消化系统疾病药物治疗课件.pptx

1、消化系统疾病药物治疗.分类（1）.抗溃疡&胃-食管反流:抗酸药,H2-antigonists,PPI；膜保护剂,铋剂,铝制剂 IBD:5-ASA&4-ASA,SASP,急性胰腺炎；胰酶替代剂 肝炎：贺普汀 Gallstone:胃肠动力药物（分类2）止泻药物:胆盐结合药物 平滑肌松弛药物 抗便秘药物 促动药物 抗动力药物 抗幽门螺杆菌药物（分类3）抗生素GI 相关药物（分类4）导泻剂 镇静剂 硬化剂 止血药物 造影剂 生长抑素 抗血清素 免疫抑制剂:Cy.A,FK506,CorticoteroidsHP96/NK/30The mechnism of gastric acid secretionG

2、astrinGastrinHistamineHistamineAcetylcholineAcetylcholineCaCa2+2+HCIProtein kinasesProtein kinasesProteinkinasesProteinkinasesCa2+Ca2+Release of Ca2+from intracellular stores Release of Ca2+from intracellular stores cAMPcAMPProteinkinasesProteinkinasesRelease of Ca2+from intracellular storesRelease

3、of Ca2+from intracellular storesAChACh(M(M3 3)Ca2+Ca2+H K K Cl Cl HClAcidAcidpumppumpH2-Receptor Antagonist(H2-RA)西米替丁 雷尼替丁 法莫替丁 尼扎替丁 罗沙替丁H2-RA A structural analogue of histamine with an aliphatic side chain attached to an imidazole ring.组胺 cAMP 激活 H，KATPase西米替丁的用药技巧西米替丁的用药技巧F抑制基础胃酸分泌 F与 H2-receptor

4、可逆结合 F快速静脉注射可致心动过缓F抗酸药会抑制其口服吸收F应激出血使用后不能控制 pH，要考虑败血症可能F某些药物低调 cimetidine作用.F男性乳房发育停药 3 months后解决 Ranitidine的技巧F唯一用于治疗GERD的 H2-antagonist(FDA)F未发现抗雄激素作用F单分子作用比 cimetidin强 510 倍FRanitidine iv 可使 sGPT升高F慢性肝病者使用时生物活性无影响.F HP根除治疗时与抗生素合用 Famotidine的技巧 西米替丁的25倍 Ranitidine 的10倍 PU治疗疗效与西米替丁、Ranitidine相同 对其他药

5、物的血清浓度无影响 未发现抗雄激素作用 5%的病人可发生头痛.不影响酒精吸收 质子泵抑制剂（PPI）奥美拉唑 达克普隆 畔妥拉唑 波立特质子泵抑制剂(PPI)直接与胃酸分泌的最后一步 H+/K+adenosinetriphosphatase(ATPase)结合,强力抑制胃酸分泌。Omeprazole,Lansolazole,Pantolazole，Pariet质子泵抑制剂 抑制基础胃酸和最大胃酸分泌 由酸敏感包膜包裹 使血清胃泌素升高质子泵抑制剂使用指症 Zollinger-Ellison综合症 反流性食管炎 消化性溃疡铋 剂 铋盐具有止泻、保护胃粘膜和选择性抗菌作用 铋 盐 溶液时可部分吸收

6、 pH6时沉淀 和受损组织易结合 抑制某些细菌生长 胃肠蠕动下降 促进胃肠蠕动 与蛋白酶鏊合，降低蛋白酶活性 Aspirin样作用*CBS抑制HP浓度 90%)溃疡愈合迅速，症状消失快)病人依从性好)不产生耐药性)疗程短，治疗简便)价格便宜全国HP科研协作组推荐方案 PPI+两种抗生素：PPI标准剂量+Cla.0.25+Amo.1.0 bid.X1周PPI标准剂量+Cla.0.5+甲硝唑0.4 bid.X1周 铋剂+两种抗生素：铋剂标准剂量+四环素 0.5+甲硝唑0.4 bid.X 2周铋剂标准剂量+Amo.0.5+甲硝唑0.4 bid.X 2周铋剂标准剂量+Cla.0.25+甲硝唑0.4 b

7、id.X 1周动力药物Metoclopramide 胃复安Dompenridone吗叮啉Cisapride西沙比利Erythromycin红霉素Metoclopramide 最早的动力制剂，极大的增强了临床医师治疗胃肠动力改变的能力胃复安 普鲁卡因酰胺的衍生物 多巴胺-receptor阻滞剂 升高 LESP,促进食管和胃窦蠕动 幽门括约肌松弛 缩短近端小肠的通过时间 胃复安指征 糖尿病胃轻瘫 胃-食管反流 化疗引起呕吐 小肠X线检查胃复安禁忌症 肠梗阻 胃肠道穿孔 癫简 嗜铬细胞瘤（Pheochromocytoma）椎体外系症状胃复安用法 防止化疗引起的呕吐,a 10 mg dose of 1

8、2 mg/kg/day is used,with 0.5 to 1.0 mg/kg given every 3 to 4 hours subsequently while the patient is receiving chemotherapy.技 巧 糖尿病人注意空腹血糖，调整胰岛素 眩晕和CNS性忧郁可因同时服用其他多巴胺受体阻滞剂而加重 肌肉震颤可用苯海拉明对抗吗叮啉特异性多巴胺受体阻滞剂，无胃复氨的CNS副作用吗叮啉药理学 峰值:po(13%).&im后 1530 mins.纳肛后(90%)12hr.组织中浓度是血浆浓度的28 times 血浆中90%与蛋白结合 脑、乳汁、胎盘中浓度

9、低吗叮啉 机理 胃肠道多巴胺受体亲和力较高 食管:LESP 升高到1520 mm Hg 胃底和幽门松弛 胃窦和十二指畅收缩 有利固体和液体食物的排空 吗叮啉止 吐 Providing antagonism of apomophine-induced emesis at the level of the chemoreceptor trigger zone 增加胃排空 吗叮啉指 征 减轻胃排空延迟和胃食管反流导致的下列症状:嗳气,腹胀,饱胀，烧灼感,恶心,呕吐吗叮啉副反应 CNS:泌乳素升高:FM.男性乳房发育和阳痿亦有报导。Circulation system:西沙比利A benzamide

10、derivative 无抗多巴胺作用第一个对结肠有促动力作用药物西沙比利Pharmacology 消化道吸收较好(95%).血浆峰值出现于 1.52 hr.首相代谢(liver metabolism)血浆中90%与蛋白结合 脑和胎盘中浓度低。动物实验中可进入乳汁西沙比利机理 通过(5-HT4)receptor非直接胆碱能机制来促进乙酰胆碱的释放.食管:LESP 升高到1520 mm Hg 胃底和幽门松弛 胃窦和十二指畅收缩 结肠:促推进作用 小肠:增加小肠运动的幅度和频率西沙比利指征 GERD 胃瘫痪胃瘫痪 FD 术后盲襻术后盲襻 慢性便秘慢性便秘 慢性假性肠梗阻慢性假性肠梗阻 其他:IBS:

11、胆汁反流性胃炎 脊髓损伤后肠功能不全 DU 维持治疗.红霉素 机理 增加胃动素浓度，并直接作用于胃动素受体.红霉素 胃瘫痪 术后应用:IV促进术后胃排空延迟.others:vagatomy,scleroderma,chemotherapy Roux en Y symdromGERD,anorexia nerosa and chronic idiopathic intestinal pseudo-obstructionErythromycinSide effect 恶心、呕吐、腹痛和腹泻.静脉炎.*诀窍 对 糖尿病者促动力作用尤佳.静脉使用较口服效佳.在其他药物无效时使用.返流性食管炎胃食管返流

12、炎的内镜诊断（Allison)鳞状上皮炎症 柱状上皮炎症发红 粘膜表面炎症孤立浅表炎症 急性粘膜糜烂溃疡融合，无狭窄 亚急性局限性溃疡溃疡融合、狭窄、易扩张 慢性穿透性溃疡溃疡融合、狭窄、不易扩张溃疡融合、狭窄、纤维化波及纵隔返流性食管炎分型（9th WGC)分型 征特 I 稀疏、垂直糜烂或溃疡 II 融合性溃疡 III 溃疡融合成环状 IV 疤痕、狭窄 食管功能检查 1.食管压力测定 2.酸返流试验 3.酸清除试验 4.酸灌注试验 5.食管闪烁照相术 小时pH监测溃疡性结肠炎的药物治疗上海市消化疾病研究所吴叔明教授炎症性肠病(IBD)病因不明 疾病难于治疗而易于复发.Criteria for

13、 Severe Colitis1.Diarrhea:6 stools/per day or more with macroscopic blood2.Fever:Mean evening temp.37.5C or a temp.of 37.8C on at least 2 days out of 4.3.Erythrocyte sedimentation rate elevation 304.Anemia:Hemoglobin level 90/min Truelove-Lancet 1974;1:1067Sulfasalazine(SASP)SASP:5-aminosalicylic ac

14、id(5-ASA)和 sulfapyridine(SP)二部分 2030%SASP 在上 GI吸收,经胆汁和尿液排泄 肠道细菌将 SASP裂解为 SP和5-ASA 脂溶吸收的 SP:side-effect 脂溶吸收差的SASP留在结肠Adverse Effects of SulfasazineDose related nausea vomiting anorexia folate mal-ab.Headache alopecia Not dose related skin rash hemolytic anemia agrannulocytosis fibrosing alveolitis h

15、epatitis male infertility colitis溃疡性结肠炎的药物治疗 各种剂型 膜包被 控释型 偶合型 Asacol Pentasa Osalazine Claversal Balsalazide Salofalk Mesalazine Rowasa Mechanisms of Steroid Action-IBD Stabilizes lysosomal membranes Reduces capillary permeability Function as inhibitors of chemotaxis and phagocytosis Impairs cell-me

16、diated immunity in experimental models Administration and Dosage Oral Dosage Tapering Intravenous Bolus or continuous infusion Topical Position,Dosage,DurationCommonly Used Glucorticoidds Equivalent Mineralo-Glucocorticoid Glucocorticoid corticoidDuraton of action Potency Dose(mg)Action Short-acting

17、 Cortisol 1 20 yes Cortisone 0.8 25 yes Prednisone 4 5 y/no Prednisolone 4 5 y/no Methylpredinisolone 5 4 y/noIntermediate-acting Triamcinolone 5 4 noLong-acting Betamethasone 25 0.60 no Dexamethasone 30 0.75 no75 nofibrosing alveolitis最早的动力制剂，极大的增强了临床医师治疗胃肠动力改变的能力Blocking pepsin bind to ulcer base

18、antibiotical effect脂酶含量:the basis of product potency for relief of steatorrheaALT高于正常，胆红素低于50umol/lmale infertilityCRF者和老人无须剂量调整含质子泵抑制剂或H2受体阻滞剂（H2RA）Bolus or continuous infusion通过(5-HT4)receptor非直接胆碱能机制来促进乙酰胆碱的释放.Ranitidine iv 可使 sGPT升高Dosage return to previous high levelA,FK506,Corticoteroidsof tab

19、lets,comliance and the cost should be considered.免疫抑制药物 药名 作 用 适应症 不良反应 用量硫唑嘌呤 干扰嘌呤的 缓解期的 胰腺炎、BM 12 生物合成 维持 抑制，过敏 6-MP 肝内转化 缓解期的 胰腺炎、硫唑嘌呤 维持 抑制，过敏 环胞素 细胞免役 对皮质激素 肝毒性 口服：5 抑制剂 疗效不好者 静滴:4UC直肠炎的治疗 推荐治疗：5ASA栓剂或类固醇灌肠的表面治疗。5-ASA有更高的缓解率，激素布地奈的为首选。23周有所缓解。缓解治疗：缓解后减至23次/周 栓剂治疗不耐受者口服SASP或美沙拉嗪远段溃疡性结肠炎（3040厘米处乙

20、结肠）轻、中度的早期：5ASA栓剂或类固醇灌肠的表面治疗。夜间灌肠（美沙拉嗪4克/天34周后每3天1次。无效时考虑加用氢考晨间灌肠。口服治疗：每天SASP 1+美沙拉嗪1.2+奥沙拉嗪。无效时每天SASP 46+美沙拉嗪4.8+奥沙拉嗪3。重度：5ASA+强的松4060毫克左半结肠炎和全结肠炎 治疗效应和剂量相关 中度：46克SASP或美沙拉嗪克 重度和无效者：强的松4060毫克，710天后减量。重度和爆发性结肠炎 主治方式：强的松30毫克/BID或甲强龙16毫克TID 直肠症状为主：加用5ASA和氢考灌肠 类固醇IV1014天无效者：手术或环孢素A治疗。对 糖尿病者促动力作用尤佳.Hypoa

21、lbuminemiaA low-fat diet should be given for severe pancritic insufficiency,if steatorrea is not reversed completely by replacementfibrosing alveolitis60 no不改变pH,对蛋白酶无影响Pearls&PitfallReducing pain in inj.消化性溃疡现代和传统治疗比较2.消化不良、恶心、呕吐、腹泻症状治疗Misoprostol作用机理预防 NSAID引起的粘膜损伤较西米替丁为佳类固醇治疗无效的UC 最大剂量口服和表面治疗的5-A

22、SA以及类固醇治疗无效者。2/3的这类病人在使用免疫抑制剂后可获缓解。硫唑嘌呤或6-巯基嘌呤50毫克/天渐增至硫唑嘌呤毫克或6-巯基嘌呤毫克/kg/天 6个月无效，可改用毫克25毫克，812周见效。类固醇依赖的UC 类固醇减量后复发病例 可应用硫唑嘌呤或6-巯基嘌呤，缓解后撤除类固醇，仍应维持免疫抑制治疗。Crohns病的药物治疗口腔Crohns病的治疗1.含氢考的甲基纤维素、果胶、或明胶作表面治疗，2/3的病人有效。2.硫糖铝表面治疗。胃十二指肠Crohns病的治疗 甲基纤维素粒剂包裹的缓释美沙拉嗪（Pentasa）部分在近端小肠释放，可用之。Pentasa无效时，类固醇治疗。类固醇依赖或类

23、固醇无效：可应用硫唑嘌呤或6-巯基嘌呤活动性回肠炎、回结肠炎和结肠炎 SASP作用有限 5-ASA治疗：美沙拉嗪4克/天一般有效。从克/天开始。无改善者加用环丙沙星克，一天二次。5-ASA无反应或伴全身症状：强的松4060毫克/天Crohns病局灶性腹膜炎的治疗 Crohns病局灶性腹膜炎指患者出现发热、腹痛腹膜刺激症状、白细胞增多。甲硝唑+第二代头孢菌素；青霉素+庆大霉素 是否使用类固醇药物尚有争议Crohns病小肠梗阻的治疗 胃肠减压+TPN+类固醇治疗 无效者手术治疗Crohns病的维持缓解治疗 Crohns病的维持缓解治疗：5-ASA、类固醇 5-ASA的作用不大 类固醇作用不明 止泻

24、药支持治疗：上述治疗无反应且无全身症状，洛呱丁胺和消胆胺控制腹泻有效类固醇无效和依赖的Crohns病 硫唑嘌呤或6-巯基嘌呤：50毫克/天，可每月增加25毫克，直至最大剂量。治疗36个月有效 硫唑嘌呤或6-巯基嘌呤无效：MTX或环孢霉素 抗肿瘤坏死因子-A嵌合抗体输注Crohns病瘘管的治疗 复发率高，先试用药物。甲硝唑1020毫克/公斤/天 可应用6-巯基嘌呤 静注环孢霉素 抗肿瘤坏死因子-A嵌合抗体输注Crohns病肛周病和瘘管的治疗 甲硝唑1020毫克/公斤/天 甲硝唑和局部切除无效：可应用6-巯基嘌呤 抗肿瘤坏死因子-A嵌合抗体输注Pearls and Pitfall-IBDIBD f

25、lare during pregnacy IBD flare may be detrimental to the outcome of pregnancy?Steroid should be used to enhance a favorable outcome:No perinatal or fetal adverse effects No fetal&newborn HPA(Hypopituitary adrenal axis)Appropriate routes&dosage Mogadam-Gastroenter.1981;80:72Pearls and Pitfall-IBD Pat

26、ient with either psychiatric disease Not affect the risk of onset and develop Hypoalbuminemia Reduce the dosage to low side-effect and toxicity(nonprotein-bound steroid)IBD flare during dosage tapering Dosage return to previous high level No inprovement in once daily usage Splitting regiment could b

27、e tried Pearls and Pitfall-IBD Retard growth in child Steroid therapy be avoided in kid 55岁2）WBC160003）血糖200mg%4）LDH350U/L5）AST250U%48小时时6）HCT下降10%以上7）BUN升高5mg%血钙低于8ng%PaO260mmHg碱缺失超过4mmol液体积聚量6000ml急性胰腺炎的CT诊断CT对重症胰腺炎的早期识别和预后判断有使用价值，“脂肪岛”的出现与继发感染关系密切。CT分级 A级：正常 B级：局限或弥漫的胰腺增大，胰腺内少量液体积聚，轮廓不规则。非出血性腺体增强

28、。C级：胰腺异常显象模糊，条纹样改变。D级：单个胰外液体积聚。E级：两个以上胰外液体积聚 F级：大量气体和液体积聚于胰腺和邻近部位，累及腹膜后间隙。急性胰腺炎 有待证实或有限作用的药物：抗酸剂、抗胆碱能药物、H2-受体拮抗剂镇静剂、胰高糖素、降钙素、生长抑素、加压素、丙基硫氧嘧啶、抑肽酶、加贝脂、肝素、抗生素、激素、前列腺素慢性胰腺炎胰腺炎的分类1963年马赛分类：急性胰腺炎 急性复发性胰腺炎 慢性复发性胰腺炎 慢性胰腺炎慢性胰腺炎的分类1988年罗马分类1.慢性钙化性胰腺炎；2.慢性阻塞性胰腺炎3.慢性炎症性胰腺炎慢性胰腺炎的确诊标准（1a）腹部B超：胰腺组织内有胰石存在（1b）CT：胰腺内

29、钙化，胰石存在（2）ERCP胰管不规则扩张、不均匀；主胰管部分或完全阻塞（3）分泌试验 重碳酸盐胰酶分泌减少（4）组织学检查（5）导管上皮增生不典型增生、囊肿形成胰脂酶胰腺外分泌不足导致脂肪泻 慢性胰腺炎导致腹痛Pancrelipase-Pharmacology 脂酶含量:the basis of product potency for relief of steatorrhea pH4不可逆性失活 Enteric-coated tablet:the coat dissolved at pH 6.(Poor bioavailability)Coated microspheres in caps

30、ule:affected by gastric empty of spheresSuggested Regimen for Pancreatic Enzyme Replacement1.Begin with a preparation providing a total of 20,000 to 40,000 lipase units per meal.2.Enteric-coated formulations work well for control or steatorrhea,but the nonenteric release protease better in the duode

31、num and are preferred for pain control.3.The preparation should be taken at the beginnning of a meal or throughout the meal for mal-absorption 4.for pain control,a nighttime dose be givenSuggested Regimen for Pancreatic Enzyme Replacement5.If nonenteric-coated enzymes are used and no clinical improv

32、ement occurs,add one 500 mg tablet of SB before and after meals,and with any nighttime enzymes.6.If there is still no improvement,consider:a.Adding a PPI or an H2-blcker b.Is the Dx correct?c.Small-bowel bacteria overgrowth may be present Pearls&Pitfall1.Tx.of stearorrhea is effective with high-lipa

33、se microsphere preparations.2.Tx.for pain relief is best by traditional uncoated preparation with high protease and attention to good acid neutralization.3.Bioavailability of the uncoated is uncertain in postgatrectomy due to rapid gastric empty4.Acid neutralization is important in cystic fibrosis.P

34、earls&Pitfall5.A low-fat diet should be given for severe pancritic insufficiency,if steatorrea is not reversed completely by replacement 6.SB may make the coat dissolved prematurely7.A high-fiber diet makes replacement less effective.8.Measuring Tx.response in 34 Wks later.Steatorrhea improve as mal

35、nutrition corrected.Pearls&Pitfall9.The magnesium or calcium form soaps with free fatty acids worsening steatorrhea.10.Replacement regimen is a life-long threrapy,No.of tablets,comliance and the cost should be considered.乳果糖LactuloseA synthetic disaccharide analogue of lactase acts as a laxative by

36、stimulating colonic peristalsis.Lactulose The most important measures in the management of hepatic encephalopathy are eliminating exogenous sources of ammonia by restricting dietary protein,controlling gastrointestinal bleeding ane reducing the number of ammonia-producing enteric bacteria.LactuloseM

37、echnism It is hydrolyzed into galactose and fructose by bacteria in colon.The monosaccharides breakdown to hydrogen,lactate,and short free acids.Acids enhanced colonic acidification,stimulated motility,inhibited coliform growth and ammonia production and increased fecal ammonia secretion.Lactulose D

38、osage&Administration1.3040 ml 3/d ,dosage may be adjusted so that patient produces two or three soft stool per day.2.Enema retention:300 ml lactulose with 700 ml water or NS is gaven per rectum and held at least 20 mins.Lactulose Side Effects Gaseousness,abdominal distention,flatulence,belching,and

39、abdominal cramping.Pearls&Pitfall Other measurement s should be included Retention enema may be used for patients at risk of aspiration from CNS abnormality.The addition of neomycin may benefit those who continues manifest CNS changes.Hypokalemia&hypernatremia was noted in chronic use.Cautious usage

40、 in DM.Antidiarrheal AgentsAntidiarrheal AgentsKaolin&Pectin Nonspecific absorbent Only subjective benefit in diarrhea Not used in intestinal obstruction or kid 3years Absorbing concomitant medication Electrolytes disorder sould be noticed Pectin(to be dietary fiber)shows inprovement of blood sugar

41、in DMLoperamide A synthetic antidiarrheal narcotic analogue,agonist activity on gut-associated mu-opiate receptor Antisecretory and prolonging gut transit Decreasing water&electrolytes absorbance from gut lumenLoperamideIndication Chronic diarrhea associated with IBD Adjunct Tx.of nondysentric diarr

42、hea Postvahotomy diarrheaDosage 48 mg/day,not excess 16 mg per dayLoperamideSide Effects Constipation,abdominal pain,distention,bloating,nausea and vomiting Central Nervous system depression:dorwsiness,dizziness,and fatigue often seen in high doseLoperamidePearls&Pitfalls Naloxone is used for CNS depression caused by loperamide overdose Never used in acute ulcerative colitis and pseudomembranous enterocolitis,as it is associated with toxic megacolon Combined with antibiotics in traveller抯 diarrhea and bacillary dysentry Option in Tx.of irritable bowel syndrom