Ivabradine reduces heart rate without negative inotropy. Which mechanism underpins this property, and in which specific patient population is it most indicated?

• A Inhibits delayed rectifier K+ current (IKr) prolonging diastolic depolarization; indicated in permanent atrial fibrillation with rapid ventricular rate
• B Blocks L-type calcium channels selectively in SA node; indicated in vasospastic angina with beta-blocker intolerance
• C Blocks I(f) funny current (HCN4 channels) in sinoatrial node pacemaker cells; indicated in HFrEF patients with HR ≥70 bpm in sinus rhythm on maximally tolerated beta-blocker ✓
• D Activates cardiac muscarinic M2 receptors slowing SA node firing; indicated in postural tachycardia syndrome

Explanation

Ivabradine selectively inhibits the I(f) 'funny current' mediated by HCN4 (hyperpolarization-activated cyclic nucleotide-gated channel 4) in sinoatrial node cells. This mixed Na+/K+ inward current depolarizes pacemaker cells during diastole; blocking it slows the rate of diastolic depolarization and reduces heart rate. Since it does not affect calcium channels or beta receptors, there is no negative inotropic effect, blood pressure change, or conduction delay beyond the SAN. In the SHIFT trial, ivabradine reduced cardiovascular death and HF hospitalization in HFrEF patients (EF ≤35%) in sinus rhythm with resting HR ≥70 bpm despite maximally tolerated beta-blocker — the approved indication. It is contraindicated in AF since the I(f) current is irrelevant in this arrhythmia.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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