1、治疗胃肠道疾病药物,消化系统最常见病有：慢性胃炎、消化性溃疡、和消化系肿瘤。肠易激综合征和功能性消化不良越来越受到关注。另外，肝胆系统疾病也是很常见疾病。近年在消化性溃疡的发病机制和治疗的研究都有了显著进展。幽门螺杆菌在胃部疾病发病中的作用有了进一步的认识。,消化性溃疡（peptic ulcer）为消化系统最常见疾病，发病率约8%10%。为一种慢性疾病，可反复发作，病情持续数年至数十年，可发生于消化道任何部位，最多见于胃和十二指肠溃疡。胃溃疡多位于胃小弯近幽门处，十二指肠溃疡一般位于球部。,消化性溃疡,一、病因及发病机制,溃疡病的发病机制过去过于强调胃酸和胃蛋白酶的攻击作用，后来开始重视粘膜屏
2、障、细胞保护因子、局部血液循环等抗溃疡因素。正常情况下两者处于平衡状态，当致溃疡因素作用超过抗溃疡因素，两者不平衡时就易发生溃疡。,攻击因子（致溃疡因素）胃酸过多：各种刺激引起胃酸和胃蛋白酶分泌，产生自身消化作用。有“无酸不成溃疡”的说法。幽门螺杆菌（Helicobacter pylori,Hp）：寄生在胃粘液层之下，破坏粘液层，减弱其保护作用。是溃疡病长期不愈，反复发作的重要因素。药物：阿斯匹林及非甾体类抗炎药 胆汁和十二指肠液的反流：可破坏胃粘膜，刺激G细胞分泌胃泌素促胃酸分泌。,防御因子（抗溃疡因素）粘膜屏障：粘液-碳酸氢盐屏障（胃腔中pH常2，粘液下为7），粘膜上皮的紧密连接。局部血液
3、循环：胃肠激素及细胞保护因子：前列腺素，表皮生长因子幽门括约肌功能：十二指肠逆蠕动及幽门松弛,The acid-peptic diseases,The acid-peptic diseases are those disorders in which gastric acid and pepsin are necessary,but usually not sufficient,pathogenic factors.While inherently caustic,acid and pepsin in the stomach normally do not produce damage or
4、symptoms because of intrinsic defense mechanisms.Barriers to the reflux of gastric contents into the esophagus comprise the primary esophageal defense.If these protective barriers fail and reflux occurs,dyspepsia and/or erosive esophagitis may result.,Enterochromaffin-Like(ECL)Cells,Enterochromaffin
5、-Like(ECL)Cells,Enterochromaffin-like or ECL cells are a distinctive type of neuroendocrine cell in the gastric mucosa underlying the epithelium.They are most prevalent in the acid-secreting regions of the stomach.ECL cells synthesize and secrete histamine in response to stimulation by the hormones
6、gastrin and pituitary adenylyl cyclase-activating peptide.Together,histamine and gastrin are primary positive regulators of acid secretion from the parietal cell.,二、主要临床表现,周期性上腹部疼痛，返酸、嗳气、烧心、腹胀等。疼痛有规律性，其特点为：周期性：疼痛发生和缓解交替，疼痛数天至数周，缓解数月。多发生在春秋季反复性：反复发作，不易痊愈。节律性：十二指肠溃疡饥饿痛，两餐之间，饭前，夜间痛（上半夜）胃溃疡饭后半1小时左右,二、诊断
7、依据,典型的临床表现只作为诊断的参考，确诊依赖于纤维胃镜和上消化道钡餐检查。钡餐造影：直接征象：龛影、浓钡点。间接征象：变形、激惹等。胃镜：溃疡、周围粘膜肿胀、出血点。查幽门螺杆菌,三、主要并发症,出血：主要由溃疡边缘及基底部血管被侵蚀出血。轻者大便潜血，重者大出血危及生命。穿孔：急性穿孔可产生休克、腹膜炎，为腹部外科急症，大多需手术治疗。慢性穿孔可在局部形成炎症包裹（常见于后壁）。幽门梗阻：因炎症水肿及幽门痉挛或瘢痕狭窄而至。癌变：只发生在胃溃疡，十二指肠溃疡一般不会发生恶变。,Left:An elderly patient presents with melena and hypotens
8、ion.Right:35-year-old woman presents with tarry stools and a hemoglobin of75 g/L.,Gastric ulcer with punched-out ulcer base with whitish fibrinoid exudates.,This image shows a benign gastric ulcer as seen with a barium study.Note the typical location(lesser curvature),with the ulcer projecting beyon
9、d the contour of the stomach.,Peptic Ulcer Disease,Peptic ulcer disease affects 10%of men and 4%of women in the United States at some time in their lives.A peptic ulcer is a mucosal break of/=3 mm in size with depth,that can involve the stomach(gastric ulcer)or duodenum(duodenal ulcer).The most impo
10、rtant contributing factors are Helicobacter pylori,nonsteroidal anti-inflammatory drugs(NSAIDs),acid,and pepsin.,Although peptic ulcers produce a variety of symptoms,none is specific for the disease.Severe pain or a rapid increase in pain suggests an ulcer complication or another diagnosis;associate
11、d dyspepsia symptoms include nausea,bloating,heartburn,and belching.Indeed,peptic ulcers are the most common cause of acute upper GI bleeding,H pylori eradication and/or antisecretory therapies are the mainstay of todays treatment strategies.,四、治疗溃疡病药物分类,（一）治疗溃疡病药物的评价治疗溃疡病主要有4个有目的：（1）控制症状；（2）促进溃疡愈合；
12、（3）防止并发症发生；（4）防止溃疡复发。现今的所有抗溃疡药物均能达到（1）和（2）的目的，有的还可减少并发症，如出血，穿孔等。但现有的抗溃疡药物都不能彻底根治溃疡病，而杀灭幽门螺旋杆菌的药物能大大降低复发率。,抗酸剂：氢氧化铝，三硅酸镁，碳酸钙等，起中和胃酸作用，现已很少用。抑制胃酸分泌：H2受体阻断剂：西咪替西，雷尼替丁，法莫替丁H+-K+-ATP酶抑制剂（质子泵抑制剂）：奥美拉唑，兰索拉唑其他还有M受体阻断剂和胃泌素受体阻断剂胃粘膜保护剂：前列腺素E，枸橼酸铋钾，硫糖铝杀灭幽门螺杆菌：三联疗法：枸橼酸铋、甲硝唑、羟氨苄青霉素二联疗法：奥美拉唑、甲红霉素，或加羟氨苄青霉素三联疗法,Acid
13、 Peptic Diseases Pharmacological Approach to Treatment,http:/,Drugs Modulating Gastric Acid,抗酸药物的发展Beginning with antacids,histamine type-2 receptor antagonists(H2RAs),and sucralfate,there has been a steady development of effective therapies for these conditions,culminating with the proton-pump inhi
14、bitors(PPIs),Antacids,现已用得越来越少了，大多被H2RAs和PPIs取代。特点：They are inexpensive,readily available,and safe in most populations.Antacids work nearly instantaneously and find utility for rapid relief of mild or sporadic symptoms.The effective time for antacids to reduce stomach acidity is relatively short on
15、an empty stomach.calcium carbonate,sodium bicarbonate,magnesium hydroxide and aluminum hydroxide.hydrotalcite铝碳酸镁,H2-receptor Antagonists,The H2RAs are reversible structural analogs of histamine that cause a decrease in the tonic activation rate of the receptor,thus,these agents act as inverse agoni
16、sts with a functional antagonism of histamine activity.Cimetidine,ranitidine,famotidine and nizatidine.（西咪替丁为肝药酶抑制剂，有抗雄激素作用）,特点：H2RAs mainly inhibit basal rate of acid release during nonfeeding periods.This is of particular importance during the nocturnal periods of fasting,which is the rational for
17、 the use of H2RA dosing at bedtime.The H2RAs are often administered once a day prior to bedtime to maximally impact nocturnal basal acid secretion.All agents have linear pharmacokinetics and are eliminated primarily by renal mechanisms.Dose adjustments are needed for patients with renal impairment.,
18、H2RAs are superior to placebo,but inferior to PPIs for the treatment of esophageal reflux disease.Histamine receptor antagonists have modest efficacy in nonulcer dyspepsia,however,they are not as effective as PPIs.,Proton Pump Inhibitors,PPIs are weak bases that act as prodrugs and need an acidic en
19、vironment in order to inhibit the H+K+-ATPase.PPIs accumulate in the secretory canaliculus of the parietal cell.The PPI becomes protonated and converted into the active sulfenamide species,which forms disulfide bonds with cysteine residues in the-subunit of the H+K+-ATPase.,By contrast,with H2RAs,PP
20、Is also decrease pepsin secretion,which serves to reduce mucosal damage.Morning dosing of PPIs is associated with significantly improved acid suppression.PPIs should be administered before breakfast.The effects of the PPIs increase with repeated administration and,generally by the third day.,PPIs un
21、dergo metabolism via hepatic CYP2C19.Of the PPIs,rabeprazole is unique as only 15-20%of its metabolism involves the CYP system.There is differential metabolism between individuals due to pharmacogenetic variation.Possible associations with hip fractures,renal complications and community-acquired pne
22、umonia have also been demonstrated.The long-term safety of the class include prolonged hypergastrinemia,the possible association of PPIs with gastric atrophy and chronic hypochlorhydria.,PPIs should not be administered concomitantly with H2-antagonists,prostaglandins or other antisecretory agents ow
23、ing to the marked reduction in their acid inhibitory effects when administered simultaneously.,Mucosal Protective Agents,Sucralfate It is a nonabsorbable medication that binds to gastric mucosa and ulcerated tissue.These properties favor healing and provide cytoprotective effects.Sucralfate has simi
24、lar efficacy in healing of duodenal ulcer and gastric ulcers when compared with H2RAs.The primary utility is in the prophylaxis of stress ulceration in critically ill patients.sucralfate is best avoided in patients with kidney failure,PPIs抗泌酸作用强，并可用于上消化道出血等,PPI infusion and high-dose oral therapy in
25、 the setting of bleeding PUD have been common practices for the last several years.The use of intravenous formulations of PPIs prior to endoscopy in patients with bleeding PUD.,PPI抑制夜间泌酸改善症状,After 1.4 months of pantoprazole(40 mg daily)therapy,any sleep disturbances had improved in more than 75%of p
26、atients,with resolution of nighttime heartburn and nighttime regurgitation in 73%and 84%of patients,respectively.,PPI新剂型增强药效,AGN,the enteric-coated novel PPI,was shown to provide faster and more profound acid suppression than esomeprazole on day 1 and also at day 5,the time point that both medicatio
27、ns should have reached steady state.Both medications were well tolerated and no adverse events were reported.Nocturnal acid suppression was also greater by 2 pH units after 5 days,长期使用PPIs的不良反就应,Adverse Effects of Proton Pump Inhibitor Drugs:Clues and Conclusions http:/,根除Hp方案的药物组成原则,合用不同机制的抗菌药物如：阿莫
28、西林，克拉霉素，甲硝唑采用抗泌酸药物影响Hp的生长环境如：PPI,H2抑制剂和铋剂,Recommendations for Treating Peptic Ulcer Disease,Helicobacter pylori infection be eradicated and antisecretory therapy,preferably with a proton pump inhibitor(PPI),be given for 4 weeks;patients with persistent symptoms should undergo endoscopy.,根除Hp有助于病愈及防止
29、复发,To facilitate healing and to decrease the risk for recurrence of gastric and duodenal ulcers,H pylori should be eradicated in patients with peptic ulcer disease.,PPIs抗酸效果较其它药好,PPIs offer suppression of acid secretion,healing,and symptom relief in patients with peptic ulcers that are superior to t
30、hose associated with other antisecretory therapies,溃疡出血应用PPIs,Patients with bleeding peptic ulcers should be treated with a PPI to decrease the need for transfusions or surgery and to reduce the duration of hospital stay.Those with bleeding peptic ulcers and positive H pylori testing should have era
31、dication therapy prescribed,穿孔性溃疡也应根除Hp,Patients with perforated ulcers should undergo eradication of coexisting H pylori infection.Successful eradication should reduce the need for long-term antisecretory therapy and additional surgery,Patients with peptic ulcers who are older than 55 years,have al
32、arm symptoms,or have ulcers that fail to respond to treatment should promptly undergo upper endoscopy,注意恶变,肠易激综合征Irritable Bowel Syndrome,是一组包括腹痛、腹胀、排便习惯改变和大便性状异常、粘液便等表现的临床综合征，持续存在或反复发作，经检查排除可以引起这些症状的器质性疾病。本病是最常见的一种功能性肠道疾病。,临床表现,最主要的临床表现是腹痛与排便习惯和粪便性状的改变。腹痛 几乎所有IBS患者都有不同程度的腹痛。部位不定，以下腹和左下腹多见。腹泻 一般每日35
33、次左右，少数严重发作期可达十数次。大便多呈稀糊状，也可为成形软便或稀水样。部分患者腹泻与便秘交替发生。便秘 排便困难，粪便干结、量少，呈羊粪状，表面可附黏液。其他消化道症状 多伴腹胀或腹胀感，可有排便不尽感、排便窘迫感。全身症状 相当部分患者可有失眠、焦虑、抑郁、头昏、头痛等精神症状。体征 无明显体征，可在相应部分有轻压痛，部分患者可触及腊肠样肠管，直肠指检可感到肛门痉挛、张力较高，可有触痛。,肠易激综合征类型,便秘型：伴有周期性便秘与较频繁的正常大便交替，大便经常有白色黏液，疼痛呈绞榨样，阵发性发作，或持续性隐痛，排便后可缓解。进食常会促发症状，也可以出现腹胀、恶心、消化不良和烧心等症状。腹泻型：特别是在进食刚开始，或结束时出现突发性腹泻。夜间腹泻很少，常有疼痛、腹胀和直肠紧迫感，也可出现大便失禁等情况。,治 疗,一般治疗建立良好的生活习惯。饮食上避免诱发症状的食物，因人而异，一般而言宜
