1 Dr M Radulovacki Dept of Pharmacology 996 3539 ANTIDIABETIC AGENTS I Insulin Preparations II Oral Hypoglycemic Drugs CLASSIFICATION OF DIABETES 2 IDDM insulin dependent diabetes mellitus NIDDM non insulin dependent diabetes mellitus Type l 10 20 of diabetics Type II 80 90 of diabetics INSULIN DEPENDENT Juvenile onset little or no extractable insulin in pancreas prone to acidosis ketosis insulin receptors usually unimpaired usually undernourished symptoms of polydipsia polyphagia and polyuria INSULIN INDEPENDENT Maturity onset near normal above normal insulin levels not prone to acidosis ketosis insulin receptors often in short supply receptor pathology is common in obese patients who comprise 75 of Type II diabetics usually obese 2 3 STRUCTURE OF HUMAN INSULIN AND PROINSULIN 4 SOME COMMONLY USED INSULIN PREPARATIONS Relative effect on blood glucose hr Type Preparation Onset Peak Duration Fast acting Regular insulin includes r DNA Humulin R 1 1 2 5 7 Insulin zinc prompt 1 1 2 12 16 Isophane NPH includes r DNA human insulin Humulin N 1 2 8 12 20 28 Insulin zinc Lente insulin 1 2 8 12 18 24 Globin zinc insulin 1 2 8 16 20 28 Protamine zinc 3 4 8 12 36 Insulin zinc extended UUUltra lente insulin 3 4 8 12 36 Intermediate acting Long acting 3 4 24 Hour Profile of Plasma Insulin and Glucose in a Normal Weight Subject 5 6 8 Type I Insulin dependent diabetics 1 Prone to ketoacidosis can lower pH of body fluids to 6 8 2 Ketoacidosis can severely decrease insulin binding to receptors Initially affinity for receptors is impaired reversible but prolonged acidosis can reduce the number of receptors Effect of pH on 123I insulin binding to human erythrocytes Binding capacity of insulin receptors near optimal at normal pH 7 4 is sharply reduced by increased acidity lower pH For this reason diabetics with ketoacidosis may not respond well to exogenous insulin until their serum pH is improved 7 8 CHARACTERISTICS OF SULFONYLUREA AGENTS 9 Generic Name Daily Duration Dosage Range of action Trade Name g hr Tolbutamide Orinase 0 5 3 0 Tolazamide Tolinase 0 l 1 0 Acetohexamide Dymeior 0 25 1 5 Chlorpropamide Diabinese 6 12 Dose Day Metabolism 2 3 By liver to inactive product 1 2 By liver to active and inactive products 12 18 1 2 By liver to active metabolites 0 10 0 5 60 1 By liver to less active metabolites and excreted by kidney intact 10 14 Glipizide Glucatrol 5 0 40 mg 12 24 1 2 GlyburideGlybenclamide Diabeta Micronase 2 5 20 12 24 1 2 10 MECHANISM OF HYPOGLYCEMIC ACTION OF SULFONYLUREAS By liver to inert products 1 Sulfonylureas stimulate secretion of patients own insulin but with chronic treatment insulin secretion decreases toward pretreatment levels see A 2 Reduction of Serum glucagon concentration 3 Continued effectiveness with chronic administration suggests sulfonylureas exert extrapancreatic effects Evidence has been obtained that sulfonylureas increase the number of insulin receptors requires presence of insulin see B and C 4 During treatment for 1 year the insulin binding to monocytes was found to be higher in patients treated with a sulfonylurea diet compared to patients treated with diet alone mainly due to an increase in the number of binding sites 9 C 10 11 SIDE EFFECTS OF SULFONYLUREAS 1 Hypoglycemia all agents but especially chlorpropamide a more likely in hepatic or renal insufficiency b drug interactions with bishydroyxycoumarin phenylbutazone sulfonamides alcohol salicylates 2 Sulfonylurea induced hypothyroidism 3 15 of patients with chronic usage 3 Antidiuretic action of chlorpropamide has caused water intoxication of dilutional hyponatremia 4 Accelerated cardiovascular disease
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