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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 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 dapsone-induced methemoglobinemia (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 to acute alcohol ingestion. Ranitidine was withdrawn from the US market in 2020 after a potentially carcinogenic impurity was found in tested formulations.
  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. Cimetidine may inhibit the formation of the oxidative metabolites of dapsone, reducing methemoglobin levels and improving tolerance for patients chronically taking the drug.
  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. One case report of a dystonic reaction after IV cimetidine administration.
    3. A reversible, dose-dependent rise in serum alanine aminotransferase activity has been reported with nizatidine. Hepatitis has also occurred with ranitidine.
    4. Cardiac dysrhythmias (bradycardia, tachycardia) and hypotension have been associated with rapid IV bolus of cimetidine (rare). Note: Maximum infusion rates provided in 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 unlikely.
  5. Drug or laboratory interactions
    1. Cimetidine reduces hepatic clearance and prolongs the elimination half-life of several drugs due to inhibition of cytochrome P450 activity and reduced hepatic blood flow. Examples of drugs affected include phenytoin, theophylline, phenobarbital, cyclosporine, morphine, lidocaine, calcium channel blockers, tricyclic antidepressants, and warfarin. Cytochrome P450 inhibition likely accounts for profound QTc prolongation reported with coingestion of loperamide and cimetidine.
    2. Cimetidine 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 of any one of the H2 blockers. Cimetidine is more likely to be associated with drug-drug interactions. The lowest-strength dosage forms are available over the counter, and several oral dosage form options (chewable tablets, oral solutions) may enhance palatability. Oral and parenteral doses are presented in Table III-5.
TABLE III-5. CIMETIDINE, FAMOTIDINE, AND NIZATIDINE
DrugRouteDosea
CimetidinePO300 mg every 6-8 hours or 400 mg every 12 hours (maximum, 2,400 mg/d). Children: 10 mg/kg (maximum, 300 mg), then 5-10 mg/kg every 6-8 hours up to 20-40 mg/kg/d.
IV, IM300 mg IV or IM every 6-8 hours. For IV administration, dilute in normal saline to a total volume of 20 mL and give over 5 minutes or longer. May give by continuous IV infusion at initial rate of 25-50 mg/h and titrate to effect (mean rates of 160 mg/h reported; maximum 2,400 mg/d). Children: 10 mg/kg (maximum, 300 mg), then 5-10 mg/kg every 6-8 hours up to 20-40 mg/kg/d.
FamotidinePO20-40 mg once or twice daily (as much as 160 mg every 6 hours has been used). Children: 0.5 mg/kg/dose once to twice daily (maximum 40 mg twice daily).
IV20 mg IV every 12 hours (dilute in normal saline to a total volume of 5-10 mL) and give at a rate of 10 mg/min or less over at least 2 minutes). Children: 0.25-0.5 mg/kg/dose (maximum dose, 20 mg) once to twice daily.
Nizatidine PO 150 mg once to twice daily (or 300 mg once daily).

aMay need to reduce dose in patients with renal insufficiency.