Medical Pharmacology Chapter 29:  Diabetes

• Oral hypoglycemics: Categories

  1. Sulfonylureas, e.g. glipizide (Glucotrol)

  2. Biguanides, e.g. metformin (Glucophage)

  3. Competitive inhibitors of intestinal brush-border alpha-glucosidases, e.g. acarbose (Precose)

  4. Thiazolidinediones

     1. Troglitazone (Rezulin)--REMOVED FROM U.S. MARKET

     2. Rosiglitazone (Avandia)--Concern about this agent responsible for excessive number of heart attack and congestive heart failure (2/2010).

        1. Still available in the U.S. with cautious use emphasized.

• Sulfonylureas

  • Mechanism of action A: promotion of insulin release for pancreatic B cells

    1. Sulfonylureas bind to a pancreaticB cell potassium channel receptor

    2. Potassium efflux is inhibited, causing depolarization

    3. Depolarization activates a voltage-gated calcium channel, causing calcium influx

    4. Insulin is released

  • Mechanism of action B: Serum glucagon concentration reduction

    1. Sulfonylureas reduce serum glucagon levels -- a possible contributor to hypoglycemic effects

    2. Unknown mechanism; probably indirect (secondary) inhibition due to enhanced release of both somatostatin and insulin

  • Mechanism of action C: Possible potentiation of insulin action at target tissues:

• Tolbutamide (Orinase)

  • Well absorbed; shorter duration of action

  • Safest sulfonylurea for use in the elderly

  • Rare acute toxic reactions but adverse effects occur more often than with newer agents such as glyburide.

  • Some drug drug interactions (dicumarol, phenylbutazone, or some sulfonamides)

• Chlorpropamide (Diabinese)

  • More side effects than other sulfonylureas and generally not recommended.  Hypoglycemic risk results in this drug typically being an unacceptable choice for elderly patients and those with mile to moderate hepatic and renal dysfunction.

  • Slowly metabolized; active metabolites

  • Some drug drug interactions (dicumarol, phenylbutazone, or some sulfonamides)

  • Chloropropamide may induce prolonged hypoglycemia in elderly patients dilutional hyponatremia -- results from enhanced vasopressin secretion and potentiation of its effect at the renal tubule by chlorpropamide (Diabinese).

  • Rare hematologic toxicity

• Tolazamide (Tolinase)

  • Comparable to chlorpropamide in potency; shorter duration of action

  • Slow absorption; delayed effect on blood glucose

  • Metabolized to biologically active compounds

• Acetohexamide

  • Discontinued in the U.S.

  • Intermediate duration of action (between Tolbutamide (Orinase) and chlorpropamide (Diabinese)-- 10-16 hours

  • Hepatically metabolized to inactive metabolite

•  Second Generation sulfonylureas: glyburide (Micronase, DiaBeta), glipizide (Glucotrol), glimepiride (Amaryl)-- fewer adverse effects

  • Glyburide (Micronase, DiaBeta)

    • Metabolized in the liver; short plasma half-life but prolonged biological effect

    • Few adverse effects (not counting hypoglycemia)

    • Does not cause water retention (as does chlorpropamide (Diabinese))

    • Contraindicated:

      1. Hepatic impairment

      2. Renal insufficiency

  • Glipizide (Glucotrol)

    • Shortest half-life (2-4 hours); extended released formulation available -- 24-hour action

    • Less likely than glyburide (Micronase, DiaBeta) to produce serious hypoglycemia {due to shorter half-life}

    • Extensively metabolized by the liver (90%); 10% excreted unchanged by the kidney

    • contraindicated:

      1. Hepatic dysfunction

      2. Renal insufficiency

  • Glimepiride (Amaryl)

    • Monotherapy -- once a day administration or in combination with insulin

    • Most potent -- lowest dose of the sulfonylureas

    • Long duration of action: half-life = 5 hours

    • Hepatic metabolism: complete to inactive products

• Secondary Failure and Tachyphylaxis to Sulfonylureas

  • Treatment failures occur

  • Possibly due to pancreatic B cell refractoriness or to loss of dietary compliance

• Combination of sulfonylureas and insulin would appear justified only in the presence of severe insulin resistance

• Metformin (Glucophage)

  • Proposed Mechanism of Action:

    1. glycolysis stimulation-- increased glucose removal from blood

    2. Decreased hepatic gluconeogenesis

    3. Decreased glucose absorption rate from the GI tract

    4. Reduced plasma glucagon

  • Clinical Use:

    • In patients with refractory obesity and insulin resistance

      • Advantages:

        • Does not cause hypoglycemia

        • Does not increased weight

    • May be used in combination with sulfonylureas when sulfonylurea monotherapy is not effective

  •   Toxic/adverse effects:

    • Most common -- gastrointestinal (20% frequency)

      • Anorexia, nausea, vomiting, diarrhea

      • Dose-related

      • Usually occurs upon initiation of therapy -- often transient in effect

  •  Decreased vitamin B₁₂ absorption; may require vitamin B₁₂ supplementation

  •   Contraindicated in:

    • Renal disease

    • Alcoholism

    • Hepatic disease

    • Chronic cardiopulmonary disease (its associated with tissue hypoxia --biguanides may increase the risk of lactic acidosis)

• Acarbose (Precose)

  • Oligosaccharide analog -- strongly binds to intestinal disaccharidases (e.g. alpha-glucosidase)

    • Competitive in addition of alpha-glucosidase reduces postprandial glucose rise (reduction: 30-50%)

  • Results in delayed carbohydrate absorption:

    • Starches, dextrins, maltose, sucrose (not lactose)

  •  Adverse Effects:

    • Most common: flatulence

    • Hypoglycemia may occur or give used in combination with insulin or sulfonylureas

  •  Drug-drug interaction: acarbose interferes with metformin absorption

• Miglitol (Glyset)

  • Similar to acarbose (Precose) but possibly with less hepatotoxicity

  • Acarbose (Precose) and miglitol (Glyset) have similar similar gastrointestinal effects

• Troglitazone (Rezulin)

  •   REMOVED FROM U.S. MARKET--MARCH 2000--Cardiovascular morbidity and mortality.

•  Rosiglitazone* (Avandia) is FDA approved for management of Type II diabetes (Concern about this agent responsible for excessive number of heart attack and congestive heart failure (2/2010))

  • Approval as monotherapy or in combination with metformin (Glucophage)

    • might be used with insulin or a sulfonylurea

    • Apparently as effective does troglitazone (Rezulin) in controlling blood glucose without liver toxicity

    • Long-term safety/benefits of rosiglitazone (Avandia) in patients with Type II diabetes: yet to be determined.

  • Pharmacokinetics:

    • Well absorbed following oral administration (half-life: 3-4 hours)

    •  Hepatic metabolism

  •  Adverse Effects:

    • Absence of liver failure; no drug-related jaundice!

    • No ALT (alanine aminotransferase) abnormalities reported in clinical trials

    • Fluid retention-- similar to that seen with troglitazone (Rezulin)

    • Increases in LDL & HDL cholesterol-- about 15%

  • Precautions:

    • Thiozolidinediones may cause hepatotoxicity--Package insert recommends:

      • ALT determination prior to treatment and every two months for one-year, then periodically

      • ALT levels > 2.5 times above upper normal limit: do not start treatment

      • After treatment initiation, ALT levels > 3 times above normal: stop treatment

• Pioglitazone (Actos)

  • Overview

    • Pioglitazone (Actos): thiozolidinedione, reduce insulin resistance

  • Clinical use:

    • May be used as monotherapy

    • May be used in combination with a sulfonylurea,metformin (Glucophage), or insulin

  •  Adverse Effects:

    • Moderate weight gain

    • edema, mild anemia

    • No reports of hepatic toxicity (Liver function monitoring every two months -- recommended)

  • Conclusion: pioglitazone (Actos) similar to rosiglitazone (Avandia) effectiveness; long-term safety unknown

• Overview

  • Glucagon, a peptide, produced by A cells of the pancreatic islets of Langerhans

  • Glucagon is arrived from a large precursor peptide (one intermediate: glicentin, 69-amino acid peptide)

  • Rapidly inactivated in plasma (degraded also at hepatic, renal, and tissue receptor sites)

• Enteroglucagons

  • Glicentin immunoreactivity: cells of the small intestine, pancreatic A cells, pancreatic effluent-- glucagon-like peptides

• Glucagon: Pharmacological activity

  • Metabolic:

    1. glucagon interacts with specific, hepatic receptors

    2. G protein activation, increase in adenylyl cyclase activity, increases cAMP production

    3. Increased catabolism of stored glycogen, increased gluconeogenesis, increased ketogenesis

  • Pharmacological consequences:

    • Increased blood glucose, decreased hepatic glycogen

    • Insulin released from normal pancreatic B cells

    • Catecholamines from pheochromocytoma

    • Calcitonin from medullary carcinoma

  • Cardiovascular Effects:

    • Positive inotropic action (increased myocardial contractility)

    • Positive chronotropic (increased heart rate)

    • These effects mediated by cAMP

  • Smooth Muscle Effects:

    • In large doses,  intestinal smooth muscle relaxation

• Clinical Use:

  • Management of Severe Hypoglycemic States

    • Emergency treatment in insulin-dependent unconscious patients in which intravenous glucose cannot be administered (a conscious patient would be treated by drinking orange juice or other high sugar content foods)

    • Glucagon is available for parenteral use.

  • Endocrine Diagnoses/Analysis:

    • Evaluation of pancreatic B cell secretory insulin reserve

    • Provocative hormonal discharge from suspected:

      • Insulinoma

      • Pheochromocytoma

      • Ihyroid medullary carcinoma

  • β-blocker Overdosage: (useful for enhancing myocardial performance independent of the β-receptor)

  • Diagnostic Radiology: glucagon-induced intestinal relaxation assists in radiological assessment of the bowel.

•   Adverse Effects

  • Transient nausea/vomiting -- generally mild

Karam, J. H., Pancreatic Hormones and Antidiabetic Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 684-703

Foster, D. W., Diabetes Mellitus, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2060-2080