Chapter 10 Diuretics and Synthetic Hypoglycemic DrugsPeiPei Yu YuCollege of pharmacy College of pharmacyJinanJinan University University1 1Synthetic Hypoglycemic Agents(降血糖药)DefinitionsA key indicator of diabetes is persistent fasting blood glucose levels above 11.1 mmol/L which arise from defective conversion of glucose into energy.The plasma levels of FPG7.0mmol/L or PPG 11.1mmol/L2 2DiabeteslHyperglycemia result in widespread damage in the body that can lead to hypertension, heart disease, stroke, impaired circulation, nerve dysfunction, pain, infection, or organ failure.lClinical diabetes mellitus（糖尿病）occurs in two forms, Type 1 and Type 2 , with different causes and methods of therapy.3 3Type 1 Diabetes (insulin-dependent)lFormerly known as insulin-dependent diabetes mellitus (IDDM, 胰岛素依赖性糖尿病). lThe cells of the pancreatic islets of Langerhans (胰岛) are destroyed, probably by an autoimmune process, such that insulin production is grossly deficient（严重缺乏）. lThere exists only a weak genetic link in the etiology(病原学)of this form of diabetes. lType 1 diabetes is invariably treated with insulin.4 45 5Type 2 Diabetes (noninsulin-dependent)lFormerly known as noninsulin-dependent diabetes mellitus (NIDDM).lFrequently associated with obesity(肥胖症)in its mainly adult victims. Serum insulin levels are normal or elevated, so in essence this is a disease of insulin resistance. lThere is a strong genetic link in the etiology（病原学）of the condition, and insulin therapy is not always required.6 67 78 8Hypoglycemic DrugsTreatments of Type 2 diabetes include： (1) agents which increase the amount of insulin secreted by the pancreas(2) agents which increase the sensitivity of target organs to insulin(3) agents which decrease the rate at which glucose is absorbed from the gastrointestinal tract.9 9Classification of Hypoglycemic Drugl Sulfonylureas (磺酰脲类)l Biguanides (双胍类)l-Glucosidase inhibitors (-葡萄糖苷酶抑制剂)l Thiazolindiones (噻唑烷 二酮类)1010l The hypoglycemic(降血糖)effect of salicylates(水杨酸盐)has been known for 100 years. Clinical use of salicylates was not feasible, since the very large doses required produced intolerable side effects. l The hypoglycemic effects of the thiadiazole sulfonamide known as IPTD, used to treat typhoid (伤寒症)fever in the 1940s. This drug produced many deaths which were subsequently attributed to prolonged drug-induced hypoglycemia. Sulfonylureas(磺酰脲类)1111Sulfonylureasl At same time these effects were noted, the synthesis of sulfonylurea such as Carbutamide, so far active as hypoglycemic agents, was reported. l Since then, about 12, 000 sulfonylureas have been tested, and about 10 are currently on the market.1212Sulfonylureas Tolbutamide 甲苯磺丁脲 Chlorpropamide 氯磺丙脲 Acetohexamide 醋磺己脲 Tolazamide 妥拉磺脲 Gliclazide 格列齐特 Glibornuride 格列波脲 Glibenclamide 格列本脲 Glipizide 格列吡嗪 Gliquidone 格列喹酮 Glimepiride 格列美脲1st generation2nd generation3rd generation1313First and second generation sulfonylureas1414Tolbutamide (甲苯磺丁脲 )1-Butyl-3-(p-tolylsulfonyl)ureaN-(butylamino)carbonyl-4-methylbenzenesulfonamideWhite, crystalline powder, insoluble in water, soluble in alcohol or aqueous alkali. It is stable in air.1515Acidic propertyTolbutamide shows acidic property，it can be dissolved in base.1616lUnstable under acidic condition.odour 1717Metabolism of Tolbutamidel Tolbutamide is absorbed rapidly in responsive diabetic patients. The blood sugar level reaches a minimum after 5-8 h. l It is oxidized rapidly in vivo to derivative with hydroxyl group (I) or derivative with carboxyl group (II), which are inactive. 1818Synthesis of Tolbutamide1919Glibenclamide(格列本脲 )1-p-2-(5-chloro-o-anisamido)ethyl-phenylsulfonyl -3-cyclohexylurea. l Second-generation oral hypoglycemic agent. l The drug has a half-life elimination of 10h, but its hypoglycemic effect remains for up to 24h.2020Hydrolysis of Glibenclamide 2121Glimepiride(格列美脲)1-p-2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl phenylsulfonyl-3-(trans-4-methylcyclohexyl)urea. l The third-generation oral hypoglycemic agent. l Instead of the benzene ring found in Glibenclamide, Glimepiride contains a pyrrolidine system. l It is metabolized primarily through oxidation of the alkyl side chain of the pyrrolidine, with a minor metabolic route involving acetylation of the amine.2222Other Antidiabetic drugs: Biguanide: ( (双胍双胍) ) l The most commonly used oral drugfor type 2 diabetes. l Increasing insulin sensitivity. l Decreasing the absorption of glucosefrom the gastroinestinal tract.2323Discoveryl The guanidine derivatives（胍衍生物）Synthalin A and B were introduced into therapy in the 1920s, but chronic toxicity forced their abandonment in the 1930s. l The widely used biguanides(双胍) Phenformin and Metformin were prepared in the 1950s, and the latter is still in widespread use