H2 Receptor Antagonists

H₂ Receptor Antagonists

Histamine-₂ receptor antagonists competitively inhibit the interaction of histamine with H₂ receptors. They are highly selective and have little or minimal effect on H₁ or other recep-tors. H₂ antagonists mainly interfere with gastric secretion, although they exert inhibitory effects on cardiovascular and other systems affected by H₂ receptors. They do not exhibitanticholinergic properties.

Important examples of this group of drugs used widely in the treatment of peptic and duodenal ulcer, include cimetidine, ranitidine, famotidine, nizatidine and roxatidine.

Cimetidine has been implicated in causing significant drug interactions with a number of other therapeutic drugs because of its ability to inhibit cytochrome P450 mixed function oxidase activity— amitryptiline, benzodiazepines, carbamazepine, imipramine, lignocaine, nifedipine, phenytoin, quinidine, terfenadine, theophylline, verapamil and warfarin.

H₂  blockers can produce the following effects during therapeutic use: cardiovascular (bradycardia, hypotension, AV block and sinus arrest (especially with rapid IV administra- tion); haematologic (agranulocytosis, pancytopenia, aplastic anaemia, and thrombocytopenia), and dermatologic (including Stevens-Johnson syndrome, toxic epidermal necrolysis). Cimetidine, ranitidine, and famotidine have been associated with drug-induced fever, which typically resolves within 48 to 72 hours after discontinuation of the drug. The most consistent adverse reaction reported with famotidine is a severe, throb-headache, with an incidence of up to 4.7%. This has also been reported for ranitidine. There are also case reports which suggest an association between ranitidine use and hepatotox- icity. Gynaecomastia and increased prolactin levels may be seen following therapeutic doses of cimetidine.

Acute toxicity is rare with these compounds. There is one report of cimetidine overdose producing tachycardia, mydriasis, and slurred speech. Other effects reported include bradycardia, confusion, and vomiting. Bradycardia, hypotension, and cardiac arrest may occur if cimetidine is given rapidly intravenously. Cimetidine has caused complete atrioventricular block, wide- complex tachycardia, and cardiac arrest after both oral and intravenous doses. Sinus bradycardia is the most frequently reported cardiovascular effect. Dry mouth, mild drowsiness, epigastric discomfort with diarrhoea, muscle pain, headache, dizziness, delirium, psychosis, elevated liver or kidney func-tion tests, leukopenia, and thrombocytopenia have also been reported. Visual hallucinations, CNS depression, seizures, dystonia and coma have occurred.

Chronic administration can cause confusion, restlessness, extrapyramidal effects, seizures, and peripheral neuropathies.

Treatment of acute toxicity involves administration of acti-vated charcoal, and supportive measures. Convulsions can be controlled with benzodiazepines or barbiturates. Bradycardia usually responds to atropine. Haemodialysis may be useful. However, according to some investigators, less than 20% of a single dose is recoverable in the dialysate of patients under- going haemodialysis.

While it appears safe to manage most accidental ingestions at home, the maximum tolerated dose has not been defined. Patients have survived ingestions of 12 to 24 grams. Ranitidine which is much more potent than cimetidine has also been very rarely implicated in overdose. There is one case report of accidental overdose in a 3 month old child producing a dystonic reaction. So far, there are no documented fatalities following an acute oral overdose of cimetidine alone or any of its related agents.