Chapter 32
drug used in digestive system
This chapter describes drugs used to
treat these common medical conditions
involving the gastrointestinal tract:
peptic ulcers, dyspepsia, vomitting,
diarrhea and constipation, etc.
Part Ⅰ
Drugs Used in Peptic Ulcer
peptic 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]
• 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)
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)
flagellum
H. Pylori on gastric mucosa
(×16,000)
Actions of H. Pylori
gastric 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 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 barrier
mucus
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.Antacids
Ⅱ.Agents decreasing secretion of
gastric acid
Ⅲ. Agents protecting mucosal barrier
Ⅳ.Agents eradicating helicobacter
pylori
Ⅰ
Antacids
• Have been used for centuries in the
treatment of patients with acid-peptic
disorders.
• Were the mainstay of treatment for acidpeptic disorders until the advent of H2receptor antagonists and proton pump
inhibitors.
Ⅰ
Antacids
weak bases : Mg(OH)2 , Al(OH)3 ,
CaCO3 , NaHCO3
actions:
1) prevent injury from H+
2) neutralize gastric acid → reduce
gastric 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
特点
作用
药物
1g药中和0.1
N的HCl ml数
抗酸作用
作用持续时间
保护溃疡面
收敛作用
产生CO2
（嗳气）
引起便秘
引起腹泻
引起碱血症
NaHCO3 Mg2SiO8 Al(OH)3 Mg(OH)2 CaCO3 MgO
120
150
弱快
短
无
无
有
弱慢
长
有
无
无
无
无
有
无
有
无
250
较强慢
较长
有
有
无
有
无
无
210
200
500
较强快
较长
无
无
无
较强快
较长
无
有
有
最强
较长
无
无
无
无
有
无
有
无
无
无
有
无
side reactions:
disorder of gastrointestinal track
diarrhea; constipation; belching
（打嗝）; flatulence （肠胃胀气）;
alkalemia
Ⅱ Agents reducing
secretion of gastric acid
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
H2-R antagonists
Cimetidine, 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
duration; high rate of healing up; rebound
Regulation of gastric acid secretion
Proglumide
Cimetidine(西咪替丁;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]
①peptic ulcers :
• effective in promoting healing of peptic
ulcers.
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
secretion, 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]
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
antiandrogenic effect
• Famotidine(法莫替丁)
•
1) Antisecretive effect is 40 times that of
Cimetidine .
2) Have no effect on hepatic microsomal
metabolism system.
• Nizatidine(尼扎替丁):
• Ebrotidine(乙溴替丁):
1) ↑Expression of EGF and
PDGF→stimulate proliferation of epithelium
2) increase mucus secretion
Inhibitors of the proton pump
Omeprazole, lansoprazole, pantoprazole
[pharmacological effects]
• Inhibits H+ being transported to gastric
lumen 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
Proglumide
[Clinical uses]
①peptic ulcer: was judged to be
superior to H2-R antagonists
②Zollinger-Ellison syndrome:
③ heartburn : the most effective agents.
④hemorrhage of upper digestive tract
⑤ H.P infection
[Adverse reactions] extremely 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 inhibitor
lansoprazole second generation
Pantoprazole and rabeprazole
third generation
weak effect on heptic enzyme
Antimuscarinic 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
Proglumide
Antimuscarinic 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 Agents protecting mucosal
barrier
(1)Prostaglandins
(2)Mucosal protective agents
Prostaglandins
• 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 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
diarrhea, stimulate uterus
Misoprostol: a stable analog of PGE2
• (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
prevention 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
contraindicated during pregnancy.
Mucosal protective agents
Sucralfate(硫糖铝)
1)In water or acidic solutions it forms a viscous,
tenacious 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 factors
4)Inhibit H.P
! Needs acid envioment; affects absorption of other
drugs
Mucosal protective agents
colloidal 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 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 2
Drugs 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:
• Metoclopramide(甲氧氯普胺)
mechanism
1) block D2-receptor in CTZ →
antinausea 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 emptying
adverse 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 chemotherapyinduced and postoperative nausea and
vomiting
Granisetron(格拉司琼)
Tropisetron（托烷司琼）
Ⅲ Antidiarrheal agents
Increased motility of the gastrointestinal
tract and decreased absorption of fluid
are major factors in diarrhea.
So antidiarrheals include anti-motility
agents, adsorbents and drugs that modify
fluid 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
relief of diarrhea.
• Is an analog of pethidine and have opioidlike actions on the gut.
• block gastrointestinal μ-receptor →
decrease vermiculation（肠蠕动）
• Is used to control acute or chronic
functional diarrhea
• difficultly penetrate BBB, have no
extrapyramidal 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,
toxins, 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)