A-34. Drugs used in peptic ulcer diseases. Pharmacotherapy of peptic ulcer diseases. Flashcards
The 4 main groups of agents in the treatment of peptic ulcer?
Antisecretory agents
Antacids
Mucosal defense enhancers
Drugs used for eradication of H. pylori
Characteristics of type 1 ulcers?
Distal, antral + duodenal ulcers due to hypersecretion of gastric acid
Characteristics of type 2 ulcers?
Upper gastric ulcers; normal / decreased gastric acid with decreased defense mechanisms
Type II ulcers tend to undergo malignant transformation
Pathomechanism of ulcer formation?
“Back diffusion” of gastric acid from the lumen to the gastric mucosa occurs when mucosal integrity is compromised, resulting in further mucosal injury.
What does the mucosal integrity depend on?
Mucosal integrity depends on mucus secreted from gastric epithelial cells and on mucosal microcirculation, which is NO dependent. Prostaglandins, specifically PGE2 and PGI2 also protect the gastric mucosa by inhibiting HCl secretion and relaxing mucosal vessels, improving blood flow.
What are the 3 groups of Anti-secretory agents used?
H2 antagonists
Proton pump inhibitors
M1 antagonists
H2 antagonists. Drugs?
Famotidine, ranitidine, nizatidine and cimetidine (longest to shortest half-life)
H2 antagonists. MOA?
Inhibit H2 on parietal cells → ↓ cAMP → ↓ H/K-ATPase activity
Inhibit both basal + stimulated (via food / pH increase) gastric acid secretion, as well as pepsin and intrinsic factor secretion
They also antagonize effects of histamine on heart + vessels; may enhance immune responses
H2 antagonists. Dosage and indications?
Famotidine 2 x 20 mg/day or 1 x 40 mg/day (on doses list)
○ Peptic ulcer - both gastric and duodenal; effective for both, but more effective for duodenal
○ Zollinger-Ellison syndrome - gastrinoma; high doses needed
○ Reflux esophagitis, stress ulcers and pre-anesthetic in emergency procedures
H2 antagonists. Side effects?
○ HA, dizziness, nausea, diarrhea, constipation, myalgia, rashes and pruritus
○ CNS disturbances - mainly in elderly
○ Hypochlorhydria - low gastric HCl; ↑ bacterial survival; candidal peritonitis; can favor growth of bacteria which produce carcinogenic nitrosamines
○ Rarely - thrombo-/leukocytopenia, hepatorenal toxicity and bradycardia (if given i.v.)
○ May slow the detection of gastric cancer
Unique side effects for Cimetidine?
■ Anti-androgenic effects - binds androgen R → ↓ libido, gynecomastia, impotence
■ CYP450 inhibition
PPIs. Drugs?
Rabeprazole, Pantoprazole, Lansoprazole, Esomeprazole, and Omeprazole (long to short T1/2)
PPIs. MOA?
They inhibit the H+/K+-ATPase proton pump on the luminal surface of parietal cells
PPIs. Dosage and Indications?
Pantoprazole 20-40 mg 1-2x/day (on doses list)
Same as H2 atgs (except stress ulcer + pre-anesthesia); better than H2 atgs for reflux esophagitis
PPIs. Side effects?
○ Hypergastrinemia - may cause hyperplasia of G cells or carcinoid tumors
○ Pneumonia - ↑ risk of nosocomial + community-acquired respiratory infections
○ Diarrhea - ↑ risk of C. diff and others (Salmonella, Shigella, E. coli, Campylobacter) or overgrowth of normal flora
○ Osteoporosis - with long-term use, ↑ hip fracture risk
○ HA, dizziness, skin rash, leukopenia
Omeprazol interaction?
Omeprazole inhibits anti-aggregation effect of clopidogrel because both are pro-drugs activated by CYP2C19 + thus compete with each other for activation
M1 antagonists. Drugs?
Pirenzepine and Telenzepine
M1 antagonists. MOA?
Selective M1 muscarinic atgs → block cholinergic vagal stimulation of gastric secretions at the level of the parasympathetic ganglia
Block gastric secretion at lower doses than those which block other cholinergic functions → ↓ sfx
M1 antagonists. Kinetics and Indications?
Poor oral absorption
Duodenal or gastric ulcers (higher dose for gastric)
M1 antagonists. Side effects?
Frequent - constipation / diarrhea, dry mouth, HA, CNS effects
Less frequent - blurred vision
Antacids. Sodium compounds?
Sodium bicarbonate and sodium citrate
● Sodium bicarb + HCl forms NaCl, water and CO2
● Can cause systemic alkalosis and fluid retention (via ↑ Na+)
Antacids. Magnesium compounds?
Magnesium hydroxide
It forms MgCl2 and water; poorly soluble, long DOA and cathartic effect (diarrhea)
Antacids. Aluminum compounds?
Aluminum hydroxide, basic Al carbonate gel and Al phosphate gel
AlCl3 formed from Al-OH and HCl; Al-OH has slow action and AlCl3 is poorly soluble → constipation, binding of tetracyclines + phosphate; can cause encephalopathy in kidney dysfunction
Antacids. Calcium compounds?
Calcium carbonate
10% of formed CaCl2 is absorbed and can cause hypercalcemia and milk-alkali syndrome; only given short-term
3 mucosal defense enhancers?
Bismuth chelate, Sucralfate, Misoprostol
Bismuth chelate
MOA, indications and side effects?
MOA: chelates with proteins to form a protective coating over ulcers; also acts weakly as an antacid
○ taken 30 mins before or 2 hours after last meal
Indication: gastric and duodenal ulcers; combined with H2 atgs → less relapse
Side Effects:
○ Darkening of oral cavity
○ In renal impairment - encephalopathy and osteodystrophy
Sucralafate
MOA, indications, side effects and interaction?
Basic aluminum salt of sucrose octasulfate
MOA: negatively charged sucrose octasulfate binds (+) charges on proteins, forming a gel; decreases back-diffusion of H+ into mucosa; stimulates PG synthesis; taken before meals
Indications: gastric and duodenal ulcers
Side Effects: obstipation - severe or complete constipation
Interaction: only effective in acidic environment → not given with antacids / H2 blockers!
Misoprostol
MOA, indications, side effects and contraindication?
Synthetic PGE1
MOA: stimulates mucus secretion; enhances mucosal blood flow; prevents back diffusion; enhances cell replication; inhibits acid secretion (via ↓ cAMP)
Indication: NSAID-induced gastric mucosa damage
(Prophylaxis of NSAID ulcers can also be via COX2-selective NSAIDs, PPIs and H2 atgs)
Side Effects: diarrhea
Contraindication: pregnancy - stimulates uterine contractions!
H. pylori classic triple therapy consists of?
Metronidazole + bismuth citrate + tetracycline or amoxicillin
Given for 14 days, or 7 days with omeprazole added; highest sfx risk
H. pylori modified triple therapy consists of?
PPI + clarithromycin + metronidazole
Given for 7 days; lowest sfx risk
H. pylori alternative triple therapy consists of?
PPI + clarithromycin + amoxicillin
Given for 7 days; middle sfx risk
3 virulent mechanisms of H. pylori
H. pylori infects the gastric mucosa by neutralization of gastric acid with urease, breaking down urea to NH3 and CO2 which neutralizes gastric acid, forming NH4Cl.
Other factors in H. pylori pathogenicity are cytotoxins, PLA2 / PLAC, induction of leukotriene + PAF release, and endotoxin-induced endothelial damage.
H. pylori infection increases risk of gastric carcinoma.
