Rechtzeitig daran denken - Unerwünschte Arzneimittelwirkungen durch Interaktionen mit Antiinfektiva

Unerwünschte Arzneimittelwechselwirkungen werden häufig durch eine Beeinflussung der Enzyme der Arzneimittelbiotransformation (v.a. CYP3A4, CYP1A2) sowie von Transporterproteinen wie dem P-Glykoprotein in Darm und/oder Leber verursacht. Antibiotika wie Makrolide, Chinolone und Azolantimykotika, die Cytochrom-P-Enzyme (CYP-Enzyme) hemmen, bedingen meist ein höheres Nebenwirkungsrisiko. Der Grad der Hemmung kann dabei von genetischen Polymorphismen abhängen (z.B. Langsamacetylierung von Isoniazid). Betroffen sind vor allem Theophyllin (Rhythmusstörungen), orale Antikoagulanzien (Blutungen), Antikonvulsiva (Ataxie, Nystagmus), CSE-Hemmer (Myopathie, Rhabdomyolyse) oder H1-Antihistaminika (Herzrhythmusstörungen). Nach der Gabe von Enzyminduktoren wie Rifampicin oder Ritonavir kann die Therapie versagen, zum Beispiel im Sinne einer Transplantatabstoßung trotz einer Cyclosporintherapie. Die meisten Inhibitoren und Induktoren der Biotransformation beeinflussen jedoch auch das P-Glykoprotein. Auf diese Weise lassen sich auch Wechselwirkungen mit Arzneimitteln wie Digoxin oder Talinolol erklären, die nicht biotransformiert werden. Besonders stark reagieren Arzneimittel mit hohem „First-pass-Effekt” (z.B. Cyclosporin, HIV-Proteaseinhibitoren, CSE-Hemmer). Der verordnende Arzt muss bei einer notwendigen Komedikation daher immer Wechselwirkungen bedenken, die bestehende Therapie überprüfen und gegebenenfalls auf Alternativpräparate mit geringerem Interaktionsrisiko ausweichen.

Adverse drug reactions are often caused by influence on drug metabolizing enzymes (e.g. CYP3A4, CYP1A2) and drug efflux transporters (e.g. P-glycoprotein) in small intestine and/ or liver. Inhibition of CYP enzymes leads to higher risk of adverse effects as caused by macrolides, chinolones and azole antifungals. The extent of inhibition may be dependent on genetic polymorphisms (e.g. slow acetylation of isoniazid). Drugs which are mainly affected by drug interactions are theophylline (cardiac arrhythmias), oral anticoagulants (bleeding), anticonvulsants (ataxia, nystagmus), lipid lowering statins (myopathy, rhabdomyolysis) and H1-antihistaminics (cardiac arrhythmias). After enzyme induction with rifampicin or ritonavir, therapeutic failure may occur; e.g. cyclosporine (graft rejection), hormonal contraceptives („pill failure”). The most inhibitors and inducers of drug metabolism also influence P-glycoprotein. This is the rationale behind interactions which drugs that are not metabolized (e.g. digoxin, talinolol). The risk of adverse drug interaction is highest for drugs with extensive „first-pass” effect (e.g. cyclosporine, HIV protease inhibitors, statins). The prescribing physician should carefully consider possible interactions in planning drug therapy, re-evaluate the existing maintenance treatment and, if necessary, select an alternative drug with lower interaction potential.

Key Words

adverse drug reaction - CYP enzymes - drug efflux transporters - theophylline - oral anticoagulants - anticonvulsants - statins - H1-antihistaminics

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