Gastrointestinal drugs 张世红 [email protected]

Gastrointestinal drugs

张世红[email protected]

1.Hepatic, pancreatic and biliary disorders

2.Acid-peptic disorders

3.Gastrointesinal motility disorders

4.Inflammatory bowel diseases

Digestive diseases

（痔疮）

（便秘）

（消化不良）

（胆石症）

（疝气）

（肠易激综合征）

（胃炎）

（消化性溃疡）


1. Drugs used for acid-peptic

disorders

2. Modulators of gastrointestinal

functions

1. Acid-peptic disorders

1) Peptic ulcer disease (PUD)

2) Gastroesophageal reflux disease (GERD)

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

3) Pathologic acid-hypersecretory conditions (e.g. Zollinger-Ellison syndrome)

5) Acute stress ulcers

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 )

Peptic ulcer disease

MucosaSubmucosaMuscle

Gastroesophageal reflux disease (GERD)

Pathologic acid-hypersecretory conditions (e.g.Zollinger-Ellison syndrome)

Tumor

Gastrin

Gastric acid

Peptic ulcer

Gastric acid

Pepsin （胃蛋白酶）Helicobacter pylori （幽门螺旋杆菌）

Mucus

Bicarbonate

Mucosa

2. Pathogenesis of peptic ulcers

Aggressive factorsDefensive factors

Mucus-bicarbonate barrier

Gastric acid secretion and regulation

(the proton pump)

Helicobacter pylori infection

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

Pathogenesis of peptic ulcers

Treatment approaches

(1) Increased gastric acid secretion

(3) Inadequate mucosal defense against gastric acid

(2) Infection with Helicobacter pylori

(1) Reducing secretion of gastric acid or neutralizing the acid

(3) Protecting the gastric mucosa from damage

(2) Eradicating 根除 H. pylori infection

(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)

4. Drugs used for peptic ulcers

Antacids (weak bases)

Chemistry of antacids:

Aluminum salts (aluminum hydroxide)

Magnesium salts (carbonate, hydroxide or oxide)

Calcium salts (carbonate)

Sodium salts (bicarbonate)

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.


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


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 help avoid or reduce drug interaction, other

medication should be taken 1-2 hours after taking an

antacid

× AntacidsProton pump inhibitors×

H2 receptor antagonists

×

M receptor antagonists ×

Gastrin receptor antagonists

×

Drugs suppressing gastric acid secretion

Cimetidine

西咪替丁，甲腈咪胍

NNN

CH2SCH2CH2NHCNHCH3

H

H3C

CN

H2 receptor antagonists

1. Pharmacological effect

Blocks H2 receptors, decreases H+ and pepsin

secretion, promots 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

Cimetidine

3. Adverse effects (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.

Cimetidine

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 (near 100%)

Omeprazole 奥美拉唑，洛赛克

N

OCH3H3C CH3

CH2

OCH3

S

O

H

N

N

H+-K+-ATPase inhibitors

1. Pharmacological effects(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, promots healing of

ulcers

(2) Used with antimicrobial regimens to eradicate H.

pylori

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 (only found in animal

experiments)

(3) Others: gynecomastia (男性乳房发育 ), hypersensitivity

4. Drug interactions

Inhibits hepatic P450, raises plasma concentrations of

warfarin, phenytoin, diazepam, etc.

Omeprazole

Others proton pump inhibitorsOthers proton pump inhibitors

Pirenzepine 哌仑西平

M receptor antagonists

http://en.wikipedia.org/wiki/File:Pirenzepine.png

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

OHCH3OCH3

O O

HO


Misoprostol 米索前列醇

A prostaglandin E analogues

Misoprostol 米索前列醇

1. Pharmacological effects Inhibits gastric acid secretion

Promots 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

Sucralfate ( 硫糖铝 )

A sulfated disaccharide （硫酸蔗糖） complex of aluminum hydroxide



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

Bismuth Compounds 铋制剂Colloidal bismuth subcitrate (CBS, 胶体次枸橼酸铋 )

Bismuth subsalicylate 次水杨酸铋


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


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.

Bismuth Compounds

Teprenone （替普瑞酮）Marzulene-S （麦滋林 -S）Smectite （蒙脱石，思密达）

Other mucosal protective drugs

Antimicrobial drugs (for Helicobacter pylori)

1. Anti-ulcer drugs H+-K+-ATPase inhibitors; bismuch; sulralfate

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 )

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”


1. Drugs used for acid-peptic disorders

2. Modulators of gastrointestinal

functions

Abnormalities of gastrointestinal functions

Nausea and vomiting ConstipationDiarrhea

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）


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）

Antiemetic drugsH1 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

5-HT3 receptor antagonists ： ondansetron 昂丹司琼 ;

grasetron 格拉司琼 ; tropisetron 托烷司琼


GI tract smooth muscle cells

NANCneuron

Postganglionic primary motor neuron

Prokinetic drugs

Metoclopramide甲氧氯普胺

( - )

(Central or peripheral)

Metoclopramide 甲氧氯普胺

Mechanism of action

1) A 5-HT4 receptor agonist and 5-HT3 receptor antagonist, enhances coordinated transmission in cholinergic nerve plexus

2) A D2 receptor antagonist

Clinical uses

1) Used for treatment of diabetic gastroparesis ( 胃瘫 )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 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)

Metoclopramide 甲氧氯普胺

Domperidone 多潘立酮

Mechanism of action

A peripheral dopamine D2 antagonist

Adverse effects

Few side effects since it can not cross the BBB

Increased serum prolactin levels ( 6% of patients)

Rare cases of prolongation of QT interval.

Antidiarrheals 止泻药

Causes of diarrhea:1) An increase in the active secretion, or an inhibition of absorption

2) Abnormally high motility


1. Antimotility drugs ( 胃肠动力抑制药 )

2. Astringents ( 收敛药 )

3. Absorbants ( 吸附药 )

Antidiarrheals

Mechanisms: Agonists for receptors in GI tract

(1) Opium preparation

(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.

Antimotility drugs

Astringents 收敛药 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）


Constipation:

Treatment

1) Increase the intake of fluids and dietary fiber

3) Laxatives

2) Physical intervention, regular exercise

An decrease in the active secretion, or an enhancement of absorption

Laxatives 泻药

2. Laxatives that work osmotically

3. Laxatives that decrease absorption

Laxatives 泻药

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)


Laxatives


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 )

Laxatives


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.

Laxatives


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

Laxatives

3. Laxatives that decrease absorption

Liquid petrolatum 液体石蜡( Lubricate the fecal mass, prevent excessive dehydration of the material , and may inhibit water reabsorption by coating the gut wall)

Laxatives


Choleretic （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）

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Gastrointestinal drugs 张世红 [email protected]