Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
European Journal of Drug Metabolism and Pharmacokinetics
Published in: European Journal of Drug Metabolism and Pharmacokinetics 3/2015

01-09-2015 | Original Paper

A metoprolol–terbinafine combination induced bradycardia

Authors: Emmanuel Bebawi, Suhail S. Jouni, Andrée-Anne Tessier, Anne Julie Frenette, Dave Brindamour, Maxime Doré

Published in: European Journal of Drug Metabolism and Pharmacokinetics | Issue 3/2015

Login to get access

Abstract

To report a sinus bradycardia induced by metoprolol and terbinafine drug–drug interaction and its management. A 63 year-old Caucasian man on metoprolol 200 mg/day for stable coronary artery disease was prescribed a 90-day course of oral terbinafine 250 mg/day for onychomycosis. On the 49th day of terbinafine therapy, he was brought to the emergency room for a decrease of his global health status, confusion and falls. The electrocardiogram revealed a 37 beats/min sinus bradycardia. A score of 7 on the Naranjo adverse drug reaction probability scale indicates a probable relationship between the patient’s sinus bradycardia and the drug interaction between metoprolol and terbinafine. The heart rate ameliorated first with a decrease in the dose of metoprolol. It was subsequently changed to bisoprolol and the heart rate remained normal. By inhibiting the cytochrome P450 2D6, terbinafine had decreased metoprolol’s clearance, leading in metoprolol accumulation which has resulted in clinically significant sinus bradycardia.
Literature
Abdel-Rahman SM, Marcucci K, Boge T, Gotschall RR, Kearns GL, Leeder JS (1999) Potent inhibition of cytochrome P-450 2D6-mediated dextromethorphan O-demethylation by terbinafine. Drug Metab Dispos 27(7):770–775PubMed
Balfour JA, Faulds D (1992) Terbinafine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial mycoses. Drugs 43(2):259–284CrossRefPubMed
Castberg I, Helle J, Aamo TO (2005) Prolonged pharmacokinetic drug interaction between terbinafine and amitriptyline. Ther Drug Monit 27(5):680–682CrossRefPubMed
Chobanian AV, Bakris GL, Black HR et al (2003) The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 289:2560–2572CrossRefPubMed
Ingelman-Sundberg M (2004) Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci 25(4):193–200CrossRefPubMed
Ingelman-Sundberg M (2005) Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 5(1):6–13CrossRefPubMed
Jin SK, Chung HJ, Chung MW, Kim JI, Kang JH, Woo SW et al (2008) Influence of CYP2D6*10 on the pharmacokinetics of metoprolol in healthy Korean volunteers. J Clin Pharm Ther 33:567–573CrossRefPubMed
Le Bourdonnec B, Leister LK (2009) Medicinal chemistry strategies to reduce CYP2D6 inhibitory activity of lead candidates. Curr Med Chem 16:3093–3121CrossRefPubMed
Lefevre G, Sedek G, Jhee SS, Leibowitz MT, Huang HL, Enz A et al (2008) Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer’s disease patients. Clin Pharmacol Ther 83(1):106–114CrossRefPubMed
Lennard MS, Silas JH, Freestone S, Ramsay LE, Tucker GT, Woods HF (1982) Oxidation phenotype-a major determinant of metoprolol metabolism and response. N Engl J Med 307(25):1558–1560CrossRefPubMed
Madani S, Barilla D, Cramer J, Wang Y, Paul C (2002) Effect of terbinafine on the pharmacokinetics and pharmacodynamics of desipramine in healthy volunteers identified as cytochrome P450 2D6 (CYP2D6) extensive metabolizers. J Clin Pharmacol 42(11):1211–1218CrossRefPubMed
Marraffa JM, Lang L, Ong G, Lehmann DF (2006) Profound metoprolol-induced bradycardia precipitated by acetaminophen-propoxyphene. Clin Pharmacol Ther 79(3):282–286CrossRefPubMed
McNeil JJ, Louis WJ (1984) Clinical pharmacokinetics of labetalol. Clin Pharmacokinet 9(2):157–167CrossRefPubMed
Murthy SS, Shetty HU, Nelson WL, Jackson PR, Lennard MS (1990) Enantioselective and diastereoselective aspects of the oxidative metabolism of metoprolol. Biochem Pharmacol 40(7):1637–1644CrossRefPubMed
Naranjo CA, Busto U, Sellers EM et al (1981) A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30:239–245CrossRefPubMed
Park-Wyllie LY, Mamdani MM, Li P, Gill SS, Laupacis A, Juurlink DN (2009) Cholinesterase inhibitors and hospitalization for bradycardia: a population-based study. PLoS Med 6:e1000157PubMedCentralCrossRefPubMed
Pfeffer MA, Braunwald E, Moye LA et al (1992) The SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. N Engl J Med 327:669–677CrossRefPubMed
Product Information: LAMISIL(R) oral tablets, terbinafine hydrochloride oral tablets. Novartis Pharmaceuticals Canada Inc, Dorval, Quebec, Canada 2013
Product Information: LOPRESOR(R) oral tablets, metoprolol tartrate oral tablets. Novartis Pharmaceuticals Canada Inc, Dorval, Quebec, Canada 2013
Stuven T, Griese EU, Kroemer HK, Eichelbaum M, Zanger UM (1996) Rapid detection of CYP2D6 null alleles by long distance- and multiplex-polymerase chain reaction. Pharmacogenetics 6(5):417–421CrossRefPubMed
Van Der Kuy PH, Van Den Heuvel HA, Kempen RW, Vanmolkot LM (2002) Pharmacokinetic interaction between nortriptyline and terbinafine. Ann Pharmacother 36(11):1712–1714
Van Duyn Graham L, Elewski BE (2011) Recent updates in oral terbinafine: its use in onychomycosis and tinea capitis in the US. Mycoses 54:e679–e685CrossRefPubMed
Venkatakrishnan K, von Moltke LL, Greenblatt DJ (2000) Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet 38:111–180CrossRefPubMed
Yasui-Furukori N, Saito M, Inoue Y, Niioka T, Sato Y, Tsuchimine S et al (2007) Terbinafine increases the plasma concentration of paroxetine after a single oral administration of paroxetine in healthy subjects. Eur J Clin Pharmacol 63(1):51–56CrossRefPubMed
Zhou H-H, Wood AJJ (1995) Stereoselective disposition of carvedilol is determined by CYP2D6. Clin Pharmacol Ther 57:518–524CrossRefPubMed
Metadata
Title
A metoprolol–terbinafine combination induced bradycardia
Authors
Emmanuel Bebawi
Suhail S. Jouni
Andrée-Anne Tessier
Anne Julie Frenette
Dave Brindamour
Maxime Doré
Publication date
01-09-2015
Publisher
Springer International Publishing
Published in
European Journal of Drug Metabolism and Pharmacokinetics / Issue 3/2015
Print ISSN: 0378-7966
Electronic ISSN: 2107-0180
DOI
https://doi.org/10.1007/s13318-014-0205-x

Other articles of this Issue 3/2015

European Journal of Drug Metabolism and Pharmacokinetics 3/2015 Go to the issue

Original Paper

Comparative study on pharmacokinetics of a series of anticholinergics, atropine, anisodamine, anisodine, scopolamine and tiotropium in rats

Original Paper

A comparative study on effect of metformin and metformin-conjugated nanotubes on blood glucose homeostasis in diabetic rats

Original Paper

Pharmacokinetic plasma behaviors of intravenous and oral bioavailability of thymoquinone in a rabbit model

Original Paper

Pharmacokinetics of micafungin in subjects with severe hepatic dysfunction

Original Paper

Excretion of tectorigenin in rat urine orally administrated at different dosages by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry

Original Paper

Role of age-related decrease of renal organic cation transporter 2 in the effect of atenolol on renal excretion of metformin in rats