CHAPTER 3-18: CIMETIDINE AND OTHER H₂ BLOCKERS

INTRODUCTION

1. Pharmacology. Cimetidine, ranitidine, famotidine, and nizatidine are selective competitive inhibitors of histamine on H₂ receptors. These receptors modulate smooth muscle, vascular tone, and gastric secretions and may be involved in clinical effects associated with anaphylactic and anaphylactoid reactions as well as ingestion of histamine or histamine-like substances (eg, scombroid fish poisoning). Cimetidine, as an inhibitor of cytochrome P450 enzymes, has been proposed or studied in animals as an agent to block the production of toxic intermediate metabolites (eg, acetaminophen, carbon tetrachloride, halothane, Amanita mushroom poisoning, dapsone), but this has not been shown to be beneficial for human poisonings or toxicity with the possible exception of patients on chronic dapsone therapy (see "Indications"). Cimetidine is also an inhibitor of alcohol dehydrogenase (see "Drug or Laboratory Interactions") and has been suggested for use in patients with an atypical aldehyde dehydrogenase enzyme to minimize a disulfiram reaction ("Oriental flushing") to acute alcohol ingestion.

2. Indications

   1. Adjunctive with H₁ blockers such as diphenhydramine in the management and prophylactic treatment of anaphylactic and anaphylactoid reactions (see chapters on various antivenoms).

   2. Adjunctive with H₁ blockers such as diphenhydramine in the management of scombroid fish poisoning.

   3. Ranitidine has been used to reduce vomiting associated with theophylline poisoning. Because cimetidine may interfere with hepatic elimination of theophylline, it should not be used.

   4. Cimetidine has been used to decrease methemoglobin levels by inhibiting oxidative metabolite formation and thereby improve tolerance for patients on chronic dapsone therapy.

3. Contraindications. Known hypersensitivity to H₂ blockers.

4. Adverse effects

   1. Headache, drowsiness, fatigue, and dizziness have been reported but are usually mild.

   2. Confusion, agitation, hallucinations, and even seizures have been reported with cimetidine use in the elderly, the severely ill, and patients with renal failure. A case was reported of a dystonic reaction after IV cimetidine administration.

   3. A reversible, dose-dependent rise in serum alanine aminotransferase activity has been reported with nizatidine, a related agent. Hepatitis has also occurred with ranitidine.

   4. Cardiac dysrhythmias (bradycardia, tachycardia) and hypotension have been associated with rapid IV bolus of cimetidine and ranitidine (rare). Note: Maximum infusion rates provided on Table III–5.

   5. Severe delayed hypersensitivity after high oral doses of cimetidine (case report).

   6. Preparations containing the preservative benzyl alcohol have been associated with "gasping syndrome" in premature infants.

   7. Use in pregnancy. FDA Category B (Introduction). Fetal harm is extremely unlikely.

5. Drug or laboratory interactions

   1. Cimetidine, and to a lesser extent ranitidine, reduces hepatic clearance and prolongs the elimination half-life of several drugs as a result of inhibition of cytochrome P450 activity and reduction of hepatic blood flow. Examples of drugs affected include phenytoin, theophylline, phenobarbital, cyclosporine, morphine, lidocaine, calcium channel blockers, tricyclic antidepressants, and warfarin.

   2. Cimetidine, ranitidine, and nizatidine inhibit gastric mucosal alcohol dehydrogenase and, therefore, increase the systemic absorption of ethyl alcohol.

   3. Increased gastric pH may inhibit the absorption of some pH-dependent drugs, such as ketoconazole, ferrous salts, and tetracyclines.

6. Dosage and method of administration. In general, there are no clinically proven advantages ...