Transcript 止吐药和促动力药_(2015V1)

Gastrointestinal drugs
Department of Pharmacology
Tang Huifang (汤慧芳)
Email: [email protected]
Content
• Part 1. Drugs used for peptic
ulcers
• Part 2. Modulators of gastroenteric
functions
Part 1.
Drugs used for peptic ulcers
Peptic ulcers and treatment
Pathogenesis of
peptic ulcers
• Infection with Hp ;
• Increased gastric
acid secretion;
• Inadequate mucosal
defense to gastric
acid.
Treatment
approaches
• Eradicating Hp ;
• Neutralizing gastric
acid,
or reducing
secretion of the acid;
• Protecting the gastric
mucosa from damage.
Drugs used for peptic ulcers
Classifiction of anti-ulcer drugs
I. Antacids: neutralizing the acid
II. Drugs suppressing gastric acid secretion
①Muscarinic receptor antagonists
②H2 receptor antagonists
③Gastrin receptor antagonists
④ H+-K+-ATPase inhibitors (proton pump
inhibitors)
III. Antimicrobial drugs (Helicobacter pylori)
IV. Mucosal protective drugs
Drugs used for peptic ulcers
Ⅰ. Antacids(抗酸药)
• Basic substances that can reduce gastric
acidity by neutralizing HCl;
• Drugs most in use:
Aluminium hydroxide(氢氧化铝),
Magnesium hydroxide(氢氧化镁),
Magnesium trisilicate(三硅酸镁),
Magnesium oxide(氧化镁), etc.
Composition resparation, such as:
Tab aluminium hydroxide compound(复方氢氧化
铝片, 胃舒平), etc.
Drugs used for peptic ulcers
(1) Antacids
1. Pharmacological effect
Neutralizing gastric acid, diminish gastric acidity and
inactivate pepsin（胃蛋白酶）activity
2. Clinical uses
Used for peptic ulcer and acid-hypersecretory
conditions.
Drugs used for peptic ulcers
3. Adverse effects
(1) Constipation and stomach cramp (salt of aluminum)
(2) Diarrhea (salt of magnesium)
(3) Hypercalcium which can cause renal failure
(Calcium)
(4) Hypernatremia (sodium-containing antacids)
4. Drug interactions
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
Drugs used for peptic ulcers
Adminstration and dosage
(1) Take antacids 1 h and 3 h after meals
Seven times a day after meals and at
bedtime.
(2) Should not be taken continuously for more
than 3 m for ulcer
(3) To help avoid or reduce drug interaction,
other medication should not be taken within 12 hours of taking an antacids
Drugs used for peptic ulcers
Ⅱ. Drugs inhibiting gastric acid secretion
①Muscarinic receptor antagonists
②H2 receptor antagonists
③Gastrin receptor antagonists
④ H+-K+-ATPase inhibitors (proton pump
inhibitors)
atropine
misoprostol
atropine
Sucralfate
carbonoxolone
A. Muscarinic receptor antagonists
(M receptor blocker):
Drugs most in use:
Atropine(阿托品)
Propantheline bromide(溴丙胺太林)
Pirenzepine(哌仑西平)
Telenzepine(替仑西平)
Drugs used for peptic ulcers
Atropine(阿托品)
CH2
CH
CH3
NCH3 CH
CH2
CH
O
O
C
CH3
CH
C6H5
CH2 OH
Non-selective M receptor blocker:
Block M1, M2, M3, M4, and M5
receptors.
Block M3 receptor in Parietal cells( 壁细胞)
Block M1 receptor in ganglion
Block M receptors in ECL and G cells.
Drugs used for peptic ulcers
Pirenzepine(哌仑西平)
O
H
N
N
COCH2
N
N
N---CH3
Selective M receptor blocker:
Only block M1 and M2receptors.
misoprostol
Sucralfate
carbonoxolone
Drugs used for peptic ulcers
1. Pharmacological effects
high affinity for M1- and low affinity
for M2-receptors of the smooth muscle of
the ileum and urinary bladder.
blocking of M1-muscarinic receptors in
autonomic ganglia, inhibiting the secretion
of HCl.
2. Clinical uses: peptic ulcers
3. Adverse effects
Atropine-like effects, at larger doses.
Telenzepine(替仑西平)
Drugs used for peptic ulcers
B. H2 receptor antagonists:
H3C
CH2SCH2CH2NHCNHCH3
HN
N
N
H3C
N
CH2
O
CN
Cimetidine
(西咪替丁)
CH2SCH2CH2NHCNHCH3 Ranitidine
(雷尼替丁)
H3C
CHNO2
misoprostol
Sucralfate
carbonoxolone
Drugs used for peptic ulcers
Cimetidine(西咪替丁)
1. Pharmacological effects
Blocking H2 receptors, decreasing H+
secretion
2. Clinical uses
(1) Duodenal and gastric ulcer:
—— relieving symptoms, promoting
healing of ulcers, and preventing ulcers.
(2) Zollinger-Ellison syndrome
(3) Reflux esophagitis;
(4) Acute stress ulcers, etc.
Drugs used for peptic ulcers
3. Adverse effects
(1)Side effects: constipation, diarhoea,
tiredness, muscular pain, etc.
(2)CNS effects: headache, dizziness,
hal-lucination, etc. (elderly, long-term
uses)
(3)Endocretion effects: antiandrogen,
gynecomastia(男性乳房发育), galactorrhea(溢乳), reduced sperm count, and
male sexual dysfunction
4. Drug interactions
Inhibiting hepatic P450: raising plasma
concentrations of warfarin, phenytoin,
diazepam, propranolol, quinidine and
theophylline, etc.
Drugs used for peptic ulcers
Drugs used for peptic ulcers
5. Elimination
Urinary excretion is the principal route
of elimination of cimetidine, the dose
should be modified in patients with renal
impairment.
Drugs used for peptic ulcers
Other H2 receptor antagonists:
Ranitidine(雷尼替丁)
Similar to cimetidine, but 5～10 times more potent,
longer acting;
Minimal side effects, no antiandrogenic and
prolactin-stimulating effects, less inhibiting P450.
Famotidine(法莫替丁)
Similar to ranitidine, but 4～8 times more potent.
Nizatidine(尼扎替丁)
The potent is similar to ranitidine.
Bioavailability is near 100%, principally eliminated by
kidney
Drugs used for peptic ulcers
4 种H2-受体阻断药的比较
药
名
西咪替丁
t1/2(h)
2
相对抑
酸活力
1
剂
量
对肝药
酶抑制
400mg, bid
1
雷尼替丁 2-3
5-10
法莫替丁 2.5-4
40
20mg, bid
0
5-10
150mg, bid
0
尼扎替丁
2
150mg, bid 0.1
Drugs used for peptic ulcers
C. H+-K+-ATPase inhibitors
(proton pump inhibitors)
Omeprazole(奥美拉唑)
OCH3
H3C
CH3
N
CH2
O
OCH3
N
S
N
H
Drugs used for peptic ulcers
Omepranzole
×
(the proton pump)
Drugs used for peptic ulcers
质子泵的分子构型
Drugs used for peptic ulcers
1. Pharmacological effects
(1)Inhibiting gastric acid secretion by various
stimuli(such as: histamine, gastrin, aspirin,
ethanol, stress, etc.)
(2)Inhibiting Hp .
(3) protection for gastric mucosa
2. Clinical uses
(1)Highly effective for duodenal and gas-tric
ulcer: relieving symptoms, and
promoting healing of ulcers
Used with antimicrobial agents to
eradicate Hp .
(2)Reflux esophagitis;
(3)Zollinger-Ellison syndrome
Drugs used for peptic ulcers
3. Adverse effects
(1)Side effects:
Less, such as: nausea, headache,
diarrhoea, constipation and rash occur.
(2)Increase of gastric carcinoid tumor
(3)Others:
hypersensitivity, gynecomastia(男性乳房发
育)
4. Drug interactions
Inhibiting hepatic P450, raising plasma
concentrations of warfarin, phenytoin,
diazepam, etc.
Drugs used for peptic ulcers
Others
• Lansoprazole(兰索拉唑)
• Pantoprazole(泮他拉唑)
• Rebeprazole(雷贝拉唑)
Drugs used for peptic ulcers
几种质子泵抑制剂的比较
药
t1/2
名 (h)
有效抑酸
时间(h)
奥美拉唑 1.0 12～24
剂量
(mg/d)
对肝药
酶影响
20～40
+
兰索拉唑 1.5
24
30

潘托拉唑 1.3
24
20～40

雷贝拉唑 1.0
24
20

胃泌素受体阻断药:
丙谷胺(Proglumide)
本品可与胃泌素竞争受体而抑制胃酸分泌;
也能促进黏液合成, 增强胃黏膜的黏液-HCO3盐屏障, 从而发挥抗溃疡病的作用.
本品口服吸收迅速, 生物利用度为60%～
74%, 达峰时间为2h.
Drugs used for peptic ulcers
Ⅲ. Mucosal protective drugs
Misoprostol(米索前列醇)
Enprostil 恩前列素
Sucralfate 硫糖铝
Colloidal bismuth subcitrate(CBS, 胶体次枸橼
酸铋)
Teprenone(替普瑞酮)
Marzulene(麦滋林)
Smectite(思密达)
misoprostol
Sucralfate
Bismuch, etc.
Drugs used for peptic ulcers
Misoprostol 米索前列醇
O
O
CH3
OCH3
OH
HO
A prostaglandin E analogues
Drugs used for peptic ulcers
Misoprostol 米索前列醇
1. Pharmacological effects
Inhibiting gastric acid secretion
Promoting mucus and HCO3- 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, nausea, headache, etc.
Contraindicated in pregnancy women
(Abortifacient 堕胎 property)
Drugs used for peptic ulcers
Sucralfate
A sulfated disaccharide（二糖） complex of
aluminum hydroxide
Drugs used for peptic ulcers
Sucralfate
1. Pharmacological effects
1) Binding to mucosal 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 advent of more effective agents
(proton pump inhibitors); reflux esophagitis; mucosa impairment.
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
Drugs used for peptic ulcers
Bismuth Compounds
Colloidal bismuth subcitrate
(CBS, 胶体次枸橼酸铋)
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
Drugs used for peptic ulcers
Bismuth Compounds
2. Clinical uses
1) Treatment of dyspepsia, peptic ulcer, chronic
gastritis.
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).
Drugs used for peptic ulcers
Smectite(蒙脱石)
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.
Drugs used for peptic ulcers
Ⅳ. Antimicrobial(anti-Hp) drugs
1. Anti-ulcer drugs:
H+-K+-ATPase inhibitors; bismuch(铋
剂); sulralfate(硫糖铝), etc.
Weaker, combined with antimicrobial
drugs.
2. Antimicrobial drugs:
Metronidazole(甲硝唑); Amoxicillin(阿
莫西林); Tetracycline(四环素); Gentamicin
(庆大霉素); Clarithromycin(克拉霉素), etc.
misoprostol
Sucralfate
Bismuch, etc.
HP根除治疗方案的变化
新进展
• --第四次全国幽门螺杆菌感染处理共识报告（2012年）
• 我国HP感染率总体上仍然很高，成人感染率在 4060%。
• 推荐用于根除治疗的6种抗菌药物中，甲硝唑耐药率
已达到60%-70%，克拉霉素达20%--38%，左氧氟沙星
达到30%--38%，耐药显著影响根除率。
• 羟氨苄青霉素、呋喃唑酮和四环素的耐药率仍很低
（1%-5%） 。
• 因此标准三联疗法（PPI+克拉霉素+羟氨苄) 或
（PPI+克拉霉素+甲硝唑）根除率已低于或远低于80%。
• 共识： 推荐四联： PPI+铋剂+2种抗菌药物
• 抗菌药物组成：
–羟氨苄青霉素+克拉霉素
–羟氨苄青霉素+左氧氟沙星
–羟氨苄青霉素+呋喃唑酮
–四环素+甲哨唑或呋喃唑酮
新进展
• 青霉素过敏者推荐的抗菌药物组成方案：
–克拉霉素+左氧氟沙星
–克拉霉素+呋喃唑酮
–四环素+甲硝唑或呋喃唑酮
–克拉霉素+甲硝唑
• 疗程： 10d--14d，放弃7d方案。
Gastrointestinal drugs
Part2
Modulators of gastrointestinal functions
Modulators of gastrointestinal functions
Abnormalities of gastrointestinal functions
Nausea and vomiting
Diarrhea
Constipation
Contents
Ⅰ. Promoting digestive drug(助消化药)
Ⅱ. Antiemetic and prokinetic drugs
1. antiemetic drugs(止吐药)
2. prokinetic drugs(胃动力药)
Ⅲ. Drugs for treatment of diarrhea
1. antimotility drugs(抗蠕动药)
2. astringents(收敛药)
3. absorbants(吸附药)
Ⅳ. Laxatives
1. contact(stimulant) laxatives
2. osmotic laxatives
3. faecal softners(emollients)
Modulators of gastrointestinal functions
Ⅰ. Promoting digestive drug
Pepsin(胃蛋白酶)
Pancreatin(胰酶)
Lactasin(乳酶生, Biofermin, 表飞
鸣) etc.
Modulators of gastrointestinal functions
Ⅱ. Antiemetic and prokinetic drugs
1. Antiemetic drugs(止吐药)
H1 receptor antagonists(H1受体阻断药):
Diphenhydramine(苯海拉明);
Dimenhydrinate(茶苯海明);
Meclozine(美克洛嗪)
M receptor antagonists(M受体阻断药):
Scopolamine(东莨菪碱)
D2 receptor antagonists(D2受体阻断药):
Chlorpromazine(氯丙嗪)
5-HT3 receptor antagonists(5-HT3受体阻断药):
Ondansetron(昂丹司琼)
Grasetron(格拉司琼)
Tropisetron(托烷司琼)
Modulators of gastrointestinal functions
2. Prokinetic drugs(胃动力药)
Metoclopramide(甲氧氯普胺, 胃复安, 灭吐灵)
D2 receptor block: antiemetic
effects(CTZ), and promoting GI motility.
Adverse effects: CNS reactions,
extrapyra-midal effects, etc.
Domperidone(多潘立酮, 吗丁啉)
D2 receptor block: promoting GI motility.
Adverse effects: headache, prolactin ,
gastric acid 
Cisapride(西沙比利)
5-HT4 receptor activitor, ACh release :
promoting intestinal & colon motility.
Prokinetic drugs
NANC
neuron
Post-ganglionic
primary motor neuron
Cholinergic
neuron
GI tract smooth muscle cells
Modulators of gastrointestinal functions
Prokinetic drugs
Metoclopramide 甲氧氯普胺
Mechanism of action
1) Block D2 receptor, to stimulate 5-HT4 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.
Modulators of gastrointestinal functions
Metoclopramide
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)
Modulators of gastrointestinal functions
Domperidone 多潘立酮
Mechanism of action
A peripherial dopamine antagonist, has no procholinergic
Effects
Clinical uses
1) Used for treatment of diabetic gastroparesis
2) Used for the prevention of nausea and vomiting
induced by dyspepsia, chemotherapy, gastroesophageal
reflux disease .
Adverse effects
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.
Modulators of gastrointestinal functions
Ⅲ. Drugs for treatment of diarrhea
(止泻药)
1. Antimotility drugs(抗蠕动药) :
agonists for  receptors in GI tract
Opium preparations(阿片制剂)
Diphenoxylate(地芬诺酯):
CNS effects at larger doses.
2. Astringents(收敛药) :
Tannalbin(鞣酸蛋白)
Bismuch subsalicylate(次硅酸铋)
Bismuch subcarbonate(次碳酸铋)
3. Absorbants(吸附药) :
Medical charchol(药用炭, 活性炭)
Agysical(矽炭银)
Modulators of gastrointestinal functions
Anti-diarrheals
1. Antimotility drugs:
Mechanisms: Agonists for  receptors in
GI tract
(1) Opium preparation 阿片制剂
(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)
Modulators of gastrointestinal functions
Anti-diarrheals
1. Antimotility drugs:
Loperamide 洛哌丁胺
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 .
Modulators of gastrointestinal functions
Ⅳ. Laxatives(泻药)
1. Stimulant laxatives(刺激性泻药)
Phenolphthalein(酚酞)
Bisacodyl(必沙可啶)
Rhubarb(大黄)、Senna(番泻叶), etc.
2. Osmotic laxatives(渗透性泻药)
Magnesium sulfate(硫酸镁);
Sodium sulfate(硫酸钠);
Lactulose(乳果糖);
Sorbitol(山梨醇);
Glycerol(甘油);
Celluloses(纤维素类)
3. Faecal softners(粪便软化药, emollients)
Liquid paraffin(液体石蜡)
Modulators of gastrointestinal functions
Laxatives
• 1. Stimulant laxatives(刺激性泻药)
Phenolphthalein 酚酞
( No longer used because of concerns about
carcigenicity)
Bisacodyl 必沙可啶
(It is active after deacetylation, stimulating
enteric nerves to cause colonic mass movements;
increases fluid and NaCl secretion. )
Modulators of gastrointestinal functions
Laxatives
Anthraquinones 蒽醌类（中药成分）
promote colon movements
Cascara
（鼠李皮）
Senna
（番泻叶）
Rhubarb
（大黄）
Modulators of gastrointestinal functions
Laxatives
2. Osmotic laxatives(渗透性泻药)
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.
magnesium sulfate
Modulators of gastrointestinal functions
Laxatives
2. Osmotic laxatives(渗透性泻药)
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, Lactic acid also has an osmotic
effect.
It is used to reduce ammonia blood
levels in the prevention and
treatment of hepatic
encephalopathy
Modulators of gastrointestinal functions
3. Laxatives that decrease absorption
Liquid petrolatum
( Lubricate the fecal mass, prevent excessive
dehydration of the material , and may inhibit
water reabsorption by coating the gut wall)