Haematological Adverse Effects of Histamine H2-Receptor Antagonists

Abstract

Histamine H2-receptor antagonists are widely used in the treatment of gastrointestinal diseases related to gastric acid hypersecretion. Cimetidine was introduced into medical practice in 1976 and ranitidine, famotidine and nizatidine in 1981, 1985 and 1987, respectively. Haematological adverse effects are relatively uncommon and most have been reported in cases of cimetidine administration. These adverse effects are reviewed under 4 main headings: (a) blood cytopenias and leucocytosis; (b) coagulation disorders related to drug interactions with oral anticoagulants; (c) reduction of dietary iron absorption; and (d) reduction of dietary cobalamin absorption. 85 reported cases of blood cytopenias attributed to these drugs are reviewed, of which 75 (88%) were associated with cimetidine therapy. In postmarketing surveillance studies, the incidence of cimetidine-associated blood cytopenia has been evaluated at about 2.3 per 100,000 patients. Neutropenia and agranulocytosis are by far the most frequently encountered. Whatever the drug or the type of cytopenia, this adverse effect is almost always rapidly reversible when treatment is stopped. Moreover, in several cases other factors such as underlying diseases or additional drugs could have been responsible, at least partly, for the cytopenia. The pathophysiological basis of these adverse effects remains poorly explained. Various mechanisms have been proposed, which in some cases are probably associated: (a) direct toxicity for haemopoietic stem cells; (b) drug-induced immune reactions leading to blood or bone marrow cell damage, and (c) drug interactions, with increased and prolonged action of potentially haematotoxic drugs. Mechanisms (a) and (c) appear to be of particular clinical importance in cases of impaired renal elimination of H2-receptor antagonists. Cimetidine and probably to a lesser extent ranitidine potentiate the action of oral anticoagulants of both coumarin and indanedione structure. This may result in haemorrhagic complications. Such action is a consequence of the reduced hepatic metabolism of oral anticoagulants through a dose-dependent, reversible inhibition of cytochrome P450. Malabsorption of dietary iron and cobalamin appears to result from inhibition of gastric secretion by the H2-receptor antagonists. This is of no clinical importance in short term treatment, but long term use of H2-receptor antagonists may theoretically contribute to the occurrence of iron or cobalamin deficiency anaemia.

Medical Surveillance Monthly Report. Volume 19, Number 7

“…High levels of consumption of coffee and tea and the excessive use of medications to inhibit stomach acid secretion may interfere with iron absorption. 19,20 While studies examining IDA in military personnel are limited, these findings are consistent with a recent study of iron status, ID and IDA prevalence among military personnel deployed to Afghanistan that found ID in 1 percent and 6 percent and IDA in 0 percent and 2 percent of males and females, respectively. 11 This report shows that 18 percent of females and 10 percent of males diagnosed with IDA experience a recurrence (i.e., recurrent or chronic) of their condition.…”

Ranitidine treatment inducing methemoglobinemia in male Wistar rats

“…Histamine H 2 -receptor antagonists are widely used in the treatment of gastrointestinal diseases related to gastric acid hypersecretion and cytoprotective effects (Penston, Wormsley, 1986;Aymard et al, 1988;MunozArrebola et al, 1989). Ranitidine, one of such antagonists was first marketed in 1981; since then, many patients have been treated with this drug, and much experience regarding its safety has been gathered (Vial et al, 1991).…”

How I treat hemochromatosis

“…Regardless, there are insufficient data to recommend the routine administration of proton-pump inhibitors to patients with hemochromatosis for the purpose of decreasing iron absorption. Histamine receptor-2 antagonists reduced dietary iron absorption in short-term studies of persons without hemochromatosis, 65 but continuous use of cimetidine for 3 years did not alter hemoglobin or plasma iron levels significantly. 66 The greater influence of PPIs than histamine receptor-2 antagonists on SF levels could be explained by the direct inhibition of gastric acid secretion and longer duration of action characteristic of PPIs.…”