Transcript gastrointestinal drugs

Gastrointestinal drugs
张世红
[email protected]
Digestive diseases
1.Hepatic, pancreatic
and biliary disorders
2.Acid-peptic disorders
3.Gastrointesinal motility
disorders
4.Inflammatory bowel
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）
Gastrointestinal drugs
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)
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
Peptic ulcer disease
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)
Mucosa
Submucosa
Muscle
Gastroesophageal reflux disease (GERD)
Pathologic acid-hypersecretory conditions (e.g.
Zollinger-Ellison syndrome)
Tumor
Gastrin
Gastric acid
Peptic ulcer
2. Pathogenesis of peptic ulcers
Defensive factors
Aggressive factors
Mucus
Gastric acid
Pepsin （胃蛋白酶）
Helicobacter pylori （幽门螺旋杆菌）
Bicarbonate
Mucosa
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
(1) Reducing secretion
of gastric acid or
neutralizing the acid
(2) Infection with
Helicobacter pylori
(2) Eradicating根除 H.
pylori infection
(3) Inadequate
mucosal defense
against gastric acid
(3) Protecting the
gastric mucosa from
damage
4. 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)
Antacids (weak bases)
Chemistry of antacids:
Aluminum salts (aluminum hydroxide)
Magnesium salts (carbonate, hydroxide or oxide)
Calcium salts (carbonate)
Sodium salts (bicarbonate)
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.
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
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
Drugs suppressing gastric acid secretion
M receptor
antagonists
×
Proton pump
inhibitors
H2 receptor
antagonists
×
×
Gastrin receptor
antagonists
×
×
Antacids
H2 receptor antagonists
Cimetidine
西咪替丁，甲腈咪胍
H3C
CH2SCH2CH2NHCNHCH3
HN
N
N
CN
Cimetidine
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.
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%)
H+-K+-ATPase inhibitors
Omeprazole
奥美拉唑，洛赛克
OCH3
H3C
CH3
N
CH2
O
OCH3
N
S
N
H
Omeprazole
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.
Others proton pump inhibitors
M receptor antagonists
Pirenzepine
哌仑西平
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
Mucosal protective drugs
Misoprostol 米索前列醇
O
O
CH3
OCH3
OH
HO
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
Mucosal protective drugs
Sucralfate (硫糖铝)
A sulfated disaccharide（硫酸蔗糖） complex of
aluminum hydroxide
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
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
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.
Other mucosal protective drugs
Teprenone （替普瑞酮）
Marzulene-S （麦滋林-S）
Smectite （蒙脱石，思密达）
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":
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.
For patients with resistant infections,
"quadruple therapy”
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.
Gastrointestinal drugs
1. Drugs used for acid-peptic disorders
2. Modulators of gastrointestinal
functions
Abnormalities of gastrointestinal functions
Nausea and vomiting
Diarrhea
Constipation
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）
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）
Modulators of gastrointestinal functions
Antiemetic drugs
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
5-HT3 receptor antagonists：ondansetron 昂丹司琼;
grasetron 格拉司琼; tropisetron 托烷司琼
Prokinetic drugs
(Central or
peripheral)
NANC
neuron
(-)
Metoclopramide
甲氧氯普胺
Postganglionic
primary motor neuron
GI tract smooth muscle cells
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.
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)
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.
Modulators of gastrointestinal functions
Antidiarrheals止泻药
Causes of diarrhea:
1) An increase in the active
secretion, or an inhibition
of absorption
2) Abnormally high motility
Antidiarrheals
1. Antimotility drugs (胃肠动力抑制药)
2. Astringents (收敛药)
3. Absorbants (吸附药)
Antimotility drugs
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.
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）
Modulators of gastrointestinal functions
Laxatives泻药
Constipation: An decrease in the active secretion,
or an enhancement of absorption
Treatment
1) Increase the intake of fluids and dietary fiber
2) Physical intervention, regular exercise
3) Laxatives
Laxatives泻药
1. Laxatives that increase secretion
2. Laxatives that work osmotically
3. Laxatives that decrease absorption
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)
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)
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.
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
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)
Modulators of gastrointestinal functions
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）