Profound Synergistic Bradycardia: Pharmacokinetic Consequences of Paxlovid-Mediated CYP3A4 and CYP2D6 Inhibition on Ranolazine, Diltiazem, and Metoprolol

Paxlovid, a codrug of nirmatrelvir/ritonavir, has established itself in the COVID-19 treatment arsenal due to numerous studies documenting clinical efficacy regardless of vaccination status. The ritonavir component, however, is a strong CYP3A4 and strong-to-moderate CYP2D6 inhibitor, reducing the clearance of many cardiovascular drugs. While existing literature documents symptomatic bradycardia from Paxlovid, and single- or dual-drug regimen, a case report of a triple-drug regimen of ranolazine, diltiazem, and metoprolol - utilizing both CYP3A4 and CYP2D6 pathways - is rare. Here we present the case of an 81-year-old female on ranolazine, diltiazem, and metoprolol who developed profound bradycardia (atrial fibrillation with slowed ventricular response) and hypotension due to reduced clearance of these drugs from CYP inhibition. An 81-year-old female with atrial fibrillation, coronary artery disease, and heart failure was prescribed Paxlovid after testing positive for COVID-19 in the outpatient setting. She subsequently experienced rapid hemodynamic collapse with a heart rate of 41 bpm (from baseline ~66 bpm) and blood pressure of 57/36 mmHg. She was intubated and initiated on multi-drug inotropic support (isoproterenol, dopamine, and epinephrine). Medication reconciliation revealed a home regimen of ranolazine (1000 mg BID), diltiazem (180 mg BID), and metoprolol tartrate (25 mg BID) - all primary CYP 3A4/2D6 substrates. The patient was successfully weaned off of vasopressors and extubated within 48 hours following Paxlovid discontinuation and supportive care. She maintained hemodynamic stability and was discharged the following day. This case demonstrates that the ritonavir component of Paxlovid can result in the supratherapeutic serum accumulation of ranolazine, diltiazem, and metoprolol through a dual-CYP 3A4 and 2D6 pathway inhibition, leading to a life-threatening bradycardic and hypotensive crisis.