AntidiabeticDrugsInsulinAndOralAntisiabeticDrugs分析教学课件教学课件

1、Antidiabetis DrugsInsulin and Oral Antisiabetis Drugs第1页，共50页。Overviewdiabetes 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.第2页，共50页。Ov

2、erviewmorbidity： 300,000 people0.67 40 years old2.531994 2564 years old2.512019 2075 years old3.21201913,500,000 people (all over the word)Prediction:202530,000,000 people第3页，共50页。OverviewCause by many of reasons chronic hyperglycemiametabolic disorderHyperglycemia a group of diseases characterized

3、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第4页，共50页。OverviewDiabetes Melli

4、tus long-term disease multisystem damagefunctional defect and failureSeverediabetic ketoacidosiscomaEtiopathogenisis heredity, autoimmunity, environmental factorDiagnosis：urine glucose, blood glucose第5页，共50页。OverviewTherapy: early treatment, long term therapy, combined therapy and therapeutic measur

5、e individualizationPurpose：blood glucosenormal, to correct metabolic disorder, increase in life span, decrease deathPrinciple：persevere (cannot cure)第6页，共50页。OverviewDrink and food：gross calorific valueKgheight105Daily Kg105125.5K（2530Kcal） (2540Kcal)Therapy：before meals第7页，共50页。Substance Metabolic

6、Disorder and Clinical Situation of Diabeticglucose utilization disorderglucose decomposition decreaseenergy insufficientstarvation condition polyphagia hyperglycemia glucosuria hypertonicity diuresis polyuriaprotein degradation accentuation athrepsy dehydration thirstpolydipsia lipolysis excessive h

7、yperosmolar nonketotic diabetic coma ketonuria lipolysis excessive ketoplasia excessiveKetonemiaacidosis coma第8页，共50页。Classification of Diabetes Mellitus (WHO 2019)Type: insulin dependent diabetes mellitus，IDDMType: non-insulin dependent diabetes mellitus，NIDDMOthers： secondary diabetes第9页，共50页。 Dia

8、betes MellitusType 1 Diabetes- cells that produce insulin are destroyed - results in insulin dependence- commonly detected before 30Type 2 Diabetes- blood glucose levels rise due to 1) Lack of insulin production2) Insufficient insulin action (resistant cells)- commonly detected after 40- effects 90%

9、- eventually leads to -cell failure (resulting in insulin dependence)Gestational Diabetes 3-5% of pregnant women in the US develop gestational diabetes第10页，共50页。Diabetes - InsulinDiscovered in 1921 by Banting and BestConsist of A & B chains linked by 2 disulfide bonds (plus additional disulfide in A

10、) A = 21amino acids B = 30 amino acids第11页，共50页。Diabetes Insulin(synthesis, storage, secretion)ZnProduced 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 reticu

11、lum generates proinsulinWithin the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulinStored as granules第12页，共50页。Diabetes Insulin(Biochemical Role)Tyrosine Kinase receptors are the locks in which t

12、he insulin key fits- Involved in signal transduction(insulin hormone being 1st messenger)第13页，共50页。Diabetes Insulin(Mechanism)第14页，共50页。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 distinguis

13、hes them and replacing it with the human version.Insulin drug evolution第15页，共50页。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 technol

14、ogy 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. 第16页，共50页。Physiological disposition of insulin Insulin must be administered parenterally, usually by s.c. injection.It is metabo

15、lised by the liver and the kidney and has a half-life of 9-10 minutes.To extend its period of action, show release preparations have been developed.第17页，共50页。Types of insulin Regular insulin Insulin analogs Pre-mixed insulin Short peptide mimics第18页，共50页。Insulin affects many organs: It stimulates sk

16、eletal muscle fibers. It stimulates liver cells. It acts on fat cells It inhibits production of certain enzyme. In each case, insulin triggers these effects by binding to the insulin receptor.glucoseuptakeglycogen synthesisprotein synthesis amino acids uptake enzymeproductionglycogenbreakingfat synt

17、hesis第19页，共50页。The Pharmacological Action of InsulinIt 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 glucose (gluconeogensis) in the liver.It inhibits breakdown of lipids.It stimulates protein

18、 synthesis.It stimulates some cell ion transport mechanisms (e.g. Na+/K+-ATPase).第20页，共50页。Who need insulin medicine?Type I (insulin dependent) diabetes patients whose body produces no insulin.Type 2 diabetes patients that do not always produce enough insulin. diabetic ketoacidosis, hypertonicity hy

19、perglycemia coma and lactic acidosis accompany with hyperglycemiadiabetes mellitus accompany with severe infection, wasting disease, hyperpyrexia, pregnancy, wound and operation.secondary diabetes is caused by pancreatectomy.第21页，共50页。Preparations and Clinical Use of insulinShort-acting preparations

20、.Intermediate acting preparations.Long acting preparations.New very-short- and very-long-acting insulin analogues.第22页，共50页。第23页，共50页。Insulin RegimensDose and choice of preparations must be determined for each patient individually.Many patients will monitor their blood glucose at home and make minor

21、 adjustments in dose accordingly.第24页，共50页。Insulin RegimensDiabetic 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, additional glucose may be given to allow continued

22、insulin administration without hypoglycemia (low blood sugar). 第25页，共50页。Insulin RegimensHyperpotassaemia: 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) Insu

23、lin shock therapy has been used to treat schizophrenia .第26页，共50页。Adverse EffectsHypoglycemia Allergic reactionInsulin resistanceHypokalemia Lipoatrophy第27页，共50页。Adverse Effects1. Allergic reaction: foreign protein enter into human bodyInsulin has antigenicity, the slight reaction includes local swe

24、lling, 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.第28页，共50页。Adverse Effects2. Hypoglycemia （

25、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.第29页，共50页。Adverse EffectsPatients and their families should be tra

26、ined 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.第30页，共50页。Adverse Effects4.Hypokalemia: may o

27、ccur in 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.第31页，共50页。Insulin Resistance (INR) Insulin resistance is a prominent feature in obese individual

28、s and in non-insulin-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.第32页，共50页。Diabetes-Insulin Action EnhancersRosiglitazonePiogl

29、itazone第33页，共50页。The Action of Insulin Action EnhancersImprove 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. 第34页，共50页。Diabetes Oral MedicationsSulfonylureasB

30、iguanidesSulfonylureas and biguanide combination drugsThiazolidinedionesAlpha-glycosidase inhibitorsMeglitinides第35页，共50页。Oral Autidiabetic DrugsSulfonylureasTolbutamideChlorpropamideGlibouclamideGlipizideGliclazipeGlurenorm第36页，共50页。Oral Autidiabetic DrugsBiguanidesPhenformin Metformin-glucosidase

31、inhibiors Acarbose第37页，共50页。Sulfonylureasphysiological 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 metabolized to inactive or less active compounds i

32、n the liver.第38页，共50页。The Mechanism of ActionSulfonylureas 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.第39页，共50页。The Pharmacological Effect of Sulfonylureas 1. Hyp

33、oglycemic 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 synthesis. 第40页，共50页。The Clinical Applicat

34、ion of SulfonylureasDiabetes 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第41页，共50页。Adverse Effects of SulfonylureasHypoglycaemiaGastrointestinal u

35、psetsHypersensitivity: rashes etc.Weight gain: stimulation of appetite can be a problem in obese patients.第42页，共50页。Drug InteractionsSulfonylureas are heavily protein bound and their actions may be increased by other drugs (e.g. sulfonamides) that compete for the binding sites.第43页，共50页。BiguanidesPh

36、ysiological 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.第44页，共50页。Mechanisms and Pharmacological EffectsMetformin is now considered a first-line drug for the treatment of type 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