Is an interaction between metoprolol and citalopram a plausible explanation for acute adverse effec

Fråga: Is an interaction between metoprolol and citalopram a plausible explanation for acute adverse effects in the form of nausea, palpitations, chest pain, shivers and dizziness? The question relates to a patient who is treated with metoprolol (50 mg/day) for hypertension. Due to depression, treatment with citalopram (20 mg/day) was started. The patient took the first tablet of citalopram at 13.00, and early evening she developed the symptoms mentioned above. She visited an emergency department where, according to the patient, the symptoms where considered to be caused by an interaction between metoprolol and citalopram. The patient did not take any more citalopram, but still had a repeat episode with the same symptoms four days later.

Sammanfattning: Both citalopram and metaprolol are partly metabolised by the same enzyme, CYP2D6, but this is not expected to lead to any clinically significant changes in plasma concentrations or effects of either of the two drugs.

Svar: About 70% of metoprolol metabolism is mediated by CYP2D6 in vivo. Other drugs that inhibit CYP2D6 can increase the concentrations of metoprolol. Paroxetine, a strong inhibitor of CYP2D6, has been reported to increase the metoprolol exposure five- to eight-fold (1). Citalopram is considered a weak inhibitor of CYP2D6-mediated metabolism (2). In one study, metaprolol was given to 15 healthy volunteers before and after 17 days of escitalopram 20 mg daily. The plasma concentration of metoprolol was approximately 50% higher with than without escitalopram (3).

However, metoprolol is considered to have a wide therapeutic window, and few concentration dependent side-effects. Also, the interindividual variability in metoprolol exposure is high, partly on genetic basis, even in the absence of drug interactions. In a prospective study of 121 patients, the mean metoprolol concentration was 17 times higher in patients with genetically determined low CYP2D6 activity (n=25), compared with patients with high CYP2D6 activity (n=96) (4). In spite of these differences, adverse effects were neither more common nor more serious in the former group. It has also been shown that in patients with the same genotyp, the metoprolol concentration can vary 40-fold without necessitating dose-adjustments (5).

One of the metabolites of citalopram, which is pharmacologically active, is also metabolised by CYP2D6 (2). Theoretically, metoprolol could increase the levels of this metabolite by competitive inhibition. However, metoprolol is not a known enzyme inhibitor and there are no clinical data supporting this interaction.

The symptoms seen in the present case resembles those of panic disorder. Citalopram can be used to treat panic disorder, but has also been reported, at least in one case, to cause such symptoms (6). It cannot be excluded that the citalopram intake alone precipitated the symptoms in the present case, and we recommend that it be reported to the regional centre of adverse drug monitoring.