Chapter 32Chapter 32

drug used in digestive systemdrug used in digestive system

This chapter describes drugs used to treThis chapter describes drugs used to treat these common medical conditions invat these common medical conditions involving the gastrointestinal tract: olving the gastrointestinal tract: peptic ulcers, dyspepsia, vomitting, diarrpeptic ulcers, dyspepsia, vomitting, diarrheahea and and constipation, etc constipation, etc..

Part ⅠPart Ⅰ

Drugs Used in Peptic UlcerDrugs Used in Peptic Ulcer

peptic ulcerpeptic ulcer A benign, localized defect in the mucosa of any part

of the gastrointestinal tract.

duodenal ulcer gastric ulcer

[Symptoms and complications]

• The most important symptom is abdominal pain and discomfort. The atypical symptoms are abdomen distention, inappetence, belching, reflux of gastric acid.

• The severe complications are hemorrhage, perforation, obstruction and canceration.

[Pathogenesis of peptic ulcer][Pathogenesis of peptic ulcer]

• although the pathogenesis of peptic ulcer disease is not fully understood,

the theory that the balance between mucosal defense and injury is broken are recognized.

[Pathogenesis of peptic ulcer]1. Aggressive factors↑ Helicobacter Pylori ( H. Pylori) gastric acid and pepsin 2. Defensive factors↓ mucus-bicarbonate barrier prostaglandins

Helicobacter Pylori ( H. Pylori)Helicobacter Pylori ( H. Pylori)

In 1983, H. pylori was found by two Australians,

Marshall and Warren.

Now, it is believed that H. pylori is the most important

pathogenic factor to peptic ulcer.

“No H.P., no ulcer.”

And the two men won the noble prize for the important

findings in 2005.

H. Pylori (×48,000)H. Pylori (×48,000)

flagellum

H. Pylori on gastric mucosaH. Pylori on gastric mucosa(×16,000)(×16,000)

Actions ofActions of H. Pylori H. Pylori

gastric acid and pepsingastric acid and pepsin

Pepsin can decompose protein molecule. But its activity is depended on the pH value. When local pH value elevates to 4, pepsin can’t work well.

Gastric acid is the key-factor of the formation of peptic ulcer. we can also say that “No acid, no ulcer.”

mucus-bicarbonate barriermucus-bicarbonate barrier

• The epithelial layer of the mucosa is composed of tightly adjoined cells that are specialized for existence in an acid medium. Their tight junctions, synthesis of PGs and secretion of mucus and bicarbonate all contribute to maintenance of the epithelial barrier.

mucus-bicarbonate barriermucus-bicarbonate barrier

mucus

Prostaglandins(PGs)Prostaglandins(PGs)

Prostaglandins are thought to enhance resistance to injury by maintaining blood flow to the mucosa.

Thus it also plays a major role in the maintenance of defensive mechanism.

Classification of drugs :Ⅰ.AntacidsⅡ.Agents decreasing secretion of gastric acid Ⅲ. Agents protecting mucosal barrierⅣ.Agents eradicating helicobacter pylori

ⅠⅠ 　　 AntacidsAntacids

• Have been used for centuries in the treatment of patients with acid-peptic disorders.

• Were the mainstay of treatment for acid-peptic disorders until the advent of H2-receptor antagonists and proton pump inhibitors.

ⅠⅠ 　　 Antacids Antacids weak bases : Mg(OH)2 , Al(OH)3 ,

CaCO3 , NaHCO3

actions: 1) prevent injury from H+ 2) neutralize gastric acid → reduce gast

ric acidity→ reduce peptic activity 3) protect face of ulcer( Mg2SiO8 Al(OH)3 )

Ⅰ Antacids NaHCO3+HCl → Nacl+H2O+CO2↑

Mg2Si3O8+4HCl → 2MgCl2+3SiO2

Al(OH)3+3HCl → AlCl3+3H2O Mg(OH)2+HCl → MgCl2+2H2O CaCO3+2HCl → CaCl2+H2O+CO2 ↑

MgO+HCl → MgCl2+H2O

表 1 、常用抗酸药的作用特点比较 NaHCO3 Mg2SiO8 Al(OH)3 Mg(OH)2 CaCO3 MgO1g 药中和 0.1 120 150 250 210 200 500N 的 HCl ml 数抗酸作用 弱快 弱慢 较强慢 较强快 较强快 最强作用持续时间 短 长 较长 较长 较长 较长 保护溃疡面 无 有 有 无 无 无收敛作用 无 无 有 无 有 无产生 CO2 有 无 无 无 有 无（嗳气）引起便秘 无 无 有 无 有 无引起腹泻 无 有 无 有 无 有引起碱血症 有 无 无 无 无 无

药物特点作用

side reactions: disorder of gastrointestinal track diarrhea; constipation; belching（打嗝） ; flatulence （肠胃胀气） ; alkalemia

ⅡⅡ 　　 Agents reducing Agents reducing secretion of gastric acidsecretion of gastric acid

Regulation of gastric acid secretion Regulation of gastric acid secretion

Proglumide

• Drugs reducing secretion of gastric acid

(1) H2-receptor antagonists (2) Antimuscarinic agents (3) Inhibitors of the proton pump (4) gastrin-receptor antagonists

HH22-R antagonists-R antagonistsCimetidine, Ranitidine, Famotidine , Nizatidine[Actions] Competitively block the binding of histamine

to H2 receptor. Completely inhibit gastric acid secretion induced by histamine.

characteristics: more effective than M-R antagonists;long d

uration; high rate of healing up; rebound

Regulation of gastric acid secretion Regulation of gastric acid secretion

Proglumide

Cimetidine(Cimetidine( 西咪替丁西咪替丁 ;; 甲氰咪胍甲氰咪胍 ))::

[ Pharmacokinetics]• Absorption: p.o F=70%• Distribution: widely• Elimination: kidney• ! Heptic microsomal enzyme inhibitor [ Action] • inhibit all kinds of gastric acid secretion

[Clinical uses][Clinical uses]

①peptic ulcers :• effective in promoting healing of peptic ulc

ers. 400 mg bid 4W→80% healing

• after treatment is stopped, recurrence is common. This can be effectively prevented by eradication of H.Pylori.

• ②Zollinger-Ellison syndrome : a fatal disorder in which a gastrin-producing tumor causes hypersecretion of gastric acid.

• In many patients, H2 receptor antagonists can effectively keep the acid secretion to safe levels so as to control symptoms related to excess acid secretion.

• ③gastroesophageal reflux disorder (GERD, heartburn): Because they act through stopping acid secr

etion, they may not relieve symptoms of heartburn for at least 45 minutes.

Antacid will be more efficiently to neutralize secreted acid already in the stomach.

[Adverse reactions][Adverse reactions]1.the common side effects are

headache, dizziness, diarrhea and muscular pain, skin rash

2.CNS effects:

confusion, disorientation and hallucination

3. Endocrine system effects: gynecomastia, impotency, galactorrhea( 溢乳 )

• Ranitidine( 雷尼替丁 ) • 1) Antisecretive effect is 10 times that

of Cimetidine . • 2)Less effect on hepatic microsomal

metabolism system.• 3)Longer duration and less antiandro

genic effect

• Famotidine( 法莫替丁 ) • 1) Antisecretive effect is 40 times that of Cim

etidine . 2) Have no effect on hepatic microsomal met

abolism system.• Nizatidine( 尼扎替丁 ): • Ebrotidine( 乙溴替丁 ): 1) ↑Expression of EGF and PDGF→stimulat

e proliferation of epithelium 2) increase mucus secretion

Inhibitors of the proton pumpInhibitors of the proton pumpOmeprazole, lansoprazole, pantoprazole

[pharmacological effects] • Inhibits H+ being transported to gastric lu

men through inhibiting the proton pump. • Potent and long-lasting effect: Can inhibit

over 95% of gastric acid secretion.• Also inhibit release of peptin and H.P

Regulation of gastric acid secretion Regulation of gastric acid secretion

Proglumide

[Clinical uses][Clinical uses]

①peptic ulcer: was judged to be superior to H2-R antagonists

②Zollinger-Ellison syndrome: ③ heartburn : the most effective agents.　④ hemorrhage of upper digestive tract　⑤ H.P infection

[Adverse reactions][Adverse reactions] extremely safeextremely safe

• 1)G.I reactions: nausea,vomitting, diarrhea, abdominal pain etc.

• 2)NS: headache, swirl, insomnia, peripheral neuritis, etc.

• 3) overgrowth of bacteria: Increases in gastric bacterial concentrations.

• 4)hypergastrinemia( 高胃泌素血症 )• 5)canceration

Omeprazole• Easily absorbed, but affected by food• Is also heptic enzyme inhibitorlansoprazole second generationPantoprazole and rabeprazole third generation weak effect on heptic enzyme

Antimuscarinic agentsAntimuscarinic agents

• Muscarinic receptor stimulation increase gastrointestinal motility and secretion.

• So cholinergic antagonists can be used as adjuncts in the management of peptic ulcer disease and Zollinger-Ellison syndrome, particularly in patients refractory to standard therapies.

Regulation of gastric acid secretion Regulation of gastric acid secretion

Proglumide

Antimuscarinic agentsAntimuscarinic agents

• In contrast to the classic anticholinergics, the relatively specific M1-receptor antagonist, Pirenzepine is a good choice as an anti-secretory agent. Because it suppresses basal and stimulated gastric acid secretion at doses having a minimal effect on other organs (salivary glands, the heart and eye.)

gastrin-receptor antagonists: • proglumide( 丙谷胺 )

Ⅲ Ⅲ Agents protecting mucosal Agents protecting mucosal barrierbarrier

(1)Prostaglandins (2)Mucosal protective agents

ProstaglandinsProstaglandins• prostaglandins E2 and I2, produced by the

gastric mucosa, inhibit secretion of gastric acid and stimulate secretion of mucus and bicarbonate (cytoprotective effect) .

• A deficiency of prostaglandins is thought to be involved in the pathogenesis of peptic ulcers.

Mucosal protective agentsMucosal protective agents

• These compounds, known as cytoprotective ones , have several actions that enhance mucosal protection mechanisms, thereby preventing mucosal injury, reducing inflammation and healing existing ulcers.

clinical uses: NSAID-induced ulcer adverse reactions: dose-dependent diarr

hea, stimulate uterus

Misoprostol:Misoprostol: a stable analog of PGEa stable analog of PGE22

• (1) inhibits secretion of gastric acid and stimulate secretion of mucus and bicarbonate.

• (2) dilate blood vessel of mucous membrane. • (3) currently the only agent approved for prevent

ion of gastric ulcers induced by NSAIDs. • (4)less effective than H2-receptor antagonists for

acute treatment of peptic ulcers.• (5)produces uterine contractions and is contrain

dicated during pregnancy.

Mucosal protective agentsMucosal protective agents

Sucralfate( 硫糖铝 )1)In water or acidic solutions it forms a viscous, te

nacious paste that binds selectively to ulcers or erosions for up to 6 hours.

2)Also stimulates prostaglandin release and mucus and bicarbonate output.

3)Promote effects of growth factors4)Inhibit H.P! Needs acid envioment; affects absorption of other

drugs

Mucosal protective agentsMucosal protective agentscolloidal bismuth subcitrate ( 枸橼酸铋钾 )• 1) binds to an ulcer crater, coating it and

protecting it from acid and pepsin.• 2) Inhibits the activity of pepsin• 3) increases mucous secretion• 4) increase prostaglandin synthesis• 5) helps to eradicate H. pylori

Antimicrobial agentsAntimicrobial agents

Optimal therapy of patients with peptic ulcer disease who are infected with H.Pylori requires antimicrobial treatment.

Eradication of H.Pylori results in rapid healing of active peptic ulcers and low recurrence rates.

Metronidazole, tetracycline, amoxiciliin, etc.Often combined with other drugs.

Section 2Drugs modulating digestive function

Ⅰ Digestants

Dilute hydrochloric acid Pepsin Pancretin biofermin

Ⅱ Antiemetic and prokinetic agents

Ⅱ Antiemetic and prokinetic agents ⅰ Antiemetic agents 1. H1-receptor antagonist Dimenhydrinate ( 乘晕宁 ) • 2. M-receptor antagonist scopolamine

3. dopamine antagonists:3. dopamine antagonists:

• Metoclopramide( 甲氧氯普胺 ) mechanism 1) block D2-receptor in CTZ → antinause

a and antiemetic action 2) block gastrointestinal D2-receptor → promote vermiculation （肠蠕动）

• Clinical use: prevention of vomitting gastrointestinal reflux disease nonulcer dyspepsia impaired gastric emptyingadverse reaction: extrapyramidal symptoms, especially dystonias （张力障碍）

• Domeperidone ( 多潘立酮 ) block gastrointestinal D2-receptor → promote vermiculation

• Cisapride （西沙必利） DA, Ach, 5-HT

• 4. 5-HT3 inhibitor ondansetron : used in the prevention of chemotherapy-in

duced and postoperative nausea and vomiting

Granisetron( 格拉司琼 ) Tropisetron （托烷司琼）

Ⅲ Ⅲ Antidiarrheal agentsAntidiarrheal agents Increased motility of the gastrointestinal tIncreased motility of the gastrointestinal tract and decreased absorption of fluid are ract and decreased absorption of fluid are major factors in diarrhea. major factors in diarrhea. So antidiarrheals include So antidiarrheals include anti-motility aganti-motility agentsents, , adsorbentsadsorbents and and drugs that modify fludrugs that modify fluid and salt transport.id and salt transport.

1.Opium receptor agonists Opium tincture Tincture camphor compound Diphenoxylate ( 苯乙哌啶 ) Loperamide （洛哌丁胺）

Diphenoxylate( 苯乙哌啶 )• Opioids are the most effective agents for r

elief of diarrhea. • Is an analog of pethidine and have opioid-l

ike actions on the gut.• block gastrointestinal μ-receptor → decre

ase vermiculation （肠蠕动）• Is used to control acute or chronic functio

nal diarrhea• difficultly penetrate BBB, have no extrapy

ramidal symptoms

2.Astringents （收敛剂） Tannalbin （鞣酸蛋白） 3.Absorbants Medical charcoal, Smectite （蒙脱石），

kaolin , and pectin They act as absorbents of bacteria, to

xins, and fluid, thereby decreasing stool liquidity and quantity. They may be useful in acute diarrhea but are seldom used on a chronic basis.

Ⅳ Laxatives( 泻药 )

1.Contact laxatives Phenolphthalein （酚酞） , Bisacodyl（比沙可啶） Anthraquinones （蒽醌） : rhubarb（大黄） .senna （番泻叶） 2.Osmotic laxatives Magnesium sulfate

• Machanism form gels in the large intestine, causing

water retention and intestinal distension, thereby increasing motility.

• Effects and uses: (1)Diarrhea (2) Cholagogic （利胆的） action (3) Relax skeletal muscles (4)Relax vascular smooth muscle

Sodium sulfate, Lactulose （乳果糖） , Glycerol （甘油） , castor oil（蓖麻油） , celluloses （纤维素）3. Stool softeners Liquid paraffin （石蜡）

Ⅴ Choleretics (learn by yourself)