Skip to main content

Main menu

  • Home
  • Articles
    • Current
    • Archive
    • Supplemental Issues
    • Collections - French
    • Collections - English
  • Info for
    • Authors & Reviewers
    • Submit a Manuscript
    • Advertisers
    • Careers & Locums
    • Subscribers
    • Permissions
  • About CFP
    • About CFP
    • About the CFPC
    • Editorial Advisory Board
    • Terms of Use
    • Contact Us
  • Feedback
    • Feedback
    • Rapid Responses
    • Most Read
    • Most Cited
    • Email Alerts
  • Blogs
    • Latest Blogs
    • Blog Guidelines
    • Directives pour les blogues
  • Mainpro+ Credits
    • About CFP Mainpro+
    • Member Login
    • Instructions
  • Other Publications
    • http://www.cfpc.ca/Canadianfamilyphysician/
    • https://www.cfpc.ca/Login/
    • Careers and Locums

User menu

  • My alerts

Search

  • Advanced search
The College of Family Physicians of Canada
  • Other Publications
    • http://www.cfpc.ca/Canadianfamilyphysician/
    • https://www.cfpc.ca/Login/
    • Careers and Locums
  • My alerts
The College of Family Physicians of Canada

Advanced Search

  • Home
  • Articles
    • Current
    • Archive
    • Supplemental Issues
    • Collections - French
    • Collections - English
  • Info for
    • Authors & Reviewers
    • Submit a Manuscript
    • Advertisers
    • Careers & Locums
    • Subscribers
    • Permissions
  • About CFP
    • About CFP
    • About the CFPC
    • Editorial Advisory Board
    • Terms of Use
    • Contact Us
  • Feedback
    • Feedback
    • Rapid Responses
    • Most Read
    • Most Cited
    • Email Alerts
  • Blogs
    • Latest Blogs
    • Blog Guidelines
    • Directives pour les blogues
  • Mainpro+ Credits
    • About CFP Mainpro+
    • Member Login
    • Instructions
  • RSS feeds
  • Follow cfp Template on Twitter
Case ReportPractice

Clinically important interaction between metoprolol and propafenone

Jana Duricova, Ilona Perinova, Nikola Jurckova, Ivana Kacirova and Milan Grundmann
Canadian Family Physician April 2013, 59 (4) 373-375;
Jana Duricova
Postgraduate student in the Department of Clinical Pharmacology at the University Hospital Ostrava in the Czech Republic.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: jankaduricova@seznam.cz
Ilona Perinova
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nikola Jurckova
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ivana Kacirova
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Milan Grundmann
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • eLetters
  • Info & Metrics
  • PDF
Loading

A combination of antiarrhythmic drugs with β1 selective blocking agents has often been used. Both these types of drugs are metabolized via the cytochrome P450 (CYP) enzyme system, and therefore potential drug interactions are of considerable clinical significance. The antiarrhythmic agent propafenone undergoes CYP 2D6–dependent metabolism.1 Propafenone is also an inhibitor of the enzyme; the inhibitory constant has been estimated at 50 nmol/L, similar to that of quinidine (60 nmol/L).2 Metoprolol, a β1 selective blocking agent, undergoes extensive presystemic elimination by CYP 2D6, and it has been shown that metabolites do not substantially contribute to the β1-blockade.3,4 Metoprolol has a dose-dependent effect; dose is commonly titrated to the highest dose tolerated in order to achieve the maximal effect in the absence of adverse effects.5 A 2- to 5-fold increase in steady-state levels of metoprolol has been described after adding propafenone to metoprolol therapy.6 The disposition of CYP 2D6 substrates also depends on the CYP 2D6 genotype. In general, 4 subgroups might be differentiated: poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM), and ultrarapid metabolizers (UM). Poor metabolizers lack any functional allele. Ultrarapid metabolizers have more than 2 functional alleles. Intermediate metabolizers are heterozygous for a specific variant allele or possess alleles with reduced activity.7

We present a case of an interaction between metoprolol and propafenone in which high metoprolol concentrations affect the patient’s condition.

Case

A 66-year-old woman (weight 81 kg) was referred to our outpatient department because of decompensated hypertension (World Health Organization classification grade III). Blood pressure in a sitting position was 154/82 mm Hg, and heart rate was 60 beats/min. The patient had undergone kidney transplantation for polycystic kidney disease several years ago and was taking 175 mg/d of cyclosporine and 50 mg/d of azathioprine. Further comorbidities were ischemic heart disease without angina pectoris syndrome (New York Heart Association class III or IV) and chronic venous insufficiency. At the time of admission, the patient was being treated with the following cardiovascular medication: 200 mg/d of metoprolol, 100 mg/d of losartan, 1 mg/d of rilmenidine, 60 mg/d of furosemide, captopril as needed, 100 mg/d of acetylsalicylic acid, and 20 mg/d of isosorbide mononitrate. To prevent atrial fibrillation, 600 mg of propafenone daily was prescribed. During her follow-up, 5 mg/d of amlodipine was introduced to the therapy. After the medication adjustment, the patient’s blood pressure was compensated (Table 1); however, she was repeatedly complaining about increased tiredness and dyspnea on exertion. Therefore, determination of metoprolol and α-hydroxymetoprolol serum concentrations was indicated.8 Three hours after the patient’s metoprolol-dose intake, her metoprolol–α-hydroxymetoprolol metabolic ratio (MR) was used for CYP 2D6 phenotyping.9 Genotyping of CYP 2D6 was also performed. A DNA direct sequencing analysis of the whole coding sequence of the CYP 2D6 gene was performed using a genetic analyzer. Copy number variants of the gene were detected using the long-range polymerase chain reaction method and amplified products were visualized on 1% agarose gel electrophoresis.

The patient had an IM genotype with detected variant alleles CYP 2D6*4/*9. However, 3 hours after the dose intake, the metoprolol–α-hydroxymetoprolol MR was 104.3, indicative of a PM phenotype. Table 1 shows metoprolol and α-hydroxymetoprolol serum concentrations. A survey of the patient’s concomitant medication revealed her use of propafenone, an inhibitor of CYP 2D6 activity. The patient’s metoprolol dose was reduced to 100 mg daily. Her condition improved, and her tiredness and dyspnea disappeared.

About half a year later the patient was admitted to the internal medicine department for chest pain on exertion and on rest lasting for about 14 days, with radiation to the right arm, dyspnea, orthopnea, and edema of the lower limbs. Blood pressure on admission was 160/80 mm Hg, and heart rate was 51 beats/min. She was diagnosed as having global cardiac failure with atrial fibrillation with slow ventricular response. Relevant therapy was initiated with an adjustment of her medication. Her metoprolol dosage was reduced to 12.5 mg daily, and propafenone was withdrawn. Two weeks later the patient was hemodynamically stable and was discharged from the hospital.

Several days after discharge, the patient herself increased her metoprolol intake to a previous dose of 100 mg daily. During the next outpatient’s visit, her CYP 2D6 phenotype after propafenone discontinuation was determined (Table 1); a substantial decrease in metoprolol–α-hydroxymetoprolol MR was revealed, switching the patient’s phenotype from PM (MR = 104.3) to EM (MR = 1.4).

View this table:
  • View inline
  • View popup
Table 1

Patient’s metoprolol and α-hydroxymetoprolol serum concentrations; metoprolol–α-hydroxymetoprolol metabolic ratio; heart rate; and blood pressure before metoprolol intake and 1 or 3 hours after metoprolol intake, with and without propafenone

Discussion

This case demonstrates an inhibitory effect of propafenone on metoprolol biotransformation resulting in the occurrence of adverse effects due to high metoprolol levels.

Propafenone has been shown to be metabolized by the same hepatic enzyme as the sparteine-debrisoquine polymorphism but with higher affinity for CYP 2D6, thereby being able to cause a shift of metabolizer phenotype.1 Metoprolol undergoes extensive presystemic elimination, with this enzyme accounting for 70% to 80% of its metabolism. In our patient, a marked decrease in metoprolol–α-hydroxymetoprolol MR was observed after propafenone therapy had been stopped, and the patient’s phenotype switched from PM to EM. Because the patient’s other medications were retained, we attribute this phenotypic shift to vanished inhibitory effect.

Labbé et al found that the addition of propafenone to CYP 2D6 substrate mexiletine in people with EM phenotypes caused pharmacokinetic changes of mexiletine to such an extent that differences between those with EM phenotypes and PM phenotypes were almost absent.10 Thus, results of phenotyping might be falsified by the presence of interfering medications, resulting in discrepancy between the phenotype and genotype. Wagner et al found that the addition of propafenone increased steady-state levels of metoprolol 2 to 5 times in 4 patients. Two patients even developed side effects while receiving the drug combination (severe nightmares and left ventricular failure), which disappeared after the metoprolol dose was reduced or discontinued.6 Our patient suffered from tiredness and dyspnea on exertion likely owing to high metoprolol serum concentrations caused by the inhibitory effect of propafenone. Substantial increases in metoprolol concentrations have also been observed after the addition of the antiarrhythmic drug amiodarone and the antihistamine diphenhydramine.11,12 The addition of selective serotonin reuptake inhibitors, fluoxetine and paroxetine, has also resulted in severe adverse effects, which subsided after discontinuation of the inhibitors.13,14

In our case the patient’s genotype was heterozygous for CYP 2D6*4/*9 alleles. Individuals who carry the CYP 2D6*9 allele have an altered ability to metabolize CYP 2D6 substrates and have IM phenotypes, whereas the CYP 2D6*4 allele results in a loss of enzyme activity.15 The combination of IM phenotype and defective alleles is not associated with a PM phenotype; however, it shows a substantially higher MR than does the EM-PM genotype.16 The S-enantiomer of propafenone has also been shown to display β-blocking action. The degree of β-blockade reflects genetically determined variations in propafenone metabolism, with subjects with the PM phenotype having considerably more β-blockade.17 Unfortunately we were not able to determine the propafenone serum concentration and subsequently assess its contribution to the occurrence of adverse effects. However, after the metoprolol dose was reduced to half (100 mg/d), the side effects disappeared.

Interestingly, blood pressure and, in particular, heart rate did not change substantially after metoprolol dose reduction and after propafenone discontinuation. Pharmacodynamic modeling of the β1-blocking effect of metoprolol shows a steep linear relationship to plasma concentration, with a maximum effect at 400 nmol/L (106.96 μg/L). However, only 30% of the maximum β1-blocking effect is necessary for a clinically significant effect; this limit was observed at a metoprolol plasma concentration of 45 nmol/L (12.03 μg/L).4 We speculate that the permanent metoprolol serum concentrations in our patient above this concentration limit preserved stable heart rate in spite of gradual decline in metoprolol concentrations.

Conclusion

Coadministration of propafenone and metoprolol might result in elevation of metoprolol serum concentration and affect a patient’s clinical condition. Clinicians should be aware of the potential interaction when prescribing this combination and start with low metoprolol doses, as well as follow up with patients carefully. Therapeutic drug monitoring could serve as a valuable tool in clarifying a patient’s condition.

Notes

EDITOR’S KEY POINTS

  • Propafenone might inhibit metoprolol metabolism, and high metoprolol serum concentrations might have clinical effects. Clinicians should be aware of this potential interaction and start with low metoprolol doses and follow up with patients carefully.

  • Therapeutic drug monitoring could serve as a valuable tool in clarifying a patient’s condition.

POINTS DE REPÈRE DU RÉDACTEUR

  • La propafénone pourrait inhiber le métabolisme du métoprolol, et des concentrations sériques élevées de métoprolol pourraient avoir des effets cliniques. Les cliniciens devraient être au fait de cette interaction potentielle, commencer par de faibles doses de métoprolol et assurer un suivi rigoureux des patients.

  • La surveillance thérapeutique du médicament pourrait s’avérer un outil précieux pour clarifier la condition du patient.

Footnotes

  • This article has been peer reviewed.

  • Cet article a fait l’objet d’une révision par des pairs.

  • Competing interests

    None declared

  • Copyright© the College of Family Physicians of Canada

References

  1. ↵
    1. Kroemer HK,
    2. Fischer C,
    3. Meese CO,
    4. Eichelbaum M
    . Enantiomer/enantiomer interaction of (S)- and (R)-propafenone for cytochrome P450IID6-catalyzed 5-hydroxylation: in vitro evaluation of the mechanism. Mol Pharmacol 1991;40(1):135-42.
    OpenUrlAbstract
  2. ↵
    1. Otton SV,
    2. Inaba T,
    3. Kalow W
    . Competitive inhibition of sparteine oxidation in human liver by beta-adrenoceptor antagonists and other cardiovascular drugs. Life Sci 1984;34(1):73-80.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Frank D,
    2. Jaehde U,
    3. Fuhr U
    . Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping. Eur J Clin Pharmacol 2007;63(4):321-33. Epub 2007 Feb 2.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Abrahamsson B,
    2. Lücker P,
    3. Olofsson B,
    4. Regårdh CG,
    5. Sandberg A,
    6. Wieselgren I,
    7. et al
    . The relationship between metoprolol plasma concentration and beta 1-blockade in healthy subjects: a study on conventional metoprolol and metoprolol CR/ZOK formulations. J Clin Pharmacol 1990;30(2 Suppl):S46-54.
    OpenUrlPubMed
  5. ↵
    1. Regårdh CG,
    2. Johnsson G
    . Clinical pharmacokinetics of metoprolol. Clin Pharmacokinet 1980;5(6):557-69.
    OpenUrlPubMed
  6. ↵
    1. Wagner F,
    2. Kalusche D,
    3. Trenk D,
    4. Jähnchen E,
    5. Roskamm H
    . Drug interaction between propafenone and metoprolol. Br J Clin Pharmac 1987;24(2):213-20.
    OpenUrlPubMed
  7. ↵
    1. Zanger UM,
    2. Raimundo S,
    3. Eichelbaum M
    . Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 2004;369(1):23-37. Epub 2003 Nov 15.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Perinova I,
    2. Duricova J,
    3. Brozmanova H,
    4. Kacirova I,
    5. Grundmann M
    . Determination of metoprolol and its metabolite α-hydroxymetabolite in serum by HPLC method with fluorescence detection [article in Czech]. Ces Farm 2008;57(6):254-9.
    OpenUrl
  9. ↵
    1. Jonkers RE,
    2. Koopmans RP,
    3. Portier EJ,
    4. van Boxtel CJ
    . Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers. J Pharmacol Exp Ther 1991;256(3):959-66.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Labbé L,
    2. O’Hara G,
    3. Lefebvre M,
    4. Lessard E,
    5. Gilbert M,
    6. Adedoyin A,
    7. et al
    . Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings. Clin Pharmacol Ther 2000;67(1):44-57.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Fukumoto K,
    2. Kobayashi T,
    3. Tachibana K,
    4. Kato R,
    5. Kazuhiko T,
    6. Komamura K
    . Effect of amiodarone on the serum concentration/dose ratio of metoprolol in patients with cardiac arrhythmia. Drug Metab Pharmacokinet 2006;21(6):501-5.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Hamelin BA,
    2. Bouayad A,
    3. Méthot J,
    4. Jobin J,
    5. Desgagnés P,
    6. Poirier P,
    7. et al
    . Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther 2000;67(5):466-77.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Walley T,
    2. Pirmohamed M,
    3. Proudlove C,
    4. Maxwell D
    . Interaction of metoprolol and fluoxetine. Lancet 1993;341(8850):967-8.
    OpenUrlPubMed
  14. ↵
    1. Onalan O,
    2. Cumurcu BE,
    3. Bekar L
    . Complete atrioventricular block associated with concomitant use of metoprolol and paroxetine. Mayo Clin Proc 2008;83(5):595-99.doi:10.4065/83.5.595
    OpenUrlCrossRefPubMed
  15. ↵
    1. The Human Cytochrome P450 (CYP) Allele Nomenclature Database [website]
    . CYP2D6 allele nomenclature. Stockholm, Sweden: The Human Cytochrome P450 (CYP) Allele Nomenclature Database; 2012. Available from: www.cypalleles.ki.se/cyp2d6.htm. Accessed 2013 Jan 11.
  16. ↵
    1. Sachse C,
    2. Brockmöller J,
    3. Bauer S,
    4. Roots I
    . Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997;60:284-95.
    OpenUrlPubMed
  17. ↵
    1. Lee JT,
    2. Kroemer HK,
    3. Silberstein DJ,
    4. Funck-Bretano C,
    5. Lineberry MD,
    6. Wood AJ,
    7. et al
    . The role of genetically determined polymorphic drug metabolism in the beta-blockade produced by propafenone. N Engl J Med 1990;322(25):1764-8.
    OpenUrlPubMed
PreviousNext
Back to top

In this issue

Canadian Family Physician: 59 (4)
Canadian Family Physician
Vol. 59, Issue 4
1 Apr 2013
  • Table of Contents
  • About the Cover
  • Index by author
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word on The College of Family Physicians of Canada.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Clinically important interaction between metoprolol and propafenone
(Your Name) has sent you a message from The College of Family Physicians of Canada
(Your Name) thought you would like to see the The College of Family Physicians of Canada web site.
Citation Tools
Clinically important interaction between metoprolol and propafenone
Jana Duricova, Ilona Perinova, Nikola Jurckova, Ivana Kacirova, Milan Grundmann
Canadian Family Physician Apr 2013, 59 (4) 373-375;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Share
Clinically important interaction between metoprolol and propafenone
Jana Duricova, Ilona Perinova, Nikola Jurckova, Ivana Kacirova, Milan Grundmann
Canadian Family Physician Apr 2013, 59 (4) 373-375;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Case
    • Discussion
    • Conclusion
    • Notes
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

  • No related articles found.
  • Scopus
  • PubMed
  • Google Scholar

Cited By...

  • No citing articles found.
  • Scopus (5)
  • Google Scholar

More in this TOC Section

Practice

  • Contrasting current challenges from the Brazilian and Canadian national health systems
  • Pregnancy-related cardiovascular risk indicators
  • Putting the fun in fungi: toenail onychomycosis
Show more Practice

Case Report

  • Myocarditis as the initial presentation of Epstein-Barr virus infection in a 17-year-old male patient
  • Palliative care in patients with severe mental illness
  • Severe localized scapular pain after a strenuous weight-lifting session
Show more Case Report

Similar Articles

Navigate

  • Home
  • Current Issue
  • Archive
  • Collections - English
  • Collections - Française

For Authors

  • Authors and Reviewers
  • Submit a Manuscript
  • Permissions
  • Terms of Use

General Information

  • About CFP
  • About the CFPC
  • Advertisers
  • Careers & Locums
  • Editorial Advisory Board
  • Subscribers

Journal Services

  • Email Alerts
  • Twitter
  • RSS Feeds

Copyright © 2019 by The College of Family Physicians of Canada

Powered by HighWire