Metoprolol is a CYP2D6-substrate. Drugs that inhibit CYP2D6 can have an effect on the plasma concentration of metoprolol. Examples of drugs that inhibit CYP2D6 are quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenone and diphenhydramine. When treatment with these drugs are initiated the dose of Betaloc might have to be reduced for patients treated with Betaloc.
The following combinations with Betaloc should be avoided: Barbituric acid derivatives: Barbiturates (investigated for pentobarbital) induce the metabolism of metoprolol by enzyme induction.
Propafenone: Upon administration of propafenone to four patients on metoprolol therapy, the plasma concentrations of metoprolol increased 2-5 fold and two patients experienced side-effects typical of metoprolol. The interaction was confirmed in eight healthy volunteers. The interaction is probably explained by the fact that propafenone, similarly to quinidine, inhibits the metabolism of metaprolol via cytochrome P450 2D6. The combination is probably difficult to handle since propafenone also has beta-receptor blocking properties.
Verapamil: In combination with beta-receptor blocking drugs (described for atenolol, propranolol and pindolol) verapamil may cause bradycardia and fall in blood pressure. Verapamil and beta-blockers have additive inhibitory effects on AV-conduction and sinus node function.
The following combinations with Betaloc may require modified drug dosage: Amiodarone: A case report suggests that patients treated with amiodarone may develop pronounced sinus bradycardia when treated simultaneously with metoprolol. Amiodarone has extremely long half-life (around 50 days), which implies that interactions can occur for a long time after withdrawal of the drug.
Antiarrythmics, class I: Class I-antiarrythmics and beta-receptor blocking drugs have additive negative inotropic effects which may result in serious haemodynamic side effects in patients with impaired left ventricular function. The combination should also be avoided in "sick sinus syndrome" and pathological AV-conduction. The interaction is best documented for disopyramide.
Non-steroidal anti-inflammatory/antirheumatic drugs: NSAID-antiphlogistics have been shown to counteract the antihypertensive effect of beta-receptor blocking drugs. Primarily, indomethacin has been studied. This interaction probably does not occur with sulindac. A negative interaction study on diclofenac has been performed.
Diphenhydramine: Diphenhydramine decreases (2.5 times) clearance of metoprolol to alpha-hydroximetoprolol via CYP 2D6 in fast hydroxylating persons. The effects of metoprolol are enhanced. Diphenhydramine may probably inhibit the metabolism of other CYP 2D6 substrates.
Digitalis glycosides: Digitalis glycosides in association with beta-blockers, may increase atrioventricular conduction time and may induce bradycardia.
Diltiazem: Diltiazem and beta-receptor blockers have additive inhibitory effects on the AV-conduction and sinus node function. Pronounced bradycardia has been observed (case reports) during combination treatment with diltiazem.
Epinephrine: There are about ten reports on patients treated with non-selective beta-receptor blockers (including pindolol and propranolol) that developed pronounced hypertension and bradycardia after administration of epinephrine (adrenaline). These clinical observations have been confirmed in studies in healthy volunteers. It has also been suggested that epinephrine in local anaesthetics may provoke these reactions upon intravasal administration. The risk is probably less with cardioselective beta-receptor blockers.
Phenylpropanolamine: Phenylpropanolamine (norephedrine) in single doses of 50 mg may increase the diastolic blood pressure to pathological values in healthy volunteers. Propranolol generally counteracts the rise in blood pressure induced by phenylpropanolamine. However, beta-receptor blockers may provoke paradoxical hypertensive reactions in patients who take high doses of phenylpropanolamine. Hypertensive crises during treatment with only phenylpropanolamine have been described in a couple of cases.
Quinidine: Quinidine inhibits the metabolism of metoprolol in so-called rapid hydroxylators (more than 90% in Sweden) with markedly elevated plasma levels and enhanced beta-blockade as a result. A corresponding interaction might occur with other beta-blockers metabolised by the same enzyme (cytochrome P450 2D6).
Clonidine: The hypertensive reaction when clonidine is suddenly withdrawn may be potentiated by beta-blockers. If concomitant treatment with clonidine is to be discontinued, the beta-blocker medication should be withdrawn several days before clonidine.
Rifampicin: Rifampicin may induce the metabolism of metoprolol resulting in decreased plasma levels.
Patients receiving concomitant treatment with other beta-blockers (i.e. eye drops) or MAO-inhibitors should be kept under close surveillance. In patients receiving beta-receptor blocker therapy, inhalation anaesthetics enhance the cardio-depressant effect. The dosages of oral antidiabetics may have to be readjusted in patients receiving beta-blockers. The plasma concentration of metoprolol can increase when cimetidine or hydralazine are administered simultaneously.