Antiulcer agents by bahar19852010

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									ANTIULCER AGENTS
            Pathogenesis of ulcer
                            Infection by
Aggressive factors      ↑   Helicobacter

(   ↑Acid and pepsin)        Phylori

                                       ↓
                                      Defensive factors
                                  ↓   Mucus,bicarbonate,
                                      Blood flow and
                                      regeneration of cell
      Pathogenesis of ulcer
                     Treatment of H phylori           Cytoprotective
                     infection (Antibiotics)           protective
                                                      agents
Aggressive factors
(Acid and pepsin)



                                               Defensive factors
                                               Mucus,bicarbonate,
                                               Blood flow and
     Antacid                                   regeneration of cell
     Antisecretory agents
                                  Antiulcer Agents

                                                     Antiulcer
                                                       agents


           Agents that reduce acid                                                 Promotes Mucosal defence


Antacids    H2 Receptor antagonists Proton Pump Inhibitors Prostaglandin Analogs          Sucralfate          Colloidal Bismuth compound
     ANTIULCER AGENTS
DRUG CLASS                             EXAMPLES
1 Agents that reduce acid:
i antacid                              NaHCO3,Al(OH)3,Mg(OH)2
ii antisecretory agents:
a. H2 receptor antgonists              Cimetidine,Ranitidine
b. Proton pump inhibitors              Omeprazole
c. Antimuscarinic                      Pirenzipine

2 Agents enhancing mucosal defense     Sulcralfate, Misoprostol
mechanism (cytoprotective)             Bismuth subsalicylate
3 Eradication of H phylori infection   Bismuth+metronidazole+tetrac
(antimicrobial agents)                 ycline or Tetracycline+
                                       Amoxicillin/Clarithromycin or
                                       ppi+cla+amox
                     Agents that reduce acid

          Antacids                                        Antisecretory

Mg(OH)2   Al(OH)3          NaHCO3              H2 Antagonists Proton Pump inhibitors
               Control of gastric Acid secretion
      Vagus
                  ACH         ECL            Gastrin

                                 H    H2 receptors

  Anticholinergic
                               X      antagonists           Gastrin
                                                         Producing cell
                                H2


  X
ACH
                ACH
                                     cAMP


                            Protein kinase
                                                        G




 Proton pump
 inhibitors     X           H+/K+-ATPase         Parietal Cell

                                K+          H+
                                                 X   Antacids
Antacids
 Neutralized acid reduce intragastric acidity
 May promote protective function of gastric
 mucosa by stimulating PG production
 Given at large dose could reduce recurrence
 rate of ulcer
 Very effective in providing pain relief
 because of faster action
Antacids
Two commonly used antacids
 Mg(OH)2
 Al(OH)3
These are weak bases and not significantly
 absorbed by Gut compared to CaCO3
 &NaHCo3
Mg----
Mg---- diarrhoea (osmotic)
Al-------
Al------- constipation
Often combined
Side effect
Milk alkali syndrome (CaCO3&NaHCO3)
metabolic alkalosis and hypercalcemia
Belching
Reduce absorption certain drug like Iron
and tetracycline
Antisecretory agents
 H2 antagonists
 Proton pump inhibitors
 Antimuscarinic-
 Antimuscarinic-Pirenzipine
H2 Antagonist
 Cimetidine
 Ranitidine
 Nizatidine          Increase potency

 Famotidine
 Differ in potency
Action
  Competitive antagonism of histamine at H2 receptors on
  gastric parietal cell

  Highly selective on H2 receptors

  Inhibits both basal and meal mediated acid secretion
               6-
  (lasting for 6-10hr )
  Inhibits acid secretion by histamin,Ach and gastrin

  Effect on meal mediated acid secretion is modest

  It reduces nocturnal acid secretion (H) by 90%
                                                      60-
  It blocks meal mediated (G,Ach,H) acid secretion by 60-
  80%
Side effects
  Endocrine: ( mainly for
 Cimetidine )
 Due to inhibition of estrogen metabolism and
  binding of testosterone on androgen receptors
 Gynecomastia
 Impotence
 Galactorrhea
  CNS
  Confusion
  Hallucination
  Agitation
  Drug interaction due enzymes inhibition
Clinical uses
 1. Gastroesophageal reflux disease (GERD)
   Intermittently
   Prophylactic ally before meal

 2.Peptic ulcer disease
                            6-
 Once daily at bedtime for 6-8 weeks, healing
 rate=80-90%
 rate=80-
Heal NSAID induced ulcer if NSAID is
 discontinued
 3. non ulcer dyspepsia
 4. Prevent bleeding of stress induce ulcer in ill
 patient (I/V)
Proton pump inhibitors:
 Omeprazol
 Lansoprazol
 Esomeprazol
 Prodrug
 Given in enteric coat form to prevent destruction
 by acid
              intestine,absorbed--          cell-
 Dissolve in intestine,absorbed-- parietal cell-
    active thiophilic sulfonamide cation form
 covalent binding with H+/K+ ATPase Enzyme
  Irreversible inhibition of proton pump
  Absorption reduce by food
  best taken on empty stomach
   better given I hr before meal
  Acid inhibition up to 24H
  3-5 days is required for full inhibition of
  enzyme
 PPI has longer duration of action up to 24
Hr
 Inhibit both fasting and meal mediated
acid secretion up to 90% (very efficacious)
Clinical uses
  1.Is a first line drug to treat symptomatic
  Gastroesophageal reflux disease
                               (70-
symptomatic relief is more (70-80%) compared to
                   (50-
  H2 antagonist (50-60%)

 2. Peptic ulcer disease
 faster healing (4/52) compared to H2
 antagonist,healing rate is >90%
 Promotes eradication of H phlori associated ulcer
 It has minimum antimicrobial effect (increase gastric pH)
prevent NSAID induced ulcer
promote healing of NSAID induced ulcer despite
continuation of Tx

3. prevent bleeding of stress induced ulcer in ill
patient

4. Tx of non ulcer dyspepsia


Gastrinoma
Side effects
  Diarrhea

  Headache

  Abdominal pain

  Reduce gastric acidity:
 Reduce B12, mineral or drug absorption
 may Increase gut colonization by harmful bacteria
Hypergastrinemia ---- hyperplasia of ECL
Prolong Tx in animal cause gastric carcinoid tumor
Mucosal protective agents
Mucosal defense mechanism includes:
Mucus
Mucosal cell tight junction prevent back diffusion
of acid and pepsin
Bicarbonate increase gastric pH
Prostaglandins stimulate mucus,bicarbonate
and increase blood flow
Repair process of the injured cells
 Mucosal protective agents
 (Cytoprotective agents)
Sucralfate
Prostaglandin analogs
Misoprostol
Colloidal Bismuth compound:
Bismuth subcitrate
Bismuth dinitrate
Bismuth subsalicylate
Sucralfate
 Is a salt of sucrose in aluminum hydroxide
 (strong negatively charged molecule)
 Viscous paste,binds selectively to ulcer base
  negatively charged compound that binds to positively
 charged protein at ulcer base. Thus form physical barrier
  stimulate prostaglandin
  bicarbonate secretion
 enhancing mucosal repair
Clinical uses
 Can heal duodenal ulcer
  however it is seldom used for ulcer
 May be used to prevent bleeding of stress
 induced ulcer.
 Not effective for NSAID induced ulcer.
Side effects
              effect-
  No systemic effect- not absorbed
  Constipation due to Aluminum hydroxide
  May reduce absorption of certain drugs
Prostaglandin Analogs
   GIT mucosa synthesizes prostaglandin E&F
   Misoprostol is Prostaglandin E analog
   Stimulate mucus
   stimulate bicarbonate secretion
   Enhance mucosal blood flow

 It inhibits histamine mediated gastric Acid
secretion
Side effects
 Diarrhea
 Abd pain

Clinical uses:
Prevent NSAID induced ulcer
Not widely used compared to proton pump
inhibitors due to side effect
Colloidal bismuth compound
Bismuth subcitrate
Bismuth dinitrate
Bismuth subsalicylate
Action:
It precipitate in acid environment,thus it binds to the
   base of the ulcer.
Protect against acid and pepsin
May stimulate prostaglandin, mucus,bicarbonate
 production
Bismuth has antimicrobial effect including H pylori
Clinical uses
 Eradication of H pylori infection
 Regime:
  Bismuth subsalicylate 2 tablet
                                         Qid for 2/52
 Tetracycline 500mg
  Metronidazol 250
Another regime for H pylori
 Proton pump inhibitor bd
Clarithromycin 500mg bd            10-14 days
 Amoxicillin 1g bd
Side effects:

 Blackening of stool (99% out by feces)
 Darkening of tongue
 Should be avoided in renal insuffiency
 Prolonged used may cause bismuth toxicity
 encephalopathy (<1% absorbed)
Agents           H2 antagonist     Proton pump          Antacid
                                   inhibitors

Acid secretion   Nocturnal acid     Inhibits both       Neutralized
                 (H)Reduce by      fasting and meal     acid
                 90%. Meal         mediated acid
                 mediated                        90-
                                   secretion by 90-
                 reduced by        98%.Effect
                             60-
                 (Ach,G,H) 60-     lasting for 24 hrs
                 80% lasted for
                 6-10hrs,may
                 inhibits 65 %
                 of acid out put
                 in 24hrs
Healing          Healing rates     >90% within 4        May heal ulcer
                 80-     6-
                 80-90% 6-         weeks                Slow response
                 8wTx
Symptom relief   Yes               Less effective       Faster
                        (6-
                 Slower (6-                             (1-
                                                        (1-2hr)
                 10hrs)

								
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