Gastrointestinal & Hepatic- Biliary Systems Chapter 5 Part II.
Chapter 32 drug used in digestive system. This chapter describes drugs used to treat these common...
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Transcript of Chapter 32 drug used in digestive system. This chapter describes drugs used to treat these common...
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..
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.
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.
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 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 NaHCO3 Mg2SiO8 Al(OH)3 Mg(OH)2 CaCO3 MgO1g 药中和 0.1 120 150 250 210 200 500
N 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
• 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 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
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 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][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 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
[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 inhibitor
lansoprazole second generation
Pantoprazole 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.
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.)
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 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 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 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 → 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 chemotherapy-induced 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)