity)
3. Duplex ultrasonographyUsed to assess anatomic location and the degree of stenosis. Often
used as a follow-up procedure after a femoral-popliteal or femoral-tibial pedal bypass
4. Continuous wave Doppler ultrasoundUsed to determine the location of the diseased
segment as well as the severity. Can be helpful to monitor disease progression
5. Magnetic resonance imagingUsed to assess anatomic location and disease severity. Most
useful in assessing patients for endovascular intervention
6. Computed tomographic angiographyUsed to determine the location of the stenosis as well
as the degree of stenosis
7. Contrast angiographyProvides detail on the anatomy of the arteries and is used to assess
patients possibly undergoing revascularization
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Table 15. PAD Risk Factors

Age > 50 years
Cigarette smoking
Diabetes
High cholesterol
Family history
Hypertension
Elevated homocysteine
hs-CRP
Male sex
hs-CRP = high-sensitivity C-reactive protein; PAD = peripheral arterial disease.
D. TreatmentGeneral
1. Diet
2. Exercise
3. Smoking cessationApplicable to all forms of tobacco
a. Single most important intervention
b. People who smoke receive a diagnosis of PAD as much as 10 years before a nonsmoker.
4. Drug therapy
a. Statins initiationGoal LDL cholesterol (LDL-C) of less than 70 mg/dL for patients
deemed very high risk
b. Fibric acid agentsUsed for patients with low high-density lipoprotein cholesterol
(HDL-C), normal low-density lipoprotein cholesterol (LDL-C), and high triglycerides
(TG)
c. AntihypertensivesGoal BP of less than 140/90 mm Hg if nondiabetic and less than
130/80 mm Hg if diabetic or with chronic kidney disease
i. -Blockers
ii. ACE inhibitors
d. Diabetes control including proper foot careGoal hemoglobin A1C less than 7%
e. Homocysteine
f. Folic acid and B12 vitamin supplements
g. Antiplatelet agents
i. Recommended for all patients with lower extremity disease
ii. Aspirin 75325 mg orally daily is effective.
iii. Clopidogrel 75 mg orally daily is an alternative to ASA.
iv. WarfarinNot indicated
E. TreatmentClaudication
1. Cilostazol (Pletal)
a. Mechanism of actionA phosphodiesterase type 3 inhibitor that causes an increase in
cyclic adenosine monophosphate. It has both vasodilatory and antiplatelet effects.
b. Precise mechanism in claudication is unknown.
c. Dose100 mg orally 2 times/day
d. This agent improves symptoms and increases walking distance.
e. Avoid use in patients with heart failure (HF).
2. Pentoxifylline (Trental)
a. Mechanism of actionA methylxanthine derivative; reduces blood and plasma viscosity,
inhibits neutrophil adhesion and activation, increases erythrocyte and leukocyte
deformability, and lowers plasma fibrinogen levels
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b. Recommend 400 mg orally 3 times/day.

c. Second-line agent
d. Questionable efficacy
3. Additional therapies evaluated: Oral vasodilator prostaglandins (beraprost or iloprost)
4. Interventional radiology
a. Reserved for patients with lifestyle-limiting symptoms
b. May include angioplasty or stents
F. TreatmentCritical Limb Ischemia
1. Pentoxifylline (Trental)Parenteral
2. Oral vasodilator prostaglandins (beraprost or iloprost)
3. Endovascular treatment
4. Thrombolysis
5. SurgeryReserved for patients with significant disease; thrombectomy, bypass grafts
IV. CHRONIC CORONARY HEART DISEASE AND CHRONIC STABLE ANGINA

A. Overview
Coronary artery disease (CAD) is a general term that does not discriminate between the various
phases the individual may cycle between for several decades. These phases include asymptomatic
disease, stable angina, progressive angina, unstable angina (UA), ST-segment elevation
myocardial infarction (STEMI), and non-STEMI (NSTEMI).
On the basis of a patients manifestations, some therapies may be added or modified. However,
several basic treatment rules apply to all individuals with CAD, regardless of the symptoms they
may experience.
The following mnemonic, developed for patients with chronic stable angina, can be applied to all
patients with CAD.
A = Aspirin and Antianginal Therapy
B = -Blocker and BP
C = Cigarette Smoking and Cholesterol
D = Diet and Diabetes
E = Education and Exercise
Although not all patients with CAD have diabetes or smoke cigarettes, the mnemonic is a way to
remember the primary areas that should be addressed, as applicable, in all patients with CAD.
Some important recommendations:
Weight reduction/maintenance to a BMI (body mass index) of 18.524.9 kg/m2;
Physical activity for 3060 minutes/day 7 days/week (minimum of 5 days/week);
LDL-C less than 100 mg/dL;
BP less than 130/80 mm Hg;
No smoking and no environmental exposure to smoke;
Reduced intake of saturated fats (to less than 7% of total calories), trans-fatty acids, and
cholesterol (to less than 200 mg/day); and
If diabetic, glycosylated hemoglobin less than 7%; and influenza vaccine each year.
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B. Therapeutic Management of CAD

1. Antiplatelet therapy
a. Aspirin
i. Inhibits synthesis of thromboxane A2
ii. Indicated in all patients with CAD, unless contraindicated
iii. Dose at 75162 mg/day.
iv. Decreases cardiovascular events by about one-third
b. Clopidogrel
i. Prevents adenosine diphosphatemediated platelet activation
ii. A dose of 75 mg/day if aspirin absolutely contraindicated
iii. Magnitude of benefit unclear; however, appears to be about the same as that of
aspirin
c. Dipyridamole: Should be avoided in symptomatic CAD
i. Increases exercise-induced myocardial ischemia
ii. No benefit over aspirin in the absence of symptomatic CAD
2. Lipid-lowering therapy (see Ambulatory CareDisorders of Lipid Metabolism)
a. LDL-C should be less than 100 mg/dL.
b. Reduction in LDL-C to less than 70 mg/dL or use of a high-dose statin is reasonable.
c. In high- or moderately high-risk patients, the intensity of lipid-lowering therapy
should be sufficient to achieve a 30%40% reduction in LDL-C.
d. If TG are 200499 mg/dL, non-HDL concentrations should be less than 130 mg/dL;
however, concentrations less than 100 mg/dL are also reasonable if TG are 200499
mg/dL or higher.
e. Can consider adding plant stanols/sterols (2 g/day) or viscous fiber (greater than 10
g/day) to lower LDL-C
f. For risk reduction, encourage omega-3 fatty acids in the form of fish or capsule (1
g/day) in all patients.
3. ACE inhibitors
a. ACE inhibitors greatly decrease cardiovascular events in patients with CAD (and no
LV dysfunction) at high risk of subsequent cardiovascular events.
b. Should be considered in patients with an LVEF of 40% or less and in patients with
hypertension and established CAD, diabetes mellitus, and/or chronic kidney disease
c. Consider using in lower-risk patients with a mildly reduced or normal LVEF in whom
cardiovascular risk factors are well controlled and revascularization has been
performed.
d. Postulated mechanisms: Plaque stabilization
4. ARBs: Recommended for those with hypertension, those with indications for and
intolerance of ACE inhibitors (e.g., cough or angioedema), those with HF, or those who
have had an MI with an ejection fraction (EF) of 40% or less
5. Additional therapies for chronic stable angina
a. Definition: Predictable angina symptoms with exertion
b. Goals: Reduce symptoms of ischemia, increase physical function, and improve
quality of life. In general, achieved by either decreasing myocardial oxygen demand
or increasing myocardial oxygen supply
c. Specific agents
i. -Blockers
(a) Pharmacologic effects: Decreased inotropy and heart rate (HR) (decreased
oxygen demand)
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(b) Goal resting HR 5560 beats/minute (less than 50 beats/minute if angina

symptoms continue)
(c) Goal exercise HR of no more than 75% HR associated with angina
symptoms
(d) Contraindications: Severe bradycardia (HR less than 50 beats/minute), highdegree atrioventricular block (without pacemaker), sick sinus syndrome
(without pacemaker)
ii. Calcium channel blockers
(a) Pharmacologic effects
(1) Decrease coronary vascular resistance and increase coronary bloodflow
(increase oxygen supply).
(2) Negative inotropy, to varying degrees; nifedipine much greater than
amlodipine and felodipine (decrease oxygen demand)
(3) Decrease HR (verapamil and diltiazem only).
(b) Place in therapy
(1) Added to -blocker therapy to achieve HR goals
(2) Instead of -blocker therapy when unacceptable adverse effects emerge
(3) Short-acting calcium channel blockers (nifedipine, nisoldipine) have
been associated with increased cardiovascular events and should be
avoided (except in slow-release formulations).
(c) Contraindications for non-dihydropyridines: Systolic HF, severe bradycardia,
high-degree atrioventricular block (without pacemaker), and sick sinus
syndrome (without pacemaker)
(d) Contraindications for dihydropyridines: LV dysfunction (except amlodipine
and felodipine)
iii. Nitrates
(a) Pharmacologic effects:
(1) Endothelium-dependent vasodilation, dilates epicardial arteries and
collateral vessels (increased oxygen supply)
(2) Decreased LV volume because of decreased preload mediated by
venodilation (decreased oxygen demand)
(1) A scheduled nitrate is useful in conjunction with a -blocker or nondihydropyridine calcium channel blocker (which blunts the reflex
sympathetic tone with nitrate therapy).
(2) As-needed sublingual or spray nitrate is necessary to relieve effort or rest
angina.
(3) In addition, as-needed nitrates can be used before exercise to avoid
ischemic episodes.
(c) Contraindications: Hypertrophic obstructive cardiomyopathy, inferior wall
MI, severe aortic valve stenosis, sildenafil and vardenafil within 24 hours,
tadalafil within 48 hours
iv. Ranolazine
(a) Pharmacologic effects
(1) Inhibits myocardial fatty acid oxidation, causing increased glucose oxidation
(2) Increases oxygen efficiency
(1) Ideal role is unclear. Currently, either as monotherapy or as an add-on to
maximally tolerated conventional therapy (-blocker plus calcium
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channel blocker plus nitrate) with continued symptoms

(2) Important points
(A) HR and BP effects are not present; thus, bradycardia and
hypotension are not a concern.
(B) Dose-related QT prolongation
(C) Metabolized by CYP3A
1. Avoid in hepatic dysfunction.
2. Avoid use with strong 3A inhibitors including ketoconazole,
itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir,
indinavir, and saquinavir.
3. Avoid use with 3A inducers such as rifampin, rifabutin,
rifapentine, phenobarbital, phenytoin, carbamazepine, and St.
Johns wort.
4. Limit the dose to 500 mg 2 times/day in patients receiving drugs
including diltiazem, verapamil, aprepitant, erythromycin, and
fluconazole and in those receiving grapefruit juice.
V. ACUTE CORONARY SYNDROMES

A. Definitions and Goals
1. Definitions
Table 16. UA, NSTEMI, and STEMI Definitions
Unstable angina
(UA)
Chest pain that often occurs at rest, can occur suddenly, may worsen suddenly, or may be
stuttering, recurring over days to weeks
Diagnosis: ST-segment depression, T-wave inversion, or no EKG changes may occur, but
no positive biomarkers for cardiac necrosis are present
NonST-elevation Symptoms similar to unstable angina but differentiated on the basis of markers and EKG
MI (NSTEMI)
Diagnosis: Positive cardiac enzyme biomarkers of necrosis (troponin I or T elevation,
CKMB fraction > 5%10% of total CK)
ST-elevation MI
(STEMI)
Classic symptoms include worsening of chest pain lasting more than 5 minutes,
accompanied by shortness of breath, nausea, or weakness. Other symptoms may include
chest discomfort with or without radiation to other areas such as the arms, back, neck, jaw,
or abdomen and diaphoresis
Diagnosis: ST elevation > 1 mm above baseline on EKG, positive biomarkers
CK = creatine kinase; CKMB = creatine kinase myocardial band; EKG = electrocardiogram; MI = myocardial infarction.
2. Therapy goals
a. Unstable angina (UA)/nonST-segment elevation myocardial infarction (NSTEMI) goals
i. Prevent total occlusion of the infarct-related artery.
(a) Glycoprotein (GP) IIb/IIIa inhibitors, other antiplatelet agents, and anticoagulants
(b) Percutaneous coronary intervention (PCI) can be either or both:
(1) Percutaneous transluminal coronary angioplasty (i.e., balloon)
(2) Stent implantation
(c) Thrombolytics have no role and have an increased bleeding risk.
ii. Control chest pain and associated symptoms.
b. STEMI goals
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i.
Restore patency of the infarct-related artery and minimize infarct size.

(a) Thrombolytic medications or door-to-needle time within 30 minutes
(b) PCI or door-to-balloon time within 90 minutes
(1) If presenting to a facility without the capability for expert, prompt
intervention with primary PCI within 90 minutes, should undergo fibrinolysis
unless contraindicated
(2) Facilitated PCI consists of planned, immediate PCI after an initial
pharmacologic regimen such as full- or half-dose fibrinolysis, a GP IIb/IIIa
inhibitor, or a combination of such; might be performed as a reperfusion
strategy in higher-risk patients when PCI is not immediately available and
bleeding risk is low
(3) Rescue PCI consists of PCI after failed thrombolysis and is indicated in
select patients if shock, severe heart failure (HF), and/or pulmonary edema,
hemodynamic or electrical instability, evidence of persistent ischemia
ii. Prevent complications such as arrhythmias or death.
iii. Control chest pain and associated symptoms.
B. Invasive or Conservative Treatment Strategy
1. Calculate thrombolysis in myocardial infarction (TIMI) score by adding 1 point for each
history or presentation finding.
2. Risk of mortality, new or recurrent MI, or severe recurrent ischemia through 14 days on the
basis of the TIMI score: score = 01, mortality 7%; score = 2, mortality 8%; score = 3,
mortality 13%; score = 4, mortality 20%; score = 5, mortality 26%; and score = 67, mortality
41%.
Table 17. TIMI Scoring
TIMI
History
Age
More than three cardiac risk factors
hypertension, diabetes mellitus, hyperlipidemia, smoking, family history
History of coronary artery disease
Presentation
Severe angina
ASA within 7 days
Elevated markers
ST-segment deviation
ASA = aspirin; TIMI = thrombolysis in myocardial infarction.
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Table 18. Selection of Initial Treatment Strategy: Invasive vs. Conservative

Initial Invasive Strategy
Recurrent angina/ischemia at rest with low-level activities despite intensive medical therapy
Elevated cardiac biomarkers (TnT or TnI)
New/presumably new ST-segment depression
Signs/symptoms of HF or new/worsening mitral regurgitation
High-risk findings from noninvasive testing
Hemodynamic instability
Sustained VT
PCI within 6 months
Prior CABG
High-risk score (e.g., TIMI, GRACE)
Reduced left ventricular function (LVEF < 40%)
Initial Conservative Strategy
Low-risk score (e.g., TIMI, GRACE) or patient/physician presence in the absence of high-risk features
CABG = coronary artery bypass grafting; GRACE = Global Registry of Acute Coronary Events; HF = heart failure; LVEF = left
ventricular ejection fraction; PCI = percutaneous coronary intervention; TIMI = thrombolysis in myocardial infarction; TnI =
troponin I; TnT = troponin T; VT = ventricular tachycardia.
C. Initial Management
1. MONA in UA/NSTEMI, MONA plus -blocker in STEMI
Table 19. MONA plus -Blocker
M = Morphine
Morphine 15 mg IV is reasonable if symptoms are not relieved despite NTG or if

symptoms recur
O = Oxygen
Oxygen if O2 saturation < 90% or high-risk features for hypoxemia
N = Nitroglycerin
Nitroglycerin spray or SL tablet 0.4 mg x 3 doses to relieve acute chest pain (if pain is
unrelieved after 1 dose, call 911)
Nitroglycerin IV 510 mcg/minute, titrate to chest pain relief or 200 mcg/minute if pain
unrelieved by morphine and SL NTG
Hold if MAP < 80 mm Hg
Used in first 48 hours for treatment of persistent chest pain, HF, and HTN
Use should not preclude other mortality-reducing therapies (ACE inhibitor, -blocker)
No mortality benefits but high placebo crossover rate
Contraindication: Sildenafil or vardenafil use within 24 hours or tadalafil use within 48
hours; SBP < 100 mm Hg or 30 mm Hg below baseline, HR < 50 beats/minute, HR > 100
beats/minute in absence of symptomatic HF or right ventricular infarction
A = Aspirin
ASA chew and swallow nonenteric-coated 162325 mg x 1 dose

ClopidogrelIf ASA allergy or considerable gastrointestinal intolerance
-Blocker
Oral or intravenous -blocker (oral route preferred)

Mortality benefit in early phases of acute MI (metoprolol 5.7% vs. placebo 8.9%)
Metoprolol 5 mg IV every 5 minutes 3 doses, followed by 2550 mg PO 2 times/day
up-titrated as tolerated
IV route reasonable if tachyarrhythmia or HTN present
Contraindications:
Hypotension, signs of HF, risk factors for cardiogenic shock, or other
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relative contraindications (third-degree heart block, active asthma)

Other early hospital therapies
ACE inhibitors
Indicated orally within first 24 hours if HF, LVEF < 40%, type 2 diabetes mellitus, or CKD
IV therapy contraindicated because of risk of hypotension
Consider in all patients with CAD
Indicated indefinitely in all patients with LVEF < 40%
ARB indicated if contraindication to ACE inhibitor
Contraindication: Hypotension
CCBs
Specifically, nondihydropyridine CCBsverapamil, diltiazem

Recommended if continuing or frequently recurring ischemia and contraindication to blocker therapy or recurrent ischemia after -blockers and nitrates fully used
No real benefit or detriment to mortality; primarily symptom relief effects
Contraindication: Clinically significant LV dysfunction; immediate-release dihydropyridine
CCBs should not be administered in the absence of a -blocker
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; ASA = aspirin; CAD = coronary artery disease;
CCBs = calcium channel blockers; CKD = chronic kidney disease; HF = heart failure; HR = heart rate; HTN = hypertension; IV
= intravenous(ly); LVEF = left ventricular ejection fraction; MAP = mean arterial pressure; N/A = not available; NTG =
nitroglycerin; PO = orally; SBP = systolic blood pressure; SL = sublingually.
2. Treatment algorithms for UA/NSTEMI and STEMI

Table 20. UA/NSTEMI Algorithm
Strategy
Early Invasive
(PCI 12 hours from
hospitalization, high-risk
patient)
Delayed PCI
(PCI > 12 hours from
hospitalization)
Early Conservative
(no PCI, low-risk patient)
Anticoagulant
therapya
Enoxaparin, UFH, fondaparinux

(+ UFH added at time of PCI),
or bivalirudin
Enoxaparin, UFH,
fondaparinux
(+ UFH added at time of
PCI), or bivalirudin
Enoxaparin or fondaparinux
Antiplatelet
therapy
Clopidogrel or prasugrelb +
abciximab or eptifibatide
initiated at time of PCIc for
patients receiving UFH,
enoxaparin, or fondaparinux
Clopidogrel or prasugrelb +
If high or moderate risk,
initiate eptifibatide or
tirofiban either before
angiography/PCI (if
recurrent ischemia) or at
time of PCIc
Clopidogrel +
If positive stress test,
abciximab or eptifibatide
with UFH or enoxaparin, or
bivalirudin at time of PCI
If high risk of bleeding, fondaparinux or bivalirudin preferred. If CABG planned, UFH preferred.
If unlikely to undergo CABG, initiate prasugrel at time of PCI.
c
After PCI, discontinue NTG and anticoagulation and continue abciximab for 12 hours or eptifibatide for at least 12 hours.
CABG = coronary artery bypass graft; NTG = nitroglycerin; PCI = percutaneous coronary intervention; UA = unstable
angina; UFH = unfractionated heparin.
b
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Table 21. STEMI Algorithm
Symptoms 12 hours
Clopidogrel or prasugrel
Clopidogrel
Primary PCI
Fibrinolysis
UFH with abciximab (alternatively eptifibatide or IV UFH for at least 48 hours or

tirofiban) or bivalirudin alone
IV and SC enoxaparin for hospitalization, up to 8 days
(preferred, selected patients) or
IV and SC fondaparinux for hospitalization, up to 8 days
a
Algorithm for patients with symptoms for 12 hours or less. If symptoms for more than 12 hours, administer clopidogrel with PCI
or coronary artery bypass grafting or fibrinolysis for selected patients. If PCI, administer UFH or enoxaparin with abciximab or
eptifibatide or bivalirudin alone at time of PCI.
IV = intravenous; PCI = percutaneous coronary intervention; SC = subcutaneous; STEMI = ST-segment elevation myocardial
infarction; UFH = unfractionated heparin.
3. Dosing of antiplatelet and anticoagulant therapy

Table 22. Oral Antiplatelet Agents
ASA
CLO (Plavix)a/PRA (Efficient)b
Initial therapy
ASA 162325 mg nonenteric orally or chewed 1
Pre-PCI
ASA 75325 mg before PCI
No stent
ASA 75162 mg/day indefinitely
Post-stent
ASA 162325 mg/day for at least 1 month (bare
metal), at least 3 months (sirolimus), at least 6
months (paclitaxel); then 75162 mg/day
indefinitely
Initial therapy
NSTEMI and STEMI CLO 300- to 600-mg LD
1
STEMI with fibrinolyticCLO 300-mg LD 1
Pre-PCI
CLO 300- to 600-mg LD or PRA 60-mg LD
No stent (STEMI with or without fibrinolytic)
CLO 75 mg/day for at least 14 days and up to 1
year
Post-stent
CLO 75 mg/day or PRA 10 mg/day (5 mg/day if <
60 kg) for at least 12 months and up to 15 months
(bare metal stent or DES)
Discontinue clopidogrel at least 5 days or PRA at least 7 days before elective CABG. Administer clopidogrel indefinitely if ASA
allergy. Avoid LD if patient is 75 years or older.
b
Initiate PRA in patients with known coronary artery anatomy only to avoid use in patients needing CABG surgery. Avoid PRA
in patients with active pathological bleeding or a history of TIA or stroke as well as in patients older than 75 years unless patient
has DM or history of myocardial infarction.
ASA = aspirin; CABG = coronary artery bypass grafting; CLO = clopidogrel; DES = drug-eluting stent; DM = diabetes mellitus;
LD = loading dose; NSTEMI = nonST-elevation myocardial infarction; PCI = percutaneous coronary intervention; PRA =
prasugrel; STEMI = ST-elevation myocardial infarction.
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Table 23. GP IIb/IIIa Inhibitor Dosing

STEMI PCI
Abciximab
(ReoPro)
UA/NSTEMI
with/without PCI
0.25-mg/kg IV bolus; then 0.125

mcg/kg/minute (maximum 10 mcg/kg)
for 12 hours
Not recommended
Notes
Renal adjustment not
necessary
Eptifibatide 180 mcg/kg IV bolus 2 (10 minutes

(Integrilin) apart); then 2 mcg/kg/minute for 1218
hours
180-mcg/kg IV bolus; then If CrCl < 50 mL/minute,

2 mcg/kg/minute for 1272 reduce infusion 50%; not
hours
studied if CrCl > 4 mg/dL
Tirofiban
(Aggrastat)
0.4 mcg/kg/minute for 30

If CrCl < 30 mL/minute,
minutes (LD infusion); then reduce infusion 50%
0.1 mcg/kg/minute for 18
72 hours
25 mcg/kg IV bolus; then 0.1

mcg/kg/minute for 18 hours
CrCl = creatinine clearance; GP = glycoprotein; IV = intravenous; LD = loading dose; NSTEMI = nonST-elevation myocardial
infarction; STEMI = ST-elevation myocardial infarction; UA = unstable angina.
Table 24. Anticoagulant Dosing

Unfractionated
Heparin
Enoxaparin
(Lovenox)
Fondaparinux
(Arixtra)
Bivalirudin
(Angiomax)
Classification
LMWH
Factor Xa
inhibitor
DTI
UA/NSTEMI
60-unit/kg IVB
(maximum 4000
units), 12
units/kg/hour IV
(maximum 1000
units/hour) for 48
hours or end of PCI,
goal aPTT of 5070
seconds
1 mg/kg SC BID for

2448 hours
(UA/NSTEMI) or
until end of PCI or
throughout
hospitalization
2.5 mg SC QD
(If STEMI, give
initial 2.5-mg
IVB)
0.1-mg/kg IVB; then

0.25 mg/kg/hour IV
PCI
Supplemental doses
to target ACTa
If last dose < 8

hours, none
If last dose > 8
hours, 0.3 mg/kg IVB
if last dose 812
hours prior
STEMI primary
PCIb
If GP IIb/IIIa, UFH
5070 units/kg IVB.
If no GP IIb/IIIa,
UFH 70- to 100unit/kg IVB.
Supplemental doses
to target ACTa
0.75-mg/kg IVB, 1.75

mg/kg/hour IV
Discontinue at end of
PCI or continue up to 4
hours postprocedure if
needed. (Hold UFH 30
minutes before
administration)
2.5 mg IVB; then
2.5 mg SC QD
0.75 mg/kg, 1.75

mg/kg/hour IV
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Table 24. Anticoagulant Dosing

Unfractionated
Heparin
Dose
adjustments/
contraindications
Avoid if history of
HIT
Enoxaparin
(Lovenox)
If CrCl < 30
mL/minute, 1 mg/kg
SC QD
Fondaparinux
(Arixtra)
Avoid if CrCl <
30 mL/minute
Bivalirudin
(Angiomax)
Adjust infusion dose in
severe renal dysfunction
(same IVB dose)
Target ACT 250300 seconds for primary PCI without GP IIb/IIIa inhibitor and 200250 seconds in patients given a
concomitant GP IIb/IIIa inhibitor.
b
If STEMI status is post-fibrinolytics, UFH dosesame as UA/NSTEMI and enoxaparin doseif younger than 75 years, 30 mg
IVB, followed immediately by 1 mg/kg subcutaneously 2 times/day (first two doses maximum 100 mg if more than 100 kg); if
older than 75 years, no IVB, 0.75 mg/kg subcutaneously 2 times/day (first two doses maximum 75 mg if more than 75 kg).
ACT = activated clotting time; aPTT = activated partial thromboplastin time; BID = twice daily; DTI = direct thrombin inhibitor;
GP = glycoprotein; HIT = heparin-induced thrombocytopenia; IV = intravenous; IVB = intravenous bolus; LMWH = lowmolecular-weight heparin; NSTEMI = nonST-elevation myocardial infarction; PCI = percutaneous coronary intervention; QD =
once daily; SC = subcutaneously; STEMI = ST-elevation myocardial infarction; UA = unstable angina; UFH = unfractionated
heparin.
4. Thrombolytic dosing and adjunctive therapy

a. Administer within 12 hours of symptom onset (preferably within 6 hours). Ideally,
administer within 30 minutes of hospital arrival.
b. Patients undergoing reperfusion with fibrinolytics should receive anticoagulant therapy
for a minimum of 48 hours and preferably for the duration of the index hospitalization, up
to 8 days.
c. Alteplase, reteplase, and tenecteplase require concomitant UFH administration of a 60unit/kg bolus (maximum 4000 units) and 12 units/kg/hour (maximum 1000 units/hour),
with provision for an activated partial prothrombin time of about 5070 seconds.
Table 25. Thrombolytic Therapy

Dosing
Alteplase (rt-PA, Activase)
15 mg IV; then 0.75 mg/kg over 30 minutes (maximum 50 mg);

then 0.5 mg/kg (maximum 35 mg) over 60 minutes
Reteplase (r-PA, Retavase)
10 units IV, repeat 10 units IV in 30 minutes
Tenecteplase
(TNK-tPA, TNKase)
< 60 kg, 30 mg IV; 6069 kg, 35 mg IV; 7079 kg, 40 mg IV; 8089 kg, 45 mg
IV, > 90 kg, 50 mg IV (about 0.5 mg/kg)
Streptokinase (Streptase)
1.5 million units IV over 60 minutes
IV = intravenously; r-PA = recombinant plasminogen activator; rt-PA = recombinant tissue plasminogen activator; tPA = tissue
plasminogen activator.
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Table 26. Contraindications to Thrombolytic Therapy

Relative Contraindications
BP > 180/110 mm Hg on presentation
History of TIA or CVA < 3 months prior
History of chronic poorly controlled HTN
INR 23 on warfarin
Recent trauma, major surgery, CPR, internal
bleeding in 24 weeks
Streptokinase exposure > 5 days earlier or prior
allergic reaction (if given streptokinase again)
Active peptic ulcer
Age > 75 years
Pregnancy
Known intracranial pathology (dementia)
Absolute Contraindications
ANY prior hemorrhagic stroke
Ischemic stroke within 3 months (except in past 3 hours)
Intracranial neoplasm or arteriovenous malformation
Active internal bleeding
Aortic dissection
Considerable facial trauma or closed-head trauma in past 3
months
BP = blood pressure; CPR = cardiopulmonary resuscitation; CVA = cerebrovascular accident; HTN = hypertension; INR =
international normalized ratio; TIA = transient ischemic attack.
D. Long-term Management
1. -Blockers
a. Indicated for all patients unless contraindicated
b. Initiate within a few days of event, if not acute, and continue indefinitely.
c. If moderate or severe left ventricular (LV) failure, initiate with gradual titration.
2. ACE inhibitors
a. Indicated for all patients even if no LV dysfunction, HTN, or diabetes mellitus
b. Give oral ACE inhibitor in low doses to all patients during the first 24 hours of anterior
STEMI, HF signs (pulmonary congestion), or LV ejection fraction (LVEF) less than
40%, provided no hypotension exists (systolic BP less than 100 mm Hg) or other
contraindication, to reduce mortality and remodeling.
c. ARB if ACE inhibitor intolerant
d. Avoid intravenous ACE inhibitor post-MI to prevent hypotension.
3. Aldosterone receptor blockers: Indicated if post-MI with LVEF less than 40%, symptomatic
HF, or diabetes mellitus and receiving ACE inhibitor; however, contraindicated if creatinine
clearance less than 30 mL/minute or K more than 5 mEq/L
4. WarfarinIndicated either without (international normalized ratio [INR] 2.53.5) or with
low-dose ASA (7581 mg/day, INR 22.5) if high CAD risk and low bleeding risk if patient
does not require, or is intolerant of, clopidogrel
5. Lipid managementStatins indicated with an LDL goal less than 100 mg/dL, with a goal of
less than 70 mg/dL reasonable
6. Other goalsHemoglobin A1c less than 7%, smoking cessation, body mass index 18.524.9
kg/m2, exercise 3 or 4 times/week
VI. HEART FAILURE

A. Background: Heart failure is a complex clinical syndrome that can result from any structural or
functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.
1. Systolic dysfunction (decreased ejection fraction [EF] less than 40%)
a. Impaired wall motion
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b. Dilated ventricle
c. Two-thirds attributable to coronary artery disease (CAD)
d. One-third attributable to nonischemic cardiomyopathy
i. Hypertension
ii. Thyroid disease
iii. Valvular disease
iv. Cardiotoxins
(a) Alcohol
(b) Chemotherapeutic agents
(1) Anthracyclines
(2) Cyclophosphamide
(3) 5-Fluorouracil
(4) Trastuzumab
v. Myocarditis
vi. Idiopathic
2. Diastolic dysfunction (preserved/normal EF greater than 40%, greater than 45%, or greater
than 50%)
a. Accounts for about 30% of patients with heart failure (HF)
b. Impaired ventricular relaxation and filling
c. Normal wall motion
d. Most are caused by hypertension and age-related decreases in the elastic properties of the
cardiovascular system.
e. Some are caused by various cardiomyopathies (e.g., restrictive, infiltrative, hypertrophic).
3. Primary symptoms
a. Dyspnea
b. Fatigue
c. Edema
d. Exercise intolerance
4. Stages of HF
Table 27.
ACC/AHA
Stage
Description
Patient Population
At high risk of HF but without

Patients with hypertension, atherosclerotic disease,
structural heart disease or symptoms diabetes mellitus, obesity, or metabolic syndrome OR
of HF
patients using cardiotoxins or having a family history of
cardiomyopathy
Structural heart disease but without

signs or symptoms of HF
Structural heart disease with prior or Patients with known structural heart disease and
current symptoms of HF
shortness of breath, fatigue, and/or reduced exercise
tolerance
Refractory HF requiring specialized Patients who have marked symptoms at rest despite
interventions
maximal medical therapy (e.g., those who are recurrently
hospitalized or cannot be safely discharged from the
hospital without specialized interventions)
Patients with a previous MI, left ventricular remodeling,

left ventricular hypertrophy, or asymptomatic valvular
disease
HF = heart failure; MI = myocardial infarction.

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5. New York Heart Association classification of HF
Table 28.
NYHA Functional Class
Description
No limitations in physical activity caused by HF symptoms
II
Symptoms of HF with normal level of activity
III
Marked limitations in physical activity because of HF symptoms
IV
Symptoms of HF at rest
HF = heart failure; NYHA = New York Heart Association.
Figure 3.
H2O = water; Na = sodium; TNF = tumor necrosis factor alpha.
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B. Pharmacologic Therapy for Systolic HF

1. Principles of therapy
a. Block the compensatory neurohormonal activation caused by decreased cardiac output
that promotes further cardiac deterioration and damage.
b. Prevent/minimize Na and water retention.
c. Eliminate or minimize symptoms of HF (increase quality of life).
d. Slow the progression of cardiac dysfunction.
e. Decrease mortality.
2. Management of fluid overload with diuretics
a. Short-term benefits (days)
i. Decreased jugular venous distension
ii. Decreased pulmonary congestion
iii. Decreased peripheral edema
b. Intermediate-term benefits (weeks to months)
i. Decreased daily symptoms
ii. Improved cardiac function
iii. Increased exercise tolerance
c. Long-term benefits (months to years): No benefit on mortality
d. Diuretic caveats
i. Never use as the only therapy for HF because diuretics have no effect on disease
progression or mortality.
ii. If a patient has fluid overload, initiate and adjust therapy to result in 12 lb of weight
loss per day (may be more aggressive in the inpatient setting).
iii. Chronic therapy should be adjusted to maintain a euvolemic state.
iv. Monitor and replace K and Mg as needed, especially with loop diuretics (goal with
cardiovascular disease is K of 4.0 mEq/L or higher and Mg of 2.0 mEq/L or higher to
minimize arrhythmias).
v. Loop diuretics are recommended because of greater diuretic capabilities; loop
diuretics retain efficacy with decreased renal function.
vi. May combine loop diuretic with another class (e.g., thiazide diuretic) for synergy
if needed
Table 29.
Diuretic Class
Examples
Increase in Sodium Excretion (%)
Loop
Furosemide, bumetanide, torsemide
2530
Thiazide
Hydrochlorothiazide, metolazone, chlorthalidone
58
Potassium sparing
Amiloride, triamterene, spironolactone
23
3. Neurohormonal blockade
a. ACE inhibitors
i. Benefits of ACE inhibitor
(a) Decreased mortality (about 25% relative risk reduction vs. placebo)
(b) Decreased hospitalizations (about 30% relative risk reduction vs. placebo)
(c) Symptom improvement
(d) Improved clinical status
(e) Improved sense of well-being
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ii. Mechanism of action

(a) Blocks production of angiotensin II
(1) Decreases sympathetic stimulation
(2) Decreases production of aldosterone and vasopressin
(3) Decreases vasoconstriction (afterload)
(b) Increases bradykinins (decreases their metabolism)
(1) Increases vasodilatory prostaglandins
(2) May affect myocardial remodeling
iii. Place in therapy: Should be used in all patients with LV dysfunction (even if
asymptomatic)
iv. Dosing considerations
(a) Start low and increase (double) dose every 14 weeks to target dose.
(b) Benefits of high versus low doses
(c) Patient may notice improvement in several weeks.
Table 30.
Drug
Starting Dosage
Target Dosage
Maximal Dosage
Captopril
6.25 mg TID
50 mg TID
50 mg TID
Enalapril
2.5 mg BID
10 mg BID
20 mg BID
Lisinopril
2.55 mg/day
20 mg/day
40 mg/day
Perindopril
2 mg/day
8 mg/day
16 mg/day
Ramipril
1.252.5 mg/day
5 mg BID
10 mg/day
Trandolapril
1 mg/day
4 mg/day
4 mg/day
Note: Fosinopril and quinapril may be used; however, they do not have the same magnitude of mortality-reducing data as the
above-listed angiotensin-converting enzyme inhibitor.
BID = 2 times/day; TID = 3 times/day.
v. Monitoring
(a) SCr, BP, and K in 12 weeks after starting or increasing the dose, especially in
high-risk individuals (e.g., those with systolic BP less than 90 mm Hg, those with
serum sodium concentrations less than 130 mEq/L, or those receiving high doses
of loop diuretics)
(1) SCr may rise (up to a 0.5-mg/dL increase is acceptable) because of renal
efferent artery dilation (results in a slightly decreased glomerular filtration
rate).
(A) Rarely, acute renal failure occurs, especially if the patient is
intravascularly depleted (be careful to avoid overdiuresis).
(B) Use cautiously in patients with a baseline SCr more than 3.0 mg/dL
(NOT a contraindication; they should still be used, just with smaller
dosage changes and increased monitoring).
(2) Monitor BP and symptoms of hypotension (e.g., dizziness, light-headedness).
(A) BP may be low to begin with because of low cardiac output.
BP = CO SVR (CO = cardiac output, SVR = systemic vascular resistance)
(B) In HF, as cardiac output increases because of decreased SVR, BP may
decrease slightly or remain about the same.
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(C) Symptoms of hypotension are often not present with small dose
increases. Remember to treat the patient, not the number.
(3) Potassium (K)may rise because of decreased glomerular filtration rate and
decreased aldosterone.
(A) Use cautiously in those with a baseline K greater than 5.0 mEq/L.
(B) Monitor K within 3 days of beginning therapy.
(b) 90% of people tolerate ACE inhibitors.
(1) Angioedema (less than 1%)Could switch to ARBs (cross-reactivity is
2.5%) or hydralazineisosorbide dinitrate
(2) Cough (20%)Could switch to ARBs (less than 1%)
b. -Blockers
i. Benefits of -blockade (when added to an ACE inhibitor)
(a) Decreased mortality (about 35% relative risk reduction vs. placebo)
(b) Decreased hospitalizations (about 25% relative risk reduction vs. placebo)
(c) Symptom improvement
(d) Improved clinical status
(e) Improved sense of well-being
ii. Mechanism of action
(a) Blocks the effect of norepinephrine and other sympathetic neurotransmitters on
the heart and vascular system
(1) Decreases ventricular arrhythmias (sudden death)
(2) Decreases cardiac hypertrophy and cardiac cell death
(3) Decreases vasoconstriction and HR
(b) Carvedilol also provides 1-blockade.
(1) Further decreases SVR (afterload)
(2) Will have a greater reduction in BP compared with metoprolol
iii. Place in therapy
(a) Should be used in all stable patients (e.g., those not receiving intravenous inotropic
or diuretic therapy, those without significant peripheral and pulmonary congestion)
with LV dysfunction (even if asymptomatic)
(b) Can be used safely in those with depression, diabetes, and heart block with a pacer
iv. Dosing considerations
(a) Added to existing ACE inhibitor therapy (at least at a low dose) when HF
symptoms are stable and patients are euvolemic
(b) Start low and increase (double) the dose every 24 weeks (or slowly, if needed)
to target dose.
(c) Avoid abrupt discontinuation; can precipitate clinical deterioration
(d) Patient may notice improvement in several months.
(e) Benefits of high versus low doses
Table 31.
Agent
Starting Dosage
Target Dosage
Bisoprolol
1.25 mg/day
10 mg/day
Carvedilol
3.125 mg BID
25 mg BIDa
Metoprolol succinate XLb (metoprolol CR/XL)
12.525 mg/day
200 mg/day
50 mg 2 times/day if weight is more than 85 kg.

Few or no data exist with metoprolol tartrate.
BID = 2 times/day; CR = controlled release; XL = extended release.
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v. Monitoring
(a) BP, HR, and symptoms of hypotension (monitor in 12 weeks)
(1) Significant hypotension, bradycardia, or dizziness occurs in about 1% of
patients on -blocker therapy when titrated slowly. If these appear, lower the
dose by 50%. Discontinue the drug only if the patient has heart block or is in
cardiogenic shock.
(2) Of importance, remember that higher -blocker doses are associated with
increased reduction in mortality. Therefore, if hypotension alone is the
problem, try reducing the dose of the ACE inhibitor first.
(3) With carvedilol, dizziness and hypotension are more common, usually
occurring within 2448 hours of a dosage increase.
(4) The net decrease in HR at goal doses of -blocker is only 1015 beats/minute
from baseline.
(b) Increased edema/fluid retention (monitor in 12 weeks)
(1) From 1% to 2% more common than placebo (in euvolemic, stable patients)
(2) Responds to diuretic increase
(c) Fatigue or weakness
(1) From 1% to 2% more common than placebo
(2) Usually resolves spontaneously in several weeks
(3) May require dosage decrease or discontinuation
c. Aldosterone blockade
i. Patient population
(a) Class III and IV HF
(b) Left ventricular dysfunction immediately after MI
ii. Benefits of spironolactone in class III and IV HF
(a) Decreased mortality (30% relative risk reduction vs. placebo)
(b) Decreased hospitalizations for HF (35% relative risk reduction vs. placebo)
(c) Improved symptoms
iii. Benefits of eplerenone in class II HF
(a) Decreased death from cardiovascular causes or hospitalization from HR (46%
relative risk reduction vs. placebo)
(b) Decreased mortality (24% relative risk reduction vs. placebo)
iv. Benefits of eplerenone (a selective aldosterone blocker) with LV dysfunction after
MI
(a) Decreased mortality (15% relative risk reduction vs. placebo)
(b) Decrease in the composite of death from cardiovascular causes or hospitalization
for cardiovascular events (13% relative reduction vs. placebo)
v. Mechanism of action: Blocks effects of aldosterone in the kidneys, heart, and
vasculature
(a) Decreases K and Mg loss: Decreases ventricular arrhythmias
(b) Decreases Na retention: Decreases fluid retention
(c) Eliminates catecholamine potentiation: Decreases BP
(d) Blocks direct fibrotic actions on the myocardium
vi. Place in therapy
(a) Should be considered in all patients with class III and IV HF who are receiving
background therapy with an ACE inhibitor, diuretic, and -blocker or after an MI
with LV dysfunction
(b) Avoid use in combination with both ACE inhibitor and ARB; the effects of all
three agents on K have not been adequately characterized.
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vii. Dosing considerations

(a) Dosing
(1) Spironolactone 12.525 mg/day
(2) Eplerenone 2550 mg/day
(b) Avoid use if SCr is greater than 2.5 mg/dL, creatinine clearance (CrCl) is less
than 30 mL/minute, or serum potassium is greater than 5.0 mEq/L.
viii. Monitoring
(a) K and SCr within 1 week of starting therapy
(1) Hyperkalemia was reported in only 2% of patients in the trial; however, in
practice, it occurs in about 20% of patients.
(2) Decrease dose by 50% or discontinue if K is greater than 5.5 mEq/L.
(b) Gynecomastia
(1) For spironolactone, gynecomastia was reported at a rate of 10% in clinical
trials.
(2) Eplerenone: A selective aldosterone blocker, it has only been studied in a
very narrow subset of the HF population (post-MI with decreased EF); may
be considered in class III and IV patients with painful gynecomastia
4. Digoxin
a. Benefits of digoxin
i. Improved symptoms
ii. Improved exercise tolerance
iii. Decreased hospitalizations
iv. No effect on mortality
b. Mechanism of action (in HF) by Na-K adenosine triphosphatase inhibition
i. Decreases central sympathetic outflow by sensitizing cardiac baroreceptors
ii. Decreases renal reabsorption of Na
iii. Minimal increase in cardiac contractility because of the inhibition of Na-K adenosine
triphosphatase. This is not thought to cause beneficial effects in HF.
c. Place in therapy: Should be considered in patients with symptomatic LV dysfunction
despite optimal ACE inhibitor (or ARB), -blocker, spironolactone (if appropriate), and
diuretic therapy
d. Dosing considerations and monitoring
i. Serum concentrations of 0.51.0 ng/dL are effective in HF.
(a) Minimizes the risk of adverse effects and ventricular arrhythmias associated with
increased concentrations
(b) Risk of toxicity increases with age and renal dysfunction.
(c) Risk of toxicity increases in the presence of hypokalemia or hypomagnesemia.
ii. SCr as the drug is cleared more than 95% renally
iii. For most patients, 0.125 mg/day is adequate to achieve the desired serum
concentration. Loading doses are not recommended in those with HF.
iv. Useful initial agent for patient with concomitant AF
v. Drug interactions. Digoxin concentrations are increased with concomitant:
(a) Clarithromycin, erythromycin
(b) Amiodarone, dronedarone
(c) Itraconazole, posaconazole, voriconazole
(d) Cyclosporine, tacrolimus
(e) Verapamil
5. Hydralazineisosorbide dinitrate
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a. Benefits
i. Decreases mortality 39% versus placebo
ii. Decreases hospitalizations 33% versus placebo
b. Mechanism of action
i. Hydralazine
(a) Vasodilator
(b) Enhances effect of nitrates
ii. Isosorbide dinitrate
(a) Stimulates nitric acid signaling in the endothelium
(b) Effective in reducing preload
c. Place in therapy
i. African Americans with NYHA class IIIV HF, already receiving an ACE inhibitor
(or ARB), -blocker, and diuretic therapy
ii. Decreases mortality versus placebo risk reduction in death compared with
hydralazineisosorbide dinitrate
iii. A reasonable alternative in patients unable to take an ACE inhibitor or ARB because
of severe renal insufficiency, hyperkalemia, or angioedema
d. Dosing consideration
i. Hydralazine (2575 mg orally 3 or 4 times/day); isosorbide dinitrate (1040 mg
orally 3 times/day). Titrate on the basis of BP.
ii. Fixed-dose BiDil (hydralazine 37.5 mg plus isosorbide dinitrate 20 mg) with a goal
dose of 2 tablets 3 times/day
e. Monitoring
i. Headache
ii. Hypotension
iii. Drug-induced lupus with hydralazine
6. Angiotensin II receptor blockers
a. Have never been proved superior to ACE inhibitors at target HF dosages
b. Current role: As ACE inhibitor substitutes for patients unable to take ACE inhibitors
because of cough. Possibly if patient has experienced ACE inhibitorinduced
angioedema
c. The best ARB to use on the basis of available data is candesartan 32 mg/day or valsartan
160 mg 2 times/day (target doses).
C. Nonpharmacologic Therapy
1. Prevent further cardiac injury
a. Discontinue smoking.
b. Reduce weight if obese.
c. Control hypertension.
d. Control diabetes mellitus.
e. Minimize alcohol to 2 or fewer drinks a day for men, 1 or fewer drinks a day for women.
f. Eliminate alcohol if cardiomyopathy is alcohol induced.
2. Limit Na to 2 g/day.
3. Restrict fluid intake to 2 L/day if serum sodium is less than 130 mEq/L or if there is fluid
retention despite aggressive diuresis and dietary Na restriction.
4. Modest exercise program benefits
a. Possible modest effects on all-cause hospitalization and all-cause mortality,
cardiovascular death or cardiovascular hospitalization, cardiovascular death or HF
hospitalization (ACTION-HF studyJAMA 2009;301:143950)
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b. Safe for patients with HF

5. Annual influenza vaccine and pneumococcal vaccine every 5 years
6. Monitor and appropriately replace electrolytes (minimize risk of arrhythmias).
7. Monitor for thyroid disease.
a. Hypothyroidism may be masked by HF symptoms.
b. Hyperthyroidism will worsen systolic dysfunction.
8. Screen for and treat depression.
D. Drugs to Avoid or Use with Caution
1. Nonsteroidal anti-inflammatory drugs (NSAIDs; including selective cyclooxygenase-2
inhibitors)
a. Promote Na and water retention.
b. Blunt diuretic response.
2. Corticosteroids: Promote Na and water retention.
3. Class I and III antiarrhythmic agents (except for amiodarone and dofetilide)
a. Negative inotropic activity
b. Proarrhythmic effects
c. Amiodarone and dofetilide have been proved safe in patients with HF.
d. Avoid dronedarone.
4. Calcium channel blockers (except for amlodipine and felodipine)
a. Negative inotropic activity
b. Neurohormonal activation
c. Amlodipine and felodipine have been proved safe in patients with HF.
5. Minoxidil
a. Fluid retention
b. Stimulation of the renin-angiotensin-aldosterone system
6. Thiazolidinediones: Fluid retention (Diabetes Care 2004;27:25663)
7. Metformin: Increased risk of lactic acidosis (black box warning)
8. Anagrelide
a. Positive inotropic activity
b. Tachycardia
9. Amphetamines (e.g., methylphenidate)
a. - and -agonist activity, tachycardia
b. Atrial and ventricular arrhythmias
10. Cilostazol: Inhibition of phosphodiesterase III, causing increased ventricular arrhythmias
11. Itraconazole: Negative inotropic activity
12. Pregabalin
a. Lower extremity edema, HF exacerbation
b. Inhibition of calcium channels
E. General Treatment Goals of Diastolic Dysfunction
In contrast to the large number of trials and the patients with systolic dysfunction who have been studied,
there is a lack of objective data to guide therapy for patients with diastolic dysfunction. The following
recommendations are based primarily on the consensus opinion of cardiovascular experts.
1. Control hypertension according to published guidelines.
a. Hypertension impairs myocardial relaxation.
b. Hypertension promotes cardiac hypertrophy.
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2. Control tachycardia.
a. Tachycardia decreases the time for the ventricles and coronary arteries to fill with blood.
b. Control of HR improves symptoms of HF.
c. Can use -blockers, non-dihydropyridine calcium channel blockers, and/or digoxin
3. Reduce preload (but not too much!).
a. Ventricular filling pressure is primarily determined by central blood volume.
b. Patients with diastolic dysfunction are more preload-dependent for ventricular filling.
Decreasing the preload too much may cause unexpected hypotension.
c. Symptoms of breathlessness can be relieved by the use of diuretics or nitrates.
4. Aggressively investigate, repair, and treat myocardial ischemia.
a. Myocardial ischemia impairs ventricular relaxation.
b. Any ischemia possibly contributing to diastolic dysfunction warrants aggressive therapy.
F. Pharmacologic Therapy for Diastolic Dysfunction
1. ACE inhibitors
a. Reduction in unplanned hospitalizations
b. Improvement in NYHA class
c. Improvement in exercise tolerance
2. ARBs: The addition does not improve outcomes in patients with maximized background
therapy and well-controlled BP.
3. Digoxin
a No effect on all-cause mortality or on all-cause or cardiovascular hospitalizations
b. Possible increase in unstable angina admissions
4. -Blockers, verapamil, and diltiazem: Benefits are targeted symptom relief.
VII. ATRIAL FIBRILLATION

A. Background
1. Prevalence
a. Most common arrhythmia: 2.2 million Americans
b. Prevalence increases with age.
c. Common comorbidity in patients with valvular heart disease or heart failure (HF)
2. Symptoms
a. Some patients have no symptoms.
b. At worst, an embolic event may occur, or symptoms of HF may be present.
c. Most patients have some degree of the following:
i. Palpitations
ii. Chest pain
iii. Dyspnea
iv. Fatigue
v. Light-headedness
d. Symptoms vary with ventricular rate, underlying LV functional status, AF duration, and
individual patient perceptions.
3. Classification (more than one of these may exist in a given patient):
a. Paroxysmalspontaneous self-termination within 7 days of onset
b. Persistentlasting more than 7 days
c. Permanenta commonly used but arbitrary classification
d. Recurrenttwo or more episodes
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B. Pathophysiology
1. Cardiac conduction
Figure 4.
2. Electrocardiogram findings
a. No P waves
b. Irregularly, irregular rhythm
c. Rate may be fast or slow (depending on the rate of atrioventricular node conduction).
Figure 5.
3. Why do these abnormal impulses develop?
Table 32.
Atrial Distension
High Adrenergic Tone
Chronic hypertension
Alcohol withdrawal
Mitral valve disease
Thyrotoxicosis
Cardiomyopathy
Sepsis
Congenital defects
Binge drinking
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Pulmonary hypertension
Cocaine
Acute pulmonary embolus
Amphetamines
Excessive theophylline, caffeine
Sympathomimetics such as cocaine or amphetamines
Surgery
C. Pharmacologic Therapy
1. Ventricular rate control
a. If patients have a rapid ventricular rate, atrioventricular node blockade is required.
b. The goal HR is 6080 beats/minute at rest and 90115 beats/minute during exercise.
However, the RACE-2 (Rate Control Efficacy in Permanent Atrial Fibrillation) trial
suggested that lenient rate control (HR less than 110 beats/minute) is not inferior to strict
rate control (HR less than 80 beats/minute) regarding the composite end point of death
from cardiovascular causes, hospitalization for HF, and stroke, systemic embolism,
bleeding, and life-threatening arrhythmic events.
c. Select the best agent on the basis of individual clinical response and concomitant disease
states that may increase or decrease the desirability of one of the three approaches.
d. These therapies have no effect on the cardioversion of AF:
i. -Blockers
(a) Any agent with -blockade can be used and dosed to the goal HR.
(b) Selective 1-antagonists, such as atenolol or metoprolol, may be preferred.
(c) Labetalol or carvedilol if additional -blockade is desirable (e.g., hypertension or
cocaine exposure)
(d) Sotalol (class III antiarrhythmic) or propafenone (class Ic antiarrhythmic) if
rhythm control is necessary
(e) Effective for controlling exercise-associated HR increases
(f) Can be considered in patients with stable HF
ii. Non-dihydropyridine calcium channel blockers: Verapamil or diltiazem
(a) Avoid use if there is concomitant systolic dysfunction.
(b) May be preferred over -blocker in patients with asthma/severe chronic
obstructive pulmonary disease
(c) Also effective for controlling exercise-associated HR increases
iii. Digoxin
(a) Often ineffective alone for controlling ventricular rate in AF, especially during
exercise or movement (because of minimal effectiveness with sympathetic
stimulation)
(b) Can be included in regimen if patient has systolic HF
(c) May also be effective if additional HR control is needed when a patient is
receiving a -blocker, diltiazem, or verapamil
2. Anticoagulation
a. The average annual stroke rate is 5% per year without anticoagulation.
i. A patients individual risk may vary from about 1% to 20% per year on the basis of
his or her risk factors.
ii. This risk is independent of current cardiac status (i.e., sinus rhythm or AF).
b. Risk stratification and treatment determination
c. Role of clopidogrel
i. ACTIVE A (N Engl J Med 2009;360:206678): Compared with aspirin alone, 75
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mg/day of clopidogrel and aspirin in patients with AF who had an increased risk of
stroke and for whom warfarin was unsuitable showed a significant reduction in major
vascular events but an increased risk of bleeding.
ii. ACTIVE W (Lancet 2006;367:190312): Compared with clopidogrel and aspirin,
warfarin had a significantly lower rate of vascular events in patients with AF plus one
or more risk factors for stroke. No difference existed in bleeding between groups.
d. Role of dabigatran
i. Direct thrombin inhibitor indicated to reduce the risk of stroke and systemic
embolism in patients with nonvalvular AF
ii. Dose: CrCl greater than 30 mL/minute150 mg 2 times/day; CrCl 1530
mL/minute75 mg 2 times/day; CrCl less than 15 mL/minuteno dosing
recommendations available; swallow capsules whole
iii. Missed doses: If a dose is not taken at the scheduled time, the dose should be taken as
soon as possible the same day; the missed dose should be skipped if it cannot be
taken at least 6 hours before the next scheduled dose. The dose of should not be
doubled to make up for a missed dose.
iv. Converting from or to warfarin
v. Drug interactions
(a) P-glycoprotein inducers (e.g., rifampin mentioned only in package labeling)
should be avoided; however, inducers such as ketoconazole, verapamil,
amiodarone, quinidine, and clarithromycin do not require dose adjustments.
(b) Proton pump inhibitors, H2 antagonists, and digoxin did not appreciably change
the trough concentration of dabigatran.
vi. RE-LY (N Engl J Med 2009;361:113951): Dabigatran 110 mg 2 times/day was noninferior to INR-adjusted warfarin but superior at 150 mg 2 times/day for preventing
thromboembolic stroke in paroxysmal or permanent AF. Compared with warfarin,
dabigatran 110 mg 2 times/day had a statistically significant lower incidence of major
bleeding, with no difference seen with the 150-mg twice-daily dose.
e. Bleeding
i. Minor hemorrhage increased with therapeutic warfarin therapy.
ii. Major hemorrhage did not increase with warfarin therapy with INR 23.
iii. Risk of intracranial hemorrhage increased with INR greater than 4.
3. Rhythm control: Since the publication of the Atrial Fibrillation Follow-up Investigation of
Rhythm Management (AFFIRM) trial (N Engl J Med 2002;34:182533), it has been known
that maintaining sinus rhythm offers no advantage over controlling the ventricular rate (in the
typical elderly patient with AF). In fact, the rhythm control group had a higher incidence of
hospitalizations, gastrointestinal adverse effects, and symptoms of HF. However, in specific
patients with intractable and intolerable symptoms or in patients for whom adequate
ventricular rate control cannot be achieved, despite adequate rate control (dyspnea and
palpitations), restoration and maintenance of sinus rhythm may be desirable.
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Table 33.
Pros
Rate control
strategy
Cons
Easy to achieve and maintain;

out-of-hospital therapy typical; and
end point relatively easy to achieve
Electrical and structural remodeling because

of continued AF makes future attainment of
SR virtually impossible; safety unproved for
younger patients
Rhythm control If patient is symptomatic with fatigue and

strategy
exercise intolerance, these may improve if SR
is attained (especially in the patient with HF);
minimized structural atrial changes; acceptable
for all age groups
Adverse effects of medications, cost of

medications and monitoring, likelihood of
AF recurrence; in-hospital stay may be
required; and high recurrence rate
AF = atrial fibrillation; HF = heart failure; SR = normal sinus rhythm.
a. If cardioversion is attempted (electric or pharmacologic), the absence of atrial thrombi

must be ensured.
i. Thrombi present plus cardioversion = 91% stroke rate
ii. Without anticoagulation (caused by decreased or stagnant bloodflow in the atria)
(a) Atrial fibrillation for greater than 48 hours = 15% rate of atrial thrombus
(b) Atrial fibrillation for greater than 72 hours = 30% rate of atrial thrombus
b. Ensure safe cardioversion by either:
i. Transesophageal echocardiogram to visualize the atria OR
ii. Three or more weeks of therapeutic anticoagulation (INR greater than 2.0)
c. Oral pharmacologic agents to induce/maintain sinus rhythm
i. Class I antiarrhythmics: Contraindicated in patients with HF
(a) These agents may be used second or third line because of frequent dosing
requirements and adverse effect profiles; some patients require hospitalization for
initiation because of proarrhythmic effects; only about 50% efficacy at 1 year
(1) Quinidine
(2) Disopyramide
(3) Propafenone
(4) Flecainide
(b) However, flecainide and propafenone may be considered first-line therapies for
patients without structural heart disease.
ii. Class III antiarrhythmics
(a) Amiodarone: 85%95% efficacy
(1) Has electrophysiologic properties of classes IIV
(2) Oral loading dose required (400 mg 2 or 3 times/day 2 weeks and then 400
mg/day for 4 weeks, followed by a 200-mg/day maintenance dose).
Achieving a loading dose of 10 g is desirable. Many different regimens exist.
(3) Long half-life of about 60 days
(4) In addition, has atrioventricular nodal blocking properties; may help control
HR if AF recurs
(5) Hepatically metabolized; inhibitor of cytochrome P450 (CYP) enzymes
CYP3A4, CYP1A2, CYP2C9, and CYP2D6 and P-glycoprotein
(6) Minimal incidence of ventricular arrhythmias
(7) Drug interactions (many)
(A) DigoxinIncreased digoxin exposure. Lower initial digoxin dose by 50%.
(B) WarfarinIncreased warfarin exposure. Lower warfarin dose by 25%30%.
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(C) SimvastatinIncreased simvastatin exposure. Do not exceed dose of 20 mg/day.

(D) -Blockers (particularly carvedilol)Additive bradycardia, increased blocker exposure
(E) Nondihydropyridine calcium channel blockersadditive bradycardia
(8) Extensive monitoring for noncardiac adverse effects
(A) Liver function tests: Baseline and every 6 months
(B) Thyroid function tests: Baseline and every 6 months
(C) Chest radiography: Baseline and annually
(D) Pulmonary function tests (including DLCO2 [carbon dioxide diffusion in
the lungs]): baseline and for unexplained dyspnea or chest radiographic
abnormalities. Discontinue if pulmonary fibrosis occurs.
(E) Ophthalmologic examination: For symptoms of visual impairment.
Discontinue if optic neuritis occurs.
(F) Skin toxicities: Blue skin syndrome and sunburn
(G) Neurologic toxicity: Monitor for neuropathy.
(b) Sotalol: 50%60% efficacy
(1) Renal excretion; hence, dose adjustment and vigilant QTc-interval
monitoring necessary in renal impairment
(2) May be initiated in outpatient setting in patients with little or no heart disease,
normal baseline QTc, normal serum electrolytes, and normal renal function
(3) Contraindicated in patients with HF and CrCl less than 40 mL/minute
(c) Dofetilide: 50%60% efficacy
(1) Must be initiated in the hospital (2- to 3-day stay). Dose titrated on the basis
of renal function and QTc-interval response
(2) Hepatically metabolized by CYP3A
(3) Renal elimination through renal cationic secretion; check QTc interval if
renal function acutely declines
(4) Safe to use in patients with HF
(5) Drug interactions:
(A) Cimetidine, verapamil, ketoconazole, hydrochlorothiazide, and
trimethoprim alone or in combination with sulfamethoxazole: AVOID
(B) CYP3A4 inhibitors: Increased dofetilide exposure, so use with caution
(C) Triamterene, metformin, amiloride: Increased dofetilide exposure, so use
with caution
iii. Class IIV agents
(a) Dronedarone: 21%25% efficacy
(1) Amiodarone analog that specifically lacks the iodine moiety that contributes
to the pulmonary, thyroid, hepatic, and ocular toxicity of amiodarone
(2) Has electrophysiologic properties of classes IIV with minimal
proarrhythmic effects
(3) Dose: 400 mg 2 times/day with morning and evening meal. No need for
loading dose
(4) Hepatically metabolized; CYP3A4 substrate and a moderate CYP3A4,
CYP2D6, and P-glycoprotein inhibitor
(5) Half-life only 24 hours
(6) Can increase SCr within 7 days (by 0.1 mg/dLnot clinically important)
(7) Contraindicated in NYHA class II or III HF with recent decompensation
requiring hospitalization, severe liver impairment, NYHA class IV HF, HR
less than 50 beats/minute, and strong CYP3A4 inhibitors
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(8) Compared with placebo in the ATHENA trial (N Engl J Med 2009;360:668
78), high-risk patients with a history of paroxysmal or persistent AF or atrial
flutter within the past 6 months receiving dronedarone had a lower incidence
of hospitalization for cardiovascular causes or death from any cause; risk of
cardiovascular death; death from arrhythmias; and incidence of stroke.
(9) On the basis of the ANDROMEDA study (N Engl J Med 2008;358:2678
87), dronedarone compared with placebo showed an increased mortality in
patients with HF (LVEF less than 35% and NYHA classes IIIV).
(10) One meta-analysis (J Am Coll Cardiol 2009;54:108995) found dronedarone
less effective than amiodarone for the maintenance of sinus rhythm, but with
fewer adverse effects.
(11) Drug interactions
(A) Digoxin: Increased digoxin exposure; lower dose of digoxin by 50%
(B) Diltiazem, verapamil, -blockers: Excessive bradycardia and increased
exposure of these agents; initiate these drugs at lowest dose. Diltiazem
and verapamil can increase dronedarone exposure, so monitor the
electrocardiogram.
(C) Statins with CYP3A metabolism: Increased statin exposure. Follow
statin package labeling for CYP3A4 inhibitors.
(D) CYP3A4 inhibitors: AVOID.
(E) Cyclosporine, tacrolimus, sirolimus: Increased exposure of these agents,
monitor serum concentrations closely
(12) U.S. Food and Drug Administration Risk Evaluation and Mitigation
Strategy. See the following Web site:
www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformat
ionforPatientsandProviders/UCM187494.pdf
(b) Vernakalant: Unique ion channel blocker currently under investigation
4. The choice of agent may depend on the comorbidities.
5. Nonpharmacologic therapies
a. Electrical cardioversion (low-energy cardioversion, sedation highly desirable, can be
used in an emergency if patient is hemodynamically unstable)
b. Atrioventricular nodal ablation: Ablate atrioventricular node and chronically pace the
ventricles.
c. Pulmonary vein ablation: Ablates the origin of the abnormal atrial foci, which is often
near the pulmonary veinatrial tissue intersection
Table 34. Antiarrhythmic Drug Properties and Dosing (class I and III agents only)
Drug
Adverse Effects, Contraindications, Drug

Interactions, Pharmacokinetics
Dosing by Indication
Class IA Na+ channel blockers

Quinidine
(Quinidex,
Quinaglute)
AEs: Nausea/vomiting/diarrhea (30%),

cinchonism(CNS and GI symptoms,
tinnitus),
TdP (first 72 hours)
DIs: Warfarin, digoxin
AF conversion:
Avoid use because of GI AEs
AF maintenance:
Sulfate: 200400 mg PO every 6 hours
Gluconate (CR): 324 mg PO every 812 hours
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Drug
Procainamide
(Pronestyl)

AEs: Lupuslike syndrome (30% if > 6 months), AF conversion:

hypotension (IV use, 5%), TdP
1 g IV for 30 minutes; then 2 mg/minute
CI: LVEF < 40%
(1-hour efficacy 51%)
PK: Reduce dose in renal and liver dysfunction AF maintenance:
(active metabolite NAPA [class III effects]
No oral agent
may accumulate)
VT conversion:
20 mg/minute IV until 17 mg/kg, arrhythmia
ceases, or QRS widens > 50%
VT maintenance:
24 mg/minute
Disopyramide AEs: Anticholinergic effects, TdP, ADHF

(potent negative inotropic effect)
(Norpace,
Norpace CR, CI: Glaucoma
Rythmodan,
RythmodanLA)
AF conversion:
IR 200 mg (if < 50 kg) or 300 mg (if > 50 kg)
PO every 6 hours
AF maintenance:
400800 mg/day in divided doses
(Recommended adult dose 600 mg/day given
as IR 150 mg PO every 6 hours or as CR 300
mg PO every 12 hours)
If < 50 kg, maximum 400 mg/day
If moderate renal dysfunction (CrCl > 40
mL/minute) or hepatic dysfunction, maximum
400 mg/day
If severe renal dysfunction, 100 mg
(IR only, avoid CR) every 8 hours if CrCl
3040 mL/minute, every 12 hours if CrCl
1530 mL/minute, or every 24 hours if CrCl
< 15 mL/minute)
Class IB Na+ channel blockers (inactive)

Lidocaine
(Xylocaine)
AEs: CNS (perioral numbness, seizures,

confusion, blurry vision, tinnitus)
CI: Third-degree AV heart block
PK: Reduce dose in those with HF, liver
disease, low body weight and renal
dysfunction and in the elderly
DI: Amiodarone (increased lidocaine
levels)
Pulseless VT/VF conversion or VT with a pulse:

11.5 mg/kg IVB; repeat 0.50.75 mg/kg
every 35 minutes (maximum 3 mg/kg)
(If LVEF < 40%: 0.50.75 mg/kg IVP)
(Amiodarone DOC in pulseless VT/VT
lidocaine acceptable if amiodarone not
available)
VT maintenance: 14 mg/minute
Mexiletine
(Mexitil)
AEs: CNS (tremor, dizziness, ataxia,

nystagmus)
CI: Third-degree AV heart block
VT maintenance: 200300 mg every 8 hours
Class IC Na+ channel blockers (Note: Avoid in patients with HF or post-MIIncreased risk of sudden death)
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Drug

Propafenone
(Rythmol,
Rythmol CR)
AEs: Metallic taste, dizziness, ADHF,

bronchospasm, bradycardia, heart block
(negative inotropy and b-blocking properties)
CIs: HF (NYHA IIIIV), liver disease,
valvular disease
DIs: Digoxin by 70%; warfarin by 50% as
well as drugs that inhibit CYP 2D6, 1A2, 3A4
(increased propafenone
AF conversion:
600 mg PO 1 (efficacy 45% at 3 hours)
AF maintenance:
HCl: 150300 mg PO every 812 hours
HCl (SR): 225425 mg PO every 12 hours
Flecainide
(Tambocor)
AEs: Dizziness, tremor, ADHF

(negative inotropy)
CIs: HF, CAD, valvular disease, LVH (TdP)
DI: Digoxin by 25%
AF conversion: 300 mg PO 1
(efficacy 50% at 3 hours)
AF maintenance: 50150 mg PO BID
Class III K+ channel blockers

Amiodarone
(Cordarone)
AEs: Pulmonary fibrosis 3%17%,

hyperthyroidism 3%, hypothyroidism 30%
50%, neurologic toxicity 20%40%,
photosensitivity, corneal deposits, hepatitis,
blue-gray skin 15%, TdP < 1%, heart block
14%, hypotension (IV), phlebitis (IV) (Ca2+
and -blocking properties)
CIs: Iodine hypersensitivity, hyperthyroidism,
third-degree AV heart block
DIs: Warfarin, digoxin, HMG-CoA reductase
inhibitors (maximum simvastatin dose 20
mg/day), phenytoin 50%, lidocaine,
and others
(inhibits CYP3A4/2D6/2C9 and gut pgp)
* Does not increase mortality in patients
with HF
PK: Half-life 58 days (average)
AF conversion:
IV: 57 mg/kg IV over 3060 minutes; then 1.21.8
g/day continuous IV or divided oral doses until 10 g
PO: 1.21.8 g/day in divided doses until 10 g
AF maintenance:
200400 mg/day PO
Pulseless VT/VF conversion:
300 mg or 5 mg/kg IVB in 20 mL of D5W or NS;
repeat 150 mg IVB every 35 minutes
Stable VT: 150 mg IVB in 100 mL of D5W for 10
minutes
VT/VF maintenance:
1 mg/minute 6 hours; then 0.5 mg/minute
(maximum 2.2 g/day)
Sotalol
AEs: ADHF, bradycardia, AV block,

wheezing, 3%8% TdP within 3 days of
initiation, bronchospasm (-blocking effects)
CI: Baseline QTc > 440 milliseconds or
CrCl < 40 mL/minute (AF only)
PK: Renally eliminated
* Hospitalization mandatory for initiation,
obtain QTc 23 hours after first 5 doses,
double-dose every 3 days; NTE QTc >
500 milliseconds
Not effective for AF conversion!
AF maintenance (based on CrCl)

80 mg PO BID (> 60 mL/minute)
80 mg PO QD (4060 mL/minute)
Contraindicated < 40 mL/minute
AEs: TdP (0.8%; 4% if no renal adjustment),

diarrhea
AF conversion (based on CrCl)

500 mcg PO BID (> 60 mL/minute)
Dofetilide
(Tikosyn)
VT maintenance (based on CrCl)

80 mg PO BID (> 60 mL/minute)
80 mg PO QD (3060 mL/minute)
80 mg PO QOD (1030 mL/minute)
80 mg PO > QOD (< 10 mL/minute)
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Drug

DIs: CYP3A4 inhibitors and drugs secreted

by kidney (cimetidine, ketoconazole,
verapamil, trimethoprim, prochlorperazine,
megestrol), HCTZ
CI: Baseline QTc > 440 milliseconds or
CrCl < 20 mL/minute
PK: Renally eliminated
* Hospitalization mandatory for initiation,
obtain QTc 23 hours after each of the first
5 doses, reduce 50% if QTc > 15%; NTE
QTc > 500 milliseconds
* Does not increase mortality in patients
with HF
250 mcg PO BID (4060 mL/minute)

125 mcg PO BID (2040 mL/minute)
Contraindicated < 20 mL/minute (efficacy 12% at 1
month)
AF maintenance:
Titrate down based on QTc NTE 500 milliseconds or
> 15% in QTc
Ibutilide
(Covert)
AEs: TdP 8%, heart block (-blocking

properties)
DIs: CYP3A4 inhibitors or QT-prolonging
drugs
CIs: Baseline QTc > 440 milliseconds, LVEF <
30%, concomitant antiarrhythmic drugs
*ECG monitoring during and 4 hours
after CV
AF conversion:
1 mg IV ( 60 kg)
or 0.01 mg/kg IV (< 60 kg),
repeat in 10 minutes if ineffective
(efficacy 47% at 90 minutes)
Dronedarone
(Multaq)
AEs: Worsening HF, QT prolongation,

AF maintenance:
hypokalemia or hypomagnesemia with
400 mg PO BID
potassium-sparing diuretics
Discontinue if QTc 500 milliseconds
DIs: CYP3A4 inhibitors, QT-prolonging drugs,
simvastatin, tacrolimus-sirolimus, and other
CYP3A4 substrates with narrow therapeutic
range, digoxin and other pgp substrates
CIs: QTc 500 milliseconds or PR 280
milliseconds, NYHA class IV HF or NYHA
class IIIII HF with recent ADHF, severe
hepatic impairment, second- or third-degree
AVB or HR < 50 beats/minute
PK: Half-life 1319 hours
ADHF = acute decompensated heart failure; AE = adverse effect; AF = atrial fibrillation; AV = atrioventricular; AVB =
atrioventricular block; BID = twice daily; CAD = coronary artery disease; CI = contraindication; CNS = central nervous system;
CR = controlled release; CrCl = creatinine clearance; CV = cardioversion; CYP = cytochrome P450; D5W = dextrose 5%; DI =
drug interactions; DOC = drug of choice; ECG = electrocardiogram; GI = gastrointestinal; HCL = hydrochloride; HCTZ =
hydrochlorothiazide; HF = heart failure; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; HR = heart rate; IR = immediate
release; IV = intravenous; IVB = intravenous bolus; IVP = intravenous push; LVEF = left ventricular ejection fraction; MI =
myocardial infarction; MOA = mechanism of action; NS = normal saline; NTE = not to exceed; NYHA = New York Heart
Association; pgp = P-glycoprotein; PK = pharmacokinetics; PO = oral; QD = once daily; QOD = once every other day; TdP =
torsades de pointes; VF = ventricular fibrillation; VT = ventricular tachycardia.
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VIII. ANTICOAGULATION
A. Warfarin Products
1. Brands: Coumadin, Jantoven, and many generics (Barr, Geneva, Taro)
2. Strengths: 1-, 2-, 2.5-, 3-, 4-, 5-, 6-, 7.5-, and 10-mg tablets. All are scored.
B. Mechanism of Action
1. Inhibits vitamin Kdependent clotting factors II, VII, IX, and X
2. Inhibits anticoagulant proteins C and S
3. Racemic mixture of R- and S-isomers
a. S-isomer more potent vitamin K antagonist
b. S-isomer metabolized primarily by cytochrome P450 (CYP) 2C9
c. R-isomer metabolized primarily by CYP3A4
C. Indications
Table 35. Recommendations for Long-term Warfarin Therapya
Thromboembolic Disorder
INR
Duration
Evidence
Comments
Venous Thromboembolism (VTE): DVT or PE

DVT/PE with reversible or
time-limited risk factor
2.5 (23) 3 months
1A
Time-limited risk factors: Surgery, immobilization,

estrogen, pregnancy
For all acute DVTs, initiate warfarin together with
LMWH (preferred), UFH, or fondaparinux (1A) and
continue for at least 5 days and until INR 2 for 24
hours (1C)
First idiopathic PE or
proximal DVT
2.5 (23) At least 3

1A
months; long
term if low
bleeding risk
and
consistent
with patient
preference
after
discussion
At 3 months, evaluate risk-benefit of long-term

therapy; if patient needs long-term treatment and
strongly prefers less-frequent INRs, after first 3
months, low-intensity therapy can be used (INR
1.51.9)
Idiopathic distal DVT: 3 months is sufficient
Treat recurrence (second episode idiopathic) with
long-term (1A)
DVT with cancer: LMWH
36 months; then long-term VKAs (1A)
For primary prevention in

patients at very high risk of
CV events
1.5
2A
For moderate-risk patients (10-year CHD risk >

10%), only ASA (75100 mg/day) is recommended
High-risk patients with MI,

including large anterior MI,
significant HF, AF, evidence
of intracardiac thrombus,
and/or history of
thromboembolic event
2.5 (23) At least 3

months
2A
Use VKA together with ASA 100 mg/day
CAD/Acute MI
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INR
Any patients post-MI

3.5 (34)
(low to high risk)
(***Aspirin 75100 mg alone
is recommended over VKA
alone or with aspirin, except
for the high-risk patients
2.5 (23)
above***)
Duration
Up to 4
years,
without
aspirin, OR
Evidence
2B
Comments
Warfarin only if meticulous INR monitoring and
highly skilled VKA dose adjustment is standard and
accessible; higher bleeding risk with warfarin at this
higher INR level
Up to 4 years 2B
with aspirin
< 100
mg/day
Atrial Fibrillation (including paroxysmal/intermittent)

AF with any previous TIA,
ischemic stroke, or systemic
embolism
2.5 (23) Long term
1A
VKAs should be used
AF and two or more of the

risk factors listed (or
CHADS2 scoreb 2)
2.5 (23) Long term
1A
Risk factors: Chronic heart failure/moderate to

severe LV dysfunction, HTN, age > 75, diabetes
AF and one of the risk factors 2.5 (23) Long term

listed (or CHADS2 scoreb 1)
ASA
Long term
75325
mg
1A
1B
VKAs are recommended over ASA, but either one is

an option. Specific patient factors should be
considered
75 years with no listed risk ASA

factors (or CHADS2 scoreb 0) 75325
mg
Long term
1B
Aspirin 75325 mg once daily; no warfarin
2.5 (23) Long term
1C
The same recommendations as for AF should be

followed
2.5 (23) 7 weeks
1C
3 weeks before and at least

4 weeks after sinus rhythm maintained
If AF is < 48 hours in duration, cardioversion can be
performed without prolonged anticoagulation;
LMWH (full treatment dose) or UFH should be used
at presentation
2.5 (23) Long term
1A
If AF and systemic embolism or LA thrombus

occurs despite therapeutic warfarin, should add ASA
50100 mg/day (alternative: increase target INR to 2
[2.53.5]) (2C)
Rheumatic mitral valve

2.5 (23) Long term
disease in sinus rhythm if LA
diameter is > 55 cm
2C
Atrial flutter
Conversion of Atrial Fibrillation

Elective direct current
cardioversion of AF 48
hours or unknown duration
Valvular Heart Disease

Rheumatic mitral valve
disease with history of
systemic embolism, LA
thrombus, or AF
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INR
MVP with documented but

Aspirin
unexplained TIA or stroke
50100
Systemic embolism or
mg/day
recurrent TIAs despite aspirin
therapy
Duration
Long term
Evidence
Comments
1B
If MVP and AF, systemic embolism or recurrent

TIAs despite ASA, use warfarin (INR 23) (2C)
1B
Switch to ASA after 3 months if sinus rhythm.

For aortic bioprosthetic valve and normal sinus
rhythm: ASA 50100 mg/day (1B)
For any bioprosthetic valve with risk factors (low
EF, AF, hypercoagulable), use long-term VKA
Bioprosthetic heart valve with 2.5 (23) Until

LA thrombus at surgery
documented
thrombus
resolution
1C
If systemic embolism, reassess at 3 months
Mechanical prosthetic heart

valve: aortic
2.5 (23) Long term
1B
If normal LA size and in sinus rhythm. Valves: St.

Jude bileaflet, Carbomedics bileaflet, Medtronic
tilting disk. 2.53.5 if AF or LA enlargement
Mechanical prosthetic heart

valve: mitral
3 (2.5
3.5)
Long term
1B
Tilting disk or bileaflet
Any mechanical valve plus

other risk factors OR
Any mechanical valve with
systemic embolism with
therapeutic INR (2C)
3 (2.5
3.5)
Long term
1B
PLUS ASA 50100 mg/day

Risk factors: AF, hypercoagulable state, low EF,
atherosclerotic vascular disease
For systemic embolism with therapeutic INR, add
ASA and/or increase target INR range by 0.5
Mechanical and Bioprosthetic Heart Valves

Bioprosthetic heart valve,
mitral
2.5 (23) 3 months;

then ASA
50100
mg/day
2C
Antiphospholipid Antibody Syndrome

Thromboembolism with lupus 2.5 (23)
inhibitor and no additional
risk factors, with no lack of
response to therapy
1A
Recurrent thromboembolic
events with therapeutic INR
or additional risk factors for
thromboembolism
2C
3 (2.5
3.5)
a
Evidence categories: 1 = strong, experts are certain; 2 = weaker, experts are less certain; A = consistent results from RCTs; B =
inconsistent results from RCTs; C+ = observational studies with very strong effects or generalizations from RCTs; C = observational
studies.
b
CHADS2 score is calculated by assigning points for the following risk factors: CHF (any history), HTN, age 75, diabetes (1 point
each); stroke, TIA, systemic embolism history (2 points).
AF = atrial fibrillation; ASA = acetylsalicylic acid; CAD = coronary artery disease; CHF = chronic heart failure; CV = cardiovascular;
DVT = deep venous thrombosis; EF = ejection fraction; HTN = hypertension; INR = international normalized ratio; LA = left atrial; LV =
left ventricular; LMWH = low-molecular-weight heparin; MI = myocardial infarction; MVP = mitral valve prolapse; PE = pulmonary
embolism; QD = every day; RCT = randomized controlled trial; TIA = transient ischemic attack; VKA = vitamin K antagonist.
From Hirsh J, Guyatt G, Albers GW, Harrington R, Schunemann HJ. Chest 2008 Guidelines. Antithrombotic and Thrombolytic Therapy:
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133:110S112S.
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D. Dosing and Administration

1. Overlap with heparin or therapeutic-dose low-molecular-weight heparin (LMWH) (see
Management of Oral Anticoagulation During Invasive Procedures section below) for 46
days for acute thromboembolism, until INR is therapeutic for at least 2 days. Heparin
discontinued when INR is therapeutic for 2 days
2. Initial dose
a. Begin warfarin on day 1 of heparin or LMWH (Hull et al. 1990).
b. Loading dose greater than 10 mg is not recommended; will not achieve therapeutic range
faster, may increase adverse effects
c. Recommend initiating at 510 mg/day (Chest 2008 guidelines) (Ann Intern Med
1997;126:1336); 10 mg for 12 days may be appropriate in outpatients younger than 75
years with venous thromboembolism (VTE), but 5 mg/day is usually sufficient
3. Adjusting dose
a. Watch for trends; remember that the INR seen today is the result of the doses given
during the past 45 days. Takes 57 days to reach full effect
b. Half-lives of vitamin Kdependent clotting factors
VII = 6 hours
IX = 24 hours
X = 36 hours
II = 72 hours
4. Recommended to increase or decrease cumulative weekly warfarin dose by 10%15% depending
on INR; if INR is high, may hold one or two doses and resume at a lower dose. Usually do not
need to adjust dose if INR is within 0.1 of goal (but monitor more closely)
5. Specific patients may need starting dose lower than 5 mg/day (23 mg/day).
a. Elderly
b. Very low body weight
c. Concurrent interacting drug (enzyme inhibitor)
d. Malnourished or nothing by mouth for more than 3 days
e. Liver disease
f. Congestive heart failure
g. High risk of bleeding
h. Prolonged fever
i. Hyperthyroid
j. Low albumin
6. Variable INR
a. Some patients on long-term warfarin have a variable INR response that is not from usual
known causes.
b. A trial of low-dose vitamin K (100200 mcg/day) may be used, with close INR
monitoring and adjustment to an initial lowering of INR (grade 2B recommendation).
7. Genetic testing
a. A variety of genetic mutations for VKORC1 and CYP2C9 exist.
b. A VKORC1 mutation results in increased sensitivity or resistance to warfarin.
c. CYP2C9 polymorphisms alter the rate of metabolism and the half-life of warfarin.
d. Mutations of either of these result in an altered initial dose and maintenance dose.
e. The CHEST guidelines recommend against the use of genetic testing to estimate initial
dose and to individualize dosing because of the lack of sufficient evidence from
randomized trials (grade 2C).
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E. Adverse Effects
1. Bleeding
a. Incidence
i. All: 2.4%29%
ii. Fatal or life threatening: 2%8%
b. Epistaxis, hematuria, gastrointestinal hemorrhage, bleeding gums
c. Easy bruising often occurs with therapeutic INR.
2. Skin necrosis (rare)
a. Extensive thrombosis of venules and capillaries within subcutaneous fat, involving
abdomen, buttocks, thighs, or breasts
b. Caused by protein C or protein S deficiency induced by warfarin early in therapy
c. Occurs between days 1 and 10
d. If occurs, discontinue warfarin and initiate heparin. Reinitiate warfarin at a low dose
(e.g., 2 mg/dose), and increase gradually for several weeks.
3. Purple toe syndrome (rare)
a. Mechanism of action: Anticoagulation treatment may enhance the release of
atheromatous plaque emboli to cause systemic cholesterol microembolism.
b. Occurs 310 weeks after warfarin is begun
c. Toes painful, purple, fluctuating from hour to hour
d. If occurs, discontinue warfarin; may take weeks to months for discoloration to disappear
4. Teratogenicity (category X)
a. First-trimester exposure: Nasal hypoplasia, small nares, chondrodysplasia
b. Second- and third-trimester exposure: Mental retardation, blindness, spasticity, seizures
c. If pregnant, subcutaneous heparin or LMWH is safe to use.
d. Breastfeeding: Can use warfarin because not excreted in breast milk
F. Patient Education
1. Indication and expected therapy duration
2. Bleeding symptoms/signs
3. Management of bleeding complicationsWhen to call health care provider
4. Need for and importance of frequent blood tests and INR goals
5. Drug interactions (especially OTCs [over-the-counter medications] and herbals)
6. Dosing/importance of adherence/pillbox
7. How to take; what to do if a dose missed
8. Dietary instructions; keep intake of vitamin Kcontaining foods consistent
9. Teratogenicity; need for reliable contraception if of childbearing age
10. Wear medic alert bracelet/necklace or carry identification card.
G. Drug Interactions (lists not all-inclusive; many drug interactions exist)
**Drug interactions are very common with warfarin. The magnitude of interactions varies
considerably; for some, concomitant use is contraindicated; others require a warfarin dose
adjustment; for others, more frequent monitoring of the INR is sufficient.**
1. Reduced warfarin absorption (e.g., cholestyramine, sucralfate)
2. Enzyme induction (decreases INR and warfarin effects)
a. CYP3A4 (e.g., rifampin, carbamazepine, phenobarbital, St. Johns wort)
b. Other (e.g., griseofulvin, nafcillin, dicloxacillin, phenytoin [inhibition; then induction])
c. Delay in onset and offset
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3. Enzyme inhibition (increases INR and warfarin effects)

a. S-warfarin* (CYP2C9) (e.g., metronidazole, trimethoprim/sulfamethoxazole,
fluconazole, isoniazid, cimetidine, fluoxetine, sertraline, zafirlukast, amiodarone,
clopidogrel, lovastatin)
b. R-warfarin (CYP3A3/4/5) (e.g., cimetidine, omeprazole, clarithromycin, erythromycin,
azole antifungals, nefazodone, zafirlukast, fluoxetine, amiodarone, cyclosporine A,
sertraline, grapefruit juice, ciprofloxacin, norfloxacin, protease inhibitors, cyclosporine,
diltiazem, verapamil, isoniazid, metronidazole, zafirlukast)
4. Antiplatelet effects (e.g., gingko, garlic, aspirin, nonsteroidal anti-inflammatory drugs
[NSAIDs] [not COX-2 {cyclooxygenase-2} inhibitors or NAS {nonacetylated salicylates}],
selective serotonin reuptake inhibitors)
5. Displacement from plasma protein binding (e.g., NSAIDs, ASA [acetylsalicylic acid],
quinolones, sulfas)
6. Reduced clearance of warfarin (e.g., propafenone)
7. Increased degradation of clotting factors (e.g., levothyroxine)
Table 36. Management of Increased INR

INR
Patient Situation
Action
<5
and
No significant
bleeding or need
for rapid reversal
Lower dose OR omit dose, monitor more often, and reinitiate at a lower dose
when INR approaches 3. If INR is only minimally above the therapeutic
range, no dose reduction may be required
<9
and
In need of rapid
reversal (e.g.,
before surgery)
Give oral vitamin K1 (24 mg) with the expectation that a reduction in the
INR will occur within 24 hours. If the INR remains high at 24 hours, an
additional dose of 12 mg of oral vitamin K1 can be given
5
and
<9
No bleeding and no Omit one or two doses of warfarin, and monitor INR more often. Reinitiate
risk factors
warfarin at a lower dose when the INR falls into the therapeutic range
and
and
No bleeding, but at Omit one dose of warfarin and give oral vitamin K1 ( 5 mg; generally 1
risk of bleeding
2.5 mg)
No clinically
Omit the next several warfarin doses and give oral vitamin K1 (510 mg),
significant bleeding with the expectation that the INR will be reduced substantially by about 24
48 hours. Monitor INR closely and repeat vitamin K1, if necessary. Resume
warfarin at a lower dose when INR is in the desired range
Serious bleeding at
any INR elevation
or warfarin
overdosage
Hold warfarin, give vitamin K1 10 mg by slow IV infusion over 2030

minutes, and supplement with FFP or prothrombin complex concentrate
(alternative: recombinant factor VIIa) (depending on urgency). If needed,
repeat vitamin K1 injection every 12 hours. If continued warfarin therapy is
indicated after high doses of vitamin K1, can give heparin until the patient is
responsive to warfarin
Life-threatening
bleeding or
warfarin overdose
Interrupt warfarin and give prothrombin complex concentrate supplemented

with vitamin K (10 mg by slow IV infusion); recombinant factor VIIa may
be considered an alternative to prothrombin complex concentrate; repeat if
necessary, depending on INR
FFP = fresh frozen plasma; INR = international normalized ratio; IV = intravenous.

Adapted from: Hirsh J, Guyatt G, Albers GW, Harrington R, Schunemann HJ. Chest 2008 Guidelines. Antithrombotic and
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Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest
2008;133:110S112S.
H. Food Interactions with Warfarin

Table 37. Foods with Medium-High Vitamin K Content
Food
Rank of Vitamin K
Meat
Liver (chicken, beef)
High
Dairy
Cheese
Medium
Grains
Oats
Medium
Beverages
Green tea
Higha
Vegetables
Asparagus
Avocado
Broccoli
Brussel sprouts
Cabbage
Cauliflower
Chick peas
Collard greens
Green peas
Kale
Lettuce (iceberg)
Lettuce (Bibb, red leaf, green leaf)
Mustard greens (raw)
Pickles
Spinach
Swiss chard (raw)
Turnip greens (raw)
Medium
Medium
High
High
High
High
High
High
Medium
High
Medium
High
High
Medium
High
High
High
a
Some controversy exists about whether brewing green tea decreases its vitamin K content.
U.S. Department of Agriculture. Provisional Table on the Vitamin K Content of Foods. Available at
www.nal.usda.gov/fnic/foodcomp/Data/Other/pt104.pdf. Accessed September 15, 2010.
ClotCare Web site. Table on Vitamin K Content of Selected Foods. Available at
www.clotcare.com/clotcare/include/vitaminkcontent.pdf. Accessed December 15, 2010.
I.
Disease Interactions: May result in increased INR and a lower warfarin dose requirement
1. Malnourished/nothing by mouth
2. Recent major surgery
3. Chronic heart failure (especially decompensated)
4. Liver disease
5. Hyperthyroidism (increased clearance of clotting factors)
6. Prolonged fever (increased clearance of clotting factors)
7. Diarrhea
J.
Monitoring Parameters
1. Signs and symptoms of bleeding
a. Mild: Nosebleeds, bleeding gums, easy bruising
b. More severe (evaluation needed): Hematuria, hematemesis, hemoptysis, melena,
hematochezia, bright red blood per rectum
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2. INR = (PTpatient/PTmean)ISI, where PT = prothrombin time; ISI = International Sensitivity Index.

K. Management of Oral Anticoagulation During Invasive Procedures
1. Discontinue warfarin around 5 days before surgery, and perform procedure when the INR has
normalized. If the INR is still elevated (1.5 or higher) 12 days before surgery, administer
low-dose (12 mg) oral vitamin K.
2. Resume warfarin 1224 hours after surgery. Resume subcutaneous LMWH (if using) and
continue until warfarin is therapeutic; initiate LMWH 24 hours after minor surgery and 4872
hours after major surgery/high bleeding risk.
3. Bridging anticoagulation with therapeutic-dose subcutaneous LMWH or intravenous
unfractionated heparin (UFH) (LMWH preferred) is recommended in patients with a
mechanical heart valve or atrial fibrillation or VTE at moderate or high risk of
thromboembolism, with the option of low-dose subcutaneous LMWH for moderate risk
(therapeutic-dose LMWH preferred). In low-risk patients, low-dose subcutaneous LMWH or
no bridging is recommended.
a. Therapeutic-dose subcutaneous LMWH:
i. Enoxaparin 1 mg/kg 2 times/day
ii. Enoxaparin 1.5 mg/kg once daily
iii. Dalteparin 200 IU/kg once daily
iv. Dalteparin 100 IU/kg 2 times/day
v. Tinzaparin 175 IU/kg once daily
b. Low-dose subcutaneous LMWH:
i. Enoxaparin 30 mg 2 times/day
ii. Dalteparin 5000 IU once daily
c. High thromboembolism risk:
i. Mechanical heart valve: Any mechanical mitral valve, older aortic valve (caged-ball
or tilting disk), recent stroke/transient ischemic attack (TIA) (past 6 months)
ii. Atrial fibrillation: CHADS2 score of 5 or 6, recent stroke/TIA (past 3 months),
presence of rheumatic valvular heart disease
iii. VTE: Recent VTE (past 3 months), severe thrombophilia (protein C, protein S or
antithrombin deficiency, antiphospholipid antibodies, or multiple abnormalities)
d. Moderate thromboembolism risk:
i. Mechanical heart valve: Bileaflet aortic valve with atrial fibrillation, stroke/TIA,
hypertension, diabetes, CHF, or age older than 75
ii. Atrial fibrillation: CHADS2 score of 3 or 4
iii. Venous thromboembolism: VTE in the past 312 months, nonsevere thrombophilic
conditions (heterozygous factor V Leiden mutation, heterozygous factor II mutation),
recurrent VTE, active cancer (treated in past 6 months or palliative)
e. Low thromboembolism risk:
i. Mechanical heart valve: Bileaflet aortic valve without atrial fibrillation or other risk
factors
ii. Atrial fibrillation: CHADS2 score of 02 and no previous stroke/TIA
iii. VTE: Single VTE more than 12 months ago with no risk factors
4. Give the last dose of LMWH 24 hours before surgery or UFH 4 hours before surgery; for
LMWH, use half the usual dose for the last dose.
5. No need to hold anticoagulation therapy for most minor dental procedures (single- or multitooth extractions or root canal), cataract removal, or minor dermatologic procedures. For
dental procedures, use local measures to control bleeding, and consider aminocaproic or
tranexamic acid mouthwash.
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6. For urgent/emergency surgical or other invasive procedures, oral or intravenous vitamin K

2.55 mg is recommended. If more immediate reversal is required, fresh frozen plasma or
prothrombin concentrate is recommended, plus intravenous or oral vitamin K.
L. New and Investigational Anticoagulants
1. Dabigatran (Pradaxa)
2. Desirudin (Iprivask)
3. Rivaroxaban (Xarelto)
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Appendix 1. Framingham Tables
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Vascular Medicine and Biology, Society of
Interventional Radiology, and the ACC/AHA
Task Force on Practice Guidelines (Writing
Committee to Develop Guidelines for the
Management of Patients with Peripheral
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Association of Cardiovascular and Pulmonary
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Hypertension
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3. Appel LJ, Brands MW, Daniels SR, et al.
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CAD and Chronic Stable Angina

1. Gibbons RJ, Abrams J, Chatterjee K, et al.
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2. Gibbons RJ, Abrams J, Chatterjee K, et al. 2007
chronic angina focused update of the
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guidelines for the management of patients with
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2007;116:276272.
3. Smith SC, Allen J, Blair SN, et al. ACC/AHA
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Dyslipidemia
1. National Institutes of Health National Heart,
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(Adult Treatment Panel III). JAMA
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al. Implications of recent clinical trials for the
National Cholesterol Education Program Adult
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3. Pasternak RC, Smith SC, Bairey-Merz CN, et
al. ACC/AHA/NHLBI advisory on the use and
safety of statins. J Am Coll Cardiol
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4. Kastelein JJP, Akdim F, Stroes ESG, et al.
Simvastatin with or without ezetimibe in
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2008;358:143143.
Acute Coronary Syndromes

1. Antman EM, Hand M, Armstrong PW, et al.
2007 focused update of the ACC/AHA 2004
guidelines for the management of patients with
ST-elevation myocardial infarction: a report of
Peripheral Arterial Disease

1. Hirsch AT, Haskal ZJ, Hertzer NR, et al.
ACC/AHA 2005 Practice Guidelines for the
Management of Patients with Peripheral
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2.
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4.
the American College of Cardiology/American

Heart Association Task Force on Practice
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Anderson JL, Adams CD, Antman EM, et al.
ACC/AHA 2007 guideline update for the
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nonST-segment elevation myocardial
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King SB III, Smith SC Jr, Hirshfeld JW Jr, et
al. 2007 focused update of the ACC/AHA/SCAI
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J Am Coll Cardiol 2008;51:172209.
Kushner FG, Hand M, Smith SC Jr, et al. 2009
focused update of the ACC/AHA guidelines for
the management of patients with ST-elevation
myocardial infarction (updating the 2004
guideline and 2007 focused update) and
ACC/AHA/SCAI guidelines on percutaneous
coronary intervention (updating the 2005
guideline and 2007 focused update): a report of
the American College of Cardiology/American
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HFSA 2010 comprehensive heart failure

practice guideline. J Card Fail 2010;16:e1
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Atrial Fibrillation
1. Fuster V, Rydn LE, Cannom DS, et al.
ACC/AHA/ESC 2006 guidelines for the
management of patients with atrial fibrillation:
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Force on Practice Guidelines and the European
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2001 Guidelines for the Management of
Patients with Atrial Fibrillation). Circulation
2006;114:e257e354.
2. Singer DE, Albers GW, Dalen JE, et al.
Antithrombotic therapy in atrial fibrillation. Chest
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3. The Atrial Fibrillation Follow-up Investigation
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Investigators. A comparison of rate control
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Anticoagulation
1. Hull RD, Raskob GE, Rosenbloom D, et al.
Heparin for 5 days as compared with 10 days in
the initial treatment of proximal venous
thrombosis. N Engl J Med 1990;322:12604.
2. Ansell J, Hirsh J, Hylek E, et al. The
pharmacology and management of the vitamin
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Chest 2008;133:160S198S.
3. Douketis JC, Berger PB, Dunn AS, et al. The
perioperative management of antithrombotic
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Antithrombotic and Thrombolytic Therapy.
Chest 2008;133:299S339S.
4. Hirsh J, Guyatt G, Albers GW, Harrington R,
Schunemann HJ. Chest 2008 Guidelines.
Antithrombotic and Thrombolytic Therapy:
American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines
(8th edition). Chest 2008;133:110S112S.
Heart Failure
1. Hunt SA, Abraham WT, Chin MH, et al. 2009
focused update incorporated into the ACC/AHA
2005 guidelines for the diagnosis and
management of heart failure in adults. A report
of the American College of Cardiology
Foundation/American Heart Association Task
Force on Practice Guidelines developed in
collaboration with the International Society for
Heart and Lung Transplantation. J Am Coll
Cardiol 2009;53:e1e90.
2. Jackevicius CA, Page RL, Chow S, et al. High
impact articles related to the management of
heart failure: 2008 update. Pharmacotherapy
2009;29:82120.
3. Amabile CM, Spencer AP. Keep your heart
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dangerous medications. Arch Intern Med
2004;164:70920.
4. Lindenfeld J, Albert NM, Boehmer JP, et al.
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1. Select and monitor appropriate acute and preventive treatment for pediatric and adult patients with
asthma and adult patients with chronic obstructive pulmonary disease (COPD), depending on
patient-specific factors.
2. Classify a patient according to his or her asthma severity class, and assess his or her control,
according to the current National Institutes of Health, National Heart Lung and Blood Institute
guidelines.
3. Educate a patient about his or her therapy for asthma and COPD, including proper use of inhalers and
holding chambers.
I. ASTHMA
Guidelines:
National Institutes of Health (NIH) National Heart Lung and Blood Institute (NHLBI). National Asthma
Education and Prevention Program (NAEPP) Guidelines. NAEPP Expert Panel Report 3. NIH
Publication 08-5846. July 2007. Available at www.nhlbi.nih.gov/guidelines/index.htm. Accessed
December 19, 2011.
A. Definition: Asthma is a chronic inflammatory disorder of the airways causing recurrent episodes
of wheezing, breathlessness, cough, and chest tightness, particularly at night or early in the
morning. During episodes, there is variable airway obstruction, often reversible spontaneously or
with treatment. There is also increased bronchial hyperresponsiveness to a variety of stimuli.
B. Diagnosis
1. Episodic symptoms of airflow obstruction are present.
2. Airway obstruction is reversible (forced expiratory volume in 1 second [FEV1]; improves by
12% or more after short-acting 2-agonists [SABAs])
3. Alternative diagnoses are excluded. Asthma versus chronic obstructive pulmonary disease
(COPD)
a. Cough is usually nonproductive with asthma and productive with COPD.
b. FEV is reversible with asthma but not with COPD.
c. Cough is worse at night and early in the morning with asthma; throughout the day with
COPD
d. Asthma is often related to allergies/environmental triggers; COPD has a common history
of smoking.
e. Asthma can be reversible; lung damage from COPD is irreversible.
4. Exercise-induced bronchospasm
a. Presents with cough, shortness of breath, chest pain or tightness, wheezing, or endurance
problems during exercise
b. Diagnosed with an exercise challenge, in which a 15% decrease in FEV or peak
expiratory flow (PEF) is seen before and after exercise, measured at 5-minute intervals
for 2030 minutes
c. Prevention and treatment of symptoms
i. Long-term control therapy, if otherwise appropriate (initiate or step-up)
ii. Pretreatment with SABA before exercise
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iii. Leukotriene modifiers (LTMs) can attenuate symptoms in 50% of patients.

C. Classification of Asthma Severity and Control
a
Table 1. Classification of Asthma Severity in Adults and Children
Components
Frequency of
symptoms
Nighttime
awakening
Age
Group
(years)
All ages
12
511
04
Mild Persistent
Moderate
Persistent
2 days/week > 2 days/week, but Daily

not daily
Severe
Persistent
Throughout
the day
2
times/month
3 or 4 times/month More than once Often 7

weekly, but not times/week
nightly
0 times
1 or 2 times/month 3 or 4
times/month
More than
once
weekly
SABA; used for

symptom control
All ages
2 days/week > 2 days/week,

but not daily
Daily
Several
times a day
Interference with
normal activity
All ages
None
Minor limitation
Some
limitations
Extremely
limited
12
Normal
Normal
Reduced 5%
Reduced >
5%
511
> 85%
> 80%
75%80%
< 75%
04
N/A
12
> 80%
(normal)
FEV1/FVCb
FEV1
(% of normal)
Exacerbations
requiring oral
steroids
Recommended step
for initiating
treatment
(see Table 4)
a
Intermittent
511
> 80%
(normal)
> 60% to <

80%
< 60%
2/year
2/year
04
N/A
12
01/year
2/year
04
0-1/year
2 in 6 months or 4 wheezing episodes/yearc
12
Step 1
Step 2
511
511
Step 3d and consider short

course of oral steroids
04
The patient is classified according to the sign or symptom that is in the most severe category.
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Normal FEV1/FVC: ages 819 years: 85%, 2039 years: 80%, 4059 years: 75%, 6080 years: 70%.
Episodes lasting more than 1 day and risk factors for persistent asthma.
d
For ages 511, initial step 3 therapy should be medium-dose ICS.
FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; SABA = short-acting 2-agonist.
Adapted from NIH Asthma Guidelines. National Institutes of Health National Heart Lung and Blood Institute. National Asthma Education and
Prevention Program (NAEPP) Guidelines. NAEPP Expert Panel Report 3. NIH P ublication 08-5846. Available at
www.nhlbi.nih.gov/guidelines/index.htm. Accessed December 19, 2011.
c
Table 2. Interpreting Spirometry

Component
What It Measures
Normal Values
FEV1 (forced
expiratory
volume)
Volume of air exhaled

forcefully in the first
second of maximal
expiration
Normal is 80% or greater of predicted value. Reported in liters per

minute and as percentage of predicted value on the basis of sex,
age, and height
In asthma, reversibility is shown by an increase in FEV1 12% after
SABA
FVC (forced
vital
capacity)
The maximum volume

of air that can be
exhaled after full
inspiration
Reported in liters and as percentage of predicted value on the basis

of sex, age, and height
Normal lungs can empty 80% of air in < 6 seconds
FEV1/FVC
ratio
Differentiates between
obstructive and
restrictive disease
Normal: Within 5% of predicted range, which varies with age;

usually 75%80% in adults
Decreased in obstructive disease (asthma, COPD) (< 70%)
Normal/high in restrictive disease (e.g., pulmonary fibrosis)
COPD = chronic obstructive pulmonary disease; SABA = short-acting 2-agonist.
Table 3. Assessing Asthma Control in Adults and Children

Component
Symptoms
Age Group
(years)
Well Controlled
Not Well Controlled
12
2 days/week
> 2 days/week
511
2 days/week but not

> 1 x each day
> 2 days/week or >

1 x/day on any day
12
2 times/month
13 times/week
4 times/week
511
1 time/month
2 times/month
2 times/week
> 1 time/month
> 1 time/week
Some limitation
Extremely limited
04
Nighttime
awakenings
04
Interference with
normal activity
All ages
None
Very Poorly
Controlled
Throughout the day
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Table 3. Assessing Asthma Control in Adults and Children

Component
Short-acting
2-agonist use
for symptom
controla
FEV1 or peak
flow
Age Group
(years)
All ages
12
511
04
Questionnaires
ATAQ
ACQ
ACT
Exacerbations
requiring oral
steroids
Well Controlled
Not Well Controlled
Very Poorly
Controlled
2 days/week
> 2 days/week
Several times a day
> 80% of
60%80% of
predicted/personal best predicted/personal best
< 60% of
predicted/personal
best
N/A
N/A
N/A
1 or 2
1.5
1619
3 or 4
N/A
15
2/year
2/year
2 or 3 times/year
> 3 times/year
12
(N/A if < 12) 0
0.75
20
12
511
0 or 1/year
04
Recommended
action for
treatment
All ages
Maintain current step;

regular follow-up every
16 months; consider
step-down if well
controlled 3 months
Step-up 1 step
Reevaluate in 26 weeks
Consider short
course of oral
steroids
Step-up 1 or 2 steps
Reevaluate in 2
weeks
Does not include 2-agonist used to prevent exercise-induced asthma.

ACQ = Asthma Control Questionnaire; ACT = Asthma Control Test; ATAQ = Asthma Therapy Assessment Questionnaire; FEV1 = forced
expiratory volume in 1 second; N/A = not applicable.
Prevention Program (NAEPP) Guidelines. NAEPP Expert Panel Report 3. NIH Publication 08-5846. Available at
a
D. Treatment Goals
1. Minimal or no chronic symptoms day or night
2. Minimal or no exacerbations
3. No limitations on activities; no school/work missed
4. Maintain (near) normal pulmonary function.
5. Minimal use of SABA
6. Minimal or no adverse effects from medications
E. Treatment Guidelines
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Pulmonary Diseases
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Table 4. Treatment Guidelines

Step
Age
Group Long-term Control
(years)
Quick Relief
All
ages
No controller needed
12
Preferred: Low-dose ICS

Alternatives: LTM, theophylline, or cromolyna
511
04
Preferred: Low-dose ICS

Alternatives: Montelukast or cromolyna
12
Preferred: Low-dose ICS plus LABA OR medium-dose ICS alone

Alternative: Low-dose ICS plus LTM or theophylline
511
Preferred: Low-dose ICS plus LABA, LTM, or theophylline OR

medium-dose ICS alone (medium-dose ICS preferred as initial
therapy)
04
Medium-dose ICS
12
Preferred: Medium-dose ICS plus LABA

Alternative: Medium-dose ICS plus LTM or theophylline
511
Use SABA PRN
04
Preferred: Medium-dose ICS plus LABA or montelukast
12
High-dose ICS plus LABA AND consider omalizumab for patients

with allergic asthma
511
Preferred: High-dose ICS plus LABA

Alternative: High-dose ICS plus LTM or theophylline
04
High-dose ICS plus LABA or montelukast
12
High-dose ICS plus LABA plus systemic corticosteroids AND

consider omalizumab for patients with allergic asthma
511
Preferred: High-dose ICS plus LABA plus systemic corticosteroids

Alternative: High-dose ICS plus LM or theophylline plus systemic
corticosteroids
04
High-dose ICS plus LABA or montelukast plus systemic

corticosteroids
SABA > 2
times/week
(excluding
preexercise
doses) indicates
inadequate
control and
need to step-up
treatment
Consider
step-down if
well controlled
3 months
Cromolyn and nedocromil are included in the National Asthma Education and Prevention Program guidelines. Cromolyn and nedocromil
inhalers have been discontinued by the manufacturer; only generic cromolyn nebulizer solution is still available.
ICS = inhaled corticosteroid; LABA = long-acting 2-agonist; LTM = leukotriene modifier; PRN = as needed; SABA = short-acting 2-agonist;
SR = sustained release.
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F. Pharmacologic Therapy for Asthma

Table 5. Pharmacologic Agent Use for Asthma and COPDa
Generic
Brand
Dose
Adverse Effects
Comments
Beclomethasone MDI
40 mcg/puff
80 mcg/puff
QVAR (HFA)
See ICS dosing table
Fluticasone MDI
44 mcg/puff
110 mcg/puff
220 mcg/puff
Flovent HFA
INHALED
Oral candidiasis
Hoarseness
May slow bone growth in
children but similar adult
height
ICSs are first line for persistent asthma

Use HOLDING CHAMBERS only if
needed for technique; not well studied
with HFA inhalers; holding chambers are
only for MDIs cannot be used for DPIs;
holding chambers with a mask can be
used for young children
RINSE MOUTH with water after
inhalations
Use corticosteroid inhaler as
SCHEDULED, not as needed
Onset of improvement is 57 days.
Additional benefit may be seen over
several weeks
Consider calcium and vitamin D
supplements in adults, particularly in
perimenopausal women
Pulmicort Respules only nebulized
steroid available
Corticosteroid inhalers
Fluticasone DPI
50 mcg/puff
100 mcg/puff
250 mcg/puff
Flovent Diskus
Mometasone DPI
220 mcg/puff
Asmanex
Twisthaler
Budesonide DPI
90 mcg/dose
180 mcg/dose
0.25-, 0.5-, and
1-mg/2-mL nebs
Pulmicort
Flexhaler and
Respules
Ciclesonide MDI
80 mcg/puff
160 mcg/puff
Alvesco (HFA)
SYSTEMIC
Cushing effects
Growth retardation
Osteoporosis
Hypertension
Cataracts
Glucose intolerance
Skin thinning
Myopathy
Euphoria
Depression
Anticholinergics
Ipratropium MDI
17 mcg/puff
Tiotropium DPI
18 mcg
Atrovent HFA
24 puffs TIDQID (up Headache

to 12 puffs/24 hours)
Flushed skin
Blurred vision
Tachycardia
Palpitations
Used mainly for COPD or for acute

asthma exacerbations requiring emergency
treatment
Duration: 28 hours
Also available as a solution for
nebulization
Spiriva
Inhale 1 capsule/day
Used for COPD; not currently

recommended for asthma.
Long acting; not for rapid relief
Duration: > 24 hours
2 puffs every 46 hours Tremor

PRN
Tachycardia
Hypokalemia
Hypomagnesemia
Hyperglycemia
Tachyphylaxis
Used for acute bronchospasm; regular use

indicates poor control
- Also available as solution for
nebulization
- Duration of effect (MDI): 34 hours (up to
6)
2-Agonists (short acting) SABA

Albuterol MDI
90 mcg/puff
Proventil HFA
Ventolin HFA
ProAir HFA
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Generic
Brand
Dose
Adverse Effects
Comments
Levalbuterol MDI
45 mcg/puff
Xopenex HFA
2 puffs every 46 hours

PRN
- R-enantiomer of albuterol
- Also available as a solution for
nebulization
- Duration (MDI): 34 hours (up to 6)
Pirbuterolb
200 mcg/puff
Maxair
Autohalerb
2 puffs every 46 hours

PRN
Breath-actuated MDI
- Duration: 5 hours
2-Agonists (long acting) LABA

Salmeterol DPI
50 mcg/puff
Serevent Diskus
Inhale 1 blister/puff
BID
Formoterol DPI
12-mcg capsule
Foradil Aerolizer
Inhale 1 capsule BID
Tremor
Tachycardia
Electrolyte
effects rare
Onset of action 13 minutes, but not acute

therapy
Should NOT be used as monotherapy
for asthma
Duration of MDI: 812 hours
Formoterol Aerolizer is indicated to prevent
exercise-induced bronchospasm; should be
used at least 15 minutes before exercise
Perforomist
Formoterol
20 mcg/2-mL nebs
20 mcg BID nebs

Brovana
Arformoterol
15 mcg/2-mL nebs
Not for acute symptoms

Should NOT be used as monotherapy for
asthma
Duration: 812 hours
15 mcg BID
nebs
Arformoterol is the R,R-isomer of racemic

formoterol
Indacaterol inhalation
powder
75-mcg capsule
Arcapta Neohaler
Inhale 1 capsule once

daily
Indacaterol is only indicated for COPD

NOT indicated for use in asthma at all
Approved by the FDA in July 2011
Duration of action: 24 hours
Albuterol 103 mcg/puff

plus
ipratropium
18 mcg/puff MDIb
Combiventb
2 puffs QID
Primarily used for COPD

Combivent Respimat (newly approved
propellant-free mist inhaler) will be available
starting mid-2012
- 100 mcg of albuterol/20 mcg of ipratropium
Combination solution for nebulization is also
available as DuoNeb or generic
Fluticasone
salmeterol DPI
100/50, 250/50,
500/50 mcg/puff
Advair Diskus
1 puff BID
Combination of ICS and LABA
Fluticasone salmeterol
MDI
45/21, 115/21, 230/21
mcg/puff
Advair HFA
2 puffs BID
Combination inhalers
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Generic
Brand
Dose
Budesonide
formoterol MDI 80/4.5,
160/4.5 mcg/puff
Symbicort (HFA)
2 puffs BID
Mometasone formoterol
MDI
100/5, 200/5 mcg/puff
Dulera
(HFA)
2 puffs BID
Theo-Dur
Uniphyl
Theo-24
10 mg/kg/day
(IBW)
Divided according to
formulation
Adjust according to
concentration
Max: 16 mg/kg/day
(children < 12 years;
800 mg/day (adults)
Adverse Effects
Comments
Methylxanthine
Theophylline
Liquids, capsules,
sustained-release capsules
(many dosage strengths)
Smokers may need

higher doses at more
frequent intervals
At high levels:
Nausea
Vomiting
CNS stimulation
Headache
Tachycardia, SVT
Seizures
Hematemesis
Hyperglycemia
Hypokalemia
At therapeutic levels:
Insomnia
GI upset
Increased hyperactivity in
some children
Difficult urination in BPH
Achieve concentrations of 515 mcg/mL

Beneficial for night symptoms
Not for acute relief
Duration: variable; up to 24 hours
Hepatotoxicity Monitor LFTs

(baseline, every month 3
months, every 23 months
for 1 year for montelukast
and zafirlukast)
Headache
GI upset
Drug interactions: Warfarin, erythromycin,

theophylline
For 5 years
Bioavailability decreases with food; take 1
hour before or 2 hours after meals
Leukotriene modifiers (note: *FDA caution)

Zafirlukast
10-mg tablet
20-mg tablet
Accolate
20 mg BID
Montelukast
Singulair
Oral 10-mg tablet
Chewable 4- and 5-mg
tablets
Oral granules 4-mg/packet
510 mg/day
Zileuton
600-mg CR tablet
Zyflo CR
1200 mg BID
Xolair
150375 mg SC every
24 weeks
Dose and frequency
based on baseline IgE
and weight in
kilograms
Drug interactions: Phenobarbital

FDA-approved for use in 1 year old; used
in 6 months and older
Churg-Strauss syndrome associated with
tapering doses of steroids
*Risk of neuropsychiatric
events (behavior and mood
changes: aggression,
agitation, anxiousness, dream
Drug interactions: Warfarin and theophylline
abnormalities, hallucinations,
Only for those 12 years and older
depression, insomnia,
irritability, restlessness,
suicidal thinking and
behavior, tremor)
Monoclonal antibody
Omalizumab
Injection site reactions

Urticaria
Thrombocytopenia
(transient)
Anaphylaxis (rare)
Malignancy
MOA: Inhibits IgE binding to high-affinity

IgE receptors on mast cells and basophils
Used in severe persistent allergy-related
asthma
Use in 12 years
Half-life: 26 days
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Generic
Brand
Dose
Adverse Effects
Comments
Do not inject > 150 mg

per injection site
Second-line therapy
Very expensive
a
The following MDIs have been discontinued by the manufacturers and are no longer available: AeroBid (flunisolide) MDI (June 2011), Azmacort
(triamcinolone) MDI (December 2009), Intal (cromolyn) MDI (August 2009), Intal (cromolyn) nebulization solution (June 2008), and Tilade (nedocromil) MDI
(April 2008). They are not included in this table. OTC Primatene Mist has also been discontinued, and it is no longer available as of 12/31/2011.
b
These inhalers, which still contain CFCs, are being phased out by the manufacturers. They may no longer be sold after the following dates: Maxair
(pirbuterol) (12/31/2013) and Combivent (albuterol/ipratropium) (12/31/2013).
BID = 2 times/day; CNS = central nervous system; COPD = chronic obstructive pulmonary disease; CR = controlled release; DOC = drug of choice; DPI =
dry powder inhaler; FDA = U.S. Food and Drug Administration; GERD = gastroesophageal reflux disease; GI = gastrointestinal; HFA = hydrofluoroalkane;
IBW = ideal body weight; ICS = inhaled corticosteroid; IgE = immunoglobulin E; LABA = long-acting 2-agonist; LFT = liver function test; MDI = metered
dose inhaler; MOA = mechanism of action; nebs = nebulizers; PRN = as needed; QID = 4 times/day; SC = subcutaneously; SVT = supraventricular
tachycardia; TID = 3 times/day.
Table 6. Inhaled Corticosteroid Daily Dosing in Children and Adultsa

Inhaled Corticosteroids
Low Dose (mcg/day)

Steps 23
Medium Dose (mcg/day)

Steps 34
Age Group (years)
04
511
12
04
Budesonide
(Pulmicort DPI 90, 180)
N/A
180400
180600
N/A
176
N/A
88176
100200
N/A
Mometasone (Asmanex
DPI 110, 220): delivers
100 and 200 mcg/puff)
Ciclesonidec
(Alvesco HFA 80, 160)
Fluticasone
Flovent HFA 44,110, 220
Flovent DPI 50, 100, 250
Beclomethasone
(QVAR HFA 40, 80)
04
511
12
N/A
> 800
> 1200
88264 > 176352 > 176352 > 264440

100300
N/A
> 200400 > 300500
> 352
N/A
> 352
> 400
> 440
> 500
80160
80240
N/A
N/A
> 320
> 480
100b
(age 4 only)
100b
200
100b
(age 4
only)
100b
400
100b
(age 4
only)
100b
> 400
N/A
N/A
160
N/A
N/A
320
N/A
N/A
640
N/A
> 0.51 mg
1 mg
N/A
> 1 mg
2 mg
N/A
Budesonide suspension for 0.250.5 mg 0.5 mg

nebulization
511
12
High Dose (mcg/day)

Steps 56
> 400800 > 600-1200
> 160320 > 240480
Effective December 31, 2009: Azmacort (triamcinolone) MDI (12/31/2009) and Aerobid (flunisolide) MDI (6/30/2011) have been discontinued by the
manufacturers and are no longer available.
b
The guidelines state the delivered dose of mometasone, not the actual dose; indicated in ages 411 after guidelines published; doses are estimated
from package insert for children 04 and 511 years.
c
Ciclesonide was not available when the National Asthma Education and Prevention Program guidelines were published. The dose ranges are estimated
from package insert.
CFC = chlorofluorocarbon; DPI = dry powder inhaler; HFA = hydrofluoroalkane; MDI = metered dose inhaler.
Adapted from NIH asthma guidelines. National Institutes of Health National Heart Lung and Blood Institute. National Asthma Education and
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G. Long-Acting -Agonists (LABAs): The U.S. Food and Drug Administration (FDA) issued a
safety announcement because of safety concerns with LABAs. This is largely because of the
results from the SMART trial (Nelson HS, et al. Chest 2006;129:1526).
1. Use of a LABA alone without another long-term asthma control medication such as an
inhaled corticosteroid (ICS) is contraindicated.
2. LABAs should not be used in patients whose asthma is adequately controlled on low- or
medium-dose ICSs.
3. LABAs should only be used as additional therapy for patients who are currently taking, but
not adequately controlled on, a long-term asthma control medication (e.g., an ICS).
4. Once asthma control is achieved and maintained, patients should be assessed at regular
intervals and stepped-down (e.g., discontinue LABA), if possible, and the patient should
continue to be treated with a long-term asthma control medication, such as an ICS.
a. Regular follow-up every 16 months.
b. Consider step-down if well controlled for 3 months or more.
5. Pediatric and adolescent patients who require a LABA and an ICS should use a combination
product, to ensure adherence to both medications.
H. New Data in Asthma Treatment
(not included in the current guidelines; more data needed before using in clinical practice)
1. Tiotropium for persistent asthma
a. A recent study evaluated adding tiotropium versus adding LABA (salmeterol) versus
doubling the ICS dose in patients uncontrolled on low-dose beclomethasone (Peters SP,
et al. TALC study. N Engl J Med 2010;363:1715-26)
b. Results: Adding tiotropium resulted in significantly greater improvements in PEF and
FEV, symptom control as well as the number of asthma control days than did doubling
the ICS dose.
c. Adding tiotropium was at least noninferior to adding LABA for all outcomes studied, and
it increased prebronchodilator FEV more than did salmeterol (p=0.003).
d. Conclusion: Adding tiotropium to low-dose ICS is an option if asthma uncontrolled,
noninferior to adding LABA and superior to doubling ICS
2. ICS/SABA for rescue treatment in children
a. Randomized, double-blind, placebo-controlled trial of children/adolescents with mild
persistent asthma randomized to four different groups (TREXA study; Lancet
2011;377:650-7):
Group
Controller Therapy
Rescue Therapy
Combined
40 mcg BID beclomethasone (BMS) BMS (80 mcg) + albuterol (2 puffs)
Daily BMS
40 mcg BID BMS
Albuterol alone
Rescue BMS
Placebo
BMS (80 mcg) + albuterol
Placebo
Placebo
Albuterol
BID = 2 times/day.
b. Results: Rescue beclomethasone compared with placebo resulted in a significantly lower
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frequency of treatment failure (8.5% vs. 23%; p=0.024).

c. Conclusion: If step-down therapy is needed in children with mild persistent asthma, then
rescue beclomethasone plus albuterol may be preferred to rescue albuterol alone.
3. LTMs versus ICSs as first-line controllers
a. Parallel, multicenter, pragmatic trial in the United Kingdom to evaluate real-world
effectiveness (N Engl J Med 2011;364:1695-707)
b. LTM: Mostly montelukast; ICS: mostly beclomethasone
c. Results: For most outcomes (Asthma Control Questionnaire [ACQ] score, asthma
exacerbations), no significant difference between LTM and ICS as first-line controller
therapy; mini-AQLQ (Asthma Quality of Life Questionnaire) scores did not all meet
equivalence; adherence was higher with LTM (65%) versus ICS (41%) [NS]
d. Conclusion: In a real-world setting, LTMs may be similar in efficacy to ICSs for first-line
controller therapy.
4. LTM versus LABA as add-on therapy
a. Parallel, multicenter, pragmatic trial in the United Kingdom to evaluate the real-world
effectiveness of adding on LTM vs. LABA in patients already receiving ICS (N Engl J
Med 2011;364:1695-707)
b. LTM: Mostly montelukast; LABA: mostly salmeterol
c. Results: For most outcomes (ACQ score, asthma exacerbations), no significant difference
between LTM and LABA as add-on controller therapy; adherence was significantly
higher with LTM (74%) versus LABA (46%) (but only 13% were given combination
ICS-LABA inhalers; most used two different inhalers; could affect adherence)
d. Conclusion: In a real-world setting, LTMs may be equivalent to LABAs as add-on
therapy in patients already receiving ICSs.
I.
Asthma Action Plan

1. Usually, symptom based (equal benefits of symptom-based or peak flow-based monitoring);
home treatment of an asthma exacerbation
2. Green zone
a. Doing well; no/minimal symptoms of coughing, wheezing, or dyspnea (or peak
expiratory flow rate [PEFR] 80%100% of personal best)
b. Take controller drug daily (if one is prescribed).
c. Use 2 puffs of SABA 515 minutes before exercise if exercise-induced asthma and
before known triggers. Use also as needed for symptoms.
3. Yellow zone
a. Getting worse; increasing frequency of symptoms (e.g., coughing, wheezing, and/or
dyspnea) (or PEFR 50%79% of personal best)
b. Use SABA: 24 puffs by MDI or 1 nebulizer treatment; may repeat in 20 minutes if
needed. May be as many as 6 puffs if needed. Reassess 1 hour after initial treatment.
i. If complete response at 1 hour, contact clinician for follow-up instructions and
consider an oral corticosteroid (OCS) burst*
ii. If incomplete response in 1 hour (still some coughing, wheezing, and/or dyspnea),
repeat SABA and add oral corticosteroid burst*; contact clinician that day for further
instructions
iii. If poor response in 1 hour (marked coughing, wheezing, and/or dyspnea), repeat
SABA immediately; add oral corticosteroid burst*; contact clinician immediately,
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a.
b.
c.
d.
e.
f.
and proceed to the emergency department (ED) if the distress is severe and
unresponsive to treatment; consider calling 9114. Red zone
Medical alert; marked coughing, wheezing, and/or dyspnea; inability to speak more than
short phrases; use of accessory respiratory muscles; drowsiness (or PEFR less than 50%
of personal best)
Begin treatment and consult clinician immediately.
Use SABA: 26 puffs by MDI or 1 nebulizer treatment; repeat every 20 minutes up to 3
times; add an OCS burst.* Higher dose of 46 puffs SABA MDI usually recommended
If incomplete or poor response, repeat SABA immediately; proceed to the ED or call 911
if distress is severe and unresponsive to treatment
Call 911 or go to the ED immediately if lips or fingernails are blue or gray or if the
patient has trouble walking or talking because of shortness of breath.
Continue to use a SABA every 34 hours regularly for 2448 hours.
*Oral prednisone burst: 4060 mg/day for 510 days (adults) or 12 mg/kg/day (maximum
60 mg/ day) for 310 days (children).
5. After initial treatment, immediate medical attention is required if patient is at high risk of a
fatal attack. Risk factors:
a. Asthma: History of severe attack (previous intubation or intensive care unit admission for
asthma), two or more asthma hospitalizations for asthma in past year, three or more ED visits
for asthma in past year, hospitalization or ED visit for asthma in past month, use of more than
two canisters of a SABA per month, difficulty perceiving asthma symptoms
b. Social: Low socioeconomic status or inner-city residence, illicit drug use, major
psychosocial problems
c. Comorbidities: Cardiovascular disease (CVD), other chronic lung disease, chronic
psychiatric disease
J.
Asthma Education for Patients

1. Control: Patients need to know what it means for their asthma not to be well controlled.
2. Medications
a. Controllers versus quick-relievers
b. How to use medication delivery devices (revisit often)
3. Self-management/asthma action plan
4. The need for continuous ongoing interaction with the clinician to step-up and step-down
therapy
5. Triggers/environmental changes
a. Dust mite interventions
i. Impermeable encasings for pillows/mattresses
ii. Wash linens in hot water.
iii. High-efficiency particulate air (HEPA) filtration
b. Animal allergens
i. Keep outside/out of bedroom.
ii. HEPA filtration
c. Roach control
i. Integrated pest management
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ii. Clean up food, spills, trash, and leaks.

d. Mold and mildew interventions
i. Air conditioning
ii. Avoid humidifiers.
iii. Repair pipes and leaks.
e. Air pollution (includes secondhand smoke)
f. Exercise (preexercise SABA)
K. Metered Dose Inhalers (pertinent for both asthma and COPD)
1. Education on proper technique with MDIs and DPIs is critically important.
a. Studies have shown MDI and DPI techniques to be poor.
b. Critical to demonstrate correct technique to patient and to assess patients technique with
initial instruction and frequently thereafter
2. As of January 1, 2009, traditional CFC MDIs are no longer recommended according to a new
FDA law; although some are still available, they are being phased out.
a. An HFA MDI or DPI is recommended.
b. Generic albuterol MDIs are no longer available.
c. HFA: Smaller particle size, better lung deposition, less oropharyngeal deposition; holding
chamber not necessary unless poor technique; not well studied with HFA MDIs
3. Important educational points for patients
a. All MDIs must be primed before first use.
i. First, shake the MDI (except for Alvesco, QVAR, and Atrovent HFA, which need not
be shaken).
ii. Spray into the air, away from the face.
iii. Priming: Number of sprays before first use varies; range 24 times
iv. Shake in between each spray.
v. Must be re-primed after dropping inhaler or if not used for a certain number of days
(range 328 days)
b. How to tell when an MDI is empty
i. Ventolin HFA, Flovent HFA, Pulmicort, Asmanex, Alvesco, Advair, Symbicort have
counters
ii. For other MDIs, best way is to use tally marks to count puffs used. Recommend a
product with a counter whenever possible, but may be limited because of insurance
coverage
iii. The old sink-or-float method (dropping the canister into a cup/bowl/sink full of
water) is unreliable, and it should not be used.
c. Cleaning MDIs
i. Clean once weekly.
ii. Remove canister and cap; rinse plastic case/mouthpiece under lukewarm water and
let air dry.
iii. For Advair HFA and Flovent HFA:
(a) Do not run under water.
(b) Open cap and swab small opening with a Q-tip where medicine sprays out (dry
for Advair and wet for Flovent).
(c) Wipe mouthpiece with wet tissue and let air dry.
4. Valved holding chambers (e.g., AeroChamber, OptiChamber)
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a. Holding chambers reduce oropharyngeal deposition and improve lung deposition with
CFC MDIs (almost 2-fold); not well studied with HFA MDIs.
b. Technique same as with MDIs, but can inhale up to 5 seconds after actuation
c. 1 puff into chamber per inhalation
d. For facemask: 5 inhalations/exhalations per puff
Table 7. Educating Patients About How to Use a Metered Dose Inhaler
Getting
ready
1. Take off the cap and inspect for loose objects in the mouthpiece.
2. Shake the inhaler (except for Alvesco, QVAR, and Atrovent HFA, which do not need to be
shaken).
3. Breathe out all the way.
4. Either put your inhaler mouthpiece in your mouth or use a holding chamber.
Breathe in 5. Press down on the inhaler once as you start breathing in slowly through your mouth. Be
slowly
sure not to breathe in through your nose. (If you use a holding chamber, first press down
on the inhaler. Within 5 seconds, begin to breathe in slowly.)
6. Keep breathing in slowly, as deeply as you can.
Hold your
breath
7. Hold your breath as you count to 10 slowly, if you can.

8. For inhaled quick relief (SABA), wait about 30 seconds between puffs. There is no need to
wait between puffs for other medications.
9. Exhale.
Table 8. Educating Patients About How to Use DPIs

Dry Powder Inhalers
Contain a small amount of powder. Do not contain aerosol
Will feel different from an MDI; will not feel a spray; may not feel/taste anything
Do not shake before inhalation.
Only budesonide (Pulmicort Flexhaler) needs to be primed once; others are not primed.
DPIs that come in foil pouches have expiration dates once opened (mometasone-Asmanex: 45 days,
fluticasone-salmeterol-Advair: 1 month).
Protect DPIs from moisture.
Each specific DPI has slightly different directions on how to get the inhaler ready for a dose.
Once the dose is prepped, breathe out fully, away from the mouthpiece.
Close lips around the mouthpiece and inhale quickly, forcefully, and deeply. This is different from the method
used with an MDI (which is a slow, deep inhalation).
Hold breath for 10 seconds; then exhale.
DPI = dry powder inhaler; MDI = metered dose inhaler.
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Table 9. Educating Patients About How to Use Peak Flow Meters

Peak Flow Meters
Move the indicator to the bottom of the numbered scale.
Stand up. Take a deep breath, filling your lungs completely.
Place the mouthpiece in your mouth and close your lips around it. Keep your tongue out of the way.
Blow out as hard and fast as you can in a single blow.
Write down the number you get. But if you cough or make a mistake, do not write down the number. Do it again.
Repeat steps 15 twice more, and write down the best of the three blows in your asthma diary.
L. Monitoring
1. Peak flow monitoring
a. Both symptom-based and peak flowbased monitoring have similar benefits; either is
appropriate for most patients. Symptom-based monitoring is more convenient.
b. Consider daily home peak flow monitoring for moderate-severe persistent asthma, if
history of severe exacerbations or if poor perception of worsening asthma symptoms
c. Personal best PEFR should be determined if using peak flowbased asthma action plan,
not predicted PEFR.
i. Personal best PEFR is the highest number obtained after daily monitoring for 2
weeks two times/day when asthma is under good control.
ii. Predicted PEFR is based on population norms using sex, height, and age.
2. Spirometry (if 5 years or older)
a. At initial assessment
b. After treatment has started and symptoms have stabilized
c. If prolonged or progressive loss of asthma control
d. At least every 12 years or more often, depending on response to therapy
M. Vaccines: Adults with asthma (aged 1964) should receive:
1. 23-valent pneumococcal polysaccharide vaccine (Pneumovax) once and then a one-time
revaccination with pneumococcal vaccine at age 65 if 5 years or more after the first
vaccination
2. Influenza vaccine every fall/winter
II. CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Guidelines:
Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for Diagnosis, Management and
Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 Revision.
Available at www.goldcopd.org/. Accessed March 1, 2012.
Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and Management of Stable Chronic Obstructive
Pulmonary Disease: A Clinical Practice Guideline Update from the American College of Physicians,
American College of Chest Physicians, American Thoracic Society, and European Respiratory Society
(ACP/ACCP/ATS/ERS Guidelines). Ann Intern Med 2011;155:179-91.
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A. Definition: Chronic obstructive pulmonary disease (COPD) is a syndrome of chronic limitation in

expiratory airflow encompassing emphysema or chronic bronchitis. Airflow obstruction may be
accompanied by airway hyperresponsiveness and may be not be fully reversible.
1. Chronic bronchitis consists of persistent cough plus sputum production for most days of 3
months in at least 2 consecutive years.
2. Emphysema is abnormal permanent enlargement of the airspaces distal to the terminal
bronchioles, accompanied by destruction of their walls without obvious fibrosis.
B. Diagnosis and Assessment
1. The diagnosis of COPD is based on a history of exposure to risk factors and the presence of
airflow limitation that is not fully reversible, with or without the presence of symptoms.
a. Symptoms: Dyspnea (described by patients as increased effort to breathe, heaviness,
air hunger, or gasping), poor exercise tolerance, chronic cough, sputum production,
wheezing
b. GOLD guidelines: Perform spirometry and consider COPD if an individual is older than
40 years and has any of the following:
i. Dyspnea that is progressive (worsens over time), persistent (present every day), and
worse on exercise
ii. Chronic cough that is present intermittently or every day; often present through the
day; seldom only nocturnal. May be nonproductive
iii. Chronic sputum production in any pattern and/or
iv. History of exposure to risk factors, especially tobacco smoke (most common risk
factor), occupational dusts and chemicals, and smoke from home cooking and heating
fuels
c. ACP/ACCP/ATS/ERS guidelines: The single best predictor of airflow obstruction is the
presence of all three of the following:
i. Smoking history of more than 55 pack years
ii. Wheezing on auscultation
iii. Patient self-reported wheezing
2. For the diagnosis and assessment of COPD, spirometry is the gold standard.
a. Spirometry showing an FEV/forced vital capacity (FVC) less than 70% of predicted is
the hallmark of COPD. Bronchodilator reversibility testing is no longer recommended.
b. Measuring arterial blood gas tension should be considered for all patients with an FEV
50% of predicted or with clinical signs suggestive of respiratory failure or right heart
failure.
3. Validated symptom scales/questionnaires
a. Modified British Medical Research Council (mMRC) breathlessness scale for assessing
severity of breathlessness (Bestall JC, et al. Thorax 1999;54:5816)
b. COPD Assessment Test (CAT) measures health status impairment in COPD
(www.catestonline.org).
C. Factors Determining COPD Severity
1. Severity of symptoms
2. Severity of airflow limitation (FEV)
3. Frequency of exacerbations
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4. Presence of comorbidities
D. Therapy Goals
1. Relieve symptoms.
2. Reduce the frequency and severity of exacerbations.
3. Improve exercise tolerance.
4. Improve health status.
5. Minimize adverse effects from treatment.
E. Management of Stable COPD
1. Description of levels of evidence/grades of recommendations
GOLD Guidelines
A
Randomized clinical trials

Rich body of data
Randomized clinical trials

Limited body of data
Nonrandomized trials
Observational studies
Panel judgment consensus

ACP/ACCP/ATS/ERS Guidelines
Recommendation
grade
Strong (S):
Benefits clearly outweigh risks and burden, or risks and burden clearly outweigh benefits
Weak (W):
Benefits finely balanced with risks and burden
Quality of
evidence
High (H)
Moderate (M)
Low (L)
2. Existing medications for COPD have not been shown to modify the long-term decline in lung
function, the hallmark of this disease (Evidence A). Therefore, pharmacotherapy for COPD is
used to decrease symptoms, complications, or both.
3. Smoking cessation is a critical component of COPD management.
4. Bronchodilator medications are central to the symptomatic management of COPD (Evidence
A).
a. They are given on an as-needed or regular basis to prevent or reduce symptoms.
b. The principal bronchodilator treatments are -agonists, anticholinergics, or a
combination of these drugs (Evidence A). Theophylline is a bronchodilator given on a
regular basis.
c. Inhaled therapy is preferred.
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d. The choice between a LABA, anticholinergic, theophylline, and combination therapy

depends on availability and individual response in symptom relief and adverse effects.
e. Regular treatment with a long-acting bronchodilator is more effective and convenient
than regular treatment with a SABA (Evidence A).
f. Combining bronchodilators from different pharmacologic classes may improve efficacy
with the same or fewer adverse effects compared with increasing the dose of a single
bronchodilator (Evidence A).
g. Adding a LABA/ICS to tiotropium improves lung function and quality of life and reduces
the number of exacerbations (Evidence B), but more studies of triple therapy are needed.
h. All bronchodilators improve symptoms and exercise capacity.
i. Treatment with a long-acting anticholinergic delays the first exacerbation, reduces
the overall number of COPD exacerbations and related hospitalizations, improves
health status (Evidence A), and improves the effectiveness of pulmonary
rehabilitation (Evidence B). Initial studies with tiotropium showed increased CV risk,
but newer strong evidence showed no increase in risk. Anticholinergics may not
significantly improve FEV .
ii. Long-acting -agonists improve health status, quality of life, and FEV and decrease
COPD 2 1 exacerbation rate (Evidence A). Salmeterol reduces hospitalization rate
(Evidence B).
5. Inhaled corticosteroids in stable COPD
a. ICSs improve symptoms, lung function, and quality of life and decrease the frequency of
exacerbations in patients with FEV less than 60% of predicted; they do not modify the
progressive decline in FEV or decrease mortality (Evidence A).
b. The dose-response with ICS in COPD is unknown (in contrast to asthma treatment).
Moderate- high doses have been used in COPD clinical trials.
c. An ICS combined with a LABA is more effective than the individual components alone
(Evidence A). An ICS-LABA combination reduces the rate of decline in FEV and
reduces the exacerbation rate; the reduction in mortality compared with placebo just fell
short of statistical significance (relative risk reduction, 17.5%; absolute risk reduction,
2.6%; adjusted p=0.052) (TORCH study: Calverley PMA, et al. N Engl J Med
2007;356:77589). A subsequent meta- analysis showed that ICS-LABA may reduce
mortality (NNT 36) (Evidence B) (Nannini LJ, et al. Cochrane Database Syst Rev
2007;4).
d. ICS use is associated with an increased incidence of pneumonia in COPD (Am J Respir
Crit Care Med 2007;176:162-6; Arch Intern Med 2009;169:219-29).
e. Monotherapy with ICS is not recommended.
f. Chronic treatment with OCSs should be avoided because of an unfavorable benefit-risk
ratio (Evidence A).
6. Patient assessment and selection of therapy
a. Previous GOLD guidelines categorized COPD severity and recommended treatment of
COPD by postbronchodilator FEV alone. Staging is no longer based on FEV alone. New
GOLD guidelines combine symptoms (based on symptom scores), airflow limitation
(based on postbronchodilator FEV), and frequency of exacerbations to determine patient
risk group and recommended treatment.
b. ACP/ACCP/ATS/ERS guidelines simplify treatment even further based on FEV in
patients with COPD with symptoms. They do not provide detailed treatment guidelines.
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Table 10. GOLD Guidelines: Assessment of COPD Severity/Risk

Patient
Spirometric GOLD
Group
Characteristic
Classificationa
A
Low risk
1 Mild (FEV1 80% of pred.) or
Less symptoms
2 Moderate (50% FEV1< 80% of pred.)
B
Low risk
1 Mild (FEV1 80% of pred.) or
More symptoms
2 Moderate (50% FEV1 < 80% of pred.)
C
High Risk
3 Severe (30% FEV1< 50% of pred.) or
Less symptoms
4 Very severe (FEV1< 30% of pred.)
D
High risk
3 Severe (30% FEV1< 50% of pred.) or
More symptoms
4 Very severe (FEV1 < 30% of pred.)
Exacerbations
per Yeara
1
1
2
2
Symptom Scoreb
mMRC 01
CAT < 10
mMRC 2
CAT 10
mMRC 01
CAT < 10
mMRC 2
CAT 10
To determine the risk of exacerbation, either the spirometric GOLD classification or the number of exacerbations per year can be used. If they
are both used and the patient would fall into two different categories, always assign patient into the category with the highest risk/symptoms.
b
CAT score is preferred, but either can be used.
CAT = COPD Assessment Test (validated questionnaire); COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1
second; mMRC = modified British Medical Research Council breathlessness scale (validated questionnaire).
Adapted from: Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for Diagnosis, Management and Prevention of COPD.
Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 Revision. Available at www.goldcopd.org/. Accessed March 1, 2012.
a
Table 11. GOLD Guidelines: Pharmacotherapy for Stable COPD

Patient
Group
A
First Choice
Second Choice
Alternativesa
SA anticholinergic PRN
or
SABA PRN
LA anticholinergic or
LABA or
SABA + SA anticholinergic
Theophyllineb
LA anticholinergic
or
LABA
LA anticholinergic + LABA
SABA
and/or
SA anticholinergic
Theophyllineb
ICS + LABA
or
LA anticholinergic
LA anticholinergic + LABA
PDE-4 inhibitor
SABA and/or
SA anticholinergic
Theophyllineb
ICS + LABA
or
LA anticholinergic
ICS + LA anticholinergic or
ICS + LABA and LA anticholinergic or
ICS + LABA and PDE-4 inhibitor or
LA anticholinergic + LABA or
LA anticholinergic + PDE-4 inhibitor
SABA and/or
SA anticholinergic
Theophyllineb
Alternative medications can be used alone or in combination with first- and second-choice columns.
Theophylline is not recommended unless other long-term bronchodilators are unavailable or unaffordable
COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroid; LA = long-acting; LABA = long-acting 2-agonist; SABA = short-acting
2-agonist.
Adapted from: Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for Diagnosis, Management and Prevention of COPD. Global
Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 Revision. Available at www.goldcopd.org/. Accessed March 1, 2012.
b
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Box 1. ACP/ACCP/ATS/ERS Guidelines: Treatment Recommendations for Stable COPD

For patients with respiratory symptoms and FEV1 between 60% and 80% of predicted, treatment with long-acting
inhaled bronchodilators is suggested.
(Grade: W, Evidence: L)
For patients with respiratory symptoms and FEV1 < 60% of predicted, treatment with long-acting inhaled
bronchodilators is recommended.
(Grade: S, Evidence: M)
Monotherapy using either long-acting inhaled anticholinergics or LABAs is recommended for symptomatic
patients with FEV1 < 60% of predicted. The choice of specific monotherapy should be based on patient
preference, cost, and adverse effect profile.
(Grade: S, Evidence: M)
Combination inhaled therapies (long-acting inhaled anticholinergics, LABAs, or ICS) may be used for
symptomatic patients with FEV1 < 60% of predicted.
(Grade: W, Evidence: M)
Qaseem A, et al. ACP/ACCP/ATS/ERS COPD guidelines. Ann Intern Med 2011;155:17991.
7. Other pharmacologic treatments

a. Phosphodiesterase-4 inhibitor: Roflumilast (Daliresp)
i. Approved by the FDA in March 2011
ii. Indication: Indicated as a daily treatment to reduce the risk of COPD exacerbations in
patients with severe COPD (FEV less than 50% of predicted) associated with chronic
bronchitis and a history of frequent exacerbations. In these patients, studies show a
reduction in exacerbations and a reduction in the composite end point of moderate
exacerbations treated with oral or systemic corticosteroids or severe exacerbations
requiring hospitalization or causing death (Evidence B). These effects are also seen
when roflumilast is added to long-acting bronchodilators (Evidence B). No
comparison has been done with ICSs.
iii. Mechanism: Reduces inflammation by inhibiting the breakdown of intracellular
cyclic adenosine monophosphate; no direct bronchodilator activity
iv. Dose: 500 mcg orally once daily
v. Contraindications: Moderate to severe liver impairment; use in nursing mothers
vi. Precautions: Weight loss (monitor), psychiatric events including suicidality (monitor;
weigh risks vs. benefits in patients with preexisting psychiatric illness); 20% of
patients studied had weight loss of 5%10% of body weight compared with 7% with
placebo; average weight loss is 2 kg
vii. Adverse reactions: Diarrhea, weight loss/decreased appetite, nausea, headache, back
pain, influenza, insomnia, and dizziness
viii. Drug interactions: Use with strong cytochrome P450 (CYP) enzyme inducers is not
recommended (e.g., rifampin, phenobarbital, carbamazepine, phenytoin); use with
CYP3A4 inhibitors or dual inhibitors of CYP 3A4 and 1A2 (e.g., erythromycin,
ketoconazole, fluvoxamine, enoxacin, cimetidine) increases roflumilast exposure and
adverse effects (risk vs. benefit must be weighed).
b. Smoking cessation (essential for all patient groups AD)
c. Influenza vaccine annually (essential for all patient groups AD)
d. Pneumococcal vaccine (essential for all patient groups AD)
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e. -Antitrypsin augmentation therapy (Evidence C)

i. For young patients with severe hereditary -antitrypsin deficiency and established
emphysema; however, it is an expensive treatment
ii. Patients with -antitrypsin deficiency usually are white, usually develop COPD at a
young age (younger than 45 years), and usually have a strong family history of
COPD. It may be worthwhile to screen such patients.
f. -Blockers
i. New observational data suggest that long-term treatment with -blockers reduces the
risk of exacerbations and improves survival, even in patients without overt CVD
(Rutten FH, et al. Arch Intern Med 2010;170:880-7).
ii. More than half of the patients in the study had CV risk factors or coronary artery
disease. Mostly cardioselective -blockers were used.
iii. Too early to recommend -blockers for the treatment of COPD, but -blockers
should not be withheld in patients with COPD who also have heart disease, chronic
heart failure, or other CV conditions in which -blockers are beneficial (Salpeter SR,
et al. Cardioselective beta blockers for chronic obstructive pulmonary disease.
Cochrane Database Syst Rev 2002;2:CD003566. Review. Update in: Cochrane
Database Syst Rev 2005 (Reviewed 2008);4:CD003566)
iv. Mechanism for benefit in COPD is unknown, but -blockers can up-regulate
-receptors in the lungs and may improve the effectiveness of inhaled -agonists
g. Antibiotics are recommended only for treating infectious exacerbations of COPD.
8. Nonpharmacologic therapy
a. Home oxygen therapy
i. Recommended in patients who have Pao of 55 mm Hg or less (or 5560 mm Hg if
pulmonary hypertension, peripheral edema, or polycythemia - Evidence D) or Sao of
88% or less, with or without hypercapnia, confirmed twice over a 3-week period
(Evidence B)
ii. Long term (more than 15 hours/day) in patients with chronic respiratory failure
improves survival
b. Pulmonary rehabilitation (essential for patient groups BD; evidence A)
i. Includes exercise training, nutrition counseling, and education
ii. Recommended for stage IIIV COPD.
Patients should be referred when they
have moderate COPD; do not wait until it is more severe.
iii. Improves many outcomes in COPD, including quality of life and survival
9. New data in COPD
a. Tiotropium versus salmeterol for COPD
i. POET-COPD study (N Engl J Med 2011;364:1093-103)
ii. 736 patients with moderate-severe COPD and 1 or more exacerbation in the past
year; 1-year randomized, double-blind, parallel-group trial
iii. Tiotropium versus salmeterol
iv. Primary end point: Time to first exacerbation
(a) Moderate exacerbation: Treated with an OCS, antibiotics, or both
(b) Severe exacerbation: Hospitalized
v. Results: Tiotropium (vs. salmeterol) significantly:
(a) Increased time to first exacerbation (187 days vs. 145 days [42-day difference]);
was significant for both moderate and severe exacerbations
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(b) Reduced annual number of exacerbations; rate for both moderate and severe
exacerbations was significant
(c) Benefit was consistent in all major subgroups and over 1year.
(d) Significantly fewer patients taking tiotropium withdrew early.
vi. Conclusion: Tiotropium may be more effective than a LABA as initial long-acting
bronchodilator therapy.
b. Chronic azithromycin for prevention of COPD exacerbations
i. Albert RK, et al. N Engl J Med 2011;365:689-98
ii. 1577 subjects at increased risk of exacerbations (stage IImoderate or worse COPD
either on continuous O or received systemic corticosteroids in past year, and history
of a COPD exacerbation requiring ED visit or hospitalization; no history of hearing
impairment
iii. Subjects randomized to daily azithromycin 250 mg or placebo for 1 year
iv. Results:
(a) Median time to exacerbation: 266 days (azithromycin group) versus 174 days
(placebo) (p<0.001)
(b) Rate of acute exacerbation: 1.48 versus 1.83 for azithromycin versus placebo
(p=0.01)
(c) Number needed to treat to prevent one acute exacerbation of COPD: 2.86
(d) Quality of life improved more with azithromycin than with placebo (based on St.
Georges Respiratory Questionnaire; p=0.03)
(e) However, hearing decrements (by audiometry) were more common with
azithromycin versus placebo (25% vs. 20%, p=0.04) (number needed to harm =
20), and in azithromycin group, there was an increased incidence of colonization
with macrolide-resistant organisms (81% vs. 41%, p<0.001).
v. Conclusion: Daily azithromycin lengthens time to first exacerbation, decreases rate of
exacerbations, and improves quality of life in patients with COPD at increased risk of
exacerbations, with the expense of risk of hearing decrements and increasing
macrolide-resistant organism colonization. The most recent GOLD guidelines still do
not recommend treatment with antibiotics, except when indicated during acute
exacerbations.
F. Management of Exacerbations of Chronic COPD
1. A COPD exacerbation is an acute worsening of a patients baseline respiratory symptoms
(dyspnea and/ or cough and/or an increase in quantity or purulence of sputum) that is worse
than normal day-to-day variation and results in a change in medication. Diagnosis is based
purely on clinical presentation.
2. Common precipitating factors include infection of tracheobronchial tree and viral upper
respiratory tract infections (most common) and air pollution, but the cause of one-third of
exacerbations cannot be determined (Evidence B).
3. Spirometry is not accurate during an exacerbation and is not recommended.
4. Pulse oximetry can be used to determine the need for supplemental oxygen, which should be
given to those with severe exacerbations.
5. Inhaled bronchodilators (inhaled SABA with or without short-acting anticholinergics) are
preferred treatment for COPD exacerbations (Evidence C).
a. Usual doses of albuterol are 2.5 mg by nebulizer every 14 hours as needed or 48 puffs
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by an MDI with holding chamber every 14 hours as needed.

b. Short-acting anticholinergics (ipratropium) are generally added for acute exacerbations.
6. Systemic corticosteroids are effective and have been shown to shorten recovery time,
improve FEV1, and improve hypoxemia (Evidence A). They may also lower the risk of
treatment failure, early relapse, and length of hospital stay. Systemic corticosteroids should
be used in most exacerbations; GOLD guidelines no longer provide criteria for use. Dose of
OCSs for outpatient treatment: 3040 mg of oral prednisolone (or equivalent) once daily for
1014 days (Evidence D)
7. Antibiotic treatment should be initiated for exacerbations if criteria below are met. Most
common pathogens in COPD exacerbations: Streptococcus pneumoniae, Haemophilus
influenzae, and Moraxella catarrhalis. In patients with Gold 3 and Gold 4 severity,
Pseudomonas aeruginosa infection becomes an important pathogen.
a. The three cardinal symptoms in COPD exacerbations are increased dyspnea, increased
sputum volume, and increased sputum purulence.
i. Antibiotics should be given if all three cardinal symptoms are present (Evidence B).
ii. Antibiotics should be given if two of the three cardinal symptoms are present and if
increased sputum purulence is one of the symptoms (Evidence C).
iii. Antibiotics should be given to patients with a severe exacerbation requiring
mechanical ventilation (Evidence B).
b. Recommended duration of antibiotic treatment is usually 510 days (Evidence D).
c. Recommended antibiotics:
i. Optimal antibiotic therapy has not been determined. Usual initial antibiotics for
uncomplicated COPD: Azithromycin, clarithromycin, doxycycline, or trimethoprim/
sulfamethoxazole. In complicated COPD with risk factors: Amoxicillin/clavulanate,
levofloxacin, moxifloxacin. If at risk of Pseudomonas infection: High-dose
levofloxacin (750 mg) or ciprofloxacin
ii. If exacerbation does not respond to initial antibiotic, then sputum culture and
sensitivity should be performed.
G. Vaccinations: All patients with COPD should receive the influenza vaccine yearly and the
polysaccharide pneumococcal vaccine once before age 65; then, a one-time revaccination with
pneumococcal vaccine 5 years or more after the first vaccination
IV. PUBLIC HEALTH
Table 12. Agencies/Associations Specific to Asthma, COPD, and/or Smoking Cessation with
Resources/Educational Programs for the Public
Agency/Association
American Lung
Association (ALA)
Web Site/
Telephone Numbers
www.lungusa.org
Programs/Resources
Information on management of asthma, COPD, and smoking
cessation
Can enter zip code and search for local associations
Many local programs available
Better Breathers Club (COPD), Breathe Well/Live Well
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Table 12. Agencies/Associations Specific to Asthma, COPD, and/or Smoking Cessation with
Resources/Educational Programs for the Public
Agency/Association
Web Site/
Telephone Numbers
Programs/Resources
Self-Management Program (asthma), Freedom From Smoking
Online program
Lung help line 1-800-LUNGUSA to help with any questions on
asthma, COPD, smoking cessation
Can also do an online CHAT
Asthma and Allergy

Association of
America (AAFA)
www.aafa.org
Educational programs (online, classroom), resources, materials,

tools (e.g., asthma action plans/cards), publications, educational
materials, etc.
Local educational support groups, including parent support groups
Allergy and Asthma

Network; Mothers of
Asthmatics (AANMA)
www.aanma.org
Ask a Nurse patient support center, educational tools and

materials, asthma and allergy topics in the news, etc.
Help for parents dealing with children with asthma and allergies
National Heart Lung

and Blood Institute
(NHLBI)
www.nhlbi.gov
Area for public; includes information on asthma, COPD, and

smoking cessation
National Asthma Control Initiative
Publications, fact sheets
Demonstration projects around the country addressing implementing
guidelines and dealing with asthma disparities
COPD Council
www.copdcouncil.org National and international organizations

Programs in many different states/areas
Local Better Breathers clubs
List of speakers available
Smokefree.gov
www.smokefree.gov
1-800-QUITNOW
(connects to state
quit lines)
From the NCI (Tobacco Control Research Branch)

Online step-by-step research guide
Local and state telephone quit lines
NCI national telephone quit line
NCI instant messaging service
Publications; resources such as a craving journal, discovering
reasons for quitting
CDC Office on
Smoking and Health
(OSH)
www.cdc.gov/tobacco Patient education materials

Data and statistics
Links to state and community resources
Nicotine Anonymous
www.nicotine-anony
mous.org
12-step program offering support to those who want to quit

smoking; similar to AA
Links to local support groups and meetings; information on
telephone meetings
AA = Alcoholics Anonymous; COPD = chronic obstructive pulmonary disease; NCI = National Cancer Institute.
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V. PRACTICE MANAGEMENT
A. Medication Therapy Management: When conducting medication therapy management in patients
with asthma or COPD, key issues to consider:
1. Inhaler technique
2. Using controller versus rescue appropriately
3. Complex medical regimens, oxygen
4. Triggers (asthma)
5. How often using rescue medication (asthma)
6. Exercise-induced symptoms (asthma)
7. Does the patient have asthma action plan (asthma)
8. Is the patient monitoring his or her condition (e.g., symptoms, SABA use, peak flow
monitoring, if applicable)
B. When developing a new asthma/COPD/smoking cessation clinic or service, key issues to consider
in writing a business/practice plan:
1. Which other health professionals should be on the team (physician, registered nurse,
counselor for smoking cessation, respiratory therapist, someone to perform spirometry)?
2. What resources would be needed to start a practice/clinic (e.g., spirometry, carbon monoxide
monitor, placebo inhaler, holding chambers)?
3. Identify criteria to evaluate the success of a service/clinic in asthma, COPD, or smoking
cessation (quality measures); see Table 13.
4. Certification: Certified Asthma Educator (AE-C)
a. National Asthma Educator Certification Board (www.naecb.org/)
b. National examination based on a detailed content outline: Pathophysiology, contributing
factors, obtainment of history from a patient with asthma, physical signs, objective
measures, educational needs, asthma management (medications, delivery devices),
behavioral and environmental modifications, asthma education plan, organizational issues
(needs assessment, program development, implementation, evaluation), referral and
professional networking
c. Many local associations offer review classes.
Table 13. Examples of Quality Measures for Asthma and COPD More Specific to Pharmacy
Asthma Quality Measuresa
COPD Quality Measuresb
Documentation of asthma severity classification

Use of inhaled corticosteroids for persistent asthma
Provision of asthma action plans
Patients have been educated on managing their asthma and avoiding triggers
Influenza vaccines given
Smoking cessation counseling completed
Daily symptom burden
- Frequency of symptoms and 2-agonist use (per week)
- Number of days of (or free from) asthma symptoms in past month
- Days with nocturnal symptoms in past month
- Number of school/workdays missed in past month
- Frequency of urgent care or acute office visits
Pneumococcal vaccination
Influenza vaccination
Number (or percentage) of
patients who received smoking
cessation counseling
Number (or percentage) of patients
prescribed long-acting
bronchodilators in patient group B
Number (or percentage) of
patients prescribed inhaled
corticosteroids in patient groups
C and D
- Frequency of ED visits or hospitalization

Number of full 2-agonist canisters used in past 3 months
Number (or percentage) of patients who have been taught how to use an MDI
or DPI by a health professional
a
From the Agency for Healthcare Research and Quality. Available at www.ahrq.gov/qual/asthmacare/asthmod4.htm. Accessed
December 21, 2011.
b
Adapted from Heffner JE, Mularski RA, Calverley PM. COPD performa measures: missing opportunities for improving care. Chest
2010;137:11819.
COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler; ED = emergency department; MDI = metered dose inhaler.
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VI. PATIENT ADVOCACY

A. For Asthma and COPD, All Inhalers are Brand Name (not available generically). Cost
may be an issue for many patients.
B. Patient Assistance Programs Are Available from Manufacturers.
1. www.rxassist.org
2. Can search by name of drug to find criteria and instructions on enrolling patients in
the program
C. Ventolin HFA Is Available in a Smaller Canister on the $4 programs of some retail
pharmacies.
1. Cost: $8 per canister (60 puffs per canister instead of 200)
2. Generic albuterol and ipratropium nebulizer solutions are also available for $4 a
month.
D. Some Manufacturers Offer Coupons on Their Web sites (e.g., GlaxoSmithKline offers
$10 coupons that can be printed and used each month and can be applied toward full
price or even co-pays).
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REFERENCES
tive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians,
American Thoracic Society, and European Respiratory Society (ACP/ACCP/ATS/ERS guidelines). Ann Intern Med 2011;155:179-91.
3. van Grunsven PM, van Schayck CP, Dereene JP,
et al. Long-term effects of inhaled corticosteroids
in chronic obstructive pulmonary disease: a meta-analysis. Thorax 1999;54:7-14.
4. McEvoy CE, Neiwoehner DE. Adverse effects
of corticosteroid therapy for COPD: a critical review. Chest 1997;111:732-43.
5. Fiore MC, Jaen CR, Baker TB, et al. Treating
Tobacco Use and Dependence: 2008 Update.
Rock- ville, MD: U.S. Department of Health and
Human Services, Public Health Service, 2008.
Available at
www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=
hsahcpr&part=A28163. Accessed December 20,
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6. Calverley PMA, Anderson JA, Celli B, et al.
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pulmonary disease. Arch Intern Med
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___________________________________________________________________________________________________________________________________________________________________________________________________________________________________
288
The American College of Clinical Pharmacy and the faculty of the Pharmacotherapy Review Program for Advanced
Clinical Pharmacy Practice would like to express their appreciation to the authors of the original previously
published material that has been adapted here into this text:
Elizabeth A. Cole, Pharm.D., FCCM, BCPS
Bruce A. Mueller, Pharm.D., FCCP
University of Houston College of Pharmacy
University of Michigan College of Pharmacy
University of Texas M.D. Anderson Cancer
University of Michigan Health Systems
Center Houston, Texas
Ann Arbor, Michigan
Anna Legreid Dopp, Pharm.D.
Robert L. Page II, Pharm.D., FCCP, FAHA, BCPS
University of Wisconsin
University of Colorado Schools of Pharmacy and
Madison, Wisconsin
Medicine
Aurora, Colorado
Edward F. Foote, Pharm.D., FCCP,

BCPS Wilkes University
Jo E. Rodgers, Pharm.D., FCCP, BCPS
Wilkes Barre, Pennsylvania
University of North Carolina School of

Pharmacy Chapel Hill, North Carolina
Ila M. Harris, Pharm.D., FCCP, BCPS

University of Minnesota Medical
Curtis L. Smith, Pharm.D., BCPS
School Bethesda Family Medicine
Ferris State University
St. Paul, Minnesota
Grand Ledge, Michigan
Brian A. Hemstreet, Pharm.D., BCPS
Kevin M. Sowinski, Pharm.D., FCCP
University of Colorado at Denver and Health

Sciences
Purdue University College of

Pharmacy Indiana University School
Center
of Medicine Indianapolis, Indiana
Aurora, Colorado
Barbara S. Wiggins, Pharm.D., FCCP, FNLA, FAHA,
Brian K. Irons, Pharm.D., BCPS, BC-ADM
BCPS (AQ Cardiology), CLS
Texas Tech School of Pharmacy and Health

Sciences
CJW Medical Center

Richmond, Virginia
Center
Lubbock, Texas
Judith L. Kristeller, Pharm.D., BCPS
Wilkes University
Wilkes Barre, Pennsylvania
289

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AMERICAN COLLEGE OF CLINICAL PHARMACY

Pharmacotherapy Review Program for

March 2022, 2013

American College of Clinical Pharmacy

Pharmacotherapy Review Program for

March 2022, 2013

American College of Clinical Pharmacy

Executive Director: Michael S. Maddux, Pharm.D., FCCP

9:00 a.m.9:30 a.m.

I. ACUTE KIDNEY INJURY (ACUTE RENAL FAILURE)

a. Has a moderate incidence (2%5%) and moderate survival rate (30%50%)

c. Urinalysis will reflect damage. Urine generally not concentrated

Intrinsic (ATN and AIN)

Rash, fever (with AIN)

Serum BUN/SCr ratio

Variable, may be normal

Muddy-brown granular casts;

II. DRUG-INDUCED KIDNEY DAMAGE

d. Most implicated medications: Aminoglycosides, NSAIDs, ACEIs, contrast dye, amphotericin

ii. Less than 2% and up to 50% of patients, depending on risk

volume depletion, concomitant nephrotoxins, rapid infusion

alkalinization of the urine.

III. CHRONIC KIDNEY DISEASE

IV. RENAL REPLACEMENT THERAPY

i. InfectionS. aureus. Need to treat aggressively. May need to remove catheter

Table 2. Iron Therapy

Initial test dose

Yes; 25-mg one-time test dose

B. CKD-Mineral Bone Disorder and Secondary Hyperparathyroidism

(5) Available as sevelamer HCl (Renagel) and sevelamer carbonate (Renvela)

VI. ASSESSMENT OF RENAL FUNCTION

b. MDRD 4-factor equation

Schwartz equation Preferred pediatric method to estimate CrCl

CrCl = (k* Ht (cm))

Original Schwartz Equation

VII. DOSAGE ADJUSTMENTS IN KIDNEY DISEASE

actual body surface area to obtain eGFR in milliliters per minute.

Atenolol, ACEIs, digoxin, nadolol, sotalol; avoid potassium-sparing diuretics if CrCl

Clofibrate, fenofibrate, statins

Table 4. Dose Adjustments in Decreased Kidney Function

Chloral hydrate, gabapentin, lithium, paroxetine, primidone, topiramate, trazodone, vigabatrin

Acarbose, chlorpropamide, glyburide, glipizide, insulins, and metformin

Allopurinol, colchicine, H2-receptor antagonists, diclofenac, ketorolac, and terbutaline

ACEIs = angiotensin-converting enzyme inhibitors; CrCl = creatinine clearance.

4. Calculate drug doses individualized for the patient.

National Kidney Foundations Kidney Disease

EBSCO Publishing, 2010. Available at http://dynaweb.ebscohost.com/

Acute Kidney Injury

Chronic Kidney Disease

Renal Replacement Therapy

Drug Therapy Adjustment in CKD

a. Glucose intolerance occurring during pregnancy

(c) Prudent to obtain hemoglobin A1c (A1c) concentration as well

Table 1.Second-Generation Sulfonylurea Dosing Strategies

Maximal Daily Dose (mg)

2.55.0 mg once or twice daily

1.53 mg once or twice daily