Drugs used in peptic ulcer diseases. Pharmacotherapy of peptic ulcer diseases. Flashcards
Etiology of peptic ulcer
Ulceration and erosion of the upper GI mucosal lining, due to imbalance between protecting and irritating factors. May be part of various clinical conditions:
- Gastroesophageal reflux disease (GERD)
- Gastric and duodenal peptic ulcers (PUD)
- Stress-related mucosal injury (ICU patients, sepsis, shock)
- Acute/chronic gastritis
Acid-suppressing agents
Antacids:
- (Sodium bicarbonate
(NaHCO3)) - Magnesium hydroxide
(Mg[OH]2) - Aluminum hydroxide
(Al[OH]3)
H2-receptor antagonists:
- Cimetidine
- Famotidine
(Ranitidine )
(Nizatidine)
Proton pump inhibitors (PPI’s):
- Omeprazole
- Esomeprazole
- Pantoprazole
(Lansoprazole)
Sodium bicarbonate
(NaHCO3)
(not on the list)
- Oral
- Absorbed from the gut
- Symptomatic relief of dyspepsia and heartburn
NaHCO3+ HCl = NaCl+H2O+CO2 Systemic alkalosis!!! Fluid retention (Na)
Side effects:
- metabolic alkalosis,
- may exacerbate fluid retention (CHF, renal failure)
Magnesium hydroxide
Mg[OH]2
- Oral
- Poorly absorbed from the bowel
Mg(OH)2-2HCl=MgCl2+2H2O
poor solubility, prolonged neutralizing effect cathartic effect
- Symptomatic relief of dyspepsia and heartburn
Side effects: diarrhea
Aluminum hydroxide
Al[OH]3
- Oral
- Poorly absorbed from the bowel
Al (OH)3+ 3HCl=ALCl3+H2O+CO2 AlCl3: insoluble, slow action constipation binds e.g. to tetracyclines, phosphate if absorbed: encephalopathy, Alzheimer?
- Symptomatic relief of dyspepsia and heartburn
Side effects: constipation
Antacids
Weak bases that neutralize stomach acid by reacting with protons in the lumen of the gut
- Sodium bicarbonate
(NaHCO3) - Magnesium hydroxide
(Mg[OH]2) - Aluminum hydroxide
(Al[OH]3)
Antacids and drug absorption :
- Oral absorption of weak bases ↑ (ex. quinidine) -
- Oral absorption of weak acids ↓ (ex. warfarin)
- Oral absorption of tetracyclines ↓ (via chelation)
H2-receptor antagonists
H2-receptor antagonists:
- Cimetidine
- Famotidine
(Ranitidine )
(Nizatidine)
- Competitive inhibitors of H2-receptors → indirect effect on proton pump activity → decrease gastric acid secretion (mainly nocturnal acid secretion)
- No H1, autonomic or anti-motion sickness effects (compared to H1 blockers)
- Acid suppressing effect is milder compared to proton pump inhibitors
Cimetidine
H2-receptor antagonists
- Competitive inhibitors of H2-receptors → indirect effect on proton pump activity → decrease gastric acid secretion (mainly nocturnal acid secretion)
- No H1, autonomic or anti-motion sickness effects (compared to H1 blockers)
- Acid suppressing effect is milder compared to proton pump inhibitors
Kinetics: - Oral, parenteral - Duration of action 6 h - bioavail: 80' - Metabolism by hepatic CYP450 (affected by drugs that induce/inhibit hepatic metabolism)
- Inhibitors of cytochrome P450 enzymes (cimetidine most potent)
Indications:
- GERD
- Peptic ulcer disease (PUD)
- H. pylori associated ulcers (part of eradication regimen)
- NSAID’s induced ulcers
- Prophylaxis against stress-related mucosal injury
- Zollinger-Ellison syndrome
- Duodenal ulcer: 85-90% are healed after 8 weeks treatment -Gastric ulcer_ 50-70% are healed after 8 weeks - Zollinger-Ellison syndrome: high doses are needed, better: PPI - Other condition: reflux esophagitis stress ulcers preanesthetic use in emergency
Side effects:
- GI distress
- Antiandrogenic effects (gynecomastia, decreased
libido) , mainly with cimetidine - Confusion, agitation (in the elderly)
1. headache, dizziness
2. nausea, diarrhea, constipation, myalgia
3. skin rashes, pruritus
4. only cimetidine: loss of libido, gynecomastia, impotency (binds to androgen receptors)
5. only cimetidine: binds to cytochrome P-450; inhibit the activity of hepatic microsomal enzym, enzym inhibition, drug interaction
6. CNS disturbance (in elderly people)
7. Rare effects: thrombo-leukocytopenia hepato-renal toxicity
i. v. inj.: bradycardia
Famotidine
Ranitidine Nizatidine
H2-receptor antagonists
- Competitive inhibitors of H2-receptors → indirect effect on proton pump activity → decrease gastric acid secretion (mainly nocturnal acid secretion)
- No H1, autonomic or anti-motion sickness effects (compared to H1 blockers)
- Acid suppressing effect is milder compared to proton pump inhibitors
- Oral, parenteral
- Duration of action 12 h
bioavailability: 40 - Metabolism by hepatic CYP450
(affected by drugs that induce/inhibit hepatic metabolism) - Inhibitors of cytochrome P450 enzymes (cimetidine most potent)
- Milder drug-interactions, milder side effects
Proton pump inhibitors (PPI’s)
- Irreversible, direct inhibitors of the proton pump (K+/H+ antiport) in gastric parietal cells
- 1st-line agents, most effective in reducing stomach acidity
MECHANISM:
- H+-K+-ATP-ase: final step in gastric acid secretion inhibited by substituted benzimdazole: Omeprazole and derivatives
- Lipophillic, weak bases,
Pro-drugs, formulated as delayed release,
Acid resisistant enteric coated capsules – against acid. Omeprazole: also as powder (with bicarbonate) , immediate release
- After absorbtion in parietal cell in canaliculi are formed the active form, reactive thiphillic, sulfenamid cation, forms a disulfide covalent bound with H+/K+ ATP-ase
- Inhibits both basal and meal-stimulated acid secretion
- Inhibits acid secretion by 90-98+ for 24h
Omeprazole
Esomeprazole (IV)
(Lansoprazole)
Pantoprazole (IV)
- Oral, IV
(oral formulation should be administered on empty stomach) - Hepatic metabolism
- Prodrug; activation occurs inside parietal cell
- T1/2 1-2 h’; acid-suppressing effect lasts up to 24 h’ owing to the irreversible inhibition of the pump
- Full acid-suppressing potential is reached within 3-4 days of treatment
- Omeprazole is an inhibitor of cytochrome P450 enzymes
(effect on: clopidogrel, warfarin, phenytoin, diazepam, cyclosporine) *Clopidogrel → bioactivation of prodrug is inhibited
CYP2C19 - GERD
Non-erosive reflux: H2 blocking intermittant course of PPI
Erosive oesophagitis: PPI, once daily (healing: 80%), daily (healing: 15%)
Extra-oeophageal reflux: twice daily - Peptic ulcer disease (PUD)
80-90% healing after 6-8 weeks gastric, after 4 week treatment duodenal ulcer - H. pylori associated ulcers (part of eradication regimen)
associated acute ulcer: PPI - NSAID’s associated ulcers
NSAID with active ulcer: stop it +PPI once or twice/day Prevention of ulcer formation, or complications: once daily (10-20 % asymptomatic ulcer, 1-2 % bleeding perforation) - Prophylaxis against stress-induced mucosal injury
PPI by nasogastric tube, i.v. : omeprazol – immediately release twice than once/day - Zollinger-Ellison syndrome
Side effects:
- Diarrhea, abdominal pain
- Headaches
- Decrease in oral bioavailability of vitamin-B12, iron,
digoxin, ketoconazole
- Increased risk of respiratory and enteric infections
- Hypergastrinemia (loss of negative feedback of H+ on
D-cells, may lead to ECL and parietal cells hyperplasia)
• Long term treatment
(reflux, NSAID-induced, aspirin-induced ulcer
prevention)
• Bacteria colonisation in the stomach
• Community aquired and nosocomial pneumonia
• Diarrhoe induced by clostridium difficile and aditional bacteria (Salmonella, Shigella, E coli, Campylobacter)
•Nutrition problem with impaired absorption of vitamin B12, iron, calcium
• Osteoporosis, increased risk of hip, spin, wrist fracture
Omeprazole Esomeprazole
Omeprazole Esomeprazole (IV)
- Irreversible, direct inhibitors of the proton pump (K+/H+ antiport) in gastric parietal cells
- 1st-line agents, most effective in reducing stomach acidity
Omeprazol inhibits the clopidogrel-induced antiaggregation reinfarction
Mechanism: the same enzyme (CYP2C19) is responsible for the formation of the active metabolite of clopidogrel and the metabolism of omeprazol.
Kinetics:
- Oral, IV
(oral formulation should be administered on empty stomach)
- esmomeprazol has better bioavailability and little longer half life
- Hepatic metabolism
- Prodrug; activation occurs inside parietal cell
- T1/2 1-2 h’; acid-suppressing effect lasts up to 24 h’ owing to the irreversible inhibition of the pump
- Full acid-suppressing potential is reached within 3-4 days of treatment
- Omeprazole is an inhibitor of cytochrome P450 enzymes
(effect on: clopidogrel, warfarin, phenytoin, diazepam, cyclosporine) *Clopidogrel → bioactivation of prodrug is inhibited
Indications:
- GERD
- Peptic ulcer disease (PUD)
- H. pylori associated ulcers (part of eradication regimen)
- NSAID’s associated ulcers
- Prophylaxis against stress-induced mucosal injury
- Zollinger-Ellison syndrome
Side effects:
- Diarrhea, abdominal pain
- Headaches
- Decrease in oral bioavailability of vitamin-B12, iron,
digoxin, ketoconazole
- Increased risk of respiratory and enteric infections
- Hypergastrinemia (loss of negative feedback of H+ on
D-cells, may lead to ECL and parietal cells hyperplasia)
- CNS: headache, dizziness skin rash, leukopenia, acute interstitial nephrits
• Long term treatment
(reflux, NSAID-induced, aspirin-induced ulcer
prevention)
• Bacteria colonisation in the stomach
• Community aquired and nosocomial pneumonia
• Diarrhoe induced by clostridium difficile and aditional bacteria (Salmonella, Shigella, E coli, Campylobacter)
•Nutrition problem with impaired absorption of vitamin B12, iron, calcium
• Osteoporosis, increased risk of hip, spin, wrist fracture
Pantropazol
- Irreversible, direct inhibitors of the proton pump (K+/H+ antiport) in gastric parietal cells
- 1st-line agents, most effective in reducing stomach acidity
Kinetics:
- Oral, IV
(oral formulation should be administered on empty stomach)
- Hepatic metabolism
- Prodrug; activation occurs inside parietal cell
- T1/2 1-2 h’; acid-suppressing effect lasts up to 24 h’ owing to the irreversible inhibition of the pump
- Full acid-suppressing potential is reached within 3-4 days of treatment
- Omeprazole is an inhibitor of cytochrome P450 enzymes
(effect on: clopidogrel, warfarin, phenytoin, diazepam, cyclosporine) *Clopidogrel → bioactivation of prodrug is inhibited
Indications:
- GERD
- Peptic ulcer disease (PUD)
- H. pylori associated ulcers (part of eradication regimen)
- NSAID’s associated ulcers
- Prophylaxis against stress-induced mucosal injury
- Zollinger-Ellison syndrome
Side effects:
- Diarrhea, abdominal pain
- Headaches
- Decrease in oral bioavailability of vitamin-B12, iron,
digoxin, ketoconazole
- Increased risk of respiratory and enteric infections
- Hypergastrinemia (loss of negative feedback of H+ on
D-cells, may lead to ECL and parietal cells hyperplasia)
Mucosal-protective agents
- Sucralfate - Aluminium sucrose sulphate
- Misoprostol - Prostaglandin (PGE1) analogue
- Bismuth subsalicylate - Bismuth-containing compounds
Sucralfate
- Aluminium sucrose sulphate; polymerizes on gastrointestinal luminal surface to form a protective gel-like coating of ulcer beds
- Enhances PGE synthesis, stimulates mucus and bicarbonate secretion, enhances mucosal defense and repair
Activation: at acidic pH, gel formation
Mechanism: a. the (-) sucrose octasulphate bind to (+) protein molecules: gel
b. decrease the back-diffusion of H+ c. stimulation of PG synthesis
Kinetics:
- Oral
- Administered 4 times daily
- Prodrug; requires acidic pH (antacids, PPI’s, H2-antagonists interfere)
Indications:
- Improves healing after mucosal damage
- Prevent reoccurrence
- gastric ulcer
- duodenal ulcer
- Side effects: constipation; generally systemic side
effects are uncommon (too insoluble to be absorbed)
Interaction: antacids, H2 antagonist should not be taken simultaneously
(sucralfate is effective only in acidic environment)
Misoprostol
Prostaglandin (PGE1) analogue
- Mucus and bicarbonate secretion ↑
- HCl secretion ↓
- Mucosal vascularity and blood flow ↑
Mechanism: a. stimulation of mucus secretion b. enhanced mucosal blood flow b. prevents H+ back-diffusion c. enhanced cell replication d. inhibition of acid secretion! (inhibition of cAMP)
Mechanism: Stimulation of prostagladin EP2, EP3, EP4 receptors, but not EP1, less toxicity than PGE2
Kinetics:
- Oral
- T1/2 < 30 min’ (administered 3-4 times daily)
Indications:
- NSAID’s induced ulcers (also as prophylaxis)
- abortion induction combined with mifepriston
Side effects:
- diarrhea (Mg-comounds enhance)
- Contraindicated in pregnancy (abortifacient)
- uterus contraction, abortion
*Misoprostol + Diclofenac → combination medication to treat arthritis pain in patients with high risk of GI bleeding/ulceration
