Antisecretory Agent PDF - H2-receptor antagonist Download
Get the comprehensive Antisecretory Agent PDF, focusing on H2-receptor antagonists. This document covers their detailed mechanism of action, pharmacological actions, adverse drug reactions (ADR), absorption, distribution, metabolism, and excretion (ADME), along with their therapeutic uses. Essential for pharmacology and medical students. Download for free or view online on Sildes By DuloMix.
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Antisecretory Agents: Focus on H2-Receptor Antagonists in Gastric Acid Management
Antisecretory agents are a class of drugs used to reduce the secretion of gastric acid in the stomach. Excessive gastric acid can lead to various gastrointestinal disorders, including peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD), and Zollinger-Ellison syndrome. Among the key classes of antisecretory agents, H2-receptor antagonists were historically significant and laid the groundwork for modern acid suppression therapies.
H2-Receptor Antagonists: Overview
H2-receptor antagonists (H2RAs) were a revolutionary class of drugs introduced in the 1970s, significantly changing the treatment paradigm for acid-related disorders. Examples include Cimetidine (the first H2RA), Ranitidine, Famotidine, and Nizatidine. These drugs primarily work by blocking the histamine H2 receptors located on the parietal cells of the stomach, which are responsible for secreting gastric acid.
Mechanism of Action
Gastric acid secretion is stimulated by three main physiological agonists: histamine, acetylcholine, and gastrin. Histamine, released from enterochromaffin-like (ECL) cells, acts on H2 receptors on parietal cells, leading to activation of adenylate cyclase and increased cyclic AMP (cAMP) levels. This, in turn, activates protein kinase A, which stimulates the H+/K+-ATPase proton pump, ultimately leading to acid secretion.
H2-receptor antagonists are competitive inhibitors of histamine at the H2 receptors. By binding to these receptors, they prevent histamine from stimulating the parietal cells, thereby reducing both basal (resting) and stimulated gastric acid secretion. While they primarily target histamine-mediated acid production, they also indirectly reduce acid secretion stimulated by gastrin and acetylcholine, as these pathways partly converge on histamine release.
Pharmacological Actions
The primary pharmacological action of H2RAs is a significant reduction in gastric acid output. They can reduce total 24-hour gastric acid secretion by about 70%. This reduction includes:
- Reduction of Basal Acid Secretion: H2RAs are particularly effective at inhibiting nocturnal acid secretion, which is largely histamine-driven.
- Reduction of Stimulated Acid Secretion: They effectively suppress acid secretion stimulated by meals, gastrin, or acetylcholine.
- Mild increase in Gastric pH: By reducing acid, H2RAs lead to an increase in gastric pH, which helps in the healing of ulcers and reduces esophageal irritation in GERD.
- No significant effect on gastric motility or emptying.
- No effect on pancreatic or bile secretion.
Adverse Drug Reactions (ADR)
H2RAs are generally well-tolerated, and their adverse effects are usually mild and transient. Common ADRs include:
- Headache
- Dizziness
- Diarrhea or Constipation
- Fatigue
- Cimetidine-specific effects: Cimetidine, due to its inhibition of cytochrome P450 enzymes (especially CYP1A2, CYP2C9, CYP2D6, CYP3A4), can cause drug interactions, leading to increased levels of drugs like warfarin, phenytoin, theophylline, and benzodiazepines. It can also cause antiandrogenic effects (e.g., gynecomastia, impotence) with prolonged high-dose use due to its weak antiandrogenic activity. These effects are less common with newer H2RAs.
- Rarely, central nervous system effects (confusion, hallucinations) especially in elderly patients or those with renal impairment.
- Rarely, blood dyscrasias (e.g., agranulocytosis) or liver abnormalities.
Absorption, Distribution, Metabolism, Excretion (ADME)
- Absorption: H2RAs are generally well absorbed orally, with bioavailability ranging from 40% (Cimetidine) to over 90% (Famotidine). Food has minimal impact on absorption.
- Distribution: They are widely distributed throughout the body, including the central nervous system to a limited extent. They bind minimally to plasma proteins.
- Metabolism: They undergo varying degrees of hepatic metabolism, primarily through cytochrome P450 enzymes (less for Ranitidine, Famotidine, Nizatidine than Cimetidine).
- Excretion: The majority of the dose is excreted unchanged in the urine. Therefore, dosage adjustments are necessary in patients with renal impairment. Their half-lives range from 1.5 to 4 hours.
Uses
H2-receptor antagonists are used for the treatment and prevention of various acid-related conditions:
- Peptic Ulcer Disease (PUD): Used for the treatment of duodenal and gastric ulcers. While still effective, proton pump inhibitors (PPIs) have largely superseded them due to superior acid suppression.
- Gastroesophageal Reflux Disease (GERD): Effective for mild to moderate GERD symptoms and for healing esophagitis. For severe GERD, PPIs are preferred.
- Zollinger-Ellison Syndrome: A condition characterized by excessive gastrin production leading to severe acid hypersecretion. High doses of H2RAs were previously used, though PPIs are now the first-line treatment.
- Stress Ulcer Prophylaxis: Used to prevent stress ulcers in critically ill patients, although PPIs are often preferred in this setting as well.
- Non-Ulcer Dyspepsia: For symptomatic relief of heartburn and indigestion.
Despite the advent of more potent acid suppressants like PPIs, H2-receptor antagonists remain valuable drugs, particularly for their generally good safety profile and effectiveness in managing mild to moderate acid-related conditions, often available over-the-counter for symptomatic relief.
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