1. Gastrointestinal drugs
张世红

2. （痔疮） （便秘） （肠易激综合征） （胃炎） （消化不良） （胆石症） （消化性溃疡） （疝气）
Irritable bowel syndrome: a group of functional bowel disorders in which discomfort or pain is associated with defecation or a change in bowel habit, and with features of disordered defecation.
（胆石症）
（消化性溃疡）
（疝气）

3. Gastrointestinal drugs
1. Drugs used for acid-peptic disorders
2. Modulators of gastrointestinal functions

4. Drugs used for peptic ulcers
Acid-peptic disorders
1) Peptic ulcer disease (PUD)
2) Gastroesophageal reflux disease (GERD)
3) Pathologic acid-hypersecretory conditions (e.g. Zollinger-Ellison syndrome)
4) Drug-induced mucosal injury, especially by non-steroidal anti-inflammatory drugs (NSAIDs)
5) Acute stress ulcers

5. Mucus-bicarbonate barrier

6. Helicobacter pylori infection

7. Marshall BJ
Warren JR
The Nobel prize in 2005: for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease

8. Pathogenesis of peptic ulcers Treatment approaches
(1) Reduce secretion of gastric acid or neutralizing the acid
(1) Increased gastric acid secretion
(2) Infection with Helicobacter pylori
(2) Eradicate根除 H. pylori infection
(3) Inadequate mucosal defense against gastric acid
(3) Protect the gastric mucosa from damage

9. Drugs used for peptic ulcers
(1) Antacids: neutralize中和 the acid
(2) Drugs suppressing gastric acid secretion
① H2 receptor antagonists
② H+-K+-ATPase inhibitors (proton pump inhibitors)
③ Muscarinic receptor antagonists
④ Gastrin receptor antagonists
(3) Mucosal protective drugs
(4) Antimicrobial drugs (Helicobacter pylori)

10. Antacids (weak bases) Chemistry of antacids:
Aluminum salts (aluminum hydroxide)
Magnesium salts (carbonate, hydroxide or oxide)
Calcium salts (carbonate)
Sodium salts (bicarbonate)

11. Antacids (weak bases) 1. Pharmacological effects
- Neutralize gastric acid, diminishing gastric acidity and inactivating pepsin（胃蛋白酶）
- Form a protective membrane on the gastric mucosa
- Depend on the dose and dosing frequency.
- Effect starting within 5-15 min, lasting 1-3 h.
2. Clinical uses
Commonly used for minor episodes of heartburn.
铝凝胶和钙盐可沉积在胃粘膜表面，形成保护膜。

12. Antacids (weak bases) 3. Adverse effects
(1) Constipation and stomach cramp (Al/Ca salts )
(2) Diarrhea (Mg salts)
(3) Hypercalcium (calcium salts)
(4) Hypernatremia (sodium salts)
4. Drug interactions
Affect rates of dissolution and absorption, bioavailability, and renal elimination of many drugs
抗酸药一般不长期单独使用。

13. NOTICE (1) Take antacids 1 hour after meals
Four times a day after meals and at bedtime.
(2) Should not be taken continuously for more than 2 weeks
(3) To avoid or reduce drug interaction, other medication should be taken 1-2 hours after taking an antacid

14. Drugs that suppress gastric acid secretion
M receptor antagonists ×
Proton pump inhibitors × ×
Antacids ×
H2 receptor antagonists ×
Gastrin receptor antagonists

15. H2 receptor antagonists
Cimetidine
西咪替丁，甲腈咪胍

16. Cimetidine 1. Pharmacological effect
Blocks H2 receptors, decreases H+ and pepsin secretion, promotes ulcer healing.
2. Clinical uses
1) Duodenal and gastric ulcer （high rate of relapse）
2) Zollinger-Ellison syndrome
3) Acute stress ulcers
4) Gastroesophageal reflux disease (heartburn)
5) Decreased immune function

17. Cimetidine 3. Adverse effects 4. Drug interactions
(1) common side effects: constipation, diarrhea, tiredness, muscular pain, etc.
(2) CNS effects: headache, dizziness, confusion, hallucination, etc. (elderly, long-term uses)
(3) Antiandrogen（抗雄激素）effects
4. Drug interactions
Inhibits hepatic P450, raises plasma concentrations of warfarin, phenytoin, diazepam, propranolol, quinidine and theophylline, etc.

18. Other H2 receptor antagonists
Ranitidine (雷尼替丁)
4～10 times more potent than cimetidine; Minimal side effects, weakly inhibits CYP
Famotidine (法莫替丁)
40-50 times more potent than cimetidine; no inhibition of CYP
Nizatidine (尼扎替丁)
High bioavailability (nearly 100%)

19. H+-K+-ATPase inhibitors
Omeprazole 奥美拉唑，洛赛克
以硫氧键为中心的对映体。

20. Omeprazole 1. Pharmacological effects 2. Clinical uses
(1) Inhibits gastric acid secretion induced by various stimuli (histamine, gastrin, aspirin, ethanol, stress)
(2) Inhibits H. pylori
2. Clinical uses
(1) Highly effective for duodenal and gastric ulcer, reflux esophagitis: relieves symptoms, promotes healing of ulcers
(2) Used with antimicrobial regimens to eradicate H. pylori
Compared with H2 antagonists, proton pump inhibitors afford more rapid symptom relief and faster
ulcer healing for duodenal ulcers and, to a lesser extent, gastric ulcers.
The most effective regimens for H pylori eradication are combinations of two antibiotics
and a proton pump inhibitor.
The best treatment regimen consists of a 10–14 day regimen of "triple therapy": a proton pump inhibitor twice daily,
clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily.

21. Omeprazole 3. Adverse effects
(1) Side effects: nausea, headache, diarrhea, constipation and rash (rare)
(2) Increase of gastric carcinoid tumor: prolongated hypochlorhydria 胃酸过少症and secondary hypergastrinemia 高胃泌素症
(3) Others: gynecomastia (男性乳房发育), hypersensitivity
4. Drug interactions
Inhibits hepatic P450, raises plasma concentrations of warfarin, phenytoin, diazepam, etc.
Proton pump inhibitors are extremely safe.
Gastrin levels are regulated by a feedback loop. During meals, intraluminal food proteins stimulate
gastrin release from antral G-cells. The rise in serum gastrin stimulates parietal cell acid secretion.
Increased intragastric acidity stimulates antral D-cells to release somatostatin, which binds to
receptors on adjacent antral G-cells, turning off further gastrin release. Acid suppression alters this
feedback inhibition so that gastrin levels rise two- to four-fold in patients taking proton pump
inhibitors. In approximately 3%, gastrin levels exceed 500 pg/mL (normal < 100 pg/mL). Upon
stopping the drug, the levels normalize

22. Other proton pump inhibitors

23. M and gastrin receptor antagonists
Pirenzepine 哌仑西平
Proglumide 丙谷胺

24. Mucosal protective drugs
Effects: Protect the gastric and duodenal mucosa from damage by acid and pepsin
Misoprostol 米索前列醇
Sucralfate 硫糖铝
Colloidal bismuth subcitrate 胶体次枸橼酸铋

25. Mucosal protective drugs
Misoprostol 米索前列醇
A prostaglandin E (PGE) analogues

26. 1. Pharmacological effects
Misoprostol 米索前列醇
1. Pharmacological effects
Inhibits gastric acid secretion
Promotes mucus and HCO3- secretion, mucosal repair
2. Clinical uses
Approved for the prevention of NSAIDs-induced gastric ulcer.
3. Adverse effects
Side effects (13%): abdominal pain, diarrhea, headache, nausea, etc.
Contraindicated in pregnancy women:
Abortifacient (堕胎) effect
Misoprostol has both acid inhibitory and mucosal protective properties.
it binds to a prostaglandin receptor on parietal cells, reducing histamine-stimulated cAMP production and
causing modest acid inhibition
Peptic ulcers develop in approximately 10–20% of patients who receive long-term NSAID therapy
Diarrhea and cramping abdominal pain occurs in 10–20% of patients.
Misoprostol stimulates uterine contractions

27. A sulfated disaccharide（硫酸蔗糖） complex of aluminum hydroxide
Mucosal protective drugs
Sucralfate (硫糖铝)
A sulfated disaccharide（硫酸蔗糖） complex of aluminum hydroxide

28. Sucralfate 1. Pharmacological effects
1) Binds to tissue proteins and forms a protective barrier
2) Enhances cell restitution修复 and re-epithelization重上皮化
3) Weakly inhibits H.Pylory growth.
2. Clinical uses and adminstration
Peptic ulcers
Take sucralfate 1 hour before meals
Four times a day before meals and at bedtime
3. Adverse effects
Constipation occurs in 2% due to the aluminum salt
Sucralfate is a salt of sucrose complexed to sulfated aluminum hydroxide.
the negatively charged sucrose sulfate binds to positively
charged proteins in the base of ulcers or erosion, forming a physical barrier that restricts further
caustic damage and stimulates mucosal prostaglandin and bicarbonate secretion. It may also bind
epithelial growth factor and fibroblast growth factor, enhancing mucosalrepair
a small amount of aluminum is absorbed, it should
not be used for prolonged periods in patients with renal insufficiency.

29. Mucosal protective drugs
Bismuth Compounds 铋制剂
Colloidal bismuth subcitrate
(CBS, 胶体次枸橼酸铋)
Bismuth subsalicylate次水杨酸铋
1. Pharmacological effects
1) Probably coats ulcers and erosions, creating a protective layer against acid and pepsin
2) Stimulates prostaglandin, mucus, and bicarbonate secretion
3) Kills H. pylori

30. Bismuth Compounds 2. Clinical uses
1) Nonspecific treatment of peptic ulcers, dyspepsia and acute diarrhea.
2) Used in multidrug regimens for the eradication of H pylori infection.
3. Adverse effects
Causes blackening of the stool
Bismuth toxicity resulting in encephalopathy (脑病，ataxia, headaches, confusion, seizures)- used for short period and contraindicated in patients with renal insufficiency.
1.bismuth subsalicylate, bismuth subcitrate and bismuth
dinitrate are also available.
2. All bismuth formulations have an excellent safety profile.
3. Bismuth agents should be used for only short periods and should be
avoided in patients with renal insufficiency.

31. Other mucosal protective drugs
Teprenone （替普瑞酮）
Marzulene-S （麦滋林-S）
Smectite （蒙脱石，思密达）

32. Antimicrobial drugs (for Helicobacter pylori) 1. Anti-ulcer drugs
H+-K+-ATPase inhibitors; bismuth; sulralfate硫糖铝
Weaker, combined with antimicrobial drugs
2. Antibiotics
metronidazole (甲硝唑); amoxicillin (阿莫西林);
tetracycline (四环素); gentamicin (庆大霉素);
clarithromycin (克拉霉素)

33. The best treatment regimen consists of a 10-14 day regimen of "triple therapy":
Program 1
1) A proton pump inhibitor twice daily,
2) Clarithromycin 500 mg twice daily,
3) Amoxicillin 1 g twice daily.
For patients who are allergic to penicillin, metronidazole
500 mg twice daily should be substituted for amoxicillin.
Program 2
1) Bismuth subsalicylate (2 tablets; 262 mg each),
2) Tetracycline (500 mg),
3) Metronidazole (250 mg), each taken four times daily for 14 days.

34. For patients with resistant infections, "quadruple therapy”
A proton pump inhibitor twice daily
2) Bismuth subsalicylate (2 tablets; 262 mg each),
3) Tetracycline (500 mg),
4) Metronidazole (250 mg), each taken four times daily for 14 days.

35. Gastrointestinal drugs
1. Drugs used for acid-peptic disorders
2. Modulators of gastrointestinal functions

36. Abnormalities of gastrointestinal functions
Dyspepsia
Nausea and vomiting
Diarrhea
Constipation

37. Modulators of gastrointestinal functions
1. Digestants （助消化药）
2. Antiemetics （止吐药）
3. Prokinetic drugs (胃肠动力药)
4. Anti-diarrheals （止泻药）
5. Laxatives （泻药）
6. Choleretics （利胆药）

38. Modulators of gastrointestinal functions
Digestants（助消化药）
Pepsin（胃蛋白酶）
Pancreatin （胰酶）
Lactasin（乳酶生）：乳酸杆菌制剂
Carnitine（肉碱，卡尼丁）

39. Modulators of gastrointestinal functions
Antiemetics
H1 receptor antagonists: diphenhydramine 苯海拉明;
dimenhydrinate 茶苯海明; meclozine 美克洛嗪
Muscarinic receptor antagonists: scopolamine 东莨菪碱
D2 receptor antagonists: chlorpromazine 氯丙嗪，metoclopramide 甲氧氯普胺，domperidone多潘立酮（吗丁啉）
5-HT3 receptor antagonists：ondansetron 昂丹司琼;
grasetron 格拉司琼; tropisetron 托烷司琼

40. GI tract smooth muscle cells
Prokinetic drugs
(Central or peripheral)
NANC
neuron
( - )
Metoclopramide
甲氧氯普胺
Postganglionic primary motor neuron
NANC：non-adrenergic non-cholinergic neuron
GI tract smooth muscle cells

41. Metoclopramide 甲氧氯普胺 Mechanism of action
A 5-HT4 receptor agonist and 5-HT3 receptor antagonist, enhances coordinated transmission in cholinergic nerve plexus
A D2 receptor antagonist
Clinical uses
Used for treatment of diabetic gastroparesis (胃瘫)
Used for the prevention of nausea and vomiting associated with cancer chemotherapy or occurring post-operatively.

42. Metoclopramide 甲氧氯普胺 Adverse effects 1) Fatigue, dizziness, faintness
2) Various extrapyramidal syndromes锥体外系综合征:
Parkinsonism帕金森症 (reversible)
tardive dyskinesia迟发性运动障碍 (irreversible)
3) Increased serum prolactin催乳素 levels (chronic uses)

43. Anti-diarrheals止泻药 Antimotility drugs (胃肠动力抑制药) 2. Astringents (收敛药)
3. Absorbants (吸附药)
Causes of diarrhea:
1) An increase in the active secretion, or an inhibition of absorption
2) Abnormally high motility

44. Antimotility drugs Mechanisms: Agonists for  receptors in GI tract
(1) Opium preparations
(2) Diphenoxylate 地芬诺酯：dose not cross the blood-brain-barrier as easily as most opioids and is relatively selective for peripheral opioid receptors.
(3) Loperamine 洛哌丁胺：more potent, rapid and longer than diphenoxylate, without analgesic effects.
Opioids increase colonic phasic segmenting activity through inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses and lead to increased colonic transit time and fecal water absorption.
Although all opioids have antidiarrheal effects, central nervous system effects and potential for addiction limit the usefulness of most.
Loperamide is a nonprescription opioid agonist that does not cross the blood-brain barrier and has no analgesic properties or potential for addiction.
Diphenoxylate is another opioid agonist that has no analgesic properties in standard doses; however, higher doses have central nervous system effects and prolonged use can lead to opioid dependence.

45. Astringents收敛药 Absorbents吸附药 Mechanism: astriction (1) Tannalbin 鞣酸蛋白
(2) Bismuch subsalicylate; bismuch
subcarbonate (铋制剂)
Absorbents吸附药
(1) Medical charchol 药用炭（活性炭）
(2) Agysical 矽炭银（活性炭+白陶土）
Tannalbin is transformed into tannic acid in intestine. Tannic acid has astriction. It is applied for acute enteritis and noninfected diarrhea.
Bismuth subsalicylate reduces stool frequency and liquidity in acute infectious diarrhea, due to salicylate
inhibition of intestinal prostaglandin and chloride secretion.
Absorbents are not absorbed in intestine after oral and can adsorb bacteria, toxins, and fluid, thereby decreasing stool liquidity and number.

46. Modulators of gastrointestinal functions
Laxatives泻药
Constipation
便秘:
An decrease in the active secretion, or an enhancement of absorption
Treatment
Increase the intake of fluids and dietary fiber
2) Physical intervention, regular exercise
3) Laxatives

47. Laxatives泻药 1. Laxatives that increase secretion刺激性泻药
2. Laxatives that work osmotically渗透性泻药
3. Laxatives that decrease absorption润滑性泻药
The overwhelming majority of people do not need laxatives, For most people, intermittent constipation is best prevented with a high
fiber diet, adequate fluid intake, regular exercise, and the heeding of nature's call.
Laxatives are drugs which can stimulate enterokinesia, or lubricate intestinal tract and soften stool.

48. Laxatives 1. Laxatives that increase secretion Phenolphthalein 酚酞
( No longer used because of concerns about carcigenicity)
Bisacodyl 必沙可啶
(It is active after deacetylation, inhibits Na+/K+-ATPase and increases the synthesis and release of PGE2)
1. Laxatives that increase secretion
Stimulant laxatives (cathartics) induce bowel movements through a number of poorly understood mechanisms. These include direct stimulation of the enteric nervous system and colonic electrolyte and fluid secretion.
Phenolphthalein will react with bile or intestinal juice to form soluble salt. The soluble salt stimulates colonic peristaltic movement and inhibits the sorption of water.
Bisacodyl is the silmilar to phenolphthalein in pharmacological action.
Anthraquinones include rhubarb and senna which both can produce anthraquinone with the help of enteric bacteria. Anthraquinone stimulates colonic peristaltic movement

49. Laxatives 1. Laxatives that increase secretion
Anthraquinones 蒽醌类（中药成分）
Glycoside conjugates free anthraquinone active anthral form
Inhibiting colonic mucosal Na+/K+-ATPase
Rhamnus (鼠李)
Rhubarb (大黄)
Senna (番泻叶)

50. Laxatives 2. Laxatives that work osmotically
1) Salt laxatives: magnesium sulfate 硫酸镁; sodium sulfate 硫酸钠；
These agents contain ions that are only slowly absorbed from the intestine. These ions retain fluid in the bowel lumen and cause a large volume of fluid to enter the colon.
Osmotic laxatives: Osmotic laxatives are soluble but no absorbable compounds that result in increased osmotic pressure, which inhibits the absorption of water and increases intestinal contents.
magnesium sulfate : It should not be used for prolonged periods in patients with renal insufficiency due to risk of
Hypermagnesemia. These hyperosmolar agents may lead to intravascular volume depletion and electrolyte fluctuations; hence they should not be used in patients who are frail, elderly, have renal insufficiency, or have significant cardiac disease.
Lactulose are nonabsorbable sugars.These sugars are metabolized into lactic acid by colonic bacteria , producing increased intestinal contents.
Sorbitol and glycerol have weak catharsis purgation effects. So they are suitable for the aged and childs
Faecal softners : liquid paraffin lubricates fecal material, retarding water absorption from the stool. It is used to prevent and treat fecal impaction in young children and debilitated adults

51. Laxatives 2. Laxatives that work osmotically 2) Lactulose 乳果糖;
In the small bowel, it is resistant to hydrolysis and has an osmotic effect.
In the large intestine, lactulose is acted upon by the endogenous flora with the production of lactic acid乳酸, Lactic acid also has an osmotic effect.
It is used to reduce ammonia blood levels in the prevention and treatment of hepatic encephalopathy

52. Laxatives 3. Laxatives that decrease absorption Liquid petrolatum液体石蜡
( Lubricate润滑 the fecal mass, prevent excessive dehydration of the material, and may inhibit water reabsorption by coating the gut wall)

53. Modulators of gastrointestinal functions
Choleretics（利胆药）
Ursodeoxycholic acid （熊去氧胆酸）
Dehydrocholic acid （去氢胆酸）
Chenodeoxycholic acid （鹅去氧胆酸）
Magnesium sulfate （硫酸镁）
促进胆汁分泌或胆囊排空的药物。用于胆固醇性胆结石，胆汁淤积性疾病，胆汁返流性胃炎等。