Chapter 42 Insulin and oral hypoglycemic drugs Different forms of diabetes mellitus Complications of diabetes mellitus Acute complications Diabetic ketoacidosis Hyperosmotic nonketotic coma Chronic complications Cardiovascular diseases Renal damage Retinal damage Nerve degeneration Infection Myopathy etc. A. Insulin and its enhancers Structure of insulin A. Insulin and its enhancers Insulin 1. Pharmacological effects (1) Carbohydrate metabolism: reducing blood glucose levels by gycogenolysis , glycogen synthesis , gluconeogenesis (ketone badies ) (2) lipid metabolism: fat synthesis , lipolysis , plasma free fatty acids (3) Protein metabolism: active transport of amino acids , incorporation of amino acids into protein , protein catabolism (4) Mechanism of insulin actions Interacting with insulin receptor Interacting with insulin receptor Structure of insulin 2. Clinical uses (1) Insulin-dependent patients with diabetes mellitus (type 1 diabetes mellitus) (2) Insulin-independent patients: failure to other drugs (3) Diabetic complications: diabetic ketoacidosis ( ), hyperosmotic nonketotic coma (4) Critical situations of diabetic patients: fever, severe infection, pregnancy, trauma, operation (5) Others: promotion of K + uptake into the cells, pshychiatric disorders A. Insulin and its enhancers 3. Preparations Properties Properties Preparations PreparationsOnsetPaekDuration Fast-acting Regular insulin h 2-3h 6-8 h Intermmediate- acting Neutral protamine hagedorn 2-4h6-10h h Long-acting Protamine zinc insulin suspension 3-6h6-10h h A. Insulin and its enhancers 4. Adverse effects (1) Hypersensitivity: treated with H 1 receptor antagonist, glucocorticoids (2) Hypoglycemia: adrenaline secretion (sweeting, hunger, weakenss, tachycardia, blurred vision, headache, etc.), treated with 50% glucose (3) Insulin resistance: acute, chronic (4) Lipoatrophy and lipohypertrophy A. Insulin and its enhancers Insulin action enhancers Thiazolidinediones (TDs) Rosiglitazone Rosiglitazone Pioglitazone Pioglitazone Troglitazone Troglitazone A. Insulin and its enhancers Rosiglitazone Pioglitazone Pioglitazone Insulin action enhancers 1. Pharmacological effects Selective agonists for nuclear peroxisome proliferator-activated receptor- (PPAR , ), increasing glucose transport into muscle and adipose tissue. Selective agonists for nuclear peroxisome proliferator-activated receptor- (PPAR , ), increasing glucose transport into muscle and adipose tissue. (1) Lowering insulin resistance (2) Lipid metabolism regulation: TG, free fatty acid (3) Antihypertensive effects A. Insulin and its enhancers 2. Clinical uses used for treatment of insulin-resistant diabetic patients or type 2 patients used for treatment of insulin-resistant diabetic patients or type 2 patients 3. Adverse effects Edema, headache, myalgia, GI reactions, hepatic damage (troglitazone) A. Insulin and its enhancers B. Oral hypoglycemic drugs SulfonylureasBiguanides -Glucosidase inhibitors Others B. Oral hypoglycemic drugs Sulfonylureas Tolbutamide (D860) Chlorpropamide Glibenclamide ( ) Glipizide Gliclazide ( ) B. Oral hypoglycemic drugs 1. Pharmacological effects Blocking K + channel: Ca 2+ inflow , insulin release , Stimulating insulin secretion Increasing insulin sensitivity (long-term use) B. Oral hypoglycemic drugs 2. Clinical uses (1) Insulin-indenpedent diabetic patients (type 2): alone or combined with insulin (2) Diabetes insipidus ( ) : Chlorpropamide ( ): antiuretic hormone (ADH) B. Oral hypoglycemic drugs 3. Adverse effects (1) GI reactions (2) CNS reactions (3) Hypoglycemia: especially in elderly, hepatic or renal insufficiencies (4) Others: leukopenia, cholestatic jaundice, hepatic damage B. Oral hypoglycemic drugs 4. Drug interactions (1) Potentiation of hypoglycemic effects replacement in plasma protein binding: salicylic acid, sulfates, indomethacin, penicillin, warfarin, etc. replacement in plasma protein binding: salicylic acid, sulfates, indomethacin, penicillin, warfarin, etc. inhibition of hepatic microsomal enzymes: chloramphenicol, warfaren inhibition of hepatic microsomal enzymes: chloramphenicol, warfaren (2) Attenuation of hypoglycemic effects induction of hepatic microsomal enzymes: phenytoin, phenobarbital, etc. induction of hepatic microsomal enzymes: phenytoin, phenobarbital, etc. interactions in pharmacodynamics: glucagon, thiazides, etc. interactions in pharmacodynamics: glucagon, thiazides, etc. B. Oral hypoglycemic drugs Biguanides Metformin Metformin Phenformin Phenformin B. Oral hypoglycemic drugs 1. Pharmacilogical effects increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles decreasing glucose absorption in gut and glucagon release decreasing glucose absorption in gut and glucagon release 2. Clinical uses 2. Clinical uses mild insulin-independent patients with obesity mild insulin-independent patients with obesity 3. Adverse effects severe lactic acidosis, malabsorption of vitamin B 12 and folic acid severe lactic acidosis, malabsorption of vitamin B 12 and folic acid B. Oral hypoglycemic drugs -Glucosidase inhibitors Acarbose Acarbose Reducing intestinal absorption of starch ( ), dextrin ( ), and disaccharides ( ) by inhibiting the action of intestinal brush border -glucosidase B. Oral hypoglycemic drugs Others Repaglinide Repaglinide Oral insulin secretagogue