Clinically important interaction between metoprolol and 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.