Towards the safer use of medicines.

In Britain the tools are now available to provide better information on safety of medicines in both hospital and community settings, and this could be done at relatively modest cost. The needs of patients, doctors, and pharmacists are changing; although more research is needed, such information as is presently available must be both better and more widely publicised and understood. Universities, government, the pharmaceutical industry, and educated journalism all have an important part to play in this process.

Monitoring of adverse drug reactions in the pharmaceutical industry--the scene in the United Kingdom.

In the United Kingdom, all suspected reactions to newly marketed drugs and serious, suspected reactions to established drugs are reported by doctors, dentists, coroners and pharmaceutical companies to the Medicines Control Agency. The information is entered onto the Agency database and analysed before being made available in regular reports. Post-marketing surveillance of newly licensed drugs is carried out in a number of ways: protocolled studies involving up to 10,000 patients, prescription tracing, and databases using input from general practitioners or hospitals. European Community pharmacovigilance requirements were due to become effective in 1992, or soon after. These may involve companies in a review of the structures of their reporting department and, without care on the part of the Community, could result in duplication of reporting. Risk/benefit analysis of drug use is led by the International Foundation based in Geneva. The aim is to improve the management of drug safety, both within the industry and the medical profession. In the UK, a risk assessment group has grown up which includes, among others, all interested UK companies and representation from the Medicines Control Agency.

The acute electrophysiological effects of intravenous metoprolol.

The cardiac electrophysiological effects of metoprolol were studied in ten patients (pts) aged 22-51 years undergoing intracardiac stimulation studies for paroxysmal palpitations. The following measurements were made: (1) basic sinus cycle length (SCL); (2) sinus node recovery time (SRT) following overdrive pacing; (3) atrio-His (A-H) and His-ventricular (H-V) conduction intervals during regular atrial pacing; (4) effective refractory periods of the atria (AERP), A-V node (AVERP) and ventricular myocardium (VERP); and (5) A-V nodal functional refractory period (AVFRP). All measurements were repeated 10-20 min after a slow bolus intravenous injection of metoprolol (0.2 mg/kg body weight). Results were analyzed by the Wilcoxon Signed Rank test. Highly significant increases in: SRT (932 +/- 166 to 1107 +/- 225 ms, p less than 0.001) and A-H (72 +/- 14 to 103 +/- 14 ms, p less than 0.001) were observed. There were also small increases of lesser significance in SCL (794 +/- 160 59 898 +/- 190 ms, p less than 0.01), AVERP (308 +/- 46 to 341 +/- 66 ms, p less than 0.02), and AVFRP (376 +/- 43 to 416 +/- 59 ms, p less than 0.01). Metoprolol did not affect the H-V interval, the AERP, or the VERP. These results are similar to those of other beta blockers.

Effect of rifampicin on metoprolol and antipyrine kinetics.

1 Effects of rifampicin on the pharmacokinetics of single oral doses of metoprolol and antipyrine are reported. 2 Rifampicin, administered daily for 15 days, reduced the area under the plasma concentration-time curve (AUC) of metoprolol but the rate constant for elimination (beta) of metoprolol from plasma did not alter significantly. 3 Administration of rifampicin for 13 days reduced AUC and increased beta of antipyrine. Thirteen days after discontinuing rifampicin. AUC and beta of antipyrine remained significantly different from the initial values. 4 Some loss of beta-adrenoceptor blockade should be anticipated if rifampicin is administered to patients who are receiving metoprolol.

Differential induction of antipyrine metabolism by rifampicin.

Antipyrine is oxidised to three main metabolites in man. There is evidence that the different metabolites are products of different forms of cytochrome P-450. The effect of rifampicin administration for two weeks on the rates of formation of these metabolites was investigated in healthy volunteers. Rifampicin increased antipyrine clearance and shortened its half-life. Two weeks after stopping rifampicin the induction had largely been reversed. Clearance to all three metabolites was increased by rifampicin. Clearance to 3-hydroxymethylantipyrine was increased from 7.8 +/- 0.9 ml/min to 13.3 +/- 1.3 ml/min, to norphenazone from 5.8 +/- 0.6 ml/min to 19.3 +/- 2.1 ml/min and to 4-hydroxyantipyrine from 14.3 +/- 2.2 ml/min to 21.9 +/- 3.9 ml/min. Thus clearance to norphenazone was increased to a much greater extent than to either of the other two metabolites. It is concluded that this provides evidence for the involvement of at least two different forms of cytochrome P-450 in antipyrine metabolism in man.

Metoprolol in anaesthesia for oral surgery. The effect of pretreatment on the incidence of cardiac dysrhythmias.

Metoprolol, a cardioselective beta-adrenergic blocking drug, was given, with a placebo as an alternative, in a double-blind trial to 60 patients who were undergoing removal of third molar teeth under general anaesthesia. Dyshythmias occurred in significantly fewer patients in the metoprolol group than in the control group, and when ventricular dyshythmias occurred they were abolished in every case by the administration of metoprolol. It is concluded that metoprolol is effective in preventing cardiac dysrhythmias occurring during oral surgery carried out under general anaesthesia.

Ocular and cardiovascular effects of local and systemic pindolol.

Ocular and cardiovascular effects of topical and intravenous pindolol have been studied in a balanced cross-0ver double-blind trial in 6 healthy volunteers. When applied to 1 eye pindolol lowered intraocular pressure in both the treated and untreated eyes with only minimal reduction in resting pupil diameter and light reflex response. The concentration in plasma was much lower and inhibiton of exercise tachycardia about half that when the same dose was administered intravenously. The findings suggest that beta-adrenoceptor blocking drugs should not be used in the treatment of glaucoma in patients who also suffer from heart failure.