胰岛素及口服降糖药.ppt

胰岛素及口服降糖药Insulin and Oral Hypoglycemic Drugs,Medical School of Nankai University Jingling Zhang and Quansheng Feng,Insulin and Oral Hypoglycemic Drugs,目的 掌握胰岛素和口服降糖药的作用原理。临床应用和应用注意，熟悉葡萄糖苷酶抑制剂的作用特点。,Insulin and Oral Hypoglycemic Drugs,内容 复习胰岛素的生化，促进肝糖元生成和糖酵解，调节机体糖的代谢。胰岛素缺乏引起糖尿病，胰岛素用于糖尿病只是补充治疗。胰岛素治疗糖尿病的剂量原则。常用之制剂分短效（如普通胰岛素）。中效（如低精蛋白锌胰岛素）。长效（如精蛋白锌胰岛素）的原理和选用原则。不良反应和应用注意。,Insulin and Oral Hypoglycemic Drugs,口服降血糖药有两类：磺酰脲类有甲苯磺丁脲，氯磺丙脲和格列苯脲（优降糖）。能刺激胰岛细胞释放胰岛素，只对胰腺功能未完全丧失的患者有效。双胍类于胰腺功能完全丧失的患者有效。引起乳酸性酸血症。,General considerations,Classification of diabetes mellitus Insulin-dependent diabetes mellitus, IDDM, type, Non-insulin-dependent diabetes mellitus, NIDDM, type,General considerations,Introduction Diabetes mellitus involves not only a deficiency of insulin but also an excess of certain other hormones, such as growth hormone, glucocorticoids and glucagons.,General considerations,not only the pancreas is involved in glucose homeostasis, but also the anterior pituitary gland and the adrenal cortex.,General considerations,3. Etiology of diabetes mellitus It is currently believed that the juvenile-onset (insulin-dependent) from has an autoimmune etiology. Viruses may also play a role in the etiology of diabetes.,General considerations,Coxsackie B, mumps and rubella viruses all have been shown to produce more pathologic changes in the islet-cell structure. The genetic role in the etiology of diabetes is controversial. Possibly a genetic trait makes an individuals pancreas more susceptible to one of the above viruses.,Insulin,Chemistry of insulin Classification of insulin preparation Pharmacokinetics Pharmacodynamics,Insulin,Chemistry of insulin Insulin is a small protein with a molecular weight in humans of 5808. it contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges, there are species differences in the amino acids of both chains.,Insulin,Proinsulin, insulin precursor, is processed within the Golgi apparatus and packaged into granules. It is hydrolyzed into insulin and a residual connecting segment called the C-peptide by removal of four amino acids.,Insulin,Insulin and C-peptides are secreted in equimolar amounts in response to all insulin secretagogues, a small quantity of unprocessed or partially hydrolyzed proinsulin is released as well.,Insulin,Classification of insulin preparation Ultra-short-acting Short-acting Intermediate-acting Long-acting,Insulin lispro, Humalog (Lilly), S.C.,Regular insulin, Crystalline zinc insulin, iv (emergence), S.C.,Isophane insulin, the most common used, S.C. Globin zinc insulin, S.C.,Protamine insulin, S.C.,Insulin,Pharmacokinetics Insulin lispro Regular insulin (Crystalline zinc insulin): Globin zinc insulin injection Protamine zinc insulin, peak,No any effect when given orally, all preparation must be given by injection. Rapid absorption by S.C. injection, with rapid onset of action and short duration.,When injected subcutaneously, it quickly dissociates into monomers and is absorbed very rapidly, reaching peak serum values as early as 1 hour.,peak action in 2-4 hrs, its duration is 5-7 hrs. It can be administered subcutaneously or intravenously. It is a good agent for exerting rapid control for diabetic ketoacidosis.,peak effect in 8-12 hours, duration of action 18-24 hours.,action in 16-18 hours, duration of action 24-36 hours.,Both the liver and the kidney are of primary importance in the degradation of insulin by a proteolytic enzyme. Each is capable of destroying 40% of the insulin.,Insulin,Pharmacodynamics Pharmacological effects Mechanism of action Clinical uses Adverse effects,Insulin,Pharmacological effects Metabolism of glucose Metabolism of fat Metabolism of protein,Insulin promotes the storage of fat as well as glucose (both sources of energy) within specialized target cells and influences cell growth and the metabolic functions of a wide variety of tissues.,Blood sugar decreases, blood pyruvate and lactate increase, inorganc phosphate decreases, potassium decreases,Insulin promotes synthesis (from circulating nutrients) and storage of glycogen, triglycerides, and protein in its major target tissues: liver, fat, and muscle. The release of insulin from the pancreas is stimulated by increased blood glucose, vagal nerve stimulation, and other factors.,Insulin,Mechanism of action,Insulin,Clinical uses Teatment of diabetes short of potassium in the cell,Type(juvenile-onset, insulindependent) diabetes Type(maturity-onset, non-insulin-dependent) Diabete Diabetes accompanied by other disease, such as fever, serious infection, operation, trauma, pregnancy, and so on. Ketoacidosis and hyperosmotic nonketonic coma.,Be administered solution which contains glucose, insulin, and potassium chloride.,Insulin,Adverse effects Hypoglycemia Insulin allergy Local reactions Immune insulin resistance,Early symptoms: sweating, tremor, anxiety, tachycardia and hunger feeling. severe symptoms include mental confusion, convulsion, and ultimately coma and death. It is best treated by administering glucose or by giving fruit juice or any sugar-containing beverage or food. If not available, 20-50 ml of 50% glucose solution by iv. over a period of 2-3 minutes, or 1 mg glucagon injected either im. or sc.,The order of antigenic potency, in descending order, is beef porkhighly purified (single peak) porkhuman insulin.,Acute resistance Chronic resistance It causes extremely high insulin requirements often more 200 units daily. Switching to a less antigenic (pork or human) purified insulin may make possible a dramatic reduction in insulin dosage or may at least shorten the duration of immune resistance.,Irritation at the site of insulin injection can lead to lipodystrophy and hypertrophy. Site of injection should be rotated.,Insulin action enhancer,Type of insulin resistance Drugs Effects and mechanism of action Clinical uses pharmacokinetics Adverse effects,Insulin action enhancer,Type of insulin resistance Acquired insulin resistance type diabetes mellitus Hereditary insulin resistance type diabetes mellitus,Insulin action enhancer,Drugs Rosiglitazone, 罗格列酮 Pioglitazone, 比格列酮 Troglitazone, 曲格列酮* Ciglitazone, 西格列酮, 1999, Englitazone, 恩格列酮, 1999,Insulin action enhancer,Effects and mechanism of action Thiazolidinediones (TDs) compounds are a recently introduced class of oral antidiabetic drugs that enhance target tissue insulin sensitivity.,Insulin action enhancer,They have an acute post-receptor insulin-mimetic activity as well as chronic effects on the transcription of genes involved with glucose and lipid metabolism mediated through the peroxisome proliferator-actived receptor-nuclear receptor.,Insulin action enhancer,Dimish insulin resistance by increasing glucose uptake and metabolism in muscle and adipose tissues, restrain hepatic gluconeogenesis and exert additional effects on lipid metabolism, systemic blood pressure and the fibrinolytic system.,Insulin action enhancer,When used alone, they can restore glucose levels into the normal or nondiabetic range without causing hypoglycemia. Chronic therapy is associated with a drop in triglyceride levels and a slight rise in HDL and LDL cholesterol values.,Insulin action enhancer,Clinical use Use in type 2 diabetes as monotherapy or in combination with a biguanide.,Insulin action enhancer,pharmacokinetics metabolized through the hepatic cytochrome P450 system, and their induction of different pathways may affect the bioavailability of other medications such as oral contraceptives.,Insulin action enhancer,Adverse effect An adverse effect common to all the agents is mild anemia. Edema, hypoglycemia.,Oral hypoglycemia agents,Classification Pharmacokinetics Pharmacodynamics,Oral hypoglycemia agents,Classification Sulfonylureas Biguanides -glucosidase inhibitors,Oral hypoglycemia agents,Sulfonylureas First-generation sulfonylureas Second-generation sulfonylureas Third-generation sulfonylureas,Oral hypoglycemia agents,Pharmacokinetics Well absorption orally administration, high blood protein binding rate, metabolism in the liver, metabolized and original production excretion by kidney,Oral hypoglycemia agents,Pharmacodynamics Mechanism Effects Clinical use Adverse effects,Oral hypoglycemia agents,Mechanism Insulin release from pancreatic cells Reduction of serum glucagon concentrations Potentiation of insulin action on target tissues.,Oral hypoglycemia agents,Effects Decrease blood glucose level Promote ADH secretion and enhance its effects Decrease the function of blood platelets,Oral hypoglycemia agents,Clinical use used in the treatment of patients who have non-insulin-dependent diabetes and who cant be treated with diet alone or who are unwilling to take insulin if dietary control fails.,Oral hypoglycemia agents,The use of these agents was associated with a higher cardiovascular mortality rate than that occurring with dietary control alone or with insulin therapy. No study to date has demonstrated that sulfonylurea agents prevent the long-term complications of diabetes.,Oral hypoglycemia agents,Diabetes (尿崩症) Chlorpropamide, 氯磺丙脲,Oral hypoglycemia agents,Untoward effects,Hypoglycemia can occur in patients with hepatic or renal insufficiency because the agent will have a longer than expected duration of action.,Cutaneous reactions include rashes and photosensitivity.,Gastrointestinal reactions include nausea and vomiting.,Hematologic reactions leukopenia, agranulocytosis, thrombocytopenia, pancytopenia and hemolytic anemia have occurred.,Transient cholestatic jaundice,Inappropriate secretion of Antidiuretic hormone,Oral hypoglycemia agents,Biguanides Pharmacodynamics Currently proposed mechanisms of action include Clinical use Adverse effects.,Metformin, 甲福明，二甲双胍 Phenformine, 苯乙福明，苯乙双胍,Oral hypoglycemia agents,Pharmacokinetics Metformin has a half-life of 1.5-3 hours, is not bound to plasma proteins, is not metabolized, and is excreted by the kidneys as the active compound.,Oral hypoglycemia agents,Phenformin is bound to plasma protein. The half-life is approximately 11 hours. In patients with renal insufficiency, unmetabolized phenformin accumulates in high concentration.,Oral hypoglycemia agents,As a consequence of metformins blockade of gluconeogenesis, the drug may impair the hepatic uptake of lactic acid, in crease the risk of lacitc acidosis, a dose-related complication.,Oral hypoglycemia agents,Pharmacodynamics Their blood glucose-lowering action does not dependent on the presence of functioning pancreatic cells.,Oral hypoglycemia agents,Currently proposed mechanisms of action include: Direct stimulation of glycolysis in tissues, with increased glucose removal from blood,Oral hypoglycemia agents,Reduced hepatic gluconeogenesis Slowing of glucose absorption from the gastrointestinal tract, with increased glucose to lactate conversion by enterocytes Reduction of plasma glucagons levels.,Oral hypoglycemia agents,Clinical use Hyperglycemia patients with refractory obesity due to ineffective insulin action. Combine with sulfonylureas is used in non-insulin-dependent diabetics in whom sulfonylurea therapy alone is inadequate.,Oral hypoglycemia agents,Adverse effects. Lactic acidosis is the most serious untoward effect. The most frequent toxic effects of metformin are gastrointestinal (nausea, vomiting, diarrhea).,Oral hypoglycemia agents,-glucosidase inhibitors Acarbose (阿卡波糖) Voglibose (伏格列波糖) Only monosaccharides, such as glucose and fructose, can be transported out of the intestinal lumen and into the bloodstream.,Oral hypoglycemia agents,Complex starches, oligosaccharides, and disaccharides must therefore be broken down into individual monosaccharide molecules before being absorbed in the duodenum and upper jejunum.,Oral hypoglycemia agents,This digestion is facilitated by enteric enzymes, including pancreatic -amylase and -glucosidases, that are attached to the brush border of the intestinal cells.,Oral hypoglycemia agents,Acarbose and miglitol are competitive inhibitors of the intestinal -glucosidases and modulate the postprandial digestion and absorption of starch and disaccharides. Miglitol is six times more potent in inhibiting sucrase.,Oral hypoglycemia agents,Both target the -glucosidases: sucrase, maltase, glycoamylase, dextranase, and isomaltase (miglitol only) and have a small effect on -amylase (acarbose only) or on -glucosidases (miglitol only) which split -linked sugars such as lactose.,Oral hypoglycemia agents,The clinical consequence of enzyme inhibition is to minimize upper intestinal digestion and defer digestion and absorption of the ingested starch and disaccharides to the distal small intestine, lowering postmeal glycemic excursions as much as 45-60 mg/dl and creating an insulin-sparing effect.,Oral hypoglycemia agents,For use in individuals with type 2 diabetes as monotherapy and in combination with sulfonylureas, where the glycemic effect is additive.,Oral hypoglycemia agents,Prominent adverse effects include flatulence, diarrhea, and abdominal pain and result from the appearance of undigested carbohydrate in the colon that is then fermented into short-chain fatty acids, releasing gas.,Thank You!,