Oral Antidiabetic Drugs

1. Oral AntidiabeticDrugs Kaukab Azim, MBBS, PhD

3. Pharmacology of Sulfonylureas Mechanisms of action • Increased pancreatic response to glucose (the main mechanism) by: Binding to a specific receptor associated with a ATP-sensitive K+ channel in beta cell membranes (the channel is normally blocked by glucose-induced increase in ATP)  Blockade of K+ efflux (depolarization)  Opening of voltage-gated Ca++ channels  Stimulating the beta islet cells of pancreas to produce insulin Release of insulin by exocytosis (Insulin synthesis is not affected) • Reduction of plasma glucagon levels after chronic treatment (mechanism is unclear but could be related to the enhanced release of both insulin and somatostatin, which inhibit A cell secretion.)

4. Pharmacology of Sulfonylureas Pharmacological effects • Hypoglycemic effect (only if insulin is available) • Stimulation of somatostatin release from pancreatic D cells. • The hypoglycemic effect of sulfonylureasdecreases over time (secondary failure).

5. Pharmacokinetics of Sulfonylureas The major differences between various sulfonylureas reside in their pharmacokinetic profiles

6. Adverse Effects of Sulfonylureas (overall incidence of adverse effects ~ 4%) Metabolic effects • Hypoglycemic reactions (up to 20%)(more likely with compounds having longer half-lives) Allergic skin reactions • Itching (3%), skin rashes (1%), urticaria (1%). Other effects • Disulfiram-like reaction in patients ingesting alcohol (10-15%) (chlorpropamide) • Dilutionalhyponatremia (1-5%), SIADH-syndrome of inapropiate secretion of anti-diuretic hormone (with symptoms of water intoxication) (mainly with chlorpropamide)

7. Drug Interactions with Sulphonylureas

8. Contraindications and Precautions of Sulfonylureas • Type I diabetes (as sole therapy) • Pregnancy (risk of hypoglycemia in the newborn). • Severe liver or kidney disease. • Sulfa drug hypersensitivity.

9. Therapeutic Uses of Sulfonylureas THERAPEUTIC USES of SULFONYLUREAS • Treatment of diabetes mellitus • Sulfonylureas are used to control hyperglycemia in type II diabetic patients who cannot achieve appropriate control with changes in diet alone. • Treatment of diabetes insipidus • Chlorpropamidecan reduce or eliminate the need for vasopressin in some patients with central diabetes insipidus when partial ADH secretion is present.

10. Therapeutic Uses of Sulfonylureas • Treatment of diabetes mellitus • Sulfonylureas are used to control hyperglycemia in type II diabetic patients who cannot achieve appropriate control with changes in diet alone. • Treatment of diabetes insipidus • Chlorpropamide can reduce or eliminate the need for vasopressin in some patients with central diabetes insipidus when partial ADH secretion is present.

11. Pharmacology of Meglitinides and congeners Drugs • Repaglinideand nateglinide are the drugs on the market. Mechanism of action • Stimulation of insulin release by closing ATP-dependent K+channels in pancreatic beta cells (the mechanism is very close to that of sulfonylureas) Pharmacokinetics • Repaglinidehas a fast onset (less than 30 minutes) and a short duration of action (about 4 hours). Repaglinideis > 95% metabolized by the liver

12. Pharmacology of Meglitinides and congeners Adverse effects • Hypoglycemic reaction (up to 15%) • Upper respiratory tract infections (10%) Contraindications and precautions • Type I diabetes (as sole therapy) • Severe hepatic disease. • Pregnancy (risk of hypoglycemia in the newborn). Therapeutic uses • To control hyperglycemia in type II diabetic patients who cannot achieve appropriate control with changes in diet alone. (unlike sulfonylureas they have a rapid onset and a short duration of action so that they are given with meals to enhance postprandial glucose utilization)

13. Pharmacology of Biguanides Drugs • Metformin is the only drug on the market in USA. Mechanism of action • It is still uncertain. Proposed mechanisms include: • Inhibition of hepatic gluconeogenesis (likely the main mechanism) • Direct stimulation of glucose uptake and utilization (glycolysis) in peripheral tissues. • Reduction of plasma glucagon levels. Pharmacological effects • Biguanidesare antihyperglycemic, not hypoglycemic. They do not cause hypoglycemia, even in large doses, but they prevent postprandial hyperglycemia.

14. Pharmacology of Biguanides Pharmacokinetics • Oral bioavailability: . 60% • All the drug is excreted unchanged in the urine • Half-life: . 6 hours Adverse effects • Anorexia, nausea and vomiting, metallic taste, abdominal discomfort, diarrhea (up to 20%) • Lactic acidosis (rare but fatal in 50% of cases) (by inhibiting gluconeogenesis the drug impairs the hepatic uptake of lactic acid) • Vit B12 deficiency

15. Pharmacology of Biguanides Contraindications and cautions • Type I diabetes • All conditions that predispose to acidosis (alcoholism, hepatic diseases, hypoxemia, chronichypoxiclungdiseases, lowcaloriediet, myocardial infarction, septicemia, dehydration, major surgery, therapy with ACE inhibitors, etc.) • Renal impairment (kidney function must be controlledsince the drug is excreted unchanged in the urine). • Therapeuticuses • In type II diabetes (alone or in combination with sulfonylureas when diabetes does not respond to diet or sulfonylurea therapy alone).

16. Pharmacology of Thiazolidinediones Drugs • Pioglitazone and rosiglitazone are the drugs on the market. Mechanism of action • These drugs are ‘insulin sensitizers’. • They bind to a nuclear receptor (peroxisome proliferator activated receptor, PPAR), located mainly in adipose tissue, skeletal muscle and liver, which regulates the transcription of several insulin responsive genes. • The overall effect is an enhancement of tissue sensitivity to insulin (that is a reduction in insulin resistance). Therefore the • need of exogenous insulin is reduced. • Diminishing insulin resistance by increasing glucose uptake and metabolism in muscle and adipose tissues

17. Pharmacology of Thiazolidinediones Pharmacological effects Reduction of hyperglycemia, hyperinsulinemia and hypertriglyceridemia that are characteristic of insulin-resistant states. The drugs are antihyperglycemic, not hypoglycemic. They do not cause hypoglycemia when given alone, but can prevent postprandial hyperglycemia. • Clinical effect is not observed for 6 to 12 weeks • Adverse effects • Diarrhea (13%) • Upper respiratory tract infections (10%) • Anemia (7%),

18. Pharmacology of Thiazolidinediones Contraindications and cautions • Type I diabetes • Severe heart failure (because of drug-induced edema) • Liver disease (the first drug of this class, troglitazone, was withdrawn from the marked because of serious liver toxicity) Therapeutic uses • In combination with insulin, biguanides or sulfonylureas, in type II diabetes which exhibits insulin resistance.

19. Pharmacology of Alpha-Glucosidase Inhibitors Drugs • Miglitoland acarbose are the compounds on the market. Mechanism of action • The drugs are competitive inhibitors of the intestinal brush border enzyme alpha-glucosidase involved in the breakdown of starches into simple sugars. • Absorption of monosaccharides from duodenum and upper jejunum is reduced.

20. Pharmacology of Alpha-Glucosidase Inhibitors Pharmacological effects • Postprandial glucose levels is reduced both in normal and diabetic subjects, so creating an insulin sparing effect. • The efficacy of the drugs is small. • Hypoglycemia does not occur even in overdosage. Pharmacokinetics • Oralbioavailability: acarbose2%; miglitol >90% • Elimination: miglitol > 90% by the kidney Adverse effects • Flatulence (up to 40%) due to the appearance of undigested carbohydrates in the colon where they ferment, so releasing gas. • Diarrhea (up to 20%), abdominal pain (7%).

21. Pharmacology of Alpha-Glucosidase Inhibitors Contraindications and cautions • Inflammatoryboweldisease • Gastrointestinal conditions worsened by gas or distension • Renal disease Therapeuticuses • Type II diabetes as monotherapy or in combination with sulfonylureas or insulin. • As monotherapy in elderly patients or in patients with predominantly postprandialhyperglycemia. • Note: if hypoglycemia occurs when administered with insulin or sulfonylureas, oral administration of sugars other than glucose is ineffective.

22. Pharmacology of Glucagon Chemistry • A single chain polypeptide of 29 amino acids. Mechanism of action • Most glucagon effects result from activation of specific receptors which leads to an increase in adenylyl-cyclase activity and production of cAMP. Metabolic effects • Stimulation of glycogenolysis. • Stimulation of gluconeogenesis. • Inhibition of glycogen synthesis. • Inhibition of glucose oxidation. • These effect are mainly on the liver. Glucagon is the most potent hyperglycemicdrug.

23. Pharmacology of Glucagon Other effects • Inotropic and chronotropic effect on the heart, due to the increase in cAMP. • Profound relaxation of intestinal smooth muscle (mechanism still uncertain). Pharmacokinetics • Rapidly inactivated in liver, kidney and other tissues. Half-life: 3-6 min. Adverse effects • Nausea and vomiting (risk of aspiration in unconscious patients) • Hypotension (after IV administration)

24. Pharmacology of Glucagon Therapeuticuses • For the emergency treatment of severe hypoglycemic reactions (but high doses stimulate insulin release) • For reversing the cardiac effect of an overdose of beta-blocking agents