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• W4248797945 abstract "A 63-year-old woman, 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 block. Three days after her initial presentation and cessation of metoprolol treatment, she was transferred to our clinic to be considered for permanent pacemaker implantation. Paroxetine treatment was discontinued on day 1 and atrioventricular block resolved on day 5, which was confirmed with a 24-hour Holter recording. No bradyarrhythmia was induced with similar doses of either metoprolol or paroxetine alone. At 2- and 3-year follow-up, the patient was still free of bradyarrhythmia documented with electrocardiography and 24-hour Holter recordings. To our knowledge, we report the first case of complete atrioventricular block associated with coadministration of paroxetine and metoprolol. Increasing physicians' awareness of drug-induced severe bradyarrhythmia might prevent unnecessary implantation of permanent pacemakers. A 63-year-old woman, 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 block. Three days after her initial presentation and cessation of metoprolol treatment, she was transferred to our clinic to be considered for permanent pacemaker implantation. Paroxetine treatment was discontinued on day 1 and atrioventricular block resolved on day 5, which was confirmed with a 24-hour Holter recording. No bradyarrhythmia was induced with similar doses of either metoprolol or paroxetine alone. At 2- and 3-year follow-up, the patient was still free of bradyarrhythmia documented with electrocardiography and 24-hour Holter recordings. To our knowledge, we report the first case of complete atrioventricular block associated with coadministration of paroxetine and metoprolol. Increasing physicians' awareness of drug-induced severe bradyarrhythmia might prevent unnecessary implantation of permanent pacemakers. 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 electrocardiography (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. 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 cardioselective β-blocker, is extensively metabolized in the liver through O-demethylation,α-hydroxylation, and N-dealkylation. In vitro studies have shown that α-hydroxylation of metoprolol is mediated by cytochrome P450 2D6 (CYP2D6) almost completely, and O-demethylation of metoprolol is mediated by CYP2D6 partially.1Otton SV Crewe HK Lennard MS Tucker GT Woods HF Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes.J Pharmacol Exp Ther. 1988; 247: 242-247PubMed Google Scholar Thus, CYP2D6 mediates an estimated 70% of metoprolol's metabolism.2Johnson JA Burlew BS Metoprolol metabolism via cytochrome P4502D6 in ethnic populations.Drug Metab Dispos. 1996; 24: 350-355PubMed Google Scholar Selective serotonin reuptake inhibitors (SSRIs) might interfere with the metabolism of metoprolol by inhibiting CYP2D6.3Harvey AT Preskorn SH Cytochrome P450 enzymes: interpretation of their interactions with selective serotonin reuptake inhibitors: part II.J Clin Psychopharmacol. 1996; 16: 345-355Crossref PubMed Scopus (82) Google Scholar Among SSRIs, paroxetine is one of the most potent CYP2D6 inhibitors.4Hemeryck A Lefebvre RA De Vriendt C Belpaire FM Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers.Clin Pharmacol Ther. 2000; 67: 283-291Crossref PubMed Scopus (79) Google Scholar In a study of 8 healthy male volunteers, Hemeryck et al4Hemeryck A Lefebvre RA De Vriendt C Belpaire FM Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers.Clin Pharmacol Ther. 2000; 67: 283-291Crossref PubMed Scopus (79) Google Scholar investigated the effect of multiple-dose 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 al4Hemeryck A Lefebvre RA De Vriendt C Belpaire FM Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers.Clin Pharmacol Ther. 2000; 67: 283-291Crossref PubMed Scopus (79) Google Scholar observed a significant decrease in the (S)/(R) AUC ratio and a significant increase in the mean metoprolol metabolic ratio. The AUC of the metoprolol-induced decrease in exercise heart rate vs time curve increased by 46% (P<.01) after multiple-dose paroxetine intake, suggesting a more sustained β-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. We searched 5 electronic databases for smiliar reports. The search was carried out using the following electronic databases from the earliest possible dates through August 2007: (1) MEDLINE; (2) EMBASE; (3) Cochrane Central Register of Controlled Trials (CCTR); (4) Cumulative Index to Nursing & Allied Health Literature (CINAHL); and (5) HealthSTAR. No language, date, or other restrictions were applied. The following strategy was used to search all these databases; capitalized terms are controlled: (1) ARRHYTHMIA/; (2) HEART BLOCK/; (3) BRADYCARDIA/; (4) ANTIDEPRESSIVE AGENTS/; (5) ANTIDEPRESSANT AGENT/; (6) ANTI-ANXIETY AGENTS/; (7) ANTIANXIETY AGENTS; (8) ANXIOLYTIC AGENT/; (9) paroxetine; (10) alprazolam; (11) or/1-3; (12) or/4-10; (13) and/11-12. Additional publications were examined using the reference lists of identified papers and published reviews. Overall, of 1477 initial hits, 3 cases of bradyarrhythmia associated with coadministration of SSRIs and β-blockers were identified.5Konig F Hafele M Hauger B Loble M Wossner S Wolfersdorf M Bradycardia after starting therapy of paroxetine and metoprolol [in German].Psychiatr Prax. 1996; 23: 244-245PubMed Google Scholar, 6Walley T Pirmohamed M Proudlove C Maxwell D Interaction of metoprolol and fluoxetine [letter].Lancet. 1993; 341: 967-968Abstract PubMed Scopus (91) Google Scholar, 7Pae CU Kim JJ Lee CU Lee SJ Chul-Lee CL Paik IH Provoked bradycardia after paroxetine administration [letter].Gen Hosp Psychiatry. 2003; 25: 142-144Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Konig et al5Konig F Hafele M Hauger B Loble M Wossner S Wolfersdorf M Bradycardia after starting therapy of paroxetine and metoprolol [in German].Psychiatr Prax. 1996; 23: 244-245PubMed Google Scholar reported the first case of bradycardia after coadministration of paroxetine and metoprolol. Walley et al6Walley T Pirmohamed M Proudlove C Maxwell D Interaction of metoprolol and fluoxetine [letter].Lancet. 1993; 341: 967-968Abstract PubMed Scopus (91) Google Scholar described a case of symptomatic bradycardia with coadministration of metoprolol and fluoxetine, another potent inhibitor of CYP2D6, in a 54-year-old man with a history of coronary bypass surgery. In this case, the patient's heart rate was 64 beats/min with metoprolol treatment (100 mg/d) alone. On the second day of adding fluoxetine treatment (20 mg/d), the patient developed symptomatic bradycardia (36 beats/min). His heart rate returned to its previous rate during the next 5 days after fluoxetine treatment was discontinued. Coadministration of fluoxetine and sotalol in this case did not cause bradyarrhythmia. Pae et al7Pae CU Kim JJ Lee CU Lee SJ Chul-Lee CL Paik IH Provoked bradycardia after paroxetine administration [letter].Gen Hosp Psychiatry. 2003; 25: 142-144Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar reported sinus bradycardia (40 beats/min) and sinus pause (4 seconds) with syncope on the 20th day of paroxetine coadministration (up to 30 mg/d) in a 78-year-old woman who was receiving carvedilol (12.5 mg/d) treatment. The patient had no bradyarrhythmia while receiving carvedilol alone before paroxetine administration. Normal heart rate was regained within 5 days after discontinuation of carvedilol and paroxetine therapy. Bradyarrhythmia had not recurred after substitution of paroxetine with mirtazapine in addition to daily treatment with 12.5 mg of carvedilol. Selective serotonin reuptake inhibitors, without concomitant use of β-blocker therapy, were also reported to be associated with bradyarrhythmia in 5 case reports.8Erfurth A Loew M Dobmeier P Wendler G ECG changes after paroxetine: three case reports [in German].Nervenarzt. 1998; 69: 629-631Crossref PubMed Scopus (29) Google Scholar, 9Rothenhausler HB Hoberl C Ehrentrout S Kapfhammer HP Weber MM Suicide attempt by pure citalopram overdose causing long-lasting severe sinus bradycardia, hypotension and syncopes: successful therapy with a temporary pacemaker.Pharmacopsychiatry. 2000; 33: 150-152Crossref PubMed Scopus (27) Google Scholar, 10Isbister GK Prior FH Foy A Citalopram-induced bradycardia and presyncope.Ann Pharmacother. 2001; 35: 1552-1555Crossref PubMed Scopus (28) Google Scholar, 11Dufour H Bouchacourt M Thermoz P et al.Citalopram—a highly selective 5-HT uptake inhibitor—in the treatment of depressed patients.Int Clin Psychopharmacol. 1987; 2: 225-237Crossref PubMed Scopus (41) Google Scholar, 12Favre MP Sztajzel J Bertschy G Bradycardia during citalopram treatment: a case report.Pharmacol Res. 1999; 39: 149-150Crossref PubMed Scopus (13) Google Scholar Erfurth et al8Erfurth A Loew M Dobmeier P Wendler G ECG changes after paroxetine: three case reports [in German].Nervenarzt. 1998; 69: 629-631Crossref PubMed Scopus (29) Google Scholar reported bradycardia in 2 cases after paroxetine administration. In a 65-year-old patient with a history of hemorrhagic stroke and depression, severe symptomatic bradycardia (34-40 beats/min) developed after the third dose of paroxetine (10 mg/d) and resolved quickly after intravenous administration of atropine (0.5 mg). In a 51-year-old patient with a history of bipolar affective disorder, asymptomatic bradycardia developed after the third dose of paroxetine treatment (10 mg/d). In this case, the heart rate was normal 13 days after cessation of paroxetine treatment. Rothenhausler et al9Rothenhausler HB Hoberl C Ehrentrout S Kapfhammer HP Weber MM Suicide attempt by pure citalopram overdose causing long-lasting severe sinus bradycardia, hypotension and syncopes: successful therapy with a temporary pacemaker.Pharmacopsychiatry. 2000; 33: 150-152Crossref PubMed Scopus (27) Google Scholar reported a case of sinus bradycardia with syncope in a 32-year-old patient who ingested a total of 800 mg of citalopram to attempt suicide. Therapeutic doses of citalopram have also been associated with symptomatic10Isbister GK Prior FH Foy A Citalopram-induced bradycardia and presyncope.Ann Pharmacother. 2001; 35: 1552-1555Crossref PubMed Scopus (28) Google Scholar and asymptomatic bradycardia.11Dufour H Bouchacourt M Thermoz P et al.Citalopram—a highly selective 5-HT uptake inhibitor—in the treatment of depressed patients.Int Clin Psychopharmacol. 1987; 2: 225-237Crossref PubMed Scopus (41) Google Scholar, 12Favre MP Sztajzel J Bertschy G Bradycardia during citalopram treatment: a case report.Pharmacol Res. 1999; 39: 149-150Crossref PubMed Scopus (13) Google Scholar In addition, Gambassi et al13Gambassi G Incalzi RA Gemma A Atrioventricular blocks associated with citalopram [letter].Am J Geriatr Psychiatry. 2005; 13: 918-919Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar described a case of various AV blocks (first-degree and Mobitz type I) associated with citalopram, which were reversed after discontinuation of the drug. Citalopram can impair AV conduction by inhibiting L-type calcium-channel current.14Hamplova-Peichlova J Krusek J Paclt I Slavicek J Lisa V Vyskocil F Citalopram inhibits L-type calcium channel current in rat cardiomyocytes in culture.Physiol Res. 2002; 51: 317-321PubMed Google Scholar Bupropion, a non-tricyclic antidepressant drug, is an increasingly prescribed aid in smoking cessation. Bupropion inhibits CYP2D6 and therefore can impair metabolism of drug substrates of this enzyme. McCollum et al15McCollum DL Greene JL McGuire DK Severe sinus bradycardia after initiation of bupropion therapy: a probable drug-drug interaction with metoprolol.Cardiovasc Drugs Ther. 2004; 18: 329-330Crossref PubMed Scopus (26) Google Scholar reported a case of bradycardia in a 56-year-old man when bupropion (150 mg twice daily) was added to metoprolol (75 mg twice daily) and diltiazem (240 mg twice daily) treatment. The patient in this case developed bradycardia with an atrial rate of 40 beats/min and a junctional escape rhythm of 43 beats/min. The patient was admitted to the hospital, and all 3 medications were withheld. The next morning, all symptoms had resolved and normal sinus rhythm returned. Ahmed et al16Ahmed I Dagincourt PG Miller LG Shader RI Possible interaction between fluoxetine and pimozide causing sinus bradycardia.Can J Psychiatry. 1993; 38: 62-63PubMed Google Scholar reported a case of sinus bradycardia with concomitant use of fluoxetine and pimozide. We found 2 cases of bradyarrhythmia associated with alprazolam use.17Tollefson G Lesar T Grothe D Garvey M Alprazolam-related digoxin toxicity.Am J Psychiatry. 1984; 141: 1612-1613PubMed Google Scholar, 18Mullins ME First-degree atrioventricular block in alprazolam overdose reversed by flumazenil.J Pharm Pharmacol. 1999; 51: 367-370Crossref PubMed Scopus (19) Google Scholar Tollefson et al17Tollefson G Lesar T Grothe D Garvey M Alprazolam-related digoxin toxicity.Am J Psychiatry. 1984; 141: 1612-1613PubMed Google Scholar described a case of digitalis intoxication when alprazolam was added to ongoing digoxin therapy. Reduced renal clearance of digoxin was postulated as the mechanism for this interaction. Mullins18Mullins ME First-degree atrioventricular block in alprazolam overdose reversed by flumazenil.J Pharm Pharmacol. 1999; 51: 367-370Crossref PubMed Scopus (19) Google Scholar reported a case of first-degree AV block in a patient with alprazolam overdose (12 mg). Weak calcium-channel blocker activity of benzodiazepines could be responsible for this effect. These data suggest that development of complete AV block in our case is related to alprazolam use. However, the alprazolam dose in our case was very small (0.5 mg/d) and we did not stop alprazolam treatment during the patient's hospital stay. Further, it should be noted that in our case the AV block disappeared despite ongoing alprazolam treatment. Metoprolol has proven to be effective in the treatment of coronary artery disease, hypertension, and chronic heart failure.19Wikstrand J Warnold I Tuomilehto J et al.Metoprolol versus thiazide diuretics in hypertension: morbidity results from the MAPHY Study.Hypertension. 1991; 17: 579-588Crossref PubMed Scopus (111) Google Scholar, 20Olsson G Rehnqvist N Sjogren A Erhardt L Lundman T Long-term treatment with metoprolol after myocardial infarction: effect on 3 year mortality and morbidity.J Am Coll Cardiol. 1985; 5: 1428-1437Abstract Full Text PDF PubMed Scopus (164) Google Scholar, 21Hjalmarson A Goldstein S Fagerberg B MERIT-HF Study Group et al.Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF).JAMA. 2000; 283: 1295-1302Crossref PubMed Scopus (1152) Google Scholar, 22MERIT-HF Study Group Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).Lancet. 1999; 353: 2001-2007Abstract Full Text Full Text PDF PubMed Scopus (4424) Google Scholar Depression is the most common psychiatric illness and is frequently present in patients with cardiovascular disease. Selective serotonin reuptake inhibitors are considered relatively safer than other antidepressants for cardiac patients.23Jiang W Davidson JR Antidepressant therapy in patients with ischemic heart disease.Am Heart J. 2005; 150: 871-881Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Thus, SSRIs are often prescribed to cardiac patients, and physicians should be aware of serious drug interactions caused by inhibition of CYP2D6. Paroxetine currently is among the most widely coprescribed drugs in patients receiving a CYP2D6 subtrate.24Molden E Garcia BH Braathen P Eggen AE Co-prescription of cytochrome P450 2D6/3A4 inhibitor-substrate pairs in clinical practice: a retrospective analysis of data from Norwegian primary pharmacies.Eur J Clin Pharmacol. 2005 Apr; 61 (Epub 2005 Feb 4.): 119-125Crossref PubMed Scopus (31) Google Scholar A study from Norway investigated how frequently CYP2D6 inhibitors are coadministered with substrates of the enzyme and reported that the CYP2D6 substrate metoprolol together with a CYP2D6 inhibitor paroxetine was one of the most frequently prescribed combinations.24Molden E Garcia BH Braathen P Eggen AE Co-prescription of cytochrome P450 2D6/3A4 inhibitor-substrate pairs in clinical practice: a retrospective analysis of data from Norwegian primary pharmacies.Eur J Clin Pharmacol. 2005 Apr; 61 (Epub 2005 Feb 4.): 119-125Crossref PubMed Scopus (31) Google Scholar In a randomized placebo-controlled study,25Graff DW Williamson KM Pieper JA et al.Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients.J Clin Pharmacol. 2001; 41: 97-106Crossref PubMed Scopus (53) Google Scholar potential interactions between carvedilol and fluoxetine were evaluated. Fluoxetine (20 mg) or matching placebo was administered to 10 patients with heart failure who were previously identified as extensive metabolizers of CYP2D6 substrates.25Graff DW Williamson KM Pieper JA et al.Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients.J Clin Pharmacol. 2001; 41: 97-106Crossref PubMed Scopus (53) Google Scholar Patients were maintained on a carvedilol dose of 25 or 50 mg twice daily and given fluoxetine or a placebo for a minimum of 28 days. Administration of fluoxetine, a potent CYP2D6 inhibitor, resulted in a stereospecific inhibition in carvedilol metabolism without significantly affecting blood pressure, heart rate, or heart rate variability. Goryachkina et al26Goryachkina K Burbello A Boldueva S Babak S Bergman U Bertilsson L Inhibition of metoprolol metabolism and potentiation of its effects by paroxetine in routinely treated patients with acute myocardial infarction (AMI).Eur J Clin Pharmacol. 2008 Mar; 64 (Epub 2007 Nov 29.): 275-282https://doi.org/10.1007/s00228-007-0404-3Crossref PubMed Scopus (39) Google Scholar noted a pronounced inhibition of metoprolol metabolism when paroxetine (20 mg/d) was coadministered to 17 depressed patients with acute myocardial infarction. 26Goryachkina K Burbello A Boldueva S Babak S Bergman U Bertilsson L Inhibition of metoprolol metabolism and potentiation of its effects by paroxetine in routinely treated patients with acute myocardial infarction (AMI).Eur J Clin Pharmacol. 2008 Mar; 64 (Epub 2007 Nov 29.): 275-282https://doi.org/10.1007/s00228-007-0404-3Crossref PubMed Scopus (39) Google Scholar They found mean metoprolol concentration AUC increased by 400% and mean α-hydroxy metoprolol concentration AUC decreased by approximately 75%. Although no serious adverse effects were noted, 2 patients required a reduction of metoprolol dose because of excessive bradycardia and severe orthostatic hypotension. Goryachkina et al suggest that the metoprolol dose be adjusted when paroxetine is initiated and withdrawn. Because of polymorphism of the CYP2D6 gene, CYP2D6 activity varies markedly among individuals. Consequently, after short-term administration, metoprolol plasma concentrations were found to be 3- to 10-fold higher in poor metabolizers than in extensive metabolizers.27Deroubaix X Lins RL Lens S et al.Comparative bioavailability of a metoprolol controlled release formulation and a bisoprolol normal release tablet after single oral dose administration in healthy volunteers.Int J Clin Pharmacol Ther. 1996; 34: 61-70PubMed Google Scholar, 28Freestone S Silas JH Lennard MS Ramsay LE Comparison of two long-acting preparations of metoprolol with conventional metoprolol and atenolol in healthy men during chronic dosing.Br J Clin Pharmacol. 1982; 14: 713-718Crossref PubMed Scopus (40) Google Scholar Accordingly, the decrease in heart rate is greatly pronounced in poor metabolizers.29Lennard MS Silas JH Freestone S Ramsay LE Tucker GT Woods HF Oxidation phenotype—a major determinant of metoprolol metabolism and response.N Engl J Med. 1982; 307: 1558-1560Crossref PubMed Scopus (265) Google Scholar, 30Lewis RV Ramsay LE Jackson PR Yeo WW Lennard MS Tucker GT Influence of debrisoquine oxidation phenotype on exercise tolerance and subjective fatigue after metoprolol and atenolol in healthy subjects.Br J Clin Pharmacol. 1991; 31: 391-398Crossref PubMed Scopus (9) Google Scholar The effect of the CYP2D6 genotype on metoprolol plasma concentrations persists during long-term treatment; poor metabolizers have steady-state concentrations that are several times higher.31Rau T Heide R Bergmann K et al.Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment.Pharmacogenetics. 2002; 12: 465-472Crossref PubMed Scopus (132) Google Scholar Some suggest that poor metabolizers are more susceptible to adverse effects than extensive metabolizers at standard doses of metoprolol.29Lennard MS Silas JH Freestone S Ramsay LE Tucker GT Woods HF Oxidation phenotype—a major determinant of metoprolol metabolism and response.N Engl J Med. 1982; 307: 1558-1560Crossref PubMed Scopus (265) Google Scholar, 32McGourty JC Silas JH Lennard MS Tucker GT Woods HF Metoprolol metabolism and debrisoquine oxidation polymorphism—population and family studies.Br J Clin Pharmacol. 1985; 20: 555-566Crossref PubMed Scopus (160) Google Scholar Consistent with this suggestion, Wuttke et al33Wuttke H Rau T Heide R et al.Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol-associated adverse effects.Clin Pharmacol Ther. 2002; 72: 429-437Crossref PubMed Scopus (168) Google Scholar observed predominantly poor metabolism of CYP2D6 in patients with serious metoprolol-associated adverse events. These findings suggest that simultaneous administration of potent inhibitors of CYP2D6 and metoprolol can lead to serious adverse effects among poor metabolizers. Sex-related differences in the pharmacokinetics of metoprolol can cause greater drug exposure in women.34Luzier AB Killian A Wilton JH Wilson MF Forrest A Kazierad DJ Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers.Clin Pharmacol Ther. 1999; 66: 594-601PubMed Google Scholar Thurmann et al35Thurmann PA Haack S Werner U et al.Tolerability of beta-blockers metabolized via cytochrome P450 2D6 is sex-dependent [letter].Clin Pharmacol Ther. 2006; 80: 551-553Crossref PubMed Scopus (27) Google Scholar investigated potential sex differences in adverse drug reactions caused by β-blockers. The number of adverse drug reactions associated with the use of CYP2D6-dependent β-blockers (metoprolol, carvedilol, nebivolol, and propranolol) was significantly higher in women than in men (P=.006), whereas frequencies for the CYP2D6-independent β-blockers (atenolol, sotalol, and bisoprolol) were not significantly different between men and women (P>.05). Further, 75% of patients with serious metoprolol-associated adverse events reported in the study of Wuttke et al33Wuttke H Rau T Heide R et al.Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol-associated adverse effects.Clin Pharmacol Ther. 2002; 72: 429-437Crossref PubMed Scopus (168) Google Scholar were women, and most were poor metabolizers. Independently of CYP2D6 genotype, women exhibit significantly higher metoprolol and propranolol plasma concentrations than men.36Jochmann N Stangl K Garbe E Baumann G Stangl V Female-specific aspects in the pharmacotherapy of chronic cardiovascular diseases.Eur Heart J. 2005 Aug; 26 (Epub 2005 Jul 4.): 1585-1595Crossref PubMed Scopus (194) Google Scholar Finally, depression associated with cardiovascular disease is particularly prevalent in elderly patients.37Freedland KE Carney RM Psychosocial considerations in elderly patients with heart failure.Clin Geriatr Med. 2000; 16: 649-661Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 38McGann PE Comorbidity in heart failure in the elderly.Clin Geriatr Med. 2000; 16: 631-648Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar The cardiac safety profiles of antidepressants in this population should be noted because patients might be particularly vulnerable to adverse effects of drugs and often receive multiple concomitant medications. The present case demonstrates that complete AV block can develop when paroxetine and metoprolol are prescribed together in susceptible patients, such as older patients, women, and poor metabolizers of metoprolol. Thus, heart rate should be closely monitored when these 2 drugs are used together in such patients. Alternatively, metoprolol can be substituted with atenolol or bisoprolol, which are not metabolized via CYP2D6-dependent pathways. In a patient with a specific indication for metoprolol, substitution of paroxetine with an alternative antidepressant or reduction of metoprolol dose should be considered. To our knowledge, we report the first case of complete AV block associated with coadministration of paroxetine and metoprolol. Metoprolol, even in relatively small doses, can lead to severe bradyarrhythmia when coadministered with therapeutic doses of paroxetine, particularly in susceptible populations. Increasing physicians' awareness of drug-induced severe bradyarrhythmia might prevent unnecessary implantation of permanent pacemakers." @default.
• W4248797945 created "2022-05-12" @default.
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• W4248797945 date "2008-05-01" @default.
• W4248797945 modified "2023-10-04" @default.
• W4248797945 title "Complete Atrioventricular Block Associated With Concomitant Use of Metoprolol and Paroxetine" @default.
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