1、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 叶菜英,Overview,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
2、 is to lower blood sugar.,Overview,morbidity： 300,000 people0.67 40 years old2.531994 2564 years old2.511996 2075 years old3.21199713,500,000 people (all over the word)Prediction:202530,000,000 people,Overview,Cause by many of reasons chronic hyperglycemiametabolic disorderHyperglycemia a group of d
3、iseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both.Insulin: B cells synthesissecretion blood circulationtarget cellsbinding with insulin receptor intracellular substance metabolismany link going wrong diabetes mellitus,Overview
4、,Diabetes Mellitus long-term disease multisystem damagefunctional defect and failureSeverediabetic ketoacidosiscomaEtiopathogenisis heredity, autoimmunity, environmental factorDiagnosis：urine glucose, blood glucose,Overview,Therapy: early treatment, long term therapy, combined therapy and therapeuti
5、c measure individualizationPurpose：blood glucosenormal, to correct metabolic disorder, increase in life span, decrease deathPrinciple：persevere (cannot cure),Overview,Drink and food：gross calorific valueKgheight105Daily Kg105125.5K（2530Kcal） (2540Kcal)Therapy：before meals,Substance Metabolic Disorde
6、r and Clinical Situation of Diabetic,glucose utilization disorderglucose decomposition decreaseenergy insufficientstarvation condition polyphagia hyperglycemia glucosuria hypertonicity diuresis polyuriaprotein degradation accentuation athrepsy dehydration thirstpolydipsia lipolysis excessive hyperos
7、molar nonketotic diabetic coma ketonuria lipolysis excessive ketoplasia excessiveKetonemiaacidosis coma,Classification of Diabetes Mellitus (WHO 1998),Type: insulin dependent diabetes mellitus，IDDMType: non-insulin dependent diabetes mellitus，NIDDMOthers： secondary diabetes,Diabetes Mellitus,Type 1
8、Diabetes- cells that produce insulin are destroyed - results in insulin dependence- commonly detected before 30,Type 2 Diabetes- blood glucose levels rise due to 1) Lack of insulin production2) Insufficient insulin action (resistant cells)- commonly detected after 40- effects 90%- eventually leads t
9、o -cell failure (resulting in insulin dependence),Gestational Diabetes 3-5% of pregnant women in the US develop gestational diabetes,Diabetes - Insulin,Discovered in 1921 by Banting and BestConsist of A & B chains linked by 2 disulfide bonds (plus additional disulfide in A),A = 21amino acids B = 30
10、amino acids,Diabetes Insulin(synthesis, storage, secretion),Zn,Produced within the pancreas by cells islets of Langerhansinsulin mRNA is translated as a single chain precursor called preproinsulinremoval of signal peptide during insertion into the endoplasmic reticulum generates proinsulinWithin the
11、 endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulinStored as granules,Diabetes Insulin(Biochemical Role),Tyrosine Kinase receptors are the locks in which the insulin key fits- Involved in signal tr
12、ansduction(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 dr
13、ug evolution,Stage 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 for
14、ms of human insulin that work faster (Humalog and NovoLog) or slower (Lantus) than regular human insulin.,Physiological disposition of insulin,Insulin must be administered parenterally, usually by s.c. injection.It is metabolised by the liver and the kidney and has a half-life of 9-10 minutes.To ext
15、end its period of action, show release preparations have been developed.,Types of insulin,Regular insulin Insulin analogs Pre-mixed insulin Short peptide mimics,Insulin affects many organs: It stimulates skeletal muscle fibers. It stimulates liver cells. It acts on fat cells It inhibits production o
16、f certain enzyme. In each case, insulin triggers these effects by binding to the insulin receptor.,The Pharmacological Action of Insulin,It allows the active uptake of glucose and its utilisation in muscle and fat cells.It stimulates synthesis of glycogen in the liver.It inhibits formation of glucos
17、e (gluconeogensis) in the liver.It inhibits breakdown of lipids.It stimulates protein synthesis.It stimulates some cell ion transport mechanisms (e.g. Na+/K+-ATPase).,Who need insulin medicine?,Type I (insulin dependent) diabetes patients whose body produces no insulin.Type 2 diabetes patients that
18、do not always produce enough insulin. diabetic ketoacidosis, hypertonicity hyperglycemia coma and lactic acidosis accompany with hyperglycemiadiabetes mellitus accompany with severe infection, wasting disease, hyperpyrexia, pregnancy, wound and operation.secondary diabetes is caused by pancreatectom
19、y.,Preparations and Clinical Use of insulin,Short-acting preparations.Intermediate acting preparations.Long acting preparations.New very-short- and very-long-acting insulin analogues.,Insulin Regimens,Dose and choice of preparations must be determined for each patient individually.Many patients will
20、 monitor their blood glucose at home and make minor adjustments in dose accordingly.,Insulin Regimens,Diabetic Ketoacidosis and diabetic coma:Insulin (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, addition
21、al glucose may be given to allow continued insulin administration without hypoglycemia (low blood sugar).,Insulin Regimens,Hyperpotassaemia: Insulin coadminidtrate with glucose（help Kget into cell）(1) Prevention and Treatment of arrhythmia caused by myocardial infarction. the combination treatment o
22、f insulin, glucose and KCl(2) Insulin shock therapy has been used to treat schizophrenia .,Adverse Effects,Hypoglycemia Allergic reactionInsulin resistanceHypokalemia Lipoatrophy,Adverse Effects,1. Allergic reaction: foreign protein enter into human bodyInsulin has antigenicity, the slight reaction
23、includes local swelling, itch, ache. It rarely occurs urticaria, angioedema and anaphylactic shock. It 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 Effects,2. Hypo
24、glycemia （the most common and serious adverse）It is the result of an imbalance between glucose intake (e.g. missing a meal), glucose utilisation (e.g. unusual exercise) and insulin dose. The result is sympathetic activation and neuroglycopenia.,Adverse Effects,Patients and their families should be t
25、rained to spot the warning signs and how to treat hypoglycaemia, including possibly administration of glucagon if the patient loses consciousness.Treatment is by administration of carbohydrate orally to a conscious patient, or i.v. glucose or i.m. glucagon.,Adverse Effects,4.Hypokalemia: may occur i
26、n the acidosis patients who use a lot of insulin and glucose, it can lead to the patient death with abnormal heart beat. 5.Lipoatrophy: is the atrophy or hypertrophy of fat at the site of injection.,Insulin Resistance (INR),Insulin resistance is a prominent feature in obese individuals and in non-in
27、sulin-dependent diabetes.Some 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 Enhancers,Rosiglitazone（罗格列酮）Pioglitazone (吡咯列酮),Th
28、e Action of Insulin Action Enhancers,Improve insulin resistance，decrease hyperglycemia.Improve fat metabolism disorder.Prevent and treat the blood vessel complication of type II diabetes mellitus. Improve pancreatic B cell function.,Diabetes Oral Medications,SulfonylureasBiguanidesSulfonylureas and
29、biguanide combination drugsThiazolidinedionesAlpha-glycosidase inhibitorsMeglitinides,Oral Autidiabetic Drugs,Sulfonylureas (磺酰脲类) 甲苯磺酰脲（Tolbutamide）氯磺丙脲（Chlorpropamide）优降糖（Glibouclamide 格列本脲）格列吡嗪（ Glipizide 吡磺环己脲）格列齐特（Gliclazipe 达美康）糖适平（Glurenorm）,Oral Autidiabetic Drugs,Biguanides (双胍类）苯乙双胍（Phenfo
30、rmin 苯乙福明）二甲双胍（Metformin 甲福明）-glucosidase inhibiors (-葡萄糖苷酶抑制剂)阿卡波糖（Acarbose）,Sulfonylureas,physiological disposition The sulfonyureas are administered orally and undergo varying degrees of hepatic metabolism and renal elimination of the parent compound and metabolites. Most of the sulfonylureas are
31、 metabolized to inactive or less active compounds in the liver.,The Mechanism of Action,Sulfonylureas interact with receptors on pancreatic b-cells to block ATP-sensitive potassium channels.This, in turn, leads to opening of calcium channels.Which leads to the production of insulin.,The Pharmacologi
32、cal Effect of Sulfonylureas,1. Hypoglycemic Activity Sulfonylureas act primarily by increasing the secretion of insulin and secondarily by decreasing the secretion of glucagon.2. Antidiuresis effect: treat with diabetes insipidus.3. Decrease platelet adhesion reaction, stimulate plasminogen synthesi
33、s.,The Clinical Application of Sulfonylureas,Diabetes Mellitus：A sulfonylurea drug is often used to treat type II DM that cannot be controlled with dietary restrictions.Diabetes Insipidus：coadministrating with Hydrochlorothiazide can improve the effect,Adverse Effects of Sulfonylureas,HypoglycaemiaG
34、astrointestinal upsetsHypersensitivity: rashes etc.Weight gain: stimulation of appetite can be a problem in obese patients.,Drug Interactions,Sulfonylureas are heavily protein bound and their actions may be increased by other drugs (e.g. sulfonamides) that compete for the binding sites.,Biguanides,P
35、hysiological 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,Metformin is now considered a first-line drug for the treatment of type
36、 II DM.In patients with type II DM, it alleviates hyperglycemia primarily by decreasing the hepatic glucose output.It also appears to decrease glucose absorption from the gut and increase insulin sensitivity in skeletal muscle and adipose tissue.,Adverse Effects of Biguanides,The most common adverse
37、 effects of metformin are gastrointestinal disturbances.Patients with renal or hepatic disease, alcoholism, or a predisposition to metabolic acidosis should not be treated with metformin, because they are at increased risk of lactic acidosis.,Acarbose,Mechanisms and Pharmacological EffectsThe digest
38、ion of dietary starch and disaccharides such as sucrose is dependent on the action of -glucosidase, an enzyme located in the brush border of the intestinal tract.It thereby slows the digestion of starch and disaccharides, decreases the rate of glucose absorption, and lowers the postprandial blood gl
39、ucose concentration.,The Indications of Acarbose,Acarbose is used in the treatment of type II DM.It is administered with each meal and is particularly effective when given with meals containing large amounts of starch.,Adverse effects of Acarbose,The most common side effect of acarbose are increased flatulence and abdominal bloating.Acarbose may increase the oral bioavailability of metformin and cause a decrease in iron absorption.,Thanks!,
