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S3 Lec
Lec 7: Anti-Diabetics by Dr. Marita Fuentes
7: Anti-Diabetics December 7, 2010
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Ma December 7, 2010
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Sulfonylureas (Chlorpropamide, Glyburide, Glipizide)
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 They are not effective for DM1 because they require some
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F. DIABETES MELLITUS TYPE 2
endogenous insulin secretion.
F.
characterized by:
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 variable degrees of insulin resistance  Newer agents have larger, less polar side groups on the
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sulfonylurea backbone, which boosts potency.
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F.  impaired insulin secretion
 Chlorpropamide is excreted without metabolism, so it should be
F.
ul  increased glucose production
avoided in renal disease. Chlorpropamide is the longest-acting
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sulfonylurea.
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Diabetes Pharmacology – Oral Agents and Insulin
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 Glipizide is metabolized in the liver, so it should be avoided in
Viv Insulin Insulin Hepatic High
liver disease. Glipizide is the shortest-acting sulfonylurea.
Viv
ee Secretion Resistance Glucose Sensitivity
Fails Persists Output to dietary  Toxicities: hypoglycemia, hepatotoxicity, allergic reaction
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Arl Increases CHO
First Generation vs Second Generation
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Insulin X
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Secretagogues 1st Gen sulfonylureas
Insulin X
Niň
 longer half-life
Niň
ng
ng Sensitizers  greater incidence of hypoglycemia
da
da HGO inhibitors X  more frequent drug interactions.
Da CHO X
2nd Gen sulfonylureas
Da
her Absorption
 more rapid onset of action
her
ac Inhibitors
 generally preferred
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Oral Hypoglycemic Agents
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ear
 First-Generation
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 Used to stimulate insulin secretion from the pancreas in patients 1. Tolbutamide
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with NIDDM  short half-life
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 Four Pharmacological Classes  safest sulfonylurea for elderly diabetics  rare incidence of
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hypoglycemia
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A. 1. Sulfonylureas
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Gla 2. Metiglinides
2. Chlorpropamide
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Je B. Biguanides
 half-life of 32 hours
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nz C. Alpha-glucosidase inhibitors
 average maintenance dosage- 250 mg daily, given as a single
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Ay D. Thiazolidinediones
dose in the morning
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E. Incretins
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Kat - GLP1 analogue (Exenetide)  contraindicated in patients with hepatic or renal insufficiency
 Prolonged hypoglycemic reactions  in elderly
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- DPP4 inhibitor (Sitagliptin, Vidagliptin, Saxagliptin)
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
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A. 1. Sulfonylureas Second Generation
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na 1. Glyburide
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Gie  **Sulfonylureas stimulate basal and glucose-mediated insulin  very low hypoglycemic activity
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secretion.  usual starting dosage is 2.5 mg/d or less
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Ed  They are “secretagogues.”  few adverse effects
Ed
elle  First class of oral hypoglycemics
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Joc  Drugs include: 2. Glipizide
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be 1. Tolbutamide (Orinase)  shortest half-life (2–4 hours)
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Jo 2. Chlorpropamide (Diabinese)  taken 30 min before breakfast  food delays absorption
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Ivz 3. Glipizide (Miinidiab)  starting dosage is 5 mg/d, up to 15 mg/d given as a single dose
Ivz
rk 4. Glyburide (Euglocon)  contraindicated in hepatic or renal impairment pt
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Ma 5. Gliclazide (Diamicron)
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el 6. Glimeperide (Solosa) 3. Glimepiride
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ch  once-daily use as monotherapy or in combination with insulin
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Ra  Increase insulin secretion for the pancreas  long duration of effect with a half-life of 5 hours
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“G”  SE: hypoglycemia, weight gain  allows once-daily dosing, thereby improving compliance
“G”
hn  Available preparation as monotherapy or with combination with
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Jo other antidiabetic drugs, e.g. SU + Metf, SU + TZD
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Ian
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Nin A. 2. Metiglinides
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Page 1 of 5
Repaglinide/Nateglinide - - produces weight loss in obese and non-obese
- Short-acting, non-sulfonylurea secretagogues that are used only pre- - - promotes satiety
prandially - - weight loss is due to loss of fat tissue
1. Repaglinide - - weight reduction can be sustained for 1 year
 very fast onset of action  peak effect within 1 hour and
duration is 5-9 hrs Multiple Mechanisms for Vascular Protection with Metformin
 indicated for use in controlling postprandial glucose excursions
 taken just before each meal in doses of 0.25–4 mg ** Metformin addresses CV risk by a range of direct and indirect mechanisms
 hypoglycemia  if meal is delayed or skipped
IMPROVED REDUCED
2. Nateglinide Insulin Sensitivity Hypertriglycerdemia
 a D-phenylalanine derivative Fibrolysis AGE Formation
 Faster onset, shorter duration Nutritive Capillary Flow Cross Linked Fibrin
 Peak effect < 1hr, Duration < 4hrs Hemorrheology Neovascularization
 Taken just before meals (60-120 mg) Post Ischemic Flow Oxidative Stress
 Amplifies the insulin secretion, but diminished effect in the
presence of normoglycemia  lowest incidence of hypoglycemia
 Safe to use in renal insufficiency

B. Biguanide
Reduced Cardiovascular Risk
 Metformin (Glucophage)
 Decreases glucose synthesis and increases glucose uptake C. Alpha-glucosidase Inhibitors
 Does not stimulate release of insulin
 SE: nausea, vomiting, decreased appetite **Alpha-glucosidase inhibitors delay the digestion of carbohydrates by
reversibly inhibiting pancreatic alpha amylase and intestinal alpha-glucoside
Biguanide (Metformin Glucophage) hydrolase. This slows the rise of blood glucose post-prandially
 Biguanides sensitize the liver to insulin, which decreases hepatic - Drugs include:
glucose output. 1. Acarbose (Precose)
 Metformin (Glucophage) will not cause hypoglycemia, and often 2. Miglitol (Glyset)
leads to mild weight loss. 3. Voglibose (Basen)
 Metformin is used for DM2  Delay carbohydrate metabolism
 Toxicities: lactic acidosis, so Metformin is CI for renal  SE: flatulence, cramps, diarrhea, abdominal distention
insufficiency, post-surgery, binge drinking, and CHF. Some
people also experience GI symptoms Alpha-glucosidase Inhibitors (Acarbose, Miglatol)

 Action  Toxicities: severe flatulence, often bad enough that patients will
not use alpha-glucosidase inhibitors
 Reduces insulin resistance without increasing insulin secretion
 Decreases hyperglycemia in type 2 DM patient D. Thiazolidinediones (Rosiglitazone, Pioglitazone)
 Hypoglycemia very rare
 Needs endogenous insulin ** Thiazolidinediones are potent peripheral insulin sensitizers. They do not
 No weight gain cause hypoglycemia.
 Improvement in lipid profile
 Improves vascular risk factors (increases fibrinolysis)  Thiazolidinediones are used to treat DM2, and act via the PPARγ
nuclear receptos
 Mechanisms  decrease insulin resistance
 Suppresses hepatic glucose production  ligands of peroxisome proliferator-activated receptor-gamma
- - decreases HLP  inhibition of gluconeogenesis and glycogenolysis (PPAR-gamma):
o receptors found in muscle, fat, and liver
 Increases insulin-mediated muscle glucose uptake o mediate differentiation of adipocytes
- - translocation of Glut4 and glycogen synthesis o ↑ lipogenesis, enhance uptake of glucose
and FFA
 Decreases fatty acid oxidation
- - inhibits hepatic and adipose tissue lipolysis  Toxicities: fluid retention, weight gain; earlier thiazolidinediones
caused fulminate liver failure
 Decreases intestinal glucose absorption  Troglitazone, Rosiglitazone was also banned because of
increased risk of CV events and fracture.
Other Effects of Metformin
 Effects on weight:

Page 2 of 5
Drugs Affecting the Pancreas Suspension
(NPH)
Insulin Preparations
Insulin Zinc
Suspension 1-3 hrs 4-8 hrs 13-20 hrs
 Three Sources
(Lente)
1. Beef
2. Pork Long Acting Extended Zinc 2-4 hrs 8-14 18-36 hrs
3. Human Suspension hrs
4. Insulin analogue (Ultralente)
 Differ primarily in their onset and duration of action and incidence of
allergic reaction. Insulin Glargine 2-4 hrs Up to 25 hrs
 Preparations may be short-acting, intermediate-acting, or long-acting None

Insulin Types and Actions

 Short-acting Insulin
 Generic name:
Regular insulin is used to cover meals.
Insulin
 - - Lispro insulin reduces hexamers and promotes insulin
 Brand names:
monomers so it is very fast-acting.
Regular Insulin, Humulin 70/30, Humulin R, Apidra, Humalog
 - - Aspart insulin reduces hexamers and promotes insulin
 Classification: monomers so it is very fast-acting.
Anti-diabetic  Intermediate-acting Insulin (modifications of the solution, not of
insulin itself)
 Endogenous insulin is anabolic in that it promotes uptake of  - - Neutral Protamine Hagedorn (NPH) insulin uses protamine to
glucose, glycolysis, glycogenesis, protein synthesis, and fat form a less soluble suspension of insulin.
storage.  - - Lente insulin has relatively large insulin crystals and high zinc
 Low insulin causes hyperglycemia, and no insulin at all causes concentration in solution.
ketoacidosis.
 Exogenous insulin reduces hepatic glucose output during fasting,  Long-acting Insulins
which helps relieve hyperglycemic overstimulation of the
 Glargine insulin is an insulin analog with acid pK, which allows the
pancreas. It is measured in units, and all U.S. insulin comes as
insulin to remain soluble in acid solution but precipitate in the
“U-100.”
subcutaneous space, prolonging absorption. This delivers a basal
 Exogenous insulin is not very physiologic because it is given in an
insulin dose over 24 hours.
“open loop” fashion (controlled by the patient, not by glucose
 Glargine insulin cannot be mixed with other insulins because of its
levels), and because it is delivered subcutaneously.
acid pK
 Exogenous insulin is often combined with sulfonylureas,
 Detemir insulin is an insulin analog that bind free fatty acids and
Metformin, and thiazolidinediones.
albumin to slow absorption
 Insulin is given to all patients with DM1, some patients with DM2 if
 UltraLente insulin has very large insulin crystals and high zinc
required, and to pregnant diabetic women (Gest Diabetes)
concentration
 Insulin is administered subcutaneously (SC) because in the blood
it has a half-life of minutes
INSULIN
 The main determinant of its absorption is the extent of its dimer
 Protein secreted by beta cells of islets of langerhans
and hexamer formation.
 Responsible for promoting the uptake of glucose by the cells
 Toxicities: hypoglycemia, weight gain due to insulin’s lipogenic
(muscle, cardiac, CNS and all other tissue)
effects, insulin allergy (IgE-mediated), lipoatrophy at the injection
 Necessary for carbohydrate, fat, and protein metabolism
site
 Converts glycogen to fat
Type Preparation Onset Peak Duration
ACTIONS
Rapid Acting Insulin Lispro 5-15 1-2 hrs 2-4 hrs
min  Allows glucose storage in the liver
 Promotes fat and protein synthesis while antagonizing fat
10-20 breakdown
Insulin Aspart min 1 hr 3-5 hrs  Produces intracellular shift of potassium and magnesium to
reduce elevated serum levels of those electrolytes
Short Acting Regular 30-60 2-3 hrs 5-7 hrs
min INDICATIONS
Prompt Insulin  Rarely used in the field – blood glucose levels are necessary
Zinc
before administering in an emergency situation
(Semilente)
 In hospital use: diabetic ketoacidosis or other hyperglycemic state
Intermediate Isophane 1-2 hrs 5-7 hrs 13-18 hrs  Hyperkalemia
Insulin

Page 3 of 5
CONTRAINDICATIONS  Inhibits insulin release
 Hypoglycemia  Typically used for patient with hyperinsulin reaction in pancreatic
 Hypokalemia tumors
 Not indicated for treating diabetes-induced hypoglycemia
INCOMPATIBLE/REACTIONS
 Incompatible in solution with all other drugs D50
 Antagonized actions of epinephrine, steroids, estrogens, thyroid  Sugar solution given IV for acute hypoglycemia
hormones, diazoxide, dilantin  Side effect: local tissue necrosis if infiltration occurs

Insulin notes
 Usually refrigerated Dextrose 50%
 Oral hypoglycemic, such as Glibenclamide, Gliclazide, Glipizide,  Rapidly increases serum glucose levels
are not substitutes for insulin, they stimulate the release of insulin  Provide short-term osmotic dieresis
from a “sluggish” pancreas  Indications:
o Coma of unknown origin
Insulin preparations o Hypoglycemia
 Modified insulin preparations include: o Status epilepticus
o Neutral protamine hagedorn (regular insulin attached  Adverse reactions:
to a protein to delay absorption) o Extravasation leads to tissue necrosis
o Lente (attached to zinc)  Dose:
 Derived from beef or pork, lentes, may lead to allergic reactions. o Adult: 25-50g IV bolus
 Natural human insulin preparations do not have allergic reactions o Pediatric: 25%, 2-4ml/kg IV bolus
 Incompatible reactions
Today’s Smart Pumps o Sodium bicarbonate
 Carb boluses o Coumadin
o Personalized carb factors for different day
 Onset: immediate
o Easy carb bolus calculations  Peak: variable
o Personalized carb database  Duration: variable
 Correction boluses
o Personalized collection factors for different times Glucose
o Easier and safer correction of high BGs  quickly absorb form of glucose to increase blood glucose levels
o Reveal when correction bolus is high, ie >8% of TDD  indication
 Combined carb/correction boluses o hypoglycemia
 Automatic bolus reduction for bolus on board (BOB) o conscious patients
 precaution:
Bolus Concepts o assure that the airway is patent
 Basal insulin
o 50% of daily insulin need Glucagon
o Limits hyperglycemia after meals  protein secreted by the alpha cells of the pancreas
o Suppresses glucose production between meals and  causes a breakdown of stored glycogen to glucose
night (glycogenesis); increases circulating blood glucose
 Bolus insulin  unknown mechanism of stabilizing cardiac rhythm in beta-blocker
o Limits hyperglycemia after meals overdose
o Immediate rise and sharp peak at 1 hour  contraindication:
o 10% to 20% of total daily insulin requirement for each o hyperglycemia
meal o known hypersensitivity
 precautions:
Hyperglycemic Agents o caution with administration to patiens with a history of
 Glucagon cardiovascular or renal disease
 Diazoxide (proglycem)  dose:
o Increase blood glucose levels o adult: 0.5-1mg IV; repeat 1-2 times if no response
 IV glucose within 20 minutes
o pediatric: not used
Glucose  incompatible/ reactions:
 Given IM if IV live is unobtainable o incompatible with solution with most other substances
 Converts glycogen stores to glucose  onset: 1 minute
 Side effects: N/V, allergic reactions (rare)  peak: 30 minutes
 duration : variable
Diazoxide  should always be used in conjuction with D5W

Page 4 of 5
  must be reconstituted before administration. Must be used or
refrigerated after reconstitution  Dose:
o Adult: 100 mg
Thiamine (Vitamin B1) o Pediatric: rarely used
 Brand name: Betalin  Incompatible/reactions:
 Required for carbohydrate metabolism o Alkaline solutions
 Deficiency leads to anemia, polyneuritis, Wernicke’s o Barbiturates
encephalopathy, cardiomyopathy o Bicarbonates
 Administration may reduce symptoms of deficiency, but effects o Cephalosporin
are dependent upon duration of illness and severity of disease
o Other antibiotic
 Onset: hours
 Contraindication:
 Peak: 3-5 days
o Known hypersensitivity
 Duration: variable
 Indications:
 Any comatose patient, especially those who are suspected to be
o Coma of unknown origin, especially if alcohol is
alcoholic, should receive IV thiamine prior to the administration of
involved D50 or Narcan
o Delirium tremens
o Other thiamine deficiency syndromes

Oral Monotherapies
SUs Meglinitides TZDs Metformin α-glucosidase DPP-4 inhibitors
inhibitors
Improves insulin + + +
secretion
Improves insulin + +
resistance
Lowers hepatic + + +
glucose production

Page 5 of 5