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The Pharmacological

Aspects of Drugs in
Gastric Disease

Eman Sutrisna
Department of Pharmacology
Medical School Jenderal Soedirman University

Learning Objectives
 To identify the drugs use in the
gastric disese
 To explain pharmacological properties
of the drugs use in the gastric disese
 To explain the principles use of the
drugs in patient with the gastric
disese

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The Gastric Disese (Problem)

 Dyspepsia: upper abdo pain/discomfort (fullness,


bloating, distension, nausea)
 Peptic ulcers  defects in mucosa extending through
muscularis mucosae
 Prevalence
 PUD 5-10% lifetime
 dyspepsia 25-40%
 Aetiology (most common)
 H.pylori
 NSAIDs

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Mucosa protective factors

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Parietal cell and acid regulation

NSAIDs
 Antiinflammatory
 Analgesic
 Antipyretic

 Chemically heterogeneous
 Reversible competitive inhibitors of COX
activity (Aspirin irreversible)

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NSAIDs
 Reduce prostaglandin synthesis (COX-1)
 Mucus
 bicarbonate
 blood flow
 proliferation of cells
 gastric acid secretion
 Reduce production of superoxide radicals,
induce apoptosis, inhibit expression of
adhesion molecules, decrease NO synthase and
proinflammatory cytokines, modify lymphocyte
activity and alter cellular membrane functions
 Biliary excretion and reflux of metabolites into
stomach

Helicobacter pylori
 Peptic ulcers
 Gastric carcinoma/lymphoma
 Mucosal atrophy

Tests
 Urea breath test (sens. and spec. ~95%)
 Endoscopic (urease, histology)
 Stool antigen (sens. and spec. ~ 95%)
 (serology)
 Omit PPI for 2 weeks prior to tests

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H. pylori

Treatment
 Goals of therapy
 Symptomatic relief
 Diminish the frequency of recurrence and
duration of symtoms
 To Treat the aetiology
 Avoid complications

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Treatment Options
Over-the-counter
Lifestyle modifications
medications
 Head of bed elevation Antacids
H2 Receptor Antagonists
 Avoidance of tight-fitting clothes
(H2RAs)
 Weight loss Proton Pump Inhibitor (PPI)

 Restriction of alcohol

 Elimination of smoking Presc medications


 Dietary therapy Prokinetics
 Refraining from lying down after
meals H2RAs
 Avoidance of evening snacks PPIs
before bedtime
Surgery

PHARMACOLOGY
ANTI-SECRETORY DRUGs

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Histamine H2-Receptor
Antagonists (H2RAs)

H2RAs
 Reversibly compete with histamine
for binding to H2 receptors on the
basolateral membrane of parietal
cells
 Less potent than PPIs but still
suppress acid by 60-70% over 24 hrs
 Predominantly inhibit basal acid
suppression (nocturnal-fasting)

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Available H2RAs

 Cimetidine
 Ranitidine
 Famotidine
 Nizatidine

**All exist in generic form

Pharmacokinetics
 Rapidly absorbed after oral administration
 Serum concentrations peak in 1-3 hr
 Therapeutic levels maintained up to 12 hrs
 Small percentage is protein bound
 10% to 35 % metabolized by the liver
 Drugs and metabolites primarily excreted
by kidneys (**reduce doses in renal
disease)
 Rebound response upon discontinuation

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Common H2RA Side Effects
 All less than 3%
 Diarrhea
 Headache
 Drowsiness
 Fatigue
 Muscular pain
 Constipation
 Much less common
 Confusion, delirium in the elderly
 Associated with thrombocytopenia
 Cimetidine anti-androgen effects

DRUG USE H2RAs


 Mainstay of treatment for mild to moderate
GERD
 H2RAs equally efficacious
 Select based on pharmacokinetics, safety profile
and cost
 Timing
 Give in divided doses for constant gastric acid
suppression
 May give at night if only nocturnal symptoms
 Give before an activity that may result in reflux
symptoms

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DOSAGE H2RAs
Cimetidine Famotidine Nizatidine Ranitidine

Low dose 200 mg 10 mg 75 mg 75 mg

Standard 400 mg 20 mg 150 mg 150 mg


dose
High 400 mg or 40 mg bid 150 mg 150 mg
dose 800 mg

Proton Pump Inhibitors


(PPIs)

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PPI Structures

PPIs
 Most potent suppressors of acid
secretion
 Diminish basal and stimulated acid
production by 80-95%
 24-48 hr effects on acid suppression
 Acid-activated pro-drugs

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PPIs

 inhibit H+/K+ATPase function to:


 Block gastric acid secretion
 Decrease pepsin concentration
 Increase gastric pH

PPI Pharmacology

 Pro-drugs with pKa of approximately 4


 Activated only when pH decreases below 4
 Occurs only in parietal cell secretory canaliculi
 Achieved only when parietal cell activation
occurs (after meals)
 Most effective after a prolonged fast when
large amounts of active proton pumps are
present (i.e. breakfast)

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Available PPIs
 Esomeprazole
 Lansoprazole
 Omeprazole
 Pantoprazole
 Rabeprazole

**All have equivalent efficacy at


comparable doses

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PPI Pharmacokinetic
 Rapidly absorbed
 Highly protein bound
 Extensively metabolized in the liver by
the P450 system (CYP2C19 and CYP3A4)
 Sulfated metabolites are excreted in the
urine or feces
 Hepatic disease reduces the clearance of
lansoprazole--reduce dose

Common PPI Side Effects


 Headache (2.9-6.9%) vs. Placebo (2.5-
6.3%)
 Diarrhea (3%) vs. Placebo (3.1%)
 Abdominal pain (2.4-5.2%) vs. Placebo
(3.1-3.3%)
 Constipation (1.1-1.5%) vs. Placebo (0-0.8%)
 B12 malabsorption reported with omeprazole

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Drug-Drug Interactions
 Warfarin
 Esomeprazole
 Lansoprazole
 Omeprazole
 Rabeprazole
 Diazepam
 Esomeprazole
 Omeprazole

Drug USE - PPIs


 Used to treat moderate to severe GERD
 PPIs for 8-16 weeks
 more rapid symptom relief and higher rate of
healing
 More effective and faster healing than
H2RAs
 May be used to treat esophagitis refractory to
H2RAs
 All agents effective BUT.for drug
selection.see the research comparison

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THE RESEARCH COMPARISON

 Kahoru Nishina, et al (2000): Kobe University School of


Medicine, Japan : A Comparison of Rabeprazole,
Lansoprazole, and Ranitidine for Improving
Preoperative Gastric Fluid Property in Adults ndergoing
Elective Surgery  Rabeprazole is the most effective to
reduce acid secretion. (not statistically significant)
 Yoshiyuki Kawakami et al (2000), Shinshu University
School of Medicine, Japan : to compare activities
among Rabeprazole, lansoprazol and OMZ combination
with AB against Helicobacter pylori  Rabeprazole
combination is the most effective

THE RESEARCH COMPARISON

 Tommy B. Andersson et al (2004) :


Comparison of inhibitory effect of PPIs
OMZ, Esomeprazol, Lansoprazole,
Pantoprazole and Rabeprazole on
Human C-450 Activities
 High : Omeprazole
 Moderate : esomeprazole, lansoprazole,
pantoprazol
 Low : Rabeprazole

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Antacids
 Mg and Al hydroxides
 May chelate other drugs (avoid concomitant
administration of other drugs)
 Side effects: diarrhoea (Mg), constipation (Al)
 Milk alkali syndrome (alkalosis, renal
insufficiency, hypercalcemia)

Sucralfate

 Forms sticky polymer in acidic environment


 Inhibits hydrolysis of mucous proteins by
pepsin
 1 g bd to 1g qds
 SE: constipation, aluminium absorption (avoid
in severe renal impairment due to risk of
encephalopathy)

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H. pylori eradication

 Eradication increases ulcer healing


 Reduces recurrence
 MALT, Ca (can lead to resolution)
Triple therapy
For 7 (14) days twice daily eg

 full dose PPI +


 Amoxicillin +
 Clarithromycin/Metronidazole

Effective in 80-85%

Misoprostol
 PGE1 analogue
 Stimulates Gi pathway (cAMP and gastric
acid)
 blood flow and mucus and bicarbonate
secretion

Use: prevention of NSAID induced injury


Side effects:diarrhoea, pain, cramps (30%)
Can cause exacerbation of IBD
Contraindication: pregnancy, caution in women of
childbearing age can induce labour!

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