抗糖尿病药胰岛素与口服降血糖药精品课件

抗糖尿病药胰岛素与口服降血糖药 (Antidiabetis DrugsInsulin and Oral Antisiabetis Drugs) 北京协和医学院基础医学院药理学系 OverviewOverview n糖尿病(diabetes mellitus) A chronic condition associated with abnormally high blood sugar. Results from either deficiency of or a resistance to insulin- a hormone produced by the pancreas whose function is to lower blood sugar. OverviewOverview nmorbidity: n 300,000 people0.67 n 40 years old2.53 n1994 2564 years old2.51 n1996 2075 years old3.21 n199713,500,000 people (all over the word) nPrediction:202530,000,000 people OverviewOverview nCause by many of reasons chronic hyperglycemiametabolic disorder nHyperglycemia a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. nInsulin: B cells synthesissecretion blood circulationtarget cellsbinding with insulin receptor intracellular substance metabolism nany link going wrong diabetes mellitus OverviewOverview nDiabetes Mellitus long-term disease multisystem damagefunctional defect and failure nSeverediabetic ketoacidosiscoma nEtiopathogenisis heredity, autoimmunity, environmental factor nDiagnosis:urine glucose, blood glucose OverviewOverview nTherapy: early treatment, long term therapy, combined therapy and therapeutic measure individualization nPurpose:blood glucosenormal, to correct metabolic disorder, increase in life span, decrease death nPrinciple:persevere (cannot cure) OverviewOverview nDrink and food:gross calorific value nKgheight105 nDaily Kg105125.5K n(2530Kcal) (2540Kcal) nTherapy:before meals Substance Metabolic Disorder and Clinical Situation of Diabetic nglucose utilization disorderglucose decomposition decreaseenergy insufficientstarvation condition polyphagia hyperglycemia glucosuria hypertonicity diuresis polyuria nprotein degradation accentuation athrepsy dehydration thirstpolydipsia n lipolysis excessive hyperosmolar nonketotic diabetic coma ketonuria lipolysis excessive ketoplasia excessiveKetonemiaacidosis coma Classification of Diabetes Mellitus (WHO 1998) n n TypeType: : insulin dependent diabetes insulin dependent diabetes mellitus,mellitus,IDDMIDDM n n TypeType: : non-insulin dependent diabetes non-insulin dependent diabetes mellitus,mellitus,NIDDMNIDDM nOthers: secondary diabetes Diabetes Mellitus nType 1 Diabetes - cells that produce insulin are destroyed - results in insulin dependence - commonly detected before 30 nType 2 Diabetes - blood glucose levels rise due to 1) Lack of insulin production 2) Insufficient insulin action (resistant cells) - commonly detected after 40 - effects 90% - eventually leads to -cell failure (resulting in insulin dependence) Gestational Diabetes 3-5% of pregnant women in the US develop gestational diabetes Diabetes - Insulin nDiscovered in 1921 by Banting and Best nConsist of A & B chains linked by 2 disulfide bonds (plus additional disulfide in A) A = 21amino acids B = 30 amino acids Diabetes Insulin (synthesis, storage, secretion) Zn nProduced within the pancreas by cells islets of Langerhans ninsulin mRNA is translated as a single chain precursor called preproinsulin nremoval of signal peptide during insertion into the endoplasmic reticulum generates proinsulin nWithin the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin nStored as granules Diabetes Insulin (Biochemical Role) -Tyrosine Kinase receptors are the locks in which the insulin key fits - Involved in signal transduction (insulin hormone being 1st messenger) Diabetes Insulin (Mechanism) Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s) Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version. Insulin drug evolution nStage 3 Insert the human insulin gene into E. coli and culture the recombinant E.coli to produce insulin (trade name = Humulin). Yeast is also used to produce insulin (trade name = Novolin) (1987). Recombinant DNA technology has also made it possible to manufacture slightly-modified forms of human insulin that work faster (Humalog and NovoLog) or slower (Lantus) than regular human insulin. Physiological disposition of insulin nInsulin must be administered parenterally, usually by s.c. injection. nIt is metabolised by the liver and the kidney and has a half-life of 9-10 minutes. nTo extend its period of action, show release preparations have been developed. Types of insulin l Regular insulin l Insulin analogs l Pre-mixed insulin l Short peptide mimics Insulin affects many organs: nIt stimulates skeletal muscle fibers. nIt stimulates liver cells. nIt acts on fat cells nIt inhibits production of certain enzyme. In each case, insulin triggers these effects by binding to the insulin receptor. glucose uptake glycogen synthesis protein synthesis amino acids uptake enzyme production glycogen breaking fat synthesis The The Pharmacological Action of Insulin nIt allows the active uptake of glucose and its utilisation in muscle and fat cells. nIt stimulates synthesis of glycogen in the liver. nIt inhibits formation of glucose (gluconeogensis) in the liver. nIt inhibits breakdown of lipids. nIt stimulates protein synthesis. nIt stimulates some cell ion transport mechanisms (e.g. Na+/K+-ATPase). Who need insulin medicine? nType I (insulin dependent) diabetes patients whose body produces no insulin. nType 2 diabetes patients that do not always produce enough insulin. ndiabetic ketoacidosis, hypertonicity hyperglycemia coma and lactic acidosis accompany with hyperglycemia ndiabetes mellitus accompany with severe infection, wasting disease, hyperpyrexia, pregnancy, wound and operation. nsecondary diabetes is caused by pancreatectomy. Preparations and Clinical Use of insulin nShort-acting preparations. nIntermediate acting preparations. nLong acting preparations. nNew very-short- and very-long-acting insulin analogues. Insulin RegimensInsulin Regimens nDose and choice of preparations must be determined for each patient individually. nMany patients will monitor their blood glucose at home and make minor adjustments in dose accordingly. Insulin RegimensInsulin Regimens nDiabetic Ketoacidosis and diabetic coma: nInsulin (S.C. Injection) will be given to lower blood sugar and to prevent further ketone formation. Once blood glucose levels have fallen to 250 mg, additional glucose may be given to allow continued insulin administration without hypoglycemia (low blood sugar). Insulin RegimensInsulin Regimens nHyperpotassaemia: Insulin coadminidtrate with glucose(help Kget into cell) (1) Prevention and Treatment of arrhythmia caused by myocardial infarction. the combination treatment of insulin, glucose and KCl (2) Insulin shock therapy has been used to treat schizophrenia . Adverse EffectsAdverse Effects nHypoglycemia nAllergic reaction nInsulin resistance nHypokalemia nLipoatrophy Adverse EffectsAdverse Effects n1. Allergic reaction: foreign protein enter into human body nInsulin has antigenicity, the slight reaction includes local swelling, itch, ache. It rarely occurs urticaria, angioedema and anaphylactic shock. nIt often uses antihistamine drug and adrenal cortex hormone to treat with severe allergic reaction,and these patients should change to use high purity insulin or human insulin. Adverse EffectsAdverse Effects n2. Hypoglycemia (the most common and serious adverse) nIt is the result of an imbalance between glucose intake (e.g. missing a meal), glucose utilisation (e.g. unusual exercise) and insulin dose. nThe result is sympathetic activation and neuroglycopenia. Adverse EffectsAdverse Effects nPatients and their families should be trained to spot the warning signs and how to treat hypoglycaemia, including possibly administration of glucagon if the patient loses consciousness. nTreatment is by administration of carbohydrate orally to a conscious patient, or i.v. glucose or i.m. glucagon. Adverse EffectsAdverse Effects n4.Hypokalemia: may occur in the acidosis patients who use a lot of insulin and glucose, it can lead to the patient death with abnormal heart beat. n n 5.5.Lipoatrophy: is the atrophy or is the atrophy or hypertrophy of fat at the site of hypertrophy of fat at the site of injection.injection. Insulin Resistance (INR)Insulin Resistance (INR) nInsulin resistance is a prominent feature in obese individuals and in non-insulin- dependent diabetes. nSome resistance may be caused by defects in binding of insulin. Other possible mechanisms include secretion of an abnormal B-cell secretory product or the presence of circulation insulin antagonists. Diabetes-Insulin Action EnhancersDiabetes-Insulin Action Enhancers n n Rosiglitazone(Rosiglitazone(罗格列酮罗格列酮) ) n n PioglitazonePioglitazone ( (吡咯列酮吡咯列酮) ) The Action of The Action of Insulin Action EnhancersInsulin Action Enhancers n n Improve Improve insulin resistance,decrease hyperglycemia. n n Improve Improve fat metabolism disorder. n n Prevent and treat the blood vessel Prevent and treat the blood vessel complication of type II diabetes mellitus. n n Improve Improve pancreatic B cell function. Diabetes Oral Medications nSulfonylureas nBiguanides nSulfonylureas and biguanide combination drugs nThiazolidinediones nAlpha-glycosidase inhibitors nMeglitinides Oral Autidiabetic Drugs Sulfonylureas (磺酰脲类) n甲苯磺酰脲(Tolbutamide) n氯磺丙脲(Chlorpropamide) n优降糖(Glibouclamide 格列本脲) n格列吡嗪( Glipizide 吡磺环己脲) n格列齐特(Gliclazipe 达美康) n糖适平(Glurenorm) Oral Autidiabetic Drugs Biguanides (双胍类) n苯乙双胍(Phenformin 苯乙福明) n二甲双胍(Metformin 甲福明) -glucosidase inhibiors (-葡萄糖苷酶抑制剂) n阿卡波糖(Acarbose) Sulfonylureas nphysiological disposition The The sulfonyureassulfonyureas are administered orally are administered orally and undergo varying degrees of hepatic and undergo varying degrees of hepatic metabolism and renal elimination of the metabolism and renal elimination of the parent compound and metabolites. Most parent compound and metabolites. Most of the of the sulfonylureassulfonylureas are metabolized to are metabolized to inactive or less active compounds in the inactive or less active compounds in the liver.liver. The Mechanism of Action nSulfonylureas interact with receptors on pancreatic b-cells to block ATP-sensitive potassium channels. nThis, in turn, leads to opening of calcium channels. nWhich leads to the production of insulin. The Pharmacological Effect of Sulfonylureas 1. 1. Hypoglycemic Activity SulfonylureasSulfonylureas act primarily by increasing act primarily by increasing the secretion of insulin and secondarily the secretion of insulin and secondarily by decreasing the secretion of by decreasing the secretion of glucagonglucagon. . 2. Antidiuresis effect: treat with diabetes insipidus. 3. Decrease platelet adhesion reaction, stimulate plasminogen synthesis. The Clinical Application of Sulfonylureas nDiabetes Mellitus:A sulfonylurea drug is often used to treat type II DM that cannot be controlled with dietary restrictions. nDiabetes Insipidus:coadministrating with Hydrochlorothiazide can improve the effect Adverse Effects of Sulfonylureas nHypoglycaemia nGastrointestinal upsets nHypersensitivity: rashes etc. nWeight gain: stimulation of appetite can be a problem in obese patients. Drug Interactions nSulfonylureas are heavily protein bound and their actions may be increased by other drugs (e.g. sulfonamides) that compete for the binding sites. Biguanides nPhysiological Disposition Metformin is administered orally from two to four times a day and is eliminated by renal excretion of the parent compound. Its duration of action is about 18 hours. Mechanisms and Pharmacological Effects nMetformin is now considered a first-line drug for the treatment of type II DM. nIn patients with type II DM, it allevia