Hypertension

most common cardiovascular

disorder
sustained BP ≥ 130/>80 (systolic/
diastolic)
 Systole: ventricles contracting
 Diastole: ventricles relaxed, filling
blood
usually asymptomatic initially
can lead to myocardial
infarction (MI), heart failure,
stroke, or kidney disease
 Hypertension
 7th Report of the Joint National Committee on Detection,
Evaluation, & Treatment of High BP (JNC-7):

Category Systolic (mmHg) Diastolic (mmHg)

Normal < 120 & < 80

Pre-hypertension 120-139 Or 80-89
Stage 1HPN 140-159 Or 90-99
Stage 2 HPN ≥ 160 Or ≥ 100
8th Report of the Joint National Committee on
Detection, Evaluation, & Treatment of High BP
(JNC-8):
Hypertension
Renin-Angiotensin-Aldosterone
System (RAAS)
 long term regulation of BP
 ↓ BP → ↓ renal blood flow → kidney
releases renin
 Renin - converts angiotensinogen
(produced by the liver) to angiotensin I
 Angiotensin converting enzyme (ACE)
(lungs) - converts angiotensin I to
angiotensin II
 Angiotensin II
vasoconstrictor → ↑ PR
aldosterone release in adrenal cortex → Na,
H2O retention → ↑ blood volume → ↑ CO
Anti-HPN…SYMPATHOLYTICS
 Centrally-Acting / α2 Agonist
Methyldopa, Clonidine, Guanabenz,
Guanfacine
presynaptic α2 agonist → ↓ NE release
by(-) feedback
activity of methyldopa: due to stimulation
of central alpha adrenoceptors by
methyldopamine & methylNE
Anti-HPN…SYMPATHOLYTICS
Centrally-Acting / α2 Agonist
 S/E:
sedation, dry mouth, depression
methyldopa: false (+) Coomb’s test for
hemolytic anemia
clonidine: rebound hypertension on
withdrawal
Anti-HPN…SYMPATHOLYTICS
α1 Blockers
 Prazosin, Terazosin, Doxazosin
 block α1 → ↓ vasoconstriction → ↓ PR
 S/E: orthostatic hypotension especially
after the 1st dose
Anti-HPN…SYMPATHOLYTICS
β Blockers
 ↓ HR, contractility → ↓ CO
 block stimulation of renin secretion
 selectivity:
Selective Non-Selective
Betaxolol Propranolol
Bisoprolol Penbutolol
Esmolol Carteolol
Atenolol CarvedILOL (α & β)
Acebutolol LabetALOL (α & β)
Metoprolol Timolol
Celiprolol Nadolol
Anti-HPN…SYMPATHOLYTICS
Ganglionic Blockers
 Trimethaphan, Hexamethonium
 rarely used due to side effects:
Parasympathetic blockade → urinary
retention, blurring of vision
Sympathetic blockade → orthostatic
hypotension, sexual dysfunction
Anti-HPN…SYMPATHOLYTICS
Postganglionic Adrenergic Neuron
Blockers
 Reserpine, Guanethidine
 deplete catecholamine stores in the
brain & in the peripheral adrenergic
system
 rarely used due to low efficacy & side
effects
Anti-HPN…Vasodilators
Hydralazine
 directly relaxes arterioles → ↓ PR
 hypertensive crisis (IV or IM)
HPN crisis: BP 210/150 or above
 S/E:
reflex tachycardia, systemic lupus
erythematosus
Anti-HPN…Vasodilators
Sodium Nitroprusside
 has potent effects on both the arterial
& venous systems
 acute hypertensive crisis (IV)
 S/E:
hypotension, cyanide toxicity
Anti-HPN…Vasodilators
Diazoxide
 exerts a direct action on the arterioles
 acute hypertensive crisis (IV)
 hypoglycemia due to hyperinsulinism
(prevents insulin release)
 S/E:
hypotension, hyperglycemia
Anti-HPN…CCBs
 Dihydropyridines:
 1st gen: Nifedipine
 2nd gen: Amlodipine, Felodipine, Isradipine,
Nicardipine, Nisoldipine, Nimodipine
(selective in cerebral vasculature)
 vascular smooth muscles
 vasodilation - ↓ PR
 Non-dihydropyridines:
 Verapamil & Diltiazem
 vascular smooth muscles & cardiac muscles
 vasodilation - ↓ PR
 (-) inotropic / chronotropic effect - ↓ CO
Anti-HPN…ACEIs
ACE Inhibitors
 ↓ angiotensin II → ↓ vasoconstriction
→ ↓ PR
 ↓ angiotensin II → ↓ aldosterone → ↓
Na, H20 retention → ↓ blood volume →
↓ CO
 ⬆ bradykinin level →vasodilation
Anti-HPN…ACEIs
 Key Terms
 Renin
 catalyzes the formation of a decapeptide,
angiotensin I, from a plasma protein
substrate.
 control the rate-limiting step in the ultimate
production of angiotensin II.
 Angiotensinogen
 ACE converts Angiotensin 1 to
Angiotensin II. The lung vascular
endothelium contains the highest
concentration of ACE (S/E: _____?)
 Note: Activation of vasoconstrictor
Angiotensin II, increase secretion of
aldosterone → inactivation of vasodilator
bradykinin. ACEIs reverse these.
Anti-HPN…ACEIs
S/E:
 First-dose hypotension
 Dry cough (most frequent symptom)
 Functional renal failure
 Hyperkalaemia
 Fetal injury
 Urticaria and angio-oedema
 Sulfhydryl group-related effects
 heavy proteinuria
Neutropenia
rash
taste disturbance
Anti-HPN…ARBs
ANGIOTENSIN II RECEPTOR
BLOCKERS (ARB)
 Candesartan cilexetil, Eprosartan,
Irbesartan, Losartan, Olmesartan,
Telmisartan, Valsartan
 block the binding of angiotensin II
to the angiotensin II receptors →
⬇ TPR (afterload) and venous
tone (preload)
 S/E:
no dry cough, hypotension,
hyperkalemia, teratogenic
Anti-HPN…Renin Inhibitor
 Aliskiren
 Direct renin inhibitor
 S/E: diarrhea, hyperkalemia
Angina Pectoris
Strategies
 ↑ O2 delivery (supply)
 ↓ O2 requirement (demand)
 ↑efficiency of oxygen utilization
Anti-anginal Drugs
Pharmacologic Treatment:
 Nitrates
 Beta-blockers
 Calcium Channel blockers
Anti-anginal Drugs
Pharmacologic Treatment:

Beta-
Parameter Nitrates CCBs
blockers
Afterload (arterial pressure,
⬇ ⬇ ⬇
peripheral resistance)
Preload (diastolic filling
heart pressure, blood ⬇⬇⬇ →⬆ →
volume)
Heart rate →⬆ ⬇⬇ ⬆⬇
Contractility →⬆ ⬇⬇ ⬆⬇
Wall tension ⬇⬇⬇ ⬆⬇ ⬇
Anti-anginal Drugs…nitrates
Nitroglycerin: SL, spray, transdermal
patch, oral, IV infusion
Isosorbide dinitrate; mononitrate:
SL, oral
Pentaerythritol tetranitrate: SL
Erythritol tetranitrate: SL, oral
converted to nitric oxide (NO) →
inc. cGMP → smooth muscle
relaxation → vasodilation
Anti-anginal Drugs…nitrates
venodilation & arterial dilation → ↓ O2
demand and overall reduction in
myocardial fiber tension
 venodilation → ↓preload (blood volume
and pressure within the heart → ↓cardiac
size and cardiac output) → ↓cardiac
workload and oxygen demand
 arterial dilation → increased blood flow
 arteriolar dilation → ↓ peripheral vascular
resistance, increased ejection (afterload)
→ ↓ systolic blood pressure → ↓cardiac
workload and oxygen demand
Anti-anginal Drugs…nitrates
 S/E:
 throbbing headache
 Flushing
 postural hypotension
 reflex tachycardia → due to increased heart
rate and contractility)
 tolerance
 prevention: smallest effective dose and
infrequency of use; nitrate-free periods,
particularly in using transdermal patch or ointment
 In workplace, “Monday Disease” → industrial
disease caused by chronic exposure to
organic nitrates; headache, dizziness and
tachycardia after 2 days absent.
Anti-anginal Drugs…nitrates
For nitrites (not nitrates) →
methemoglobinemia
 Cyanide toxicity: CN-cytochrome oxidase
complex → oxidative metabolism and cell
death. Methemoglobin, however, has
higher affinity to cyanide than in
cytochrome oxidase.
Amyl nitrite
sodium nitrite
sodium thiosulfate (to convert
cyanomethemoglobin to thiocyanate (less
toxic than cyanide and is excreted in the
kidney)
Anti-anginal Drugs…nitrates
C/I: sildenafil (PDE5 inhibitor)
 synergism → dangerous hypotension
 PDE converts cGMP (smooth muscle
relaxation) to GMP
Caution
 Nitrate increases intracranial pressure
→ caution to patients with cerebral
bleeding and head trauma
Anti-anginal Drugs…CCBs
CALCIUM CHANNEL BLOCKERS
 Nifedipine
 Amlodipine
 Felodipine
 Isradipine
 Nicardipine
 Nisoldipine
 Nitrendipine
 Bepridil
 Diltiazem
 Verapamil
Anti-anginal Drugs…CCBs
CALCIUM CHANNEL BLOCKERS
 DOC for Prinzmetal’s angina
 Verapamil and Diltiazem (used also in
supraventricular tachycardia,
pulmonary hypertension and
Raynaud’s phenomenon)
 blockade of L-type voltage
dependent calcium channels → ⬇
contractility; ⬇ heart rate;
vasodilation
Anti-anginal Drugs…CCBs
B. CALCIUM CHANNEL BLOCKERS
S/E:
 Constipation (verapamil)
 Nausea
 Flushing
 Dizziness
 heart failure
 AV blockade
 sinus node depression
Anti-anginal Drugs…-blockers
β BLOCKERS
 Propranolol
 Metoprolol
 Atenolol
 Nadolol
 Timolol
 Acebutolol
 Betaxolol
 Bisoprolol
 Esmolol
 Pindolol
Anti-anginal Drugs…-blockers
β BLOCKERS
 ↓ HR, contraction→ ↓ O2 demand →
vasoconstriction (opposing to calcium
channel blockers)
 ⬆ diastolic filling time → ⬆ oxygen
supply
 prophylaxis only, not for acute attack
 beneficial if combined with nitrates
because the latter causes reflex
tachycardia which is counteracted by
the former.
Anti-anginal Drugs…-blockers
β BLOCKERS
 Caution
abrupt interruption of propranolol to
patient with angina has been
associated to reappearance of
angina, acute myocardial
infarction, or death due to sudden
increase in sympathetic tone in the
heart (due to upregulation of
receptors)
Anti-anginal Drugs…-blockers
β BLOCKERS
 S/E:
Bradycardia
arteriovenous nodal block
decompensated congestive heart failure
Anti-anginal Drugs
D. Others
 Ranolazine & Trimetazedine
pFOX inhibitors
 Ivabradine (investigational)
Congestive Heart Failure
Strategy:
 1. ↑ contractility - inotropics
 2. ↓ resistance - vasodilators
 3. ↓ fluid retention – diuretics
 DIURETICS SUMMARY
DIURETICS SITE OF ACTION EXAMPLES

CAI PCT BAD

LOOP LOH(THICK Fun To BE

ASCENDING)

THIAZIDE DCT CHIC

K-SPARING CT- CORTICAL SEAT

OSMOTIC DIURETIC PCT/LOH(thin SUM

descending)
DIURETICS MOA SIDE EFFECTS

CAI Inhibits Carbonic anhydrase Dec.Na/K

Metabocic acidosis
LOOP (-)Na/K/2Cl cotransport Dec.Na/K/Ca/Mg
Hypovolemia
Ototoxicity
hyperuricemia
THIAZIDE (-)Na/2Cl cotransport Dec.Na/K/Mg
Inc Ca
Hyperlipidemia
Hyperglycemia
hyperuricemia

K-SPARING inhibit Na reabsorption, K secretion at Dec Na/ Inc K/H

the collecting tubule Metabolic acidosis
Impotence
gynecomastia

OSMOTIC osmosis hypovolemia

DIURETIC
DIURETICS SPECIAL USES SIDE EFFECTS

CAI Mountain sickness dse Dec.Na/K

glaucoma Metabocic acidosis

LOOP CHF/ acute PE Dec.Na/K/Ca/Mg

Acute hypercalcemia Hypovolemia
HPN emergency Ototoxicity
hyperuricemia

THIAZIDE HPN/renal stone Dec.Na/K/Mg

formation Inc Ca
hypocalcemia Hyperlipidemia
Hyperglycemia
hyperuricemia

K-SPARING Digoxin tx. Dec Na/ Inc K/H

Hypokalemia Metabolic acidosis
CONNS syndrome Impotence
gynecomastia

OSMOTIC DIURETIC Inc ICP hypovolemia

LITHIUM Toxicity
Congestive Heart Failure
Strategy:
 1. ↑ contractility - inotropics
 2. ↓ resistance - vasodilators
 3. ↓ fluid retention – diuretics
Congestive Heart Failure
 complex clinical syndrome that can result
from any cardiac disorder that impairs the
ability of the ventricle to deliver adequate
quantities of blood to the metabolizing
tissues during normal activity or at rest
 Chronic CHF:
 an individual expels less than 40% of the
blood from the left ventricle per heartbeat
(ejection fraction [EF] < 40%).
 A normal individual expels about 55 to 65%
of the blood from the left ventricle per
heartbeat (EF = 55–65%).
 ↓ CO
Arrhythmias
deviations from the normal
heartbeat pattern
they include:
 abnormalities of impulse formation
 conduction disturbances
Membrane Action Potential
Phase 0: Rapid Depolarization or
fast upstroke
 rapid opening of voltage gated
sodium channels resulting in a fast
inward current.
 Genetic mutations in the sodium
channel resulting in a sustained
inward leak current can cause long
QT syndrome (LQTS 3).
Cardiac Action Potential
Membrane Action Potential
Phase 1: Partial repolarization
 Initial rapid phase of repolarization is due
to inactivation of sodium channel.
 K+ channels that rapidly open and close,
causing a transient outward current.
 produces a spike and dome
configuration of the action potential
Abnormalities in the function of It
have been implicated in Brugada
syndrome, a potentially lethal genetic
disease resulting in ventricular
tachycardia and fibrillation.
Cardiac Action Potential
Membrane Action Potential
Phase 2: Plateau
 net balance between inward
(depolarizing) and outward
(repolarizing) ion currents maintaining
the myocyte in a depolarized state.
 Voltage-sensitive Ca2+channels open,
resulting in a slow inward
(depolarizing) current that balances
the slow outward (polarizing) leak of
K+
Cardiac Action Potential
Membrane Action Potential
Phase 3: Repolarization (late
phase)
 Ca2+ channels close
 K+ channels open, resulting in an
outward current that leads to
membrane repolarization.
 The net result of the action to this point
is a net gain of Na+ and loss of K+. This
imbalance is corrected by Na+/K+-
ATPase
Cardiac Action Potential
Membrane Action Potential
Phase 4: FORWARD CURRENT
 Increasing depolarization results from
gradual increase in sodium
permeability.
 The spontaneous depolarization
automatically brings the cell to the
threshold of the next action potential.
Cardiac Action Potential
ECG Patterns of Arrhythmias
Na channel blockers - CLASS I IA

IB

IC

Beta – blockers - CLASS II P

E
A
K- channel blockers- CLASS III A Big Dog Is Scary

CaCB- CLASS IV D
V
Classification of Anti-Arrhythmics
 Vaughan Williams’ Classification of
Antiarrhythmic Drugs
 Class I (Na Channel Blockers)
A: Quinidine, Procainamide, Disopyramide
B: Phenytoin, Lidocaine, Mexiletine,
Tocainide
C: Flecainide, Propafenone, Moricizine
Classification of Anti-Arrhythmics
 Vaughan Williams’ Classification of
Antiarrhythmic Drugs
 Class II (β Blockers)
Propranolol, Esmolol, Acebutolol
 Class III (K Channel Blockers)
Bretylium, Amiodarone, Sotalol, Ibutilide,
Dofetilide (Ami’s Breast Is SO doffirent!)
 Class IV (Ca Channel Blockers)
Verapamil, Diltiazem
Classification of Anti-Arrhythmics
Others:
 Adenosine
 Atropine
 Digoxin
 Magnesium sulfate
Common S/E: Proarrhythmia
Sodium Channel Blockers
Na Channel Blockers
 Suppress abnormal automaticity and
permit the sinoatrial node to again
assume the role of the dominant
pacemaker
Sodium Channel Blockers
Na Channel Blockers
Sodium Channel Blockers
all group 1 drugs reduce both
phase 0 (rate of rise/upstroke) and
phase 4 sodium currents (wavy
lines) in susceptible cells.
Group 1A
 ⬇ upstroke
 ⬇ phase 3 potassium current (IK)
 ⬆ action potential (AP) duration
 ⬆ effective refractory period (ERP)
 ⬇ conduction velocity
Sodium Channel Blockers
 Group 1B
 ⬇ action potential duration
 ⬆ outward K+ current
 Minimal ⬇ in upstroke
Group IC
 No effect on action potential
 Marked ⬇ in upstroke
 ⬇ conduction velocity
 However, all group 1 drugs prolong
the ERP by slowing recovery of sodium
channels from inactivation.
Class IA
Procainamide
 Atrial and ventricular arrhythmias,
especially after myocardial infarction
 Procainamide is a particularly useful
antiarrhythmic drug, effective in the
treatment of supraventricular,
ventricular, and digitalis-induced
arrhythmias.
 Increased arrhythmias, drug fever,
agranulocytosis, SLE-like syndrome
(fatigue, arthralgia, myalgia & low-
grade fever)
Class IA
Disopyramide
 Similar to procainamide but longer
duration of action
 toxicity includes antimuscarinic effects
and heart failure
Class IA
Disopyramide
 Similar to procainamide but longer
duration of action
 toxicity includes antimuscarinic effects
and heart failure
Quinidine
 Similar to procainamide but toxicity
includes cinchonism (tinnitus,
headache, gastrointestinal
disturbance) and thrombocytopenia.
Na Channel Blockers
Moricizine
 life-threatening arrhythmias
 Not classified as IA or IB, but shows
effect as them
Class IB
Lidocaine
 DOC for digitalis-induced arrhythmia
 DOC for sustained ventricular
arrhythmia after acute MI
 S/E: CNS reactions (most
pronounced); sedation or excitation
Class IB
Mexiletine
 Similar to lidocaine but oral activity
and longer duration of action
 For acute or chronic ventricular
arrhythmias
 While it is not at present an indication
for use, there is interest in using
mexiletine to treat the congenital long
QT syndrome when an abnormality in
the SCN5A gene (LQTS 3) has been
found.
Class IB
Phenytoin
 an anticonvulsant and not a true local
anesthetic
 sometimes classified with the group 1B
antiarrhythmic agents because it can
be used to reverse digitalis-induced
arrhythmias
 Also in ventricular arrhythmias in
children
Class IB
Tocainide
 structural similarity to Lidocaine
 For symptomatic ventricular
arrhythmias refractory to more
conventional therapy
Class IC
Flecainide
 Refractory arrhythmias
 intractable supraventricular
arrhythmias
 most types of atrial arrhythmias
 Now restricted to use in persistent
arrhythmias that fail to respond to
other drugs
 Increased arrhythmias; CNS excitation
Class IC
Propafenone
 supraventricular arrhythmias and life-
threatening
 ventricular arrhythmias in the absence
of structural heart disease
Moricizine
Beta-Blockers
Cardiac membrane stabilization
Prolong ERP
Beta-adrenoceptor block
Beta-Blockers
Propranolol
 Postmyocardial infarction as
prophylaxis against sudden death
ventricular fibrillation & thyrotoxicosis
 S/E: Bronchospasm; cardiac
depression, atrioventricular (AV)
block, hypotension
Beta-Blockers
Esmolol
 Selective B1-receptor blockade
 Given via IV only, 10-min duration.
 Used in perioperative and
thyrotoxicosis arrhythmias
Potassium Channel Blocker
Class III:
 ⬆ AP duration
 ⬆ ERP
 delaying repolarization without
altering phase 0
 Class III drugs have a significant risk of
proarrhythmia because of the
prolongation of action potential and
the induction of torsades de pointes
Potassium Channel Blocker
Potassium Channel Blocker
Amiodarone
 Refractory arrhythmias; used off-label in
many arrhythmias (broad spectrum of
therapeutic action)
 1st choice antiarrhythmic for shock-
refractory ventricular
fibrillation/ventricular tachycardia
 S/E:
Thyroid abnormalities, deposits in skin and
cornea, pulmonary fibrosis, optic neuritis
Torsades de pointes
Photosensitivity
Peripheral neuritis
Potassium Channel Blocker
Sotalol
 Ventricular arrhythmias and atrial
fibrillation
 Dose-related torsade de pointes;
cardiac depression
Potassium Channel Blocker
Ibutilide
 Treatment of acute atrial fibrillation
 Ibutilide is IV only
 Torsade de pointes
Dofetilide
 Treatment and prophylaxis of atrial
fibrillation
 Torsades de pointes
Calcium Channel Blocker
Group 4
 reduce inward calcium current during
the AP and during phase 4 (wavy
lines)
 Major effect: ⬇ conduction velocity
is slowed in the AV node
 refractoriness is prolonged
Calcium Channel Blocker
Calcium Channel Blocker
Verapamil & Diltiazem
 AV nodal arrhythmias, especially in
prophylaxis
 1st line agents for the suppression of
paroxysmal supraventricular
tachycardia stemming from AV nodal
reentry
 S/E: Cardiac depression; constipation,
hypotension
 Nifedipine and the other
dihydropyridines are not useful as
antiarrhythmics
Miscellaneous Anti-Arrhythmics
Adenosine
 AV node that causes marked
hyperpolarization and conduction block
 endogenous product of the metabolism
of adenosine triphosphate
 Acute nodal tachycardias
 DOC for paroxysmal supraventricular
tachycardia
 If asthmatic: verapamil
 S/E: Flushing, bronchospasm, chest pain,
headache
Miscellaneous Anti-Arrhythmics
Potassium ion
 Digitalis toxicity and other arrhythmias
if serum K is low
 Both hypokalemia and hyperkalemia
are associated with arrhythmogenesis.
 Severe hyperkalemia causes cardiac
arrest
Miscellaneous Anti-Arrhythmics
Magnesium sulfate
 Poorly understood, possible increase in
Na+/K+ ATPase activity
 Indications:
Digitalis arrhythmias and other arrhythmias
if serum Mg is low
Torsades de Pointes
 S/E: Muscle weakness, severe
hypermagnesemia can cause
respiratory paralysis
Hyperlipidemia
Hyperlipidemia
 high LDL, low HDL
 increases the risk of atherosclerosis →
stroke, MI
 Low density lipoproteins LDL (bad
cholesterol)
 transport cholesterol to cells
 High density lipoproteins (good
cholesterol)
 removes cholesterol from tissues and
transport it to the liver
Hypolipidemic Agents
HMG-CoA REDUCTASE INHIBITORS
 Lovastatin
 Simvastatin
 Atorvastatin (most potent of the
available statins)
 Pravastatin
 Fluvastatin
inhibit 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG CoA) reductase
(rate limiting enzyme in cholesterol
biosynthesis) which converts HMG-
CoA to mevalonic acid
Hypolipidemic Agents
HMG-CoA REDUCTASE INHIBITORS
 S/E:
elevated liver function tests,
myositis (inflammation of skeletal muscle);
rhabdomyolysis (disintegration of muscle
and excretion of myoglobin and kidney
damage)→ cerivastatin
teratogenic
 (+) fibrates: increased risk of statin
toxicity; (+) grapefruit: ⬆ statin
plasma level
Hypolipidemic Agents
HMG-CoA REDUCTASE INHIBITORS
 liver is the target organ (decreased
hepatic cholesterol synthesis → ⬇ LDL
particles
 reduced blood cholesterol of patients
with homozygous familial
hypercholesterolemia (fatal in childhood
or early adulthood)
 Recent studies: ⬇ the risk of stroke,
dementia and Alzheimer’s disease and
may improve bone density in
postmenopausal women
 effects: ↓LDL, ↑HDL, ↓TG
Hypolipidemic Agents
NIACIN / NICOTINIC ACID
 Vitamin B3
 most widely available hypolipidemic
agent
 multiple beneficial effect on may
lipoproteins; least expensive and is least
tolerated
 mechanisms:
participation in tissue respiration REDOX
reactions (↓ hepatic LDL & VLDL production)
inhibition of adipose tissue lipolysis
decreased hepatic TG esterification
increase in lipoprotein lipase activity
Hypolipidemic Agents
Niacin S/E:
 GI effects
 flushing (reduced compliance)
250 mg twice daily and increasing the dose
monthly by 500 to 1000 mg/day to a
maximum of 3000 mg per day)
taking aspirin 30 mins before meal needed to
reduce flushing)
 itchy skin,
 liver toxicity (especially at high doses);
 hyperglycemia and decrease glucose
tolerance,
 hyperuricemia
Hypolipidemic Agents
 FIBRIC ACID DERIVATIVES
 Clofibrate, Fenofibrate, Gemfibrozil
 PPAR agonist (peroxisomal proliferation
activated receptor )
 (1)increased transcription of lipoprotein lipase (LPL)
that catabolizes VLDL triglyceride;
 (decreased transcription of the apolipoprotein CIII
gene (inhibitor of LPL activity)
 inhibit cholesterol synthesis
 increase activity of lipoprotein lipase
 effects: ↓LDL, ↓TG, ↑HDL
 S/E: GI disturbance; myositis and erectile
dysfunction (clofibrate)
FIBRATES
Hypolipidemic Agents
BILE ACID-BINDING RESINS
 or bile acid sequestrant resins (anion
exchange resins that remain in the
gut, bind intestinal bile acids, prevents
their reabsorption and greatly
increase their fecal excretion).
 ⬇ feedback inhibition of 7 alpha
hydroxylase → ⬆ synthesis of new bile
salts → ⬇liver cholesterol → ⬆LDL
receptors → ⬇ plasma LDL.
 alternative for patients intolerant to a
statin
BILE ACID-BINDING RESINS MOA
Hypolipidemic Agents
BILE ACID-BINDING RESINS
 Cholestyramine, Colestipol,
Colesevelam
 effect: ↓ LDL (20-25%)
Note: Resins can ⬆ TG‼
 S/E: constipation, ↓ absorption of
many other drugs (should always be
taken atleast 1 hr before or 4-6hrs after
the resin)
 (+) statin → safe! (50% LDL reduction)
Hypolipidemic Agents
CHOLESTEROL ABSORPTION
INHIBITOR
 EZETIMIBE
 inhibits the intestinal absorption of
cholesterol & related phytosterols
 effects: ↓LDL, ↓TG, ↑HDL
 in combination with the HMG-CoA
reductase inhibitors
1. NPCL1
2. CLATHRIN AP2
Hypolipidemic Agents
CHOLESTEROL ABSORPTION INHIBITOR
 PCSK9 INHIBITOR
1. EVALOCUMAB
2. ALIRACUMAB
CHOLESTEROL ABSORPTION INHIBITOR

PCSK9 INHIBITOR
Venous Thromboembolic Disease
occurs when 1 or more of the
elements of Virchow’s triad are
present, resulting in deep venous
thrombosis (DVT) &/ or pulmonary
embolism (PE)
 Vascular injury
 Venous stasis
 Hypercoagulable state
Blood Drugs
Anticoagulants
Fibrinolytic Agents
Anti-platelet Drugs
Pro-coagulants
Anti-anemics
Heparin vs Warfarin
Heparin vs Warfarin
Fibrin Clot Inhibitors: Anticoagulants

Warfarin
 PO (oral anticoagulant of choice), IV
 monitor: prothrombin time (PT),
international normalized ratio (INR)
 target: 2-3 or 2.5-3.5
 S/E: hemorrhage, teratogenic, purple
toes
 antidote: (phytonadione) vitamin K1
Fibrin Clot Inhibitors: Anticoagulants

Direct Thrombin Inhibitors

 from medicinal leech (Hirudo
medicinalis)
Lepirudin (recombinant leech hirudin)
Desirudin
Bivalirudin
Argatroban
dabigatran
 MOA: binds to active site of thrombin
and to thrombin substrates
Fibrin Clot Inhibitors: Anticoagulants

Direct Xa Inhibitors
1. Apixaban
2. Rivaroxaban
Fibrin Clot Inhibitors: Anticoagulants

Direct Thrombin Inhibitors

 alternatives to heparin primarily in
patients with heparin-induced
thrombocytopenia (HIT)
 monitor: aPPT
 S/E: bleeding (no reversal agents
exists), anaphylaxis
Thrombolytics/ Fibrinolytics
dissolves clot
converts plasminogen →
plasmin (fibrinolytic enzyme
→degrades clot by splitting
fibrin into fragments)
Thrombolytics/ Fibrinolytics
dissolves clot
converts plasminogen →
plasmin (fibrinolytic enzyme
→degrades clot by splitting
fibrin into fragments)
Thrombolytics/ Fibrinolytics
First -Generation
Streptokinase
 protein from Group C β-hemolytic
Streptococci
 indirectly acting activator of
plasminogen
 MI, DVT, PE
 S/E: hemorrhage, allergy
Urokinase
 from cultured human kidney cells
 coronary artery thrombosis & PE
 S/E: hemorrhage, allergy
Thrombolytics/ Fibrinolytics
Second -Generation
Alteplase, Reteplase, Tenecteplase
 tissue plasminogen activator (t-PA)
 binds to fibrin to cause a selective activation
of fibrin-bound plasminogen
 stroke, MI, PE
 S/E: hemorrhage
 Note: cerebral hemorrhage must be
positively ruled out first
 Anistreplase
 coronary artery thrombosis & MI
 S/E: hemorrhage, allergy, arrhythmia,
hypotension
ANTIPLATELET
inhibits platelet aggregation
prolongs bleeding time
ANTIPLATELET
Aspirin
 inhibits thromboxane A2 synthesis
 prevents MI, transient ischemic
attacks, stroke
 S/E: GI ulcer, bleeding
ANTIPLATELET
Ticlopidine & Clopidogrel
Ticagretor & Prasugrel
P2Y12
 interfere with ADP-induced
membrane-mediated platelet-
fibrinogen binding → inhibition of
platelet-platelet aggregation
 prevention of stroke, MI (Clopidogrel)
who cannot tolerate aspirin
 S/E: diarrhea, rash, nausea, vomiting,
GI pain, neutropenia (Ticlopidine)
ANTIPLATELET
Tirofiban, Eptifibatide,
Abciximab
 GPIIb/IIIa-receptor antagonists
 for patients undergoing percutaneous
transluminal coronary angioplasty
(PTCA)
 S/E: hemorrhage
ANTIPLATELET
Cilostazol & Dipyridamole
 inhibits the following:
Uptake of adenosine by endothelial cells
and erythrocytes → ⬆ adenosine (⬆
cAMP→ ⬇ aggregation)
PDE III
thromboxane A2 formation
 prevention against thromboembolism
after cardiac valve replacement
 for intermittent claudication
 C/I: CHF (cilostazol)
ANTIPLATELET
Anagrelide
 decreases platelet production
 for patients with essential
thrombocythemia
Coagulating Agents
Indication:
 bleeding problems such as
hemophilia [(deficiency in blood
coagulation factors
frequently factors VIII (Hemophilia
A) and
 IX (hemophilia B)]
Coagulating Agents
Vitamin K
 Forms:
K1- phytonadione (found in food)
K2 – menaquinone (found in
human tissue synthesized by
intestinal bacteria)
K3 – menadione (not used in
therapeutics)
 fat-soluble vitamin
Coagulating Agents
Desmopressin acetate
 vasopressin agonist
 increases plasma
concentration of von
Willebrand factor and factor
VIII
 Hemophilia A and von
Willebrand disease
Coagulating Agents
Antiplasmin agents
 prevention of management of
acute bleeding episodes in
patients with hemophilia
 Aminocaproic acid and
Tranexamic acid → inhibits
plasminogen activation →
⬇fibrinolysis
 Aprotinin (serine protease inhibitor)
→ inhibits fibrinolysis by plasmin
and plasmin-streptokinase
complex
Coagulating Agents
Protamine sulfate
 Antidote of Heparin toxicity
 fish sperm or testes
 basicity is due to arginine
content