ANTACIDS
&
ACID-SUPRESSANTS
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Stomach anatomy
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Gastric acid regulation
three main pathways:
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Gastric acid regulation
three main pathways inducing acid secretion:
• acetylcholine release form post-ganglionic vagal neurons
• gastrin release from antral G cells
• histamine release from mast cells
counteracting mechanisms:
• bicarbonate release (neutraliztion)
• mucus production (protection)
• prostaglandin effect (inhibition)
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Anti-ulcer pharmacotherapy
• antacids
• sucralfate
• histamine-2 receptor antagonists (H2A)
• proton-pump inhibitors (PPIs)
• misoprostol
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Anti-ulcer pharmacotherapy
• antacids
• sucralfate
• histamine-2 receptor antagonists (H2A)
• proton-pump inhibitors (PPIs)
• misoprostol
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Anti-ulcer pharmacotherapy - antacids
• calcium-carbonate based (Tums®, …)
• aluminum/magnesium-based (Magel®, Maalox®, … )
action:
• chemical neutralization of acid
• as-needed use: may require frequent dosing
• effective in relieving symptoms, allow healing
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Anti-ulcer pharmacotherapy - antacids
ADEs - calcium carbonate:
• hypercalcemia
• renal dysfunction
• absorbed calcium may ↑ gastrin release
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Anti-ulcer pharmacotherapy - antacids
ADEs - magnesium salts:
• diarrhea
• hypermagnesemia (in renal insufficiency)
ADEs - aluminium salts:
• constipation
• hyperaluminemia (in renal insufficiency)
combination products
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Anti-ulcer pharmacotherapy - antacids
DDIs
complexation/chelation of various drugs
• digoxin, ciprofloxacin, ferrous sulfate (iron)
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Anti-ulcer pharmacotherapy
• antacids
• sucralfate
• histamine-2 receptor antagonists (H2A)
• proton-pump inhibitors (PPIs)
• misoprostol
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Anti-ulcer pharmacotherapy - sucralfate
sucralfate (Ulsanic®)
• aluminum salt of sulfated disaccharide
• forms protective gelatinous layer on gastric mucosa
• facilitates ulcer healing by additional mechanisms
• negligible absorption
• few ADEs (constipation, flatulence, nausea, metallic taste)
• DDIs: may bind phenytoin, warfarin, theophylline
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Anti-ulcer pharmacotherapy
• antacids
• sucralfate
• histamine-2 receptor antagonists (H2RA)
• proton-pump inhibitors (PPIs)
• misoprostol
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Anti-ulcer pharmacotherapy - H2RA
• cimetidine (Cimetag®, Cemidin®)
• ranitidine (Zantab®, Zanidex®)
• famotidine (Gastro®)
inhibition of gastric
acid secretion by
competitive-reversible
binding to H2-receptors
on parietal cells
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Anti-ulcer pharmacotherapy - H2RA
PK (oral)
• onset: ~1hr
• duration: 6hr (cime) – 10hr (famo)
• metabolism: hepatic CYP (cime>rani), non-CYP (famo)
• excretion: mostly renal
• T1/2: cemi, rani: 1.5-3hr; famo: 2.5-4hr
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Anti-ulcer pharmacotherapy - H2RA
ADEs (oral)
• diarrhea
• headache
• dizziness
• altered mental status (severely ill, elderly)
• mild ↑ LFTs
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Anti-ulcer pharmacotherapy - H2RA
DDIs (oral)
• PK, due to hepatic effects: cime>rani>>famo
• cime ↑ effect of warfarin, amiodarone, CCBs, CBZ, pehnytoin, …
• rani ↑ effect of cyclosporin, glibenclamide, metoprolol, pehnytoin
• all ↓ effect of azole antifungals
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Anti-ulcer pharmacotherapy
• antacids
• sucralfate
• histamine-2 receptor antagonists (H2RA)
• proton-pump inhibitors (PPIs)
• misoprostol
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Anti-ulcer pharmacotherapy - PPI
• omeprazole (Losec®, Omepradex®)
• esomeprazole (Nexium®)
• lansoprazole (Zoton®)
• pantoprazole (Controloc®)
inhibition of gastric
acid secretion by
irreversible binding to
H+/K+ ATPase pump
on luminal surface of
parietal cells
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I
PP
Anti-ulcer pharmacotherapy - PPI
• oral administration as prodrugs
• administer before meals
• not in fasting conditions or with other drugs affecting
gastric acidity (acidic environment required for systemic action)
• PPIs formulated as coated granules for prevention of
early breakdown in gastric acidic environment:
- do not crush/chew
- difficulty swallowing:
open capsule, sprinkle granules into apple sauce
- administration via nasogastric tube:
mix with water, flush into tube
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Anti-ulcer pharmacotherapy - PPI
PK (omeprazole)
• onset - 1hr, peak 1-3hr, duration up to 72hr
• extensive hepatic CYP metabolism
• urinary excretion (metabolites); lansoprazole - combined
• short PK T1/2 (prodrug, long PD effect)
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Anti-ulcer pharmacotherapy - PPI
ADEs (omeprazole)
• generally considered extremely safe
• GI …
• headache, cough
• long-term concerns:
- hypergastrinemia, gastrinoma, gastric cancer ? (rats…)
- gastric infections (impaired protective acidic environment): C. difficile
- osteoporosis? B12 deficiency ?
- cardiovascular complications (slightly ↑ MI/HF/cardiac death) ?
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Anti-ulcer pharmacotherapy - PPI
ADEs (omeprazole)
Based on everything we know now, FDA’s preliminary
conclusion is that the observed difference in risk of heart
attacks and other heart related problems seen in early analyses
of the two small long-term studies is not a true effect.
[FDA, 12/2007]
- cardiovascular complications (slightly ↑ MI/HF/cardiac death) ?
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Anti-ulcer pharmacotherapy - PPI
DDIs (omeprazole)
• extensive CYP metabolism …
• … but few clinically significant DDIs
• ↓ absorption of azole antifungals, iron salts, digoxin
• ↑ levels of simvastatin, fluoxtine, phenytion, warfarin, diazepam, …
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Anti-ulcer pharmacotherapy - PPI
DDIs (omeprazole)
• CYP2C19-inhibition reduces clopidogrel activation
• clinically significance??
Nov 17th 2009
“The concomitant use of omeprazole and clopidogrel should be avoided
because of the effect on clopidogrel's active metabolite levels and anticlotting activity. Patients at risk for heart attacks or strokes, who are
given clopidogrel to prevent blood clots, may not get the full protective
anti-clotting effect if they also take prescription omeprazole or the OTC
form (Prilosec OTC).”
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Anti-ulcer pharmacotherapy - PPI
DDIs (omeprazole)
Should Omeprazole or
Clopidogrel Be Substituted
When Given Concomitantly?
Omeprazole and
clopidogrel: Should
clinicians be worried?
Influence of Omeprazole on the
Antiplatelet Action of Clopidogrel
Omeprazole reduces antiplatelet effect of clopidogrel?
Clopidogrel and omeprazole –
interaction now confirmed
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Anti-ulcer pharmacotherapy - PPI
esomeprazole
• S-enantiomer of racemic omperazole
• manufacturer claim: superior efficacy
• many disagree …
(dose-effect? marketing?)
• ↓ inter-individual variability?
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Anti-ulcer pharmacotherapy
• antacids
• sucralfate
• histamine-2 receptor antagonists (H2RA)
• proton-pump inhibitors (PPIs)
• misoprostol
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Anti-ulcer pharmacotherapy - misoprostol
misoprostol (Arthrotec® = combined with diclofenac; Cytotec®)
• synthetic prostaglandin-E1 analog
↓ parietal cell cAMP
↓ gastric acid secretion
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Anti-ulcer pharmacotherapy - PPI
for acid-related disorders: only combined with an NSAID
• S-enantiomer of racemic omperazole
• rapid, short action
• main ADE: diarrhea, abdominal pain (↓
↓ with food)
• main concern: abortifacient and teratogenic
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Pharmacotherapy - antacids + acid-suppressants
DRUGS FOR EXAM
• antacids
• sucralfate
• ranitidine
• omeprazole
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