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
combination of NSAIDS to treat arthritis pain with high risk of GI bleed
*Misoprostol + Diclofenac → combination medication to treat arthritis pain in patients with high risk of GI bleeding/ulceration
Bismuth subsalicylate
Bismuth-containing compounds
- Form a protective coating on ulcerated tissue
- Stimulate mucosal protective mechanisms
- Direct antimicrobial effects (potential activity against H. pylori)
Mechanism: a. chelating with protein forms coating b. antipeptic activity
Indication: gastric, duodenal ulcer
(= with H2 blocking drugs, less relapse)
- Oral
- Over-the-counter drug
indications:
- Used to treat nausea, heartburn, indigestion, upset stomach, diarrhea, and other temporary discomfort conditions of the GI tract
- H. pylori associated ulcers (part of eradication regimen)
Side effects: black stools, constipation, darkening of the tongue - darkening of oral cavity - encephalopathy, osteodistrophy: only: if renal damage!!
Therapy of H. pylori
Multiple drugs have been evaluated in the therapy and eradication of H. pylori infection.
No single agent is effective in eradicating the organism; combination therapy for 14 days provides the greatest efficacy.
Choice of a particular regimen is influenced by several factors, including efficacy, patient tolerance, antibiotic resistance, and cost.
Triple therapy:
R. #1
(‘BMT regimen’)
- Bismuth subsalicylate
- Metronidazole
- Tetracycline
R. #2
- Ranitidine bismuth citrate
- Tetracycline
- Clarithromycin or Metronidazole
R. #3
(‘PPI-based regimen’)
- Omeprazole
- Clarithromycin
- Amoxicillin or Metronidazole
Duration: 14 days Side effect: 80 % (1+2)
+ omeprazol Duration: 7 days (3+4)
Quadruple therapy:
R. #1
- Bismuth subsalicylate
- Omeprazole
- Metronidazole
- Tetracycline
“Rescue” therapy • PPI2x • Amoxicillin • Levofloxacin OR • Rifabutin Or • furazolidon
Peptic ulcer disease – definition
The term encompasses both gastric and duodenal ulcers.
Ulcers are defined as breaks in the mucosal surface > 5 mm in size, with depth penetrating to the submucosa.
May be acute or chronic, both penetrate the muscularis mucosae, but acute ulcer shows no evidence of fibrosis.
Erosions do not penetrate the muscularis mucosae.
Duodenal ulcers and gastric ulcers share many common features in terms of pathogenesis, diagnosis, and treatment.
risk factors for peptic ulcer disease
- H. pylori infection
- NSAID’s
- Smoking
- Older age
- Obesity
- D.M.
- GERD
- Bile reflux
- COPD
- Chronic renal insufficiency
Differential diagnosis – GI ulcers
- H. pylori-induced ulcer
- NSAID’s-induced ulcer
- Malignancy
- Stress-induced ulcer
- Curling ulcer (burn injury)
- Cushing ulcer (ICP ↑)
- Gastrinoma (Z-E syndrome)
Clinical presentation ans Symptoms
- Epigastric pain improves
with meal (duodenal ulcer) - Epigastric pain worsens with meal (gastric ulcer)
- Nausea, vomiting
- Anorexia
- Anemia (iron-deficiency)
- Hematemesis, melena
- Acute perforation
*Persistent daily vomiting suggests gastric outlet obstruction
H. pylori associated pathology
- Peptic ulcer disease
- Chronic gastritis
- MALT lymphoma
- Gastric metaplasia → predisposes to gastric adenocarcinoma
Diagnosis of H. pylori
Non-invasive methods:
Urea breath test:
Simple, rapid
Useful for early follow-up
False negatives with recent therapy Exposure to low-dose radiation with C14 test
Serology:
Inexpensive, convenient
Not useful for early follow-up
Stool antigen:
inexpensive, convinient
Invasive methods (endoscopy- based):
Rapid urease test:
Simple, high specificity
False negatives with recent use of PPI’s, antibiotics, or bismuth compounds
Histology:
High sensitivity and specificity
Requires pathology processing and staining
Culture:
Gold-standard
Time-consuming, expensive
Allows determination of antibiotic susceptibility
integrity of gastric mucose
Agressive factors: HCl, Pepsin, H. Pylori NSAIDs
Protective factors: Mucus-bicarbonate layer Phospholipids Tight junction protein PG, NO
ULCER - TYPE I.
In case of distal, antral and duodenal ulcers hypersecretion is observed
DOMINANCY OF AGRESSIVE FACTORS
ULCER - TYPE II.
In case of upper gastric ulcers the acid secretion is normal or decreased
(tends to malignant transformation!)
DECREASED DEFENSIVE MECHANISMS
ULCER THERAPY
I. INHIBITION OF AGRESSIVE FACTORS
Anti-secretory agents Antacids
II. INCREASE OF MUCOSAL RESISTENCE
Sucralfat
Bismuth salts
III. INHIBITION OF AGRESSIVE FACTORS + INCREASE OF MUCOSAL RESISTENCE
prostaglandins
IV. ERADICATION OF HELICOBACTER PYLORI
I. ANTI-SECRETORY AGENTS
- HISTAMINE H2 RECEPTOR ANTAGONISTS
- Cimetidine
- Famotidine
(Ranitidine )
(Nizatidine) - PROTON-PUMP INHIBITORS
- OMEPRAZOLE (pro-drug)
- PANTOPRAZOLE
- ESOMEPRAZOLE
(LANSOPRAZOLE)
(DEXLANSOPRAZOLE)
(RABEPRAZOLE) - M1 MUSCARIN RECEPTOR ANTAGONIST
Pirenzepine
Telenzepine
COMMON PROBLEMS OF ANTISECRETORY DRUGS
Hypochlorohydria
a) favors the survival of bacteria; candidal peritonitis b) growth of bacteria that form from ingested nitrates
carcinogen nitrosamines (??)
Diagnosis of gastric cancer can be retarded in the presence of H2 blockers
Profilaxis of NSAID-induced gastric mucosal damage
Profilaxis of NSAID-induced gastric mucosal damage
- Risk factors: GI ulcer, bleeding from GI tarct!!,
Age above 60,
Smoking
Parallel treatment with additional NSAID, glucocrticoids. anticoagulants
-Prevention
- Proton pump inhibitors (but not against intestinal
mucosal injury)
- H2 blocking drugs
- Misoprostol
- Selctive COX-2 inhibitors
Indication of H. pylori eradication
- Peptic ulcer (actíve, inactive)
- MALT (mucosa associated lymphoid tissue)-lymphoma
- Atrophic gastritis
- After resetion due to gastric carcinoma
- Family member of patient with gastric cc • (Patients,s desire)
THERAPY OF GASTRO-OESOPHAGEAL REFLUX DISEASE
Causes by: insufficiency of lower esophagus sphincter
Therapy: symptomatic, antisecretory drugs
Symptoms:
Localized for esophagus:
classic reflux symptoms, chest pain (angina!)
lesions in esophagus: esophagitis, strictures Barett metaplasia, adenocc.
Extra-esophageal symptoms: coughing, laryngitis, asthma.
Principle of therapy:
„Step down” !!
Start with highly effective drug, in high dose
“Step up”
Start with less effective drug, in lower dose
Short-term treatment: 3-6 months
Maintaining therapy: (e.g. in esophagitis) prevention of recidivate “step down” high dose PPI, half dose PPI, H2 blocking drug
- PPI
- H2RA
- antacid
