Gastro-oesophageal reflux disease is probably the most common acid-peptic disease in Western countries, and the successful treatment of mild to moderate disease with pharmacotherapy has become commonplace. A large number of effective drugs are now available, and so the decision-making process for physicians increasingly relies on considerations other than pure efficacy. Cost, adverse effects and drug interactions have therefore become important, particularly in the most vulnerable patients - children, the elderly and patients who are ill and are taking medications that may influence the efficacy of antireflux therapy. Important drug interactions with antacids include the prevention of the absorption of antibacterials such as tetracycline, azithromycin and quinolones. H2 antagonists, proton pump inhibitors and prokinetic agents undergo metabolism by the cytochrome P450 (CYP) system present in the liver and gastrointestinal tract. Cimetidine is an inhibitor of CYP3A and it may cause significant interactions with drugs of narrow therapeutic range and low bioavailability that are metabolised by these enzymes. The gastroparietal proton pump inhibitors lansoprazole, omeprazole and pantoprazole are all primarily metabolised by a genetically polymorphic enzyme, CYP2C19, that is absent from approximately 3% of Caucasians and 20% of Asians. These drugs may also interact with CYP3A, but to a lesser extent. Interactions with prokinetic agents carry the greatest potential for harm. Metoclopramide is a dopamine antagonist that may cause extrapyramidal effects when administered alone at high concentrations, or when coadministered with antipsychotic agents such as haloperidol or phenothiazines. Cisapride is clearly able to prolong the electrocardiographic QT interval and cause lethal ventricular arrhythmias when its metabolism is slowed by interaction with inhibitors of CYP3A, such as erythromycin, ketoconazole or itraconazole.

Ranitidine hydrochloride (Zantac) is one of the most extensively studied and widely used drugs of all time. This has provided an excellent opportunity to define its safety profile.

Data from 189 controlled clinical trials in which more than 26,000 patients received daily doses of ranitidine for 4 weeks or more were reviewed. More than 80% of patients were treated with up to 300 mg ranitidine daily; the remaining patients received doses of up to 1200 mg daily. Eighty-seven trials were placebo controlled. Analyses of post-marketing surveillance and a database of all spontaneously reported adverse events were also evaluated.

Overall in the clinical trial programme adverse events were reported by 20% of those receiving ranitidine compared with 27% of those receiving placebo. The pattern of events was similar in all treatment groups with no evidence of dose-related toxicity in regimens encompassing an eightfold range of therapeutic doses. Similarly in a programme of studies designed to evaluate a dose of ranitidine of 75 mg for non-prescription (over-the-counter) use in the treatment of heartburn, ranitidine was not associated with an adverse event profile distinct from that of placebo. Analysis of spontaneously reported adverse event data allowed identification of rare idiosyncratic events.

Review of data from a large population of controlled clinical trials with analyses of postmarketing surveillance studies and spontaneously reported adverse events confirmed the excellent safety profile of ranitidine.

Part I of this article, which appeared in the previous issue of the Journal, covered the effects or lack of effects on theophylline clearance of sympathomimetics, corticosteroids, antihistamines and other antiallergy drugs, antimicrobial agents, phenytoin, carbamazepine, barbiturates, antacids and activated charcoal. In Part II, this discussion is extended to the effects of other agents. Overall summaries, both textual and tabular, appear in Part I.

Ranitidine is a H2-receptor antagonist widely used in the treatment of a variety of gastrointestinal disorders. Since cimetidine--the predecessor drug of ranitidine--interacts with a variety of other agents and moreover ranitidine is often administered in combination with other drugs the interaction potential of ranitidine has been subject to extensive investigations. This review updates the information available from 1988 to present. Pharmacokinetic interactions of ranitidine with other drugs may occur at the site of absorption, metabolism and renal excretion. Most of the interactions reported at each of the three levels are minor and of low clinical significance. In view of some uncontrolled anecdotal reports, one cannot completely rule out the possibility that ranitidine might have some limited interaction potential in special patient populations under certain clinical conditions. However, it must be emphasized that numerous controlled studies have proven that ranitidine can be safely coadministered with other drugs.