Cimetidine

General adverse effects and adverse reactions

The main varieties of adverse effects attributed to cimetidine relate to its antiandrogenic properties and its actions in sufficient concentrations on the central nervous system. There is also a spectrum of drug interactions, mainly attributable to inhibition of hepatic CYP isoforms, but they only have clinical consequences under special circumstances. Occasional adverse effects, which are generally minor, include bradycardia and conduction defects, thrombocytopenia, neutropenia, interstitial nephritis, mild hepatic dysfunction, and headache. Intestinal infection due to loss of the gastric acid barrier also occurs, and myalgia, fever, monoamine oxidase-like interactions, and neuropathies have been well documented occasionally. Allergic reactions, such as bronchospasm, have rarely been described. Anaphylaxis with recurrence on rechallenge is on record, as are asthma and skin effects.

Cardiovascular

Rapid infusion of cimetidine causes an increase in plasma histamine concentration, and this could be one reason for its cardiac effects. A marked degree of bradycardia (for example a 30% reduction in heart rate) is uncommon although well recognized [ ]; sinoatrial and atrioventricular conduction effects and dysrhythmias of every possible type have occasionally been noted, particularly after infusion but also with oral therapy. It has been suggested that if a patient is particularly at risk (for example because of poor renal function) the electrocardiogram should be monitored [ ].

Symptoms of vasodilatation have been attributed to cimetidine [ ].

• A 31-year-old white man taking maintenance hemodialysis had frequent episodes of hot flushes, sweating, palpitation, and dizziness, which started after about 1 month of treatment with cimetidine 400 mg/day. When the drug was temporarily discontinued and later when it was totally withdrawn, he noted marked improvement in 2–5 days.

Respiratory

Bronchospasm is occasionally reported, reflecting the possibility of allergy to cimetidine, and the need for some caution with its initial use in any patient with asthma [ ]. In pre-existing atopic asthma, H ₂ receptor antagonists can enhance bronchial reactivity [ ]. Central nervous system effects can lead to respiratory depression, although this is rare.

Loss of the gastric acid barrier can predispose to intestinal infection, and pulmonary aspiration of infected gastrointestinal secretions can very occasionally cause pneumonia after anesthesia or during intensive care [ ]. Interstitial lung disease can occur under these conditions.

Nervous system

Cimetidine crosses the blood–brain barrier and its adverse events include central respiratory depression and extrapyramidal and cerebellar disturbances. There have been convincing isolated reports of choreiform movements [ , ].

Severe central neurological problems are not common with cimetidine. In one intensive survey of nearly 10 000 patients followed for 3 months there were only five cases of confusion, though there were 34 with sensations of dizziness, 23 with headache, and 74 with other milder central nervous effects [ ]. The overall incidence of adverse neurological effects reported to the US public health authorities (which naturally represent only a small proportion of those that actually occur) was 8.6 per million prescriptions for cimetidine and virtually the same for ranitidine. Healthy elderly people are probably not at particular risk.

Occasionally, neuropathies have been documented [ ]. The fear that cimetidine or ranitidine might increase the incidence of motor neuron disease was raised in the light of case–control work, but seems to have been allayed by data from the Oxford Record Linkage Study published in 1993 [ ].

A dystonic reaction has been attributed to cimetidine [ ].

• A 39-year-old woman developed a dystonic reaction (masseter spasm, lip smacking, oculogyric crisis, and mild neck spasm) within 5 minutes of intravenous administration of cimetidine 300 mg for epigastric pain. She had epilepsy and had not taken her antiepileptic medication regularly. She had developed a similar dystonic reaction to prochlorperazine 1 week before. She recovered within 5 minutes of treatment with intravenous diphenhydramine and lorazepam.

Psychiatric

Cimetidine crosses the blood–brain barrier and can cause confusion, particularly in elderly or sick individuals with compromised hepatic or renal function, and especially after intravenous treatment. Very rarely an acute confusional psychosis has been seen in a younger person [ ]. Delirium has been thought to be a particular problem with intravenous use, but this is more likely to be a reflection of patient selection. Depression has occasionally been attributed to cimetidine [ , ].

Metabolism

In the earlier years of cimetidine use there were scattered (although well-documented) reports of the drug having destabilized severe diabetes, resulting in impaired control [ ]; however, most people with diabetes are unlikely to be affected.

Modest increases in serum high-density lipoproteins have occasionally been noted in patients taking cimetidine [ ].