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Pathogenesis of peptic ulcer disease:
infection with gram-negative Helicobacter pylori the use of nonsteroidal anti-inflammatory
drugs (NSAIDs) increased hydrochloric acid secretion Inadequate mucosal defense against gastric acid.
Treatment approaches:
1. Eradicating H. pylori infection 2. Reducing secretion of gastric acid or neutralizing the
acid with the use of PPIs or H2-receptor antagonists
3. Providing agents that protect the gastric mucosa from damage such as misoprostol and sucralfate.
Bismuth subsalicylate
Dicyclomine
PantoprazoleEsomeprazoleRabeprazole
Regulation of gastric acid secretion
Gastric acid secretion by parietal cells of the gastric mucosa is controlled by acetylcholine, histamine, prostaglandins E2 and I2, and gastrin. The receptor-mediated binding of acetylcholine, histamine, or gastrin results in the activation of a proton pump (H+/K+- ATPase) that secretes hydrochloric acid (HCI) into the lumen of the stomach. In contrast, receptor binding of prostaglandins E2 and I2 diminishes gastric acid production.
Histamine binding causes activation of adenylyl cyclase, whereas binding of prostaglandin E2 and I2 inhibits this enzyme. Gastrin and acetylcholine act by inducing an increase in intracellular calcium levels.
H2-receptor antagonists
Mechanism of Actions
The histamine H2-receptor antagonists - cimetidine, ranitidine, famotidine, and nizatidine - act on H2-receptors in the stomach, blood vessels, and other sites. They are competitive antagonists of histamine and are fully reversible. By competitively blocking the binding of histamine to H2 receptors, these agents reduce intracellular concentrations of cyclic AMP and thereby, secretion of gastric acid.
These agents completely inhibit gastric acid secretion induced by histamine, or gastrin. However, they only partially inhibit gastric acid secretion induced by acetylcholine or bethanechol.
Therapeutic uses:
Peptic ulcers: All four agents are equally effective in promoting healing of duodenal and gastric ulcers. However, recurrence is common after treatment with H2 antagonists is stopped (60 to 100% per year). This can be effectively prevented by eradication of H. pylori, and H2 antagonists continue to be widely used in peptic ulcer therapy in combination with antimicrobial drugs.
Zollinger-Ellison syndrome: Zollinger-Ellison syndrome is a rare condition in which a gastrin-producing tumor causes hypersecretion of HCI. With H2 antagonists, the hypersecretion of gastric acid can be kept at safe levels in patients with Zollinger-Ellison syndrome.
Acute stress ulcers: These drugs are useful in managing acute stress ulcers associated with major physical trauma in high-risk patients in intensive care units.
Gastroesophageal reflux disease (heartburn): Low doses of H2 antagonists appear to be effective for prevention and treatment of heartburn (gastroesophageal reflux). Because they act by stopping acid secretion, they may not relieve symptoms for at least 45 minutes. Antacids more efficiently neutralize secreted acid already in the stomach.
ADVERSE REACTIONS
The H2 receptor antagonists generally are well tolerated, with a low (<3%) incidence of adverse effects; including diarrhea, headache, drowsiness, fatigue, muscular pain, and constipation.
Less common adverse effects include those affecting the CNS (confusion, delirium, hallucinations, slurred speech, and headaches), which occur primarily with intravenous administration or in elderly subjects. Long-term use of cimetidine at high doses decreases testosterone binding to the androgen receptor and inhibits a CYP that hydroxylates estradiol.
Clinically, these effects can cause galactorrhea in women and gynecomastia, reduced spermcount, and impotence in men. Several reports have associated H2 receptor antagonists with various blood dyscrasias, including thrombocytopenia. H2 receptor antagonists cross the placenta and are excreted in breast milk.
PHARMACOKINETICS
The H2 receptor antagonists are rapidly absorbed after oral administration, with peak serum concentrations within 1–3 hours. Therapeutic levels are achieved rapidly after intravenous dosing and are maintained for 4–5 hours (cimetidine), 6–8 hours (ranitidine), or 10–12 hours (famotidine).
Unlike proton pump inhibitors, only a small percentage of H2 receptor antagonists are protein-bound. Liver disease by itself is not an indication for dose adjustment. The kidneys excrete these drugs and their metabolites by filtration and renal tubular secretion, and it is important to reduce doses of H2 receptor antagonists in patients with decreased creatinine clearance. Neither hemodialysis nor peritoneal dialysis clears significant amounts of the drugs.
