胰岛素及口服降糖药课件

,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2020/9/14,#,胰岛素和抗糖尿病药,Insulin&Antidiabetic Drugs,1,Diabetes Mellitus,糖尿病,(diabetes mellitus),：,由遗传、环境等因素所致体内胰岛素分泌绝对或相对不足引起的代谢性疾病。,以慢性,高血糖,为特征。,显著高血糖的症状：多尿、多饮、多食及体重减轻。,2,Diabetes Mellitus,【,临床表现,】,1,、代谢紊乱综合症：胰岛素,高血糖多饮,多食,多尿,体重减轻；,2,、急性并发症：高渗性非酮症糖尿病昏迷，酮症酸中毒；,3,Diabetes Mellitus,【,临床表现,】,3,、慢性并发症：,（,1,）糖尿病肾病,（,2,）糖尿病视网膜病变,（,3,）糖尿病性心脏病变,（,4,）糖尿病性脑血管病变,（,5,）糖尿病神经病变,（,6,）眼的其他病变,（,7,）糖尿病足,4,ADA Classification of Diabetes,Type 1 DM,Type 2 DM,Other specific types of diabetes,due to other causes,genetic defects in,-cell function,genetic defects in insulin action,diseases of the exocrine pancreas,drug or chemical induced.,Gestational diabetes mellitus(GDM),Diabetes diagnosed during pregnancy.,Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.,Diabetes Care,26(Supp 1):S5-S20,2003.,Standards of Medical Care in Diabetes-2010.American Diabetes Association.Diabetes Care 33(1):S11-61,2010.,5,第一节 胰岛素,Insulin,胰岛,A,细胞分泌：胰高血糖素,B,细胞分泌：胰岛素,D,细胞分泌：生长抑素,相互产生旁分泌调节。,6,Charles Best(left)and Frederick Banting(right),Extracted insulin and treated dogs(1921),7,The photograph below is of a young girl aged 13 years suffering from diabetes.She weighs just 45lbs and her chances of surviving for much longer are very,very poor.She was one of the first patients to be treated with insulin extracted from the pancreases of slaughtered cattle.Much of the early work leading to the identification and extraction of insulin involved experiments using dogs and rabbits.,8,胰岛素,Insulin,Human insulin consists of 51 AA in two chains connected by 2 disulfide bridges(a single gene product cleaved into two chains during post-translational modification).,T1/2 5-10 minutes,degraded by glutathione-insulin transhydrogenase(insulinase)which cleaves the disulfide links.,Bovine insulin differs by 3 AAs,pork insulin differs by 1 AA.,Insulin is stored in a complex with Zn+2 ions.,9,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,10,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 forms of human insulin that work faster(Humalog and NovoLog)or slower(Lantus)than regular human insulin.,11,Seipke et al.,Diabetologia.,1992;35(suppl 1):A4.Lantus package insert.,Glargine rDNA origin,Asparagine at position A21 replaced by glycine,Provides stability in the acidic solution,Addition of two arginines at the C-terminus of the B-chain,More soluble at slightly acidic pH and less soluble at physiologic pH of subcutaneous tissue,microprecipitates at injection site,with slowed absorption and prolonged duration.,1,15,10,5,10,15,20,Asn,30,Gly,Arg,Arg,Substitution,Extension,A-chain,B-chain,5,10,15,20,25,1,12,Insulin,【,生理及药理作用,】,1.,代谢作用,糖代谢,：,促葡萄糖的转运、有氧氧化、无氧酵解、糖原合成，抑制糖原分解、异生,血糖；,脂肪代谢,：,促合成、抑分解游离脂肪酸,酮体,蛋白质代谢,：,促氨基酸转运、蛋白质合成，抑制蛋白质分解；,促,K,+,内流,，,提高细胞内,K,+,浓度。,13,Diabetes Mellitus,14,Insulin,【,生理及药理作用,】,2.,促生长作用,：,结构似生长因子，对胎儿生长，组织修复或再生尤为重要，与其促进蛋白质、脂肪、核酸等合成有关。,15,Mechanism of Insulin Action,16,Insulin,【,临床应用,】,1.,糖尿病 各型均有效。,型；,饮食及口服药物不能控制的,型（重症），,酮症酸中毒时；,合并感染、应激时；,全胰腺切除引起的继发性糖尿病。,2.,细胞内缺,K,+,（,GIP,）防治心梗时心律失常。,17,胰岛素,基本特征,18,Insulin,Syringe,Portable Pen Injector,Insulin Pumps,Inhaled Insulin,19,20,21,Glargine,21,22,Fast action of insulin in the abdomen,22,Pre-mixed Insulin,Pre-mixed combinations of short and intermediate acting insulins(biphasic),Cloudy(needs re-suspending),5 different combinations(10,20,30,40,50),e.g.30/70 Mixture =30%fast acting,+70%intermediate acting,Onset 30 minutes,Peak 2-8 hours,Duration up to 24 hours,23,Normal Insulin Profiles,Mealtime insulin,Background insulin,Blood sugar,Daily Requirements,Breakfast,Lunch,Evening Meal,24,Examples of three regimens that provide both prandial and basal insulin replacement.B=breakfast;L=lunch;S=supper.,25,Insulin,【,不良反应,】,1.,血糖过低,严重可致低血糖昏迷，处置不当可致死。,2.,过敏,一般轻微、短暂，偶致过敏性休克。,3.,胰岛素耐受（抵抗性）,急性：多见于应激时，抗胰岛素物质增加。,慢性：体内生成胰岛素抗体。,4.,脂肪萎缩,（注射部位，女,男）。应用高纯度反应。,26,第二节,口服降糖药,磺酰脲类：,甲苯磺丁脲，氯磺丙脲，格列苯脲，,格列喹酮，格列齐特，格列吡嗪；,双胍类：,二甲双胍,胰岛素增敏剂：,罗格列酮,吡格列酮,恩格列酮,-,葡萄糖苷酶抑制剂,：阿卡波糖,其他,27,Type 2 Diabetes,80%are obese,10%non-obese,10%unstable:may look more like a Type 1 Diabetic,28,Release of insulin that occurs in response to an IV glucose load in normal subjects and diabetic patients.,29,Oral Hypoglycemic Drugs,磺酰脲类,：,-sulfonylureas,甲苯磺丁脲,(tolbutamide,，,D-860,甲糖宁）,氯磺丙脲（,chlorpropamide,）,格列本脲（,glibenclamide,，优降糖）,格列喹酮（,gliqridone,，糖适平）,格列齐特（,gliclazide,，达美康）,30,Oral Hypoglycemic Drugs -sulfonylureas,【,药理作用与机制,】,.,降血糖,：对功能尚存者促,B,细胞释放,Insulin,；增强其作用（降低代谢）；久用促生长抑素释放，使胰高血糖素。,.,抗利尿,：,氯磺丙脲,有此作用，可用于尿崩症。,.,影响凝血功能,：格列齐特，格列波脲：降低血小板粘附力；刺激纤溶酶原的合成，降低微血管对血管活性胺类的敏感性预防、减少并发症。,31,【,作用机制,】,主要作用是刺激胰岛素分泌：,胰岛,细胞膜含有,磺酰脲受体,及与之相偶联的,ATP,敏感的钾通道,I,k(ATP),，以及,电压依赖性的钙通道,。当磺酰脲类药物与其受体相结合后，,可阻滞,I,k(ATP),而,阻钾外流,，致使细胞膜去极化，增强电压依赖性钙通道开放，,胞外钙内流。胞内游离钙浓度增加,后，触发胞吐作用及,胰岛素的释放,。,32,Mechanism of Insulin Release in the Pancreas,33,Oral Hypoglycemic Drugs -sulfonylureas,【,体内过程,】,口服吸收好，,2-6h,达峰浓度，血浆蛋白结合率高，格列美脲达,99.5%,，肝代谢、肾排。除氯磺丙脲外，消除快。,氯磺丙脲大部分原形肾排。易蓄积。,34,Oral Hypoglycemic Drugs -sulfonylureas,【,临床应用,】,1.,糖尿病：胰岛素功能未全丧失的轻、中度病人。,2.,尿崩症（氯磺丙脲）。,35,Oral Hypoglycemic Drugs -sulfonylureas,【,不良反应,】,胃肠、肝损伤（氯磺丙脲更易发生），应定期查肝功。,低血糖，老年、肝肾功能不良者易发生。,少数：过敏、共济失调、白细胞减少，血小板减少等。,长效制剂突发性严重低血糖死亡，不可逆脑损伤，需反复注射,GS,解救。,36,Oral Hypoglycemic Drugs -sulfonylureas,【,相互作用,】,蛋白结合率高，故与,Aspirin,、磺胺、保泰松、青霉素、消炎痛、香豆素等合用因竞争蛋白而作用增强。,酶诱导剂、抑制剂也影响本类药作用。氯磺丙脲可与有机酸竞争肾小管分泌排泄。,37,Oral Hypoglycemic Drugs,双胍类,：,-biguanides,二甲双胍（甲福明、降糖片）,丁双胍（丁福明）；,苯乙双胍（苯乙福明、降糖灵）,有些国停用。,38,Oral Hypoglycemic Drugs -biguanides,【,药理作用,】,仅降糖尿病患者血糖，对正常人无影响。,.,促组织摄取葡萄糖糖；,.,增加无氧酵解；,.,减少肠道,GS,吸收；,.,减少肝内糖异生；,.,增强胰岛素作用；,.,拮抗胰高血糖素。,二甲双胍还能降低高血脂病人甘油三酯、胆固醇、,LDL,、,VLDL.,39,Oral Hypoglycemic Drugs -biguanides,【,临床应用,】,用于轻、中度,II,型糖尿病，特别是有胰岛素抵抗的肥胖患者。,也可与胰岛素及,/,或磺酰脲类合用于中、重度病人 增强疗效，减少胰岛素用量。,40,Oral Hypoglycemic Drugs -biguanides,【,不良反应,】,一般：口臭，胃肠道反应发生率高。抑制,VB,12,吸收巨幼红细胞贫血。,严重：,乳酸性酸中毒，酮尿,。,禁用于：肝、肾功能不良，慢性心、肺功能不全，重度贫血，尿酮体阳性者。,苯乙双胍控制使用（每日不超过,75mg,）。,41,胰岛素增敏剂,：,噻唑烷二酮类,-thiazolidinediones,一类新型的治疗糖尿病的药物。,吡格列酮,(pioglitazone),、,罗格列酮,(rosiglitazone),、,恩格列酮,(englitazone),、,环格列酮,(ciglitazone),42,Oral Hypoglycemic Drugs -thiazolidinediones,1.,降血糖,改善胰岛素抵抗性，降低血糖、三酰甘油，提高肌肉、脂肪组织对胰岛素的敏感性。,机制未明，可能是过氧化物增殖体活性,受体,(PPAR-),的激活剂。,2.,改善脂肪代谢紊乱,纠正胰岛素抵抗者的脂质代谢异常。降低血中游离脂肪酸、三酰甘油、提高,HDL,。,用于他药疗效不佳的,型病人，尤胰岛素抵抗者，单用或与磺脲类或胰岛素合用。,不良反应少，低血糖发生率低。,43,44,thiazolidinediones,2.,改善脂肪代谢紊乱,纠正胰岛素抵抗者的脂质代谢异常。降低血中游离脂肪酸、三酰甘油、提高,HDL,。,用于他药疗效不佳的,型病人，尤胰岛素抵抗者，单用或与磺脲类或胰岛素合用。,不良反应少，低血糖发生率低。,45,Oral Hypoglycemic Drugs -,-glucosidase inhibitors,阿卡波糖,（,acarbose),，,伏格列波糖,(voglibose),【,药理作用,】,在小肠竞争抑制,-,葡萄糖苷酶延缓葡萄糖产生血糖。,【,临床应用,】,轻，中度,型病人，单用餐后血糖值，波动。,用胰岛素，磺酰脲治疗效果不佳时，可加用本药。,46,Oral Hypoglycemic Drugs -,-glucosidase inhibitors,【,不良反应,】,产气腹胀，嗳气，排气增加。,慎用或禁用于：溃疡病，肠道炎症，孕妇，乳妇。,本身不宜低血糖，但与其他降糖药合用协同降糖低血糖，需补葡萄糖。,47,糖尿病的治疗原则,饮食控制,：,控制进食的总热量，,适量的蛋白质、脂肪和碳水化合物,运动疗法,：,适当的运动，控制体重,药物疗法,：遵医嘱，,教育,：学习糖尿病相关的知识,监测血糖水平,：,48,49,写在最后,成功的基础在于好的学习习惯,The foundation of success lies in good habits,谢谢,大家,荣幸,这,一路，与你同行,ItS An Honor To Walk With You All The Way,讲师,：,XXXXXX,XX,年,XX,月,XX,日,