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Complete Atrioventricular Block Associated With Concomitant Use of Metoprolol and Paroxetine
A 63-year-old woman with a history of hypertension and depression, who had been treated with 20 mg of paroxetine and 0.5 mg of alprazolam daily for 1 year and with 50 mg of metoprolol daily for 15 days, presented to a facility elsewhere with presyncope and complete atrioventricular (AV) block. Three days after her initial presentation and cessation of metoprolol treatment, she was transferred to our clinic to be considered for implantation of a permanent pacemaker. At presentation she was asymptomatic: blood pressure was 110/70 mm Hg, heart rate was 40 beats/min, and 12-lead electrocardiograph^ (ECG) showed complete AV block with a narrow QRS escape rhythm of 40 beats/min (Figure, A). Results of all diagnostic tests, including cardiac enzymes, complete blood cell count, renal function test, electrolytes, thyroid function tests, chest radiography, and echocardiography, were normal, and the coronary angiogram was unremarkable.
We thought that AV block could be associated with coadministration of paroxetine and metoprolol. Therefore, we referred the patient to the psychiatry department, and the paroxetine treatment was discontinued on day 1. The AV block completely resolved on day 5 (Figure, B and C), which was confirmed with a 24-hour Holter recording. Metoprolol therapy (50 mg/d) was reinstated on day 6, and the patient was closely monitored for bradyarrhythmia for the next 5 days. No bradyarrhythmia was seen during this period (Figure, D and F). Metoprolol treatment was discontinued on day 10, and the patient was discharged with alprazolam (0.5 mg/d), acetylsalicylic acid (100 mg/d), and amlodipine (5 mg/d) on day 12 (Figure, F). One week (Figure, G) and 2 weeks (Figure, H) after hospital discharge, the patient was still free of bradyarrhythmia. Two weeks after hospital discharge, the patient visited the psychiatry department for consultation. Alprazolam was discontinued, and paroxetine was reinstated at 10 mg/ d and gradually increased to 20 mg/d. A 24-hour Holter recording, performed 3 weeks after hospital discharge, was normal. At the patient's 2-year follow-up, the absence of bradyarrhythmia was documented by means of 12-lead ECG (Figure, I) and 24-hour Holter recording. At that time the patient was still receiving paroxetine treatment of 20 mg/d. At the latest available follow-up, performed on April 26, 2007, the patient was taking clonazepam, escitalopram, diltiazem, and acetylsalicylic acid, and again was shown to be free of bradyarrhythmia by ECG (Figure, J) and a 24-hour Holter recording.
DISCUSSION
We have several reasons to conclude that AV block in this case was associated with coadministration of metoprolol and paroxetine. First, the patient was asymptomatic while she received paroxetine and alprazolam treatment alone and presented with presyncope and complete AV block after taking metoprolol. second, discontinuation of metoprolol treatment alone for 3 days did not restore normal rhythm, but complete recovery was observed after discontinuation of paroxetine. Third, and most important, similar doses of either metoprolol or paroxetine alone induced no bradyarrhythmia.
Metoprolol, a widely prescribed cardioseleclive beta-blocker, is extensively metabolized in the liver through O-demethylation, alpha- hydroxylation, and N-dealkylation. In vitro studies have shown that alpha-hydroxylation of metoprolol is mediated by cytochrome P450 2D6 (CYP2D6) almost completely, and O-demethylation of metoprolol is mediated by CYP2D6 partially.1 Thus, CYP2D6 mediates an estimated 70% of metoprolol's metabolism.2 Selective serotonin reuptake inhibitors (SSRIs) might interfere with the metabolism of metoprolol by inhibiting CYP2D6.3 Among SSRIs, paroxetine is one of the most potent CYP2D6 inhibitors.4 In a study of 8 healthy male volunteers, Hemeryck et al4 investigated the effect of multipledose paroxetine intake on the stereoselective pharmacokinetics and pharmacodynamics of metoprolol. Volunteers were given a single oral dose of racemic metoprolol (100 mg) before and after paroxetine treatment (20 mg/d) for 6 days. Paroxetine treatment increased the mean area under the curve (AUC) of (R)- and (S)-metoprolol significantly (from 169 to 1340 ng * h/mL; P<.001 for [R]-metoprolol and from 279 to 1418 ng * h/mL; P<.001 for [S]-metoprolol), approximately doubling both maximum plasma concentration and terminal elimination half-life. In addition, Hemeryck et al4 observed a significant decrease in the (S)/ (R) AUC ratio and a significant increase in the mean metoprolol metabolic ratio. The AUC of the metoprololinduced decrease in exercise heart rate vs time curve increased by 46% (P<.01) after multiple-dose paroxetine intake, suggesting a more sustained beta- blockade. Therefore, it is likely that long-term pretreatment with paroxetine in this case greatly reduced metoprolol metabolism and enhanced its negative effect on the AV node.