INSULIN & ANTI DIABETIC DRUGS

1. INSULIN & ANTI DIABETIC DRUGS Dept. of Pharmacology CIPS

2. Diabetes mellitus • Type I – (IDDM ,10% of cases) • “Childhood” diabetes • Loss of pancreatic β cells • Decreased insulin • Develops suddenly, usually before age 15. • Caused by inadequate production of insulin because T cell-mediated autoimmune response destroys beta cells. • Controlled by insulin injections. • Type II (NIDDM, 90% of cases) • “Adult” diabetes • Defective signal reception in insulin pathway • Decreased insulin • Usually occurs after age 40 and in obese individuals, but genetics, aging, and peripheral insulin resistance also.

3. Insulin levels are normal or elevated but there is either a decrease in number of insulin receptors or the cells cannot take it up. • Controlled by dietary changes and regular exercise. • Both cause hyperglycemia, glycosuria, lipid breakdown because tissues are deficient in glucose, ketone bodies • Complications: • Acute: Diabetic ketoacidosis (DKA), Nonketotichyperosmolar coma • Chronic: • Microvascular disease: impotence & poor wound healing • Atherosclerosis : Strokes, coronary heart disease • Renal failure, retinal damage, nerve damage • Infective disease: Tuberculosis

4. AA mobilization PLASMA AA LIPOLYSIS PLASMA FFA KETOSIS ACIDOSIS INSULIN DEFICIENCY – DIABETES MELLITUS GLUCOSE UPTAKE HYPERGLYCEMIA GLYCOSURIA DEHYDRATION, Glucose

5. Insulin secretion: • Insulin secretion is regulated by glucose levels, certain amino acids, hormones and autonomic mediators. • Secretion is most commonly elicited by elevated glucose levels; • increased glucose levels in β-cells results in increased ATP levels, this results in a block of K+ channels causing membrane depolarization which opens Ca2+ channels. • The influx of Ca2+ results in a pulsatile secretion of insulin; continued Ca2+ influx results in activation of transcription factors for insulin. • Oral glucose elicits more insulin secretion than IV glucose; oral administration elicits gut hormones which augment the insulin response. • Insulin is normally catabolized by insulinase produced by the kidney.

6. INSULIN: • Insulin is a peptide hormone synthesized as a precursor (pro-insulin) which undergoes proteolytic cleavage to form a dipeptide; the cleaved polypeptide remnant is termed protein C. • Both are secreted from the β-cell, normal individuals secrete both insulin and (but much less) pro-insulin. • Type 2s are found to secrete high levels of pro-insulin (pro-insulin is inactive) measuring the level of C-protein is a more accurate estimation of normal insulin secretion in type 2s. • Human insulin consists of 51 AA in two chains connected by 2 disulfide bridges (a single gene product cleaved into 2 chains during post-translational modification). • T1/2 ~5-10 minutes, degraded by glutathione-insulin transhydrogenase (insulinase) which cleaves the disulfide links. • Bovine insulin differs by 3 AAs, pork insulin differs by 1 AA. • Insulin is stored in a complex with Zn2+ ions.

7. Insulin Degradation: • Hydrolysis of the disulfide linkage between A&B chains. • 60% liver, 40% kidney(endogenous insulin) • 60% kidney,40% liver (exogenous insulin) • Half-Life 5-7min (endogenous insulin) Delayed-release form( injected one) • Category B ( not teratogenic) • Usual places for injection: upper arm, front& side parts of the thighs& the abdomen. • Not to inject in the same place ( rotate) • Should be stored in refrigerator& warm up to room temp before use. • Must be used within 30 days. Mechanism of action : • Insulin binds to insulin receptors on the plasma membrane and activates tyrosine kinase – primarily in adipose tissue, liver and skeletal muscle. • The Nerves, RBC’s, Kidney, and Lens of the eye do not require insulin for glucose transport.

8. FAT LIPOLYSIS PROTEIN AMINO ACID UPTAKE (PROTEIN SYTHESIS) POTASSIUM K+ UPTAKE INTO CELLS PHYSIOLOGICAL & PHARMACOLOGICAL ACTIONSOF INSULIN CARBOHYDRATES GLUCOSE UPTAKE GLYCOGEN SYNTHESIS (STORAGE) GLUCONEOGENEIS(LIVER) GLYCOLYSIS (MUSCLE) CONVERSION OF CARBOHYDRATE TO FAT (LIPOGENESIS)

9. Liver : • Insulin increase the storage of glucose as glycogen in the liver. • It inhibits gluconeogenesis – thus significantly ↓ glucose output by the liver. • It decrease the protein catabolism. Muscle : • Insulin stimulates the glycogen synthesis and protein synthesis. • It inhibits the protein catabolism. Adipose tissue : • Insulin facilitates the storage of triglyceride by activating plasma lipoprotein lipase and inhibiting intracellular lipolysis.

11. Sources of Insulin : • Beef pancreas / Pork pancreas • Human insulin: recombinant DNA origin Human Insulin : • Do not contain measurable amounts of proinsulin or contaminants. • Diminished antibody • Less allergic reactions • Less lipodystrophy • Preferred in gestational diabetes TYPES OF INSULIN PREPARATIONS • Rapid acting insulin :Lispro, Aspart and Glulisine • Short acting insulin : Regular (crystalline) • Intermediate acting insulin : NPH (isophane) and Lente (insulin zinc) • Long acting insulin : Ultralente,Detimir and Glargine

14. Adverse effects of Insulin : • Severe Hypoglycemia (< 50 mg/dl )– Life threatening • Overdose of insulin • Excessive (unusual) physical exercise • A meal is missed • Lipodystrophy • Others includes • Seizures • Coma • Weight gain • Local or systemic allergic reactions (rare) • Insulin resistance • Hypokalemia

15. Oral Hypoglycemics All taken orally in the form of tablets. Pts with type II diabetes have two physiological defects: • Abnormal insulin secretion • Resistance to insulin action in target tissues associated with decreased number of insulin receptors Oral Anti-Diabetic Agents • Sulfonylureas • Drugs other than Sulfonylurea

16. Sulfonylureas (Oral Hypoglycemic drugs) First generation Second generation Long acting Long acting Short acting Short acting Intermediate acting Acetohexamide Tolazamide Chlorpropamide Tolbutamide Glipizide Glyburide (Glibenclamide) Glimepiride

17. FIRST GENERATION SULPHONYLUREA COMPOUNDS *Good for pts with renal impairment **Pts with renal impairment can expect long t1/2

18. SECOND GENERATION SULPHONYLUREA COMPOUNDS

19. MOA: • 1) Release of insulin from β-cells • 2) Reduction of serum glucagon concentration • 3) Potentiation of insulin action on target tissues • Side effects: • Nausea, vomiting, abdominal pain, diarrhea • Hypoglycaemia • Dilutionalhyponatraemia & water intoxication (Chlorpropamide) • Disulfiram-like reaction with alcohol(Chlorpropamide) • Weight gain • Blood dyscrasias (not common; less than 1% of patients) • - Agranulocytosis, Haemolyticanaemia • - Thrombocytopenia • Cholestatic obstructive jaundice (uncommon) • Dermatitis (Mild) • Muscle weakness, headache, vertigo (not common) • Increased cardio-vascular mortality with longterm use

20. Contraindications: • Type 1 DM ( insulin dependent) • Parenchymal disease of the liver or kidney • Pregnancy, lactation • Major stress • Drugs that augment the hypoglycemic action of sulphonylureas: • Warfarin, Sulfonamides, Salicylates, Phenylbutazone, Propranolol, Alcohol, Chloramphenicol, Fluconazole • Drugs that antagonize the hypoglycemic action of sulphonylureas: • Diuretics (thiazide, furosemide), Diazoxide, Corticosteroids, Oral contraceptives, Phenytoin, Phenobarb., Rifampin, Alcohol ( chronic pts )

21. Drugs other than Sulfonylurea Meglitinides Biguanides α-Glucosidase Inhibitors Thiazolidinediones Repaglinide Nateglinide Metformin Rosiglitazone Pioglitazone Acarbose

22. MEGLITINIDES • e.g. Repaglinide, Nateglinide • MOA: • Bind to the same KATP Channel as do Sulfonylureas, to cause insulin release from β-cells. • Pharmacokinetics: • Taken orally • Rapidly absorbed ( Peak approx. 1hr ) • Metabolized by liver • t½ = 1 hr • Duration of action 4-5 hr • Clinical use: • Approved as monotherapy and in combination with metformin in type 2 diabetes • Taken before each meal, 3 times / day • Does not offer any advantage over sulfonylureas;Advantage: Pts. allergic to sulfur or sulfonylurea • Side effects: • Hypoglycemia, Wt gain ( less than SUs ), Caution in pts with renal & hepatic impairement.

23. BIGUANIDES • e.g. Metformin • MOA: • Increase peripheral glucose utilization • Inhibits gluconeogenesis • Impaired absorption of glucose from the gut • Pharmacokinetics: • Given orally • Not bind to plasma proteins • Not metabolized • Excreted unchanged in urine • t ½ -2 hr • Advantages of Metformin over SUs: • Does not cause hypoglycemia • Does not result in wt gain ( Ideal for obese pts ) • Side effects: • Metallic taste in the mouth, Gastrointestinal (anorexia, nausea, vomiting, diarrhea, abdominal discomfort), Vitamin B 12 deficiency (prolonged use), Lactic acidosis ( rare – 01/ 30,000-exclusive in renal & hepatic failure)

24. Contraindications: • Hepatic impairment • Renal impairment • Alcoholism • Heart failure • Indications: • Obese patients with type II diabetes • Alone or in combination with sulfonylureas • α-GLUCOSIDASE INHIBITORS • e.g. Acarbose • MOA: • Inhibits intestinal alpha-glucosidases and delays carbohydrate absorption, reducing postprandialincrease in blood glucose • Pharmacokinetics: • Given orally • Not absorbed from intestine except small amount • t½ - 3 - 7 hr • Excreted with stool

25. Acarbose Acarbose Acarbose α-GLUCOSIDASE INHIBITORS MOA: Acarbose

26. Side effects: • Flatulence • Loose stool or diarrhea • Abdominal pain • Alone does not cause hypoglycemia • Indications: • Patients with Type 11 inadequately controlled by diet with or without other agents( SU, Metformin) • Can be combined with insulin may be helpful in obese Type 11 patients (similar to metformin) • Thiazolidinedione derivatives • New class of oral antidiabetics • e.g.: Rosiglitazone, Pioglitazone • MOA: • Increase target tissue sensitivity to insulin by: • reducing hepatic glucose output & increase glucose uptake & oxidation in muscles & adipose tissues. • They do not cause hypoglycemia (similar to metformin and acarbose ) .

27. Pharmacokinetics: • 99% absorbed • Metabolized by liver • 99% of drug binds to plasma proteins • Half-life 3 – 4 h • Eliminated via the urine 64% and feces 23% • Adverse effects: • Mild to moderate edema • Wt gain • Headache • Myalgia • Hepatotoxicity • Indications: • Type II diabetes alone or in combination with metformin or sulfonylurea or insulin in patients • resistant to insulin treatment.

28. Glucagon : • Glucagon is a single chain polypeptide containing 29 amino acids, MW 3500. • Beef and pork glucagon are identical to human glucagon. • It is secreted by the α cells of the islets of Langerhans. Regulation of Secretion: • Like insulin, glucagon is also derived by cleavage of a larger peptide prohormone. • Its secretion is regulated by glucose levels, other nutrients, paracrine hormones and nervous system. • Glucose has opposite effects on insulin and glucagon release, i.e high glucose level inhibits glucagon secretion and it is more sensitive to orally administered glucose which evoke insulin release may be inhibiting glucagon secretion • FFA and ketone bodies also inhibit glucagon release. • Amino acids, however, induce both insulin and glucagon secretion.

29. MOA: • Glucagon, through its own receptor and coupling Gs protein activates adenylylcyclase and increases cAMP in liver, fat cells, heart and other tissues. • most ot its actions are mediated through the cyvclic nucleotides. • Glucagon is inactive orally; that released from pancreas is broken down in liver, kidney, plasma and other tissues. • Its t½ is 3-6 min USES: • Hypoglycaemia due to insulin or oral hypoglycaemics; use of glucagon is secondary to that of glucose; It may not work if hepatic glycogen is already depleted: 0.5-1 mg i.v. or i.m. • Cardiogenic shock to stimulate the heart in β-adrenergic blocker treated patients. • Diagnosis of pheochromocytoma 1 mg i.v. causes release of catecholamines from the tumour and markedly raises BP • Phentolamine should be at hand to counter excessive rise in BP.