Gastrointestinal drugs Weiwei HU Phone:

1.Hepatic, pancreatic and biliary disorders 2. Acid-peptic disorders 3.Gastrointesinal motility disorders 4. Inflammatory bowel diseases

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

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

1)

The feature of peptic ulcer disease: High incidence, Recurrence frequently, Drug treatment is the main way Symptoms: Upper abdominal burning or hunger pain Emesia ( 呕吐 ), belching ( 嗳气 ) Ulcer complication Ulcer bleeding ( 出血 ) Ulcer perforation ( 穿孔 ) Pyloristenosis ( 幽门狭窄 ) Canceration ( 癌变 )

2) Gastroesophageal reflux disease (GERD) Abnormal reflux in the esophagus

3) Drug-induced mucosal injury, especially by non-steroidal anti-inflammatory drugs (NSAIDs)

4) Pathologic acid-hypersecretory conditions (e.g. Zollinger-Ellison syndrome) Tumor Gastrin Gastic acid Peptic ulcer

5) Acute stress ulcers

2. Gastric acid secretion and regulation Gastric cells of mucosa (1)Surface epithelial cells (secrete mucus) (2)Mucus neck cells (secret mucus and are the source of proliferating cells); (3)Chief cells (secret pepsinogens) (4)G cells (release gastrin in the antrum); (5)Parietal cells in the gastric fundus ( secrete HCI and intrinsic factor)

2. Gastric acid secretion and regulation Basolateral membane (the proton pump)

Mucus-bicarbonate barrier

Helicobacter pylori infection

Gastric acid Pepsin Helicobacter pylori Mucus bicarbonate Mucosa 2.Pathogenesis of peptic ulcers Aggressive factors Defensive factors

Pathogenesis of peptic ulcers Treatment approaches Increased gastric acid secretion (1)Increased gastric acid secretion (3)Inadequate mucosal defense against gastric acid (2)Infection with gram- negative Helicobacter pylori (1)Reducing secretion of gastric acid or neutralizing the acid (3)Protecting the gastric mucosa from damage (2)Eradicating H. pylori infection

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

§(1) Antacids (Weak bases) Chemistry of antacids: Salts of aluminum (aluminum hydroxide), Salts of magnesium (carbonate, hydroxide, trisilicate), aluminum magnesium carbonate ( Al 2 Mg 6 (OH)16CO 3 ·4H 2 O ) calcium(carbonate) sodium (bicarbonate)

§(1) Antacids × Antacids Mechamism of action (the proton pump)

(1) Antacids 1. Pharmacological effect Neutralizing gastric acid, diminish gastric acidity and inactivate pepsin （胃蛋白酶） activity Neutralizing gastric acid, diminish gastric acidity and inactivate pepsin （胃蛋白酶） activity The effect depends on the dose and dosing frequency. The effect depends on the dose and dosing frequency. Starting effect within 5-15 min after taking the drugs. Starting effect within 5-15 min after taking the drugs. 2. Clinical uses Commonly used for dyspepsia symptom and Commonly used for dyspepsia symptom and minor episodes of heartburn.

3. Adverse effects (1) Constipation and stomach cramp (salt of aluminum) (2) Diarrhea (salt of magnesium ) Combination products such as maalox (3) Hypercalcium which can cause renal failure (Calcium) (4) Hypernatremia (sodium-containing antacids) All antacids are generally regarded as safe in pregnancy. 4. Drug interactions Avoid concurrent administration of antacids and a variety of drugs. Avoid concurrent administration of antacids and a variety of drugs. (1) Affect rates of dissolution and absorption, bioavailbility, and renal elimination of many drugs (2) By binding to drugs (for example, tetracycline 四环素 ), form insoluble complexes that are not absorbed

Adminstration and dosage (1)Take antacids after meals and at bedtime (2)Should taken continuously for a long time (3)To help avoid or reduce drug interaction, other medication should not be taken within 1-2 hours of taking an antacids

Cimetidine (2) Drugs affecting gastric acid secretion ② H 2 receptor antagonists

(Proton pump) × cimetidine Mechamism of action

1. Pharmacological effect Blocking H 2 receptors, decreasing H + secretion Blocking H 2 receptors, decreasing H + secretion 2. Clinical uses 1) Duodenal and gastric ulcer 1) Duodenal and gastric ulcer 2) Zollinger-Ellison syndrome, 2) Zollinger-Ellison syndrome, 3) Acute stress ulcers 3) Acute stress ulcers 4) Gastroesophageal reflux disease (heartburn) 4) Gastroesophageal reflux disease (heartburn) Cimetidine

3. Adverse effects (1) common side effects: constipation, diarrhea, tiredness, muscular pain, etc. (1) common side effects: constipation, diarrhea, tiredness, muscular pain, etc. (2) CNS effects: headache, dizziness, confusion, hallucination, etc. (elderly, long-term uses) (2) CNS effects: headache, dizziness, confusion, hallucination, etc. (elderly, long-term uses) (3)Endocretion effects: antiandrogen （抗雄激素）, gynecomastia, galactorrhea, reduced sperm count, and male sexual dysfunction (3)Endocretion effects: antiandrogen （抗雄激素）, gynecomastia, galactorrhea, reduced sperm count, and male sexual dysfunction 4. Drug interactions Inhibiting hepatic P 450, raising plasma concentrations of warfarin, phenytoin, diazepam, propranolol, quinidine and theophylline Inhibiting hepatic P 450, raising plasma concentrations of warfarin, phenytoin, diazepam, propranolol, quinidine and theophylline Cimetidine

5. Elimination Urinary excretion is the principal route of elimination of cimetidine, the dose should be modified in patients with renal impairment.

Other H 2 receptor antagonists Ranitidine 4-10 times more potent than cimetidine 4-10 times more potent than cimetidine Minimal side effects, weakly inhibiting CYP Minimal side effects, weakly inhibiting CYPFamotidine 7-10 times more potent than ranitidine, but no inhibiting CYP 7-10 times more potent than ranitidine, but no inhibiting CYPNizatidine Bioavailability is near 100%, principally eliminated by kidney Bioavailability is near 100%, principally eliminated by kidney

Omeprazole 奥美拉唑 (2) Drugs affecting gastric acid secretion ③ H + -K + -ATPase inhibitors ③ H + -K + -ATPase inhibitors (proton pump inhibitors) (proton pump inhibitors)

Omepranzole × (the proton pump)

§1. Pharmacological effects §(1) Inhibiting gastric acid secretion by various stimuli (histamine, gastrin, aspirin, ethanol, stress) §(2) Inhibiting H. pylori §(3) protection for gastric mucosa §2. Clinical uses §(1) Highly effective for duodenal and gastric ulcer: relieving symptoms, promoting healing of ulcers, with antimicrobial regimens to eradicate H. pylori §(2) Gastro-esophageal reflux disease §(3) Zollinger-ellison syndromeUsed Omeprazole

§3. Adverse effects §(1) Side effects: nausea, headache, diarrhea, constipation and rash occur but are uncommon §(2) Increase of gastric carcinoid tumor: prolongated hypochlorhydria and secondary hypergastrinemia (only found by animal experiments)  (3) Others: gynecomastia ( 男性乳房发育 ), hypersensitivity §4. Drug interactions §It is metabolized by hepatic P450; §Inhibiting hepatic P450, raising plasma concentrations of warfarin, phenytoin, diazepam, etc. Omeprazole

Others proton pump inhibitors

§Non-selective: atropine (block M3 receptor in Parietal cells, block M1 receptor in ganglion, block M receptors in ECL and G cells), seldom use now. §Selective: pirenzepine (block M1 receptor) M receptor antagonists

(3) Mucosal protective drugs Effects: Protecting the gastric and duodenal mucosa from damage by acid and pepsin Effects: Protecting 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

(3) Mucosal protective drugs Misoprostol 米索前列醇 A prostaglandin E1 analogues

Misoprostol 米索前列醇 1. Pharmacological effects Inhibiting gastric acid secretion Promoting mucus and HCO 3 - secretion, and mucosal repair 2. Clinical uses Only 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 property) (Abortifacient 堕胎 property) (3) Mucosal protective drugs

Sucralfate A sulfated disaccharide （二糖） complex of aluminum hydroxide

1. Pharmacological effects 1) Binding to tissue surface and forms a protective barrier 2) Enhancing cell restitution and re-epithelization. 3) Weakly inhibiting H.Pylory growth. 4) Promote PGE2 production 5) Binding to pepsin and then reduce its activity 2. Clinical uses and Adminstration Peptic ulcers, but with the more effective agents (proton pump inhibitors. Gastro-esophageal reflux disease. H pylori infection. 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, not together with alkaline agents (3) Mucosal protective drugs Sucralfate

(3) Mucosal protective drugs Bismuth Compounds Colloidal bismuth subcitrate (CBS) Bismuth subslicylate 1. Pharmacological effects 1) Probably coats ulcers and erosions, creating a protective layer against acid and pepsin 2) Inhibit pepsin activity, stimulate prostaglandin, mucus, and bicarbonate secretion 3) Have direct antimicrobial activity against H pylori

2. Clinical uses 1) Peptic ulcers, chronic gastritis, duodenitis, functional dyspepsia 2) Used in multidrug regimens for the eradication of H pylori infection. 3. Adverse effects Causes blackening of the stool, which may be confused with gastrointestinal bleeding Bismuth toxicity resulting in encephalopathy (ataxia, headaches, confusion, seizures). Bismuth Compounds

(3) Mucosal protective drugs Smectite 1)Bind to the glycoprotein in the mucus to increase its coverage ability, enhancing cell restitution, antimicrobial activity against H pylori. 2) Use for acute or chronic diarrhea and ulcer.

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

The best treatment regimen consists of a 10–14 day regimen of "triple therapy": 1) Bismuth subsalicylate (2 tablets; 262 mg each), 2) Tetracycline (500 mg), 3) Metronidazole (250 mg), each taken four times daily for 14 days. Program 2 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.

1)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. For patients with resistant infections, "quadruple therapy”

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

Abnormalities of gastrointestinal functions Nausea and vomitingConstipation Diarrhea

Modulators of gastrointestinal functions 1. Antiemetic drugs 2. Prokinetic drugs 3. Anti-diarrheals 4. Laxatives

Antiemetic drugs There are various sources of input to the vomiting center: 1.The chemoreceptor trigger zone at the base of the fourth ventricle has numerous dopamine D2 receptors, serotonin 5-HT3 receptors, opioid receptors, acetylcholine receptors, and receptors for substance P. Stimulation of different receptors are involved in different pathways leading to emesis, in the final common pathway substance P appears involved. 2.The vestibular system, which sends information to the brain via cranial nerve VIII (vestibulocochlear nerve), plays a major role in motion sickness, and is rich in muscarinic receptors and histamine H1 receptors. 3.The Cranial nerve X (vagus nerve) is activated when the pharynx is irritated, leading to a gag reflex. 4.The Vagal and enteric nervous system inputs transmit information regarding the state of the gastrointestinal system. Irritation of the GI mucosa by chemotherapy, radiation, distention, or acute infectious gastroenteritis activates the 5-HT3 receptors of these inputs. 5.The CNS mediates vomiting that arises from psychiatric disorders and stress from higher brain centers.

Antiemetic drugs 1.H1 antagonists: sedative effect, antiemetic effect, use for motion sickness and Meniere disease. 2.M receptor antagonists: scopolamine, use for motion sickness. 3.D receptor antagonists: chloropromazine, thiethylperazine ( 硫乙拉嗪 ). 4.5-HT3 receptor antagonists: ondansetron, granisetron, tropisetron, et al. Use for vomiting induced by chemotherapy for cancer, but not for motion sickness.

GI tract smooth muscle cells NANC neuron Cholinergic neuron Post-ganglionic primary motor neuron Prokinetic drugs

prokinetic drugs Metoclopramide 甲氧氯普胺 Mechanism of action 1)Block D2 receptor, to stimulate 5-HT 4 receptors and enhance coordinated transmission in cholinergic nerve plexues 2) An dopaminergic neuron antagonist in the central nervous system; at higher doses, 5-HT3 antagonist activity may also contribute to the anti-emetic effect. Clinical uses 1) Used for treatment of diabetic gastroparesis 2) Used for the prevention of nausea and vomiting associated with cancer chemotherapy or occurring post-operatively.

Adverse effects 1) Fatigue, dizziness, faintness 2) Various extrapyramidal syndromes caused by its central anti-dopaminergic activity. Parkinsonism (reversible) tardive dyskinesia (irreversible) 3) Increased serum prolactin levels (chronic uses) Metoclopramide

Domperidone 多潘立酮 prokinetic drugs Mechanism of action A peripherial dopamine antagonist, has no procholinergic effects Adverse effects Has few side effects because it can not cross the BBB Has few side effects because it can not cross the BBB Increased serum prolactin levels ( 6% of patients) Rare cases of prolongation of QT interval.

Anti-diarrheals Modulators of gastrointestinal functions Modulators of gastrointestinal functions Diarrhea 1) An increase in the active secretion, or an inhibition of absorption 2) Abnormally high motility

Modulators of gastrointestinal functions Modulators of gastrointestinal functions Antimotility drugs 1. Antimotility drugs Astringents 2. Astringents Absorbants 3. Absorbants Anti-diarrheals

Antimotility drugs: Mechanisms: Agonists for  receptors in GI tract (1) Opium preparation (1) Opium preparation (2) Diphenoxylate 地芬诺酯 (2) Diphenoxylate 地芬诺酯 Diphenoxylate dose not cross the blood-brain-barrier as easly as most opioids do and is relatively selective for peripheral opioid receptors. Has CNS effects at larger doses) Anti-diarrheals

(3) Loperamide 洛哌丁胺 Anti-diarrheals Antimotility drugs: It is two to three times potent than diphenoxylate, and its action is more rapid in onset and more prolonged. Use for acute or chronic diarrhea but not induced by infection. It has less CNS or cardiovascular effects It has less CNS or cardiovascular effects.

Astringents: Mechanism: astriction (1) Tannalbin 鞣酸蛋白 (1) Tannalbin 鞣酸蛋白 (2) Bismuch subsalicylate; bismuch (2) Bismuch subsalicylate; bismuch subcarbonate ( 铋制剂 ) subcarbonate ( 铋制剂 ) Absorbants ： (1) Medical charchol 药用炭（活性炭） (1) Medical charchol 药用炭（活性炭） (2) Agysical 矽炭银 (2) Agysical 矽炭银 Anti-diarrheals

Modulators of gastrointestinal functions Constipation Laxatives Treatment 1)Increase the intake of fluids and dietary fiber Regular exercise 2) Laxatives 3) Physical intervene An decrease in the active secretion, or an enhancement of absorption

Modulators of gastrointestinal functions Modulators of gastrointestinal functions 2. Osmotic laxatives （渗透性泻药） 3. Emollient Laxatives （润滑性泻药） Laxatives 1. Contact laxatives （接触性、刺激性泻药） 4. Bulk-forming Laxatives （膨胀性、容积性泻药）

Laxatives Phenolphthalein 酚酞 Phenolphthalein 酚酞 ( No longer used because of concerns about carcigenicity) ( No longer used because of concerns about carcigenicity) Bisacodyl 必沙可啶 Bisacodyl 必沙可啶 (It is active after deacetylation, stimulating enteric nerves to cause colonic mass movements; increases fluid and NaCl secretion. ) (It is active after deacetylation, stimulating enteric nerves to cause colonic mass movements; increases fluid and NaCl secretion. ) 1. Contact laxatives （接触性泻药）

Laxatives Anthraquinones 蒽醌类（中药成分） promote colon movements promote colon movements Cascara （鼠李皮） Rhubarb （大黄） Senna （番泻叶） 1. Contact laxatives （接触性泻药）

2. Osmotic laxatives （渗透性泻药） 1) Salt laxatives: magnesium sulfate 硫酸镁 ; 1) Salt laxatives: magnesium sulfate 硫酸镁 ; sodium sulfate 硫酸钠； sodium sulfate 硫酸钠； Laxatives 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. magnesium sulfate

2. Osmotic laxatives （渗透性泻药） 2) Lactulose 乳果糖 ; 2) Lactulose 乳果糖 ; Laxatives 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, Lactic acid also has an osmotic effect. It is used to reduce ammonia blood levels in the prevention and treatment of hepatic encephalopathy

3. Emollient Laxatives （润滑性泻药） Liquid petrolatum ( Lubricate the fecal mass, prevent excessive dehydration of the material, and may inhibit water reabsorption by coating the gut wall)

Celluloses: used for functional constipation 4. Bulk-forming Laxatives （膨胀性、容积性泻药）