Pharmacology of Ivabradine
Ivabradine is a selective inhibitor of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel that blocks the If (funny) current in the sinoatrial node, thereby reducing heart rate without affecting myocardial contractility, ventricular repolarization, or blood pressure. 1
Mechanism of Action
By blocking the If current, ivabradine reduces the slope of the slow diastolic depolarization phase of the action potential in sinus node cells, thereby selectively reducing heart rate. 2 The drug enters the HCN channels and binds to the intracellular side, subsequently inhibiting the If current. This prolongs the slow spontaneous phase in diastolic depolarization, resulting in heart rate reduction. 3
Key Pharmacodynamic Properties
- Use-dependent inhibition: The heart rate reduction with ivabradine is greater when the initial heart rate is high, and lower when the initial heart rate is low 2
- No negative inotropic or lusitropic effects: Unlike beta-blockers or calcium channel blockers, ivabradine does not depress myocardial contractility 2
- No effect on blood pressure or renal function: This makes it well-tolerated in patients unable to initiate or titrate beta-blockers for these reasons 4
- Dose-dependent heart rate reduction: At recommended doses, heart rate reduction is approximately 10 bpm at rest and during exercise, with a plateau effect at doses >20 mg twice daily 1
Pharmacokinetics
The drug is metabolized primarily by CYP3A4 5, 6. Ivabradine is contraindicated with strong CYP3A4 inhibitors (boceprevir, clarithromycin, indinavir, itraconazole, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, telaprevir, posaconazole, voriconazole) and strong CYP3A4 inducers (carbamazepine, phenytoin, rifampin, St. John's wort), as well as with diltiazem, verapamil, and grapefruit juice. 5, 6
Dosing Considerations
- No dose adjustment required for mild or moderate hepatic impairment or for creatinine clearance 15-60 mL/min 1
- Contraindicated in severe hepatic impairment (Child-Pugh C) 1
- Can be initiated at 2.5 mg twice daily in older adults 4
- Standard dosing: 5 mg twice daily initially, with maintenance dose of 7.5 mg twice daily 5, 6
Adverse Effects
The most clinically relevant adverse effects include:
- Visual phenomena (phosphenes): Occur in 5.4% of patients due to If channels in the retina that resemble those in the sinus node; described as transient enhanced brightness in a limited area of the visual field. These are mild, transitory, and rarely lead to treatment withdrawal (<1%) 2
- Bradycardia: Treatment withdrawal due to bradycardia occurred in only 1% of patients in the SHIFT trial, despite 89% taking concomitant beta-blockers 2
- Atrial fibrillation: Increases absolute incidence by 0.7%, with most cases being paroxysmal in nature 2
Clinical Pharmacology Context
Ivabradine requires sinus rhythm to provide its pharmacological effect and thus has no utility in patients with atrial fibrillation. 4 The heart rate reduction is similar to that achieved with beta-blockers, but the synergistic effect between beta-blockers and ivabradine suggests that in patients receiving beta-blockers who remain symptomatic, adding ivabradine is more efficient than uptitrating beta-blockers. 2
The drug does not affect atrioventricular or intraventricular conduction times beyond the expected effects of heart rate reduction, though prolongation of the AH interval and PR interval can occur. 1 Importantly, ivabradine increases the uncorrected QT interval with heart rate slowing but does not cause rate-corrected prolongation of QT. 1