胰岛素及口服降糖药21279ppt课件

胰岛素及口服降糖药胰岛素及口服降糖药 Insulin and Oral Insulin and Oral Hypoglycemic Hypoglycemic DrugsDrugs Medical School of Nankai UniversityMedical School of Nankai University Jingling Zhang and Quansheng FengJingling Zhang and Quansheng Feng Insulin and Oral Hypoglycemic DrugsInsulin 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 DrugsInsulin 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 DrugsInsulin 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。 Insulin and oral Insulin and oral hypoglycemic drugshypoglycemic drugs General considerationsGeneral considerations Insulin Insulin action enhancerInsulin action enhancer Oral hypoglycemia agentsOral hypoglycemia agents General considerationsGeneral considerations 1. Classification of diabetes mellitus Insulin-dependent diabetes mellitus, IDDM, type, Non-insulin-dependent diabetes mellitus, NIDDM, type, General considerationsGeneral considerations 2. 2. IntroductionIntroduction Diabetes mellitus involves not only Diabetes mellitus involves not only a deficiency of insulin but also an a deficiency of insulin but also an excess of certain other hormones, excess of certain other hormones, such as growth hormone, such as growth hormone, glucocorticoids and glucagons.glucocorticoids and glucagons. General considerationsGeneral considerations not only the pancreas is involved in not only the pancreas is involved in glucose homeostasis, but also the glucose homeostasis, but also the anterior pituitary gland and the anterior pituitary gland and the adrenal cortex.adrenal cortex. General considerationsGeneral considerations 3. Etiology of diabetes mellitus 3. Etiology of diabetes mellitus It is currently believed that the It is currently believed that the juvenile-onset (insulin-dependent) juvenile-onset (insulin-dependent) from has an autoimmune etiology.from has an autoimmune etiology. Viruses may also play a role in the etiology of diabetes. General considerationsGeneral considerations Coxsackie B, mumps and rubella Coxsackie B, mumps and rubella viruses all have been shown to viruses all have been shown to produce more pathologic changes in produce more pathologic changes in the islet-cell structure.the islet-cell structure. The genetic role in the etiology of The genetic role in the etiology of diabetes is controversial. Possibly a diabetes is controversial. Possibly a genetic trait makes an individuals genetic trait makes an individuals pancreas more susceptible to one of pancreas more susceptible to one of the above viruses.the above viruses. Insulin and oral Insulin and oral hypoglycemic drugshypoglycemic drugs General considerationsGeneral considerations Insulin Insulin action enhancerInsulin action enhancer Oral hypoglycemia agentsOral hypoglycemia agents InsulinInsulin 1. 1. Chemistry of insulinChemistry of insulin 2. 2. Classification of insulin Classification of insulin preparationpreparation 3. 3. PharmacokineticsPharmacokinetics 4. 4. PharmacodynamicsPharmacodynamics InsulinInsulin 1. 1. Chemistry of insulinChemistry of insulin Insulin is a small protein with a Insulin is a small protein with a molecular weight in humans of 5808. molecular weight in humans of 5808. it contains 51 amino acids arranged it contains 51 amino acids arranged in two chains (A and B) linked by in two chains (A and B) linked by disulfide bridges, there are species disulfide bridges, there are species differences in the amino acids of differences in the amino acids of both chains.both chains. InsulinInsulin Proinsulin, insulin precursor, is Proinsulin, insulin precursor, is processed within the Golgi apparatus processed within the Golgi apparatus and packaged into granules. It is and packaged into granules. It is hydrolyzed into insulin and a residual hydrolyzed into insulin and a residual connecting segment called the C-connecting segment called the C- peptide by removal of four amino peptide by removal of four amino acids.acids. InsulinInsulin Insulin and C-peptides are secreted in Insulin and C-peptides are secreted in equimolar amounts in response to all equimolar amounts in response to all insulin secretagogues, a small insulin secretagogues, a small quantity of unprocessed or partially quantity of unprocessed or partially hydrolyzed proinsulin is released as hydrolyzed proinsulin is released as well.well. InsulinInsulin 2. Classification of insulin preparation Ultra-short-acting Short-acting Intermediate-acting Long-acting Insulin lispro, Insulin lispro, Humalog (Lilly), S.CHumalog (Lilly), S.C . . Regular insulin, Regular insulin, Crystalline zinc insulin, Crystalline zinc insulin, iv (emergence), S.C.iv (emergence), S.C. Isophane insulin, the Isophane insulin, the most common used, most common used, S.C.S.C. Globin zinc insulin, S.C.Globin zinc insulin, S.C. Protamine insulin, S.C.Protamine insulin, S.C. InsulinInsulin 3. 3. Pharmacokinetics Pharmacokinetics Insulin lisproInsulin lispro Regular insulin (Crystalline zinc Regular insulin (Crystalline zinc insulin):insulin): Globin zinc insulin injectionGlobin zinc insulin injection Protamine zinc insulin, peakProtamine 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 When injected subcutaneously, it subcutaneously, it quickly dissociates quickly dissociates into monomers and into monomers and is absorbed very is absorbed very rapidly, reaching rapidly, reaching peak serum values peak serum values as early as 1 hour.as early as 1 hour. peak action in 2-4 hrs, peak action in 2-4 hrs, its duration is 5-7 hrs. its duration is 5-7 hrs. It can be administered It can be administered subcutaneously or subcutaneously or intravenously. It is a intravenously. It is a good agent for exerting good agent for exerting rapid control for rapid control for diabetic ketoacidosis.diabetic ketoacidosis. peak effect in peak effect in 8-12 hours, 8-12 hours, duration of duration of action 18-24 action 18-24 hours.hours. action in 16-action in 16- 18 hours, 18 hours, duration of duration of action 24-36 action 24-36 hours.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. InsulinInsulin 4. 4. PharmacodynamicsPharmacodynamics Pharmacological effectsPharmacological effects Mechanism of actionMechanism of action Clinical usesClinical uses Adverse effectsAdverse effects InsulinInsulin Pharmacological effects Pharmacological effects a. a. Metabolism of glucoseMetabolism of glucose Metabolism of fatMetabolism of fat Metabolism of proteinMetabolism of protein Insulin promotes the storage of fat as well as Insulin promotes the storage of fat as well as glucose (both sources of energy) within glucose (both sources of energy) within specialized target cells and influences cell specialized target cells and influences cell growth and the metabolic functions of a wide growth and the metabolic functions of a wide variety of tissues.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. InsulinInsulin Mechanism of actionMechanism of action InsulinInsulin Clinical usesClinical uses a. a. Teatment of diabetesTeatment of diabetes short of potassium in the cell short of potassium in the cell TypeType(juvenile-onset, insulindependent) diabetes(juvenile-onset, insulindependent) diabetes TypeType(maturity-onset, non-insulin-dependent)(maturity-onset, non-insulin-dependent) Diabete Diabete Diabetes accompanied by other disease, such as Diabetes accompanied by other disease, such as fever, serious infection, operation, trauma, fever, serious infection, operation, trauma, pregnancy, and so on. pregnancy, and so on. Ketoacidosis and hyperosmotic nonketonic coma. Ketoacidosis and hyperosmotic nonketonic coma. Be administered solution which Be administered solution which contains glucose, insulin, and contains glucose, insulin, and potassium chloride.potassium chloride. InsulinInsulin Adverse effectsAdverse effects a. a. HypoglycemiaHypoglycemia b. b. Insulin allergyInsulin allergy c. c. Local reactionsLocal reactions d. d. Immune insulin resistanceImmune insulin resistance Early symptoms: sweating, tremor, anxiety, tachycardia Early symptoms: sweating, tremor, anxiety, tachycardia and hunger feeling. severe symptoms include mental and hunger feeling. severe symptoms include mental confusion, convulsion, and ultimately coma and death. confusion, convulsion, and ultimately coma and death. It is best treated by administering glucose or by giving It is best treated by administering glucose or by giving fruit juice or any sugar-containing beverage or food. If fruit juice or any sugar-containing beverage or food. If not available, 20-50 ml of 50% glucose solution by iv. not available, 20-50 ml of 50% glucose solution by iv. over a period of 2-3 minutes, or 1 mg glucagon injected over a period of 2-3 minutes, or 1 mg glucagon injected either im. or sc. either im. or sc. The order of antigenic potency, in descendingThe order of antigenic potency, in descending order, is beef order, is beef porkpork highly purified (singlehighly purified (single peak) pork peak) pork human insulin.human insulin. Acute resistanceAcute resistance Chronic resistanceChronic resistance It causes extremely high insulin requirements often more It causes extremely high insulin requirements often more 200 units daily. 200 units daily. Switching to a less antigenic (pork or human) purified Switching to a less antigenic (pork or human) purified insulin may make possible a dramatic reduction in insulin may make possible a dramatic reduction in insulin dosage or may at least shorten the duration of insulin dosage or may at least shorten the duration of immune resistance.immune resistance. Irritation at the site of insulin injection can lead to Irritation at the site of insulin injection can lead to lipodystrophy and hypertrophy. Site of injection lipodystrophy and hypertrophy. Site of injection should be rotated.should be rotated. Insulin and oral Insulin and oral hypoglycemic drugshypoglycemic drugs General considerationsGeneral considerations Insulin Insulin action enhancerInsulin action enhancer Oral hypoglycemia agentsOral hypoglycemia agents Insulin action enhancerInsulin action enhancer 1. 1. Type of insulin resistanceType of insulin resistance 2. 2. Drugs Drugs 3. 3. Effects and mechanism of action Effects and mechanism of action 4. 4. Clinical usesClinical uses 5. 5. pharmacokineticspharmacokinetics 6. 6. Adverse effectsAdverse effects Insulin action enhancerInsulin action enhancer 1. 1. Type of insulin resistanceType of insulin resistance Acquired insulin resistanceAcquired insulin resistance type diabetes mellitustype diabetes mellitus Hereditary insulin resistance Hereditary insulin resistance type diabetes mellitus type diabetes mellitus Insulin action enhancerInsulin action enhancer 2. 2. Drugs Drugs Rosiglitazone, Rosiglitazone, 罗格列酮罗格列酮 Pioglitazone, Pioglitazone, 比格列酮比格列酮 Troglitazone, Troglitazone, 曲格列酮曲格列酮* * Ciglitazone, Ciglitazone, 西格列酮西格列酮, 1999, 1999, Englitazone, Englitazone, 恩格列酮恩格列酮, 1999, 1999, Insulin action enhancerInsulin action enhancer 3. 3. Effects and mechanism of actionEffects and mechanism of action Thiazolidinediones (TDs) Thiazolidinediones (TDs) compounds are a recently compounds are a recently introduced class of oral antidiabetic introduced class of oral antidiabetic drugs that enhance target tissue drugs that enhance target tissue insulin sensitivity.insulin sensitivity. Insulin action enhancerInsulin action enhancer They have an acute post-receptor They have an acute post-receptor insulin-mimetic activity as well as insulin-mimetic activity as well as chronic effects on the transcription of chronic effects on the transcription of genes involved with glucose and lipid genes involved with glucose and lipid metabolism mediated through the metabolism mediated through the peroxisome proliferator-actived peroxisome proliferator-actived receptor-nuclear receptor.receptor-nuclear receptor. Insulin action enhancerInsulin action enhancer Dimish insulin resistance by Dimish insulin resistance by increasing glucose uptake and increasing glucose uptake and metabolism in muscle and adipose metabolism in muscle and adipose tissues, restrain hepatic tissues, restrain hepatic gluconeogenesis and exert additional gluconeogenesis and exert additional effects on lipid metabolism, systemic effects on lipid metabolism, systemic blood pressure and the fibrinolytic blood pressure and the fibrinolytic system.system. Insulin action enhancerInsulin action enhancer When used alone, they can restore When used alone, they can restore glucose levels into the normal or glucose levels into the normal or nondiabetic range without causing nondiabetic range without causing hypoglycemia. Chronic therapy is hypoglycemia. Chronic therapy is associated with a drop in triglyceride associated with a drop in triglyceride levels and a slight rise in HDL and levels and a slight rise in HDL and LDL cholesterol values.LDL cholesterol values. Insulin action enhancerInsulin action enhancer 4. 4. Clinical useClinical use Use in type 2 diabetes as Use in type 2 diabetes as monotherapy or in combination monotherapy or in combination with a biguanide. with a biguanide. Insulin action enhancerInsulin action enhancer 5. 5. pharmacokineticspharmacokinetics metabolized through the hepatic metabolized through the hepatic cytochrome Pcytochrome P450 450 system, and their system, and their induction of different pathways may induction of different pathways may affect the bioavailability of other affect the bioavailability of other medications such as oral medications such as oral contraceptives. contraceptives. Insulin action enhancerInsulin action enhancer 6. 6. Adverse effectAdverse effect An adverse effect common to all the An adverse effect common to all the agents is mild anemia. Edema, agents is mild anemia. Edema, hypoglycemia.hypoglycemia. Insulin and oral Insulin and oral hypoglycemic drugshypoglycemic drugs General considerationsGeneral considerations Insulin Insulin action enhancerInsulin action enhancer Oral hypoglycemia agentsOral hypoglycemia agents Oral hypoglycemia agents Oral hypoglycemia agents 1. 1. ClassificationClassification 2. 2. PharmacokineticsPharmacokinetics 3. 3. PharmacodynamicsPharmacodynamics Oral hypoglycemia agentsOral hypoglycemia agents 1. 1. ClassificationClassification Sulfonylureas Sulfonylureas BiguanidesBiguanides -glucosidase inhibitors-glucosidase inhibitors Oral hypoglycemia agentsOral hypoglycemia agents SulfonylureasSulfonylureas a. a. First-generation sulfonylureasFirst-generation sulfonylureas b. b. Second-generation sulfonylureasSecond-generation sulfonylureas c. c. Third-generation sulfonylureasThird-generation sulfonylureas Not only decrease blood glucose Not only decrease blood glucose level but also improve the level but also improve the function of blood plateletfunction of blood platelet Gliclazipe, Gliclazipe, 格列齐特格列齐特, , 达美达美 康康 Gliquidone, Gliquidone, 格列喹酮格列喹酮 The more efficacious, the The more efficacious, the fewer adverse effects than fewer adverse effects than first-generationfirst-generation Glibenclamide, Glibenclamide, 格列本脲格列本脲 ，优降糖，优降糖 Glipizide, Glipizide, 吡磺环己脲吡磺环己脲 Glimepiride, Glimepiride, 格列美脲格列美脲 Well absorbed, rapidly or Well absorbed, rapidly or slowly metabolized in the slowly metabolized in the liver, t1/2=4-5 or 32 hours, liver, t1/2=4-5 or 32 hours, excretion by kidneyexcretion by kidney Tolbutamide, D860 Tolbutamide, D860 甲甲 苯磺丁脲苯磺丁脲 Chlorpropamide, Chlorpropamide, 氯磺氯磺 丙脲丙脲 Oral hypoglycemia agentsOral hypoglycemia agents 2. 2. PharmacokineticsPharmacokinetics Well absorption orally Well absorption orally administration, high blood protein administration, high blood protein binding rate, metabolism in the binding rate, metabolism in the liver, metabolized and original liver, metabolized and original production excretion by kidney,production excretion by kidney, Oral hypoglycemia agentsOral hypoglycemia agents 3. 3. Pharmacodynamics Pharmacodynamics MechanismMechanism EffectsEffects Clinical useClinical use Adverse effectsAdverse effects Oral hypoglycemia agentsOral hypoglycemia agents MechanismMechanism a. a. Insulin release from pancreatic cellsInsulin release from pancreatic cells b. b. Reduction of serum glucagon Reduction of serum glucagon concentrationsconcentrations c. c. Potentiation of insulin action on target Potentiation of insulin action on target tissues.tissues. Oral hypoglycemia agentsOral hypoglycemia agents EffectsEffects a. a. Decrease blood glucose levelDecrease blood glucose level b. b. Promote ADH secretion and Promote ADH secretion and enhance its effectsenhance its effects c. c. Decrease the function of blood Decrease the function of blood platelets platelets Oral hypoglycemia agentsOral hypoglycemia agents Clinical useClinical use a. a. used in the treatment of patients used in the treatment of patients who have non-insulin-dependent who have non-insulin-dependent