Summary
Histamine H2receptor antagonists have been used in the treatment of gastrointestinal diseases for more than a decade and during this period have become one of the most commonly prescribed groups of drugs in the world.
The deserved popularity of the H2 receptor antagonists reflects, in part, their therapeutic efficacy, which has revolutionised the treatment of peptic ulcer disease. An equally, or more, important reason for the widespread use of H2 receptor antagonists is their remarkably low toxicity. We have attempted, in this review, to present a detailed account of the minor and more serious adverse reactions, while emphasising the low incidence of the former and the rarity of the latter.
The toxicology of the H2-receptor antagonists is discussed under two main headings: (a) adverse effects; and (b) drug interactions. The latter category is potentially the more significant, since the frequent use of therapy with multiple drugs may give rise to drug interactions, some of which are serious and may even be lethal. These drug interactions occur especially in the gastrointestinal tract, the liver and the kidneys. Thus, the absorption of other drugs may be altered because the H2 receptor antagonists inhibit gastric secretion-an effect illustrated by ketoconazole, the absorption of which is reduced when given in combination with cimetidine. Very important drug interactions are caused by inhibition of the hepatic microsomal enzyme cytochrome P450 by some of the H2 receptor antagonists. This effect appears to be related to the chemical structure of the individual H2 receptor antagonists and is not attributable to histamine H2-receptor blockade. For example, cimetidine is a powerful inhibitor of cytochrome P450, while the interaction of ranitidine with this system is weaker. Consequently, cimetidine reduces the metabolism of many drugs which are normally degraded by phase I reactions, leading to potentially toxic plasma concentrations of therapeutic agents such as some oral anticoagulants, β-blockers, anticonvulsants, benzodiazepines and xanthines. Some of the Hrreceptor antagonists are actively secreted by the renal tubules and may thus compete with other drugs for cationic tubular transport mechanisms, resulting in reduced urinary excretion and hence potentially toxic plasma concentrations. This type of drug interaction has been reported after administration of both cimetidine and ranitidine with procainamide or quinidine.
Adverse reactions that have been reported to occur during treatment with H 2receptor antagonists are outlined in the present review according to the system involved. Of the minor side effects, diarrhoea is the most frequent, affecting 1 to 7% of patients receiving treatment with H2receptor antagonists. In the past, confusion and drowsiness were quite frequent complaints in elderly patients or patients with impaired renal or hepatic function who received H2receptor antagonists. This type of reversible central nervous system reaction is now very uncommon since patients in these high risk groups are given reduced doses of these drugs. Anti-androgenic side effects of cimetidine, such as gynaecomastia and impotence, occur in considerably less than 1% of treated patients, unless the patients are receiving very high doses of the drug (for the treatment of gastrinoma).
Severe adverse reactions with the H2-receptor antagonists are exceptionally rare. Idiosyncratic reactions have involved many organs, resulting in disorders such as interstitial nephritis, hepatitis and dermatological reactions. The incidence of these reactions is, at most, only a few individuals per million exposed to the drugs. Serious cardiovascular complications following treatment with H2receptor antagonists (such as bradycardia and hypotension) have only been recorded after rapid intravenous injection of the drugs in very few individuals, and have been avoided by intravenous infusion. In view of the neutropenia associated with metiamide therapy, much attention has been paid to the detection of potentially adverse effects of the newer H2receptor antagonists on the bone marrow. The reports of neutropenia during treatment with H2-receptor antagonists have been very rare and other factors, such as additional drug treatment or underlying serious illness, have usually made the interpretation of the haematological abnormalities difficult or impossible.
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Pension, J., Wormsley, K.G. Adverse Reactions and Interactions with H2-Receptor Antagonists. Medical Toxicology 1, 192–216 (1986). https://doi.org/10.1007/BF03259837
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DOI: https://doi.org/10.1007/BF03259837