1Dr. M. Radulovacki Dept. of Pharmacology 996-3539ANTIDIABETIC AGENTSI Insulin Preparations II Oral Hypoglycemic Drugs #2CLASSIFICATION OF DIABETESIDDM = insulin dependent diabetes mellitus Type l (10-20% of diabetics) ! INSULIN DEPENDENT! (Juvenile - onset)! little or no extractable insulin inpancreas! prone to acidosis, ketosis! insulin receptors usually unimpaired! usually undernourished! symptoms of polydipsia, polyphagia,and polyuria NIDDM = non-insulin dependent diabetes mellitus Type II (80-90% of diabetics) ! 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 obesepatients who comprise 75% of Type IIdiabetics)! usually obese2#3 STRUCTURE OF HUMAN INSULIN AND PROINSULIN#4 SOME COMMONLY USED INSULIN PREPARATIONSRelative effect on blood glucose (hr.)Type Preparation Onset Peak DurationFast-acting Regular insulin includesr-DNA Humulin (R)½ - 1 1 - 2 5 - 7Insulin zinc prompt ½ - 1 1 - 2 12 - 16Intermediate acting Isophane (NPH), includesr-DNA human insulin (Humulin N)1½ - 2 8 - 12 20 - 28Insulin zinc (Lenteinsulin)1½ - 2 8 - 12 18 - 24Globin zinc insulin 1½ - 2 8 - 16 20 - 28Long acting Protamine zinc 3 - 4 8 - 12 36Insulin zinc extended(UUUltra-lente insulin)3 - 4 8 - 12 363424 Hour Profile of Plasma Insulin andGlucose in a Normal Weight Subject56 #8 Type I: Insulin-dependent diabetics1.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 (lowerpH). For this reason, diabetics with ketoacidosis may not respond well to exogenous insulin until their serum pH isimproved.78#9CHARACTERISTICS OF SULFONYLUREA AGENTSGeneric Name Trade NameDaily Dosage Range(g)Duration of action(hr) Dose/Day MetabolismTolbutamide Orinase 0.5-3.0 6-12 2-3By liver to inactive product Tolazamide Tolinase 0.l-1.010-141-2 By liver to active and inactive productsAcetohexamide Dymeior 0.25-1.5 12-181-2By liver to active metabolitesChlorpropamide Diabinese 0.10-0.5 60 1 By liver to less active metabolites and excreted by kidney intact.Glipizide Glucatrol 5.0-40 (mg) 12-24 1-2 Glyburide-GlybenclamideDiabetaMicronase2.5-20 12-24 1-2 By liver to inert products#10 MECHANISM OF HYPOGLYCEMIC ACTION OF SULFONYLUREAS1. Sulfonylureas stimulate secretion of patients own insulin, but with chronic treatment insulinsecretion decreases toward pretreatment levels. (see A)2. Reduction of Serum glucagon concentration3. Continued effectiveness with chronic administration suggests sulfonylureas exert extrapancreaticeffects. 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 patientstreated with a sulfonylurea + diet, compared to patients treated with diet alone (mainly due to anincrease in the number of binding sites).9 C10#11 SIDE EFFECTS OF SULFONYLUREAS1.Hypoglycemia - all agents but especially chlorpropamidea.more likely in hepatic or renal insufficiencyb.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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