Chapter 32 drug used in digestive system

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Chapter 32drug used in digestive system
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• This chapter describes drugs used to treat these
  common medical conditions involving the
  gastrointestinal tract
• peptic ulcers, dyspepsia, vomitting, diarrhea and
  constipation, etc.

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Part ? Drugs Used in Peptic Ulcer
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peptic ulcer

• A benign, localized defect in the mucosa of
  any part of the gastrointestinal tract.
• duodenal ulcer
  gastric ulcer

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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.

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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.

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

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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.

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H. Pylori (48,000)
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H. Pylori on gastric mucosa(16,000)
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Actions of H. Pylori
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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 cant work well.
• Gastric acid is the key-factor of the formation
  of peptic ulcer. we can also say that No acid,
  no ulcer.

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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.

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mucus-bicarbonate barrier
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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.

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• Classification of drugs
• ?.Antacids
• ?.Agents decreasing secretion of
• gastric acid
• ?. Agents protecting mucosal barrier
• ?.Agents eradicating helicobacter
• pylori

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? Antacids

• 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.

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? 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 )

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• ? Antacids
• NaHCO3HCl ? NaclH2OCO2?
• Mg2Si3O84HCl ? 2MgCl23SiO2
• Al(OH)33HCl ? AlCl33H2O
• Mg(OH)2HCl ? MgCl22H2O
• CaCO32HCl ? CaCl2H2OCO2 ?
  
• MgOHCl ? MgCl2H2O

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• ?1?????????????
• NaHCO3 Mg2SiO8 Al(OH)3 Mg(OH)2
  CaCO3 MgO
• 1g???0.1 120 150
  250 210 200 500
• N?HCl ml?
• ???? ?? ?? ???
  ??? ??? ??
• ?????? ? ?
  ?? ?? ?? ??
• ????? ? ?
  ? ? ? ?
• ???? ? ?
  ? ? ? ?
• ??CO2 ? ?
  ? ? ? ?
• (??)
• ???? ? ?
  ? ? ? ?
• ???? ? ?
  ? ? ? ?
• ????? ? ?
  ? ? ? ?

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??
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• side reactions
• disorder of gastrointestinal track
• diarrhea constipation belching(??)
  flatulence (????)
• alkalemia

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? Agents reducing secretion of gastric acid
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Regulation of gastric acid secretion
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• Drugs reducing secretion of gastric acid
• (1) H2-receptor antagonists
• (2) Antimuscarinic agents
• (3) Inhibitors of the proton pump
• (4) gastrin-receptor antagonists

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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 antagonistslong
  duration high rate of healing up rebound

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Regulation of gastric acid secretion
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Cimetidine(????????)

• Pharmacokinetics
• Absorption p.o F70
• Distribution widely
• Elimination kidney
• ! Heptic microsomal enzyme inhibitor
• Action
• inhibit all kinds of gastric acid secretion

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Clinical uses

• ?peptic 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.

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• ?Zollinger-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.

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• ?gastroesophageal 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.

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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(??)

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• Ranitidine(????)
• 1) Antisecretive effect is 10 times that
  of Cimetidine .
• 2)Less effect on hepatic microsomal
  metabolism system.
• 3)Longer duration and less
  antiandrogenic effect

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• Famotidine(????)
• 1) Antisecretive effect is 40 times that of
  Cimetidine .
• 2) Have no effect on hepatic microsomal
  metabolism system.
• Nizatidine(????)
• Ebrotidine(????)
• 1) ?Expression of EGF and
  PDGF?stimulate proliferation of epithelium
• 2) increase mucus secretion

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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

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Regulation of gastric acid secretion
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Clinical uses

• ?peptic ulcer was judged to be superior to
  H2-R antagonists
• ?Zollinger-Ellison syndrome
• ? heartburn the most effective agents.
• ?hemorrhage of upper digestive tract
• ? H.P infection

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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(??????)
• 5)canceration

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• 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

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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.

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Regulation of gastric acid secretion
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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.)

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• gastrin-receptor antagonists
• proglumide(???)

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? Agents protecting mucosal barrier

• (1)Prostaglandins
• (2)Mucosal protective agents

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• 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.

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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

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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.

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Mucosal protective agents

• Sucralfate(???)
• 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

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Mucosal protective agents

• colloidal bismuth subcitrate (?????)
• 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

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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.

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• Section 2
• Drugs modulating digestive function
  
• ? Digestants
• Dilute hydrochloric acid
• Pepsin
• Pancretin
• biofermin

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? Antiemetic and prokinetic agents
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• ? Antiemetic and prokinetic agents
• ? Antiemetic agents
• 1. H1-receptor antagonist
• Dimenhydrinate (???)
• 2. M-receptor antagonist
• scopolamine

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3. dopamine antagonists

• Metoclopramide(?????)
• mechanism
• 1) block D2-receptor in CTZ ? antinausea and
  antiemetic action
• 2) block gastrointestinal D2-receptor
• ? promote vermiculation(???)

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• Clinical use
• prevention of vomitting
• gastrointestinal reflux disease
• nonulcer dyspepsia
• impaired gastric emptying
• adverse reaction
• extrapyramidal symptoms,
• especially dystonias(????)

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• Domeperidone (????)
• block gastrointestinal D2-receptor
• ? promote vermiculation
• Cisapride(????)
• DA, Ach, 5-HT

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• 4. 5-HT3 inhibitor
• ondansetron
• used in the prevention of chemotherapy-induced
  and postoperative nausea and vomiting
• Granisetron(????)
• Tropisetron(????)

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• ? 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.

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• 1.Opium receptor agonists
• Opium tincture
• Tincture camphor compound
• Diphenoxylate (????)
• Loperamide(????)

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• Diphenoxylate(????)
• Opioids are the most effective agents for relief
  of diarrhea.
• Is an analog of pethidine and have opioid-like
  actions on the gut.
• block gastrointestinal µ-receptor ? decrease
  vermiculation(???)
• Is used to control acute or chronic functional
  diarrhea
• difficultly penetrate BBB, have no extrapyramidal
  symptoms

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• 2.Astringents(???)
• Tannalbin(????)
• 3.Absorbants
• Medical charcoal, Smectite(???),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.

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• ? Laxatives(??)
• 1.Contact laxatives
• Phenolphthalein(??), Bisacodyl(????)
• Anthraquinones(??) rhubarb(??).senna(???)
• 2.Osmotic laxatives
• Magnesium sulfate

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• Machanism
• form gels in the large intestine, causing
  water retention and intestinal distension,
  thereby increasing motility.
• Effects and uses
• (1)Diarrhea
• (2) Cholagogic(???) action
• (3) Relax skeletal muscles
• (4)Relax vascular smooth muscle

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• Sodium sulfate, Lactulose(???), Glycerol
  (??), castor oil(???) , celluloses(???)
• 3. Stool softeners
• Liquid paraffin(??)
• ? Choleretics (learn by yourself)

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Thank you!