hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers

Introduction

hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers are used to Mx congestive cardiac failure

hyperpolarization-activated cyclic nucleotide-gated (HCN) channels
- belong to the family of voltage-gated K+ (Kv) channels but are activated by hyperpolarization instead of by depolarization
- allowing the flow of sodium (Na+) and potassium (K+) ions across the cell membrane which generates pacemaker currents, known as I(f) or I(h) currents, which play a pivotal role in setting the pace of spontaneous electrical activity in cardiac and neuronal cells.
- are essential for rhythmic activity in the heart and brain, and mutations in HCN channels are linked to heart arrhythmia and epilepsy
- are activated by cyclic nucleotides like cyclic adenosine monophosphate (cAMP), which modulate their activity
- four known isoforms of HCN channels (HCN1-HCN4), each with distinct distribution patterns and physiological roles
  - HCN1 channels are predominantly found in the brain
  - HCN4 channels are predominantly found in the heart
HCN blockers
- reduce the excitability of cells, leading to a decrease in heart rate and neuronal firing
- results in hyperpolarization of the cell membrane, making it less likely for the cell to reach the threshold potential required for action potential generation
- HCN1 blockers may have roles in epilepsy, neuropathic pain, and depression
- HCN4 blockers slow heart rate without affecting myocardial contractility

ivabradine
- used to treat chronic stable angina and heart failure
- selectively inhibits the HCN4 channels in the sinoatrial node of the heart, reduces the heart rate without affecting myocardial contractility
- PBS Auth in Australia for ch heart failure (symptomatic with NYHA classes II or III) in SR with LVEF < 35% and resting HR > 77bpm despite max tolerated dose of beta blocker (unless contraindicated)