148849-67-6

Description

In an effort to develop angina agents without the unwanted negative inotropic and hypotensive effects associated with b-adrenergic blockers and calcium channel blockers, a new class of heart-rate reducing compounds that act specifically on the sinoatrial (SA) node has been explored. These bradycardic agents interact directly with the pacemaking cell of the SA node and the hyperpolarization- activated If , the primary pacemaking current. Ivabradine has evolved as a specific inhibitor of If current through its contact with f-channels on the intracellular side of the plasma membrane. As a consequence, ivabradine reduces the speed of diastolic depolarization and decreases heart rate. It has been approved for the treatment of chronic stable angina and provides a viable alternative to patients with a contraindication or intolerance of b-blockers. Evaluation is also underway for the potential treatment of ischemic heart disease. Using a patch-clamp technique on rabbit sinoatrial node cells, inhibition of If current ranged from 6% (0.03 mM) – 80% (10 mM). .

Chemical Properties

White to Off-White Solid

Originator

Servier (France)

Uses

Ivabradine hydrochloride has been used as a potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel (HCN)2 blocker in embryoid body (EB) and rat engineered heart tissue (EHT).

Definition

ChEBI: A hydrochloride obtained by combining ivabradine with one molar equivalent of hydrochloric acid. Used to treat patients with angina who have intolerance to beta blockers and/or heart failure.

Brand name

Procoralan

Biochem/physiol Actions

Ivabradine is used to treat chronic heart failure.

Clinical Use

Symptomatic treatment of chronic stable angina pectoris in patients with sinus rhythm Treatment of mild to severe chronic heart failure

Drug interactions

Potentially hazardous interactions with other drugs Anti-arrhythmics: increased risk of ventricular arrhythmias with amiodarone and disopyramide. Antibacterials: concentration possibly increased by clarithromycin and telithromycin - avoid; increased risk of ventricular arrhythmias with erythromycin - avoid. Antifungals: concentration increased by ketoconazole - avoid; concentration increased by fluconazole - reduce initial ivabradine dose; concentration possibly increased by itraconazole - avoid. Antimalarials: increased risk of ventricular arrhythmias with mefloquine. Antipsychotics: increased risk of ventricular arrhythmias with pimozide. Antivirals: concentration possibly increased by ritonavir - avoid. Beta-blockers: increased risk of ventricular arrhythmias with sotalol. Calcium-channel blockers: concentration increased by diltiazem and verapamil - avoid. Grapefruit juice: ivabradine concentration increased. Pentamidine: increased risk of ventricular arrhythmias. St John’s wort: ivabradine concentration reduced - avoid.

Metabolism

Ivabradine is extensively metabolised by the liver and the gut by oxidation through cytochrome P450 3A4 (CYP3A4) only. The major active metabolite is N-desmethyl-ivabradine (S 18982) with an exposure about 40% of that of the parent compound. This active metabolite undergoes further metabolism by CYP3A4. Excretion of metabolites occurs to a similar extent via faeces and urine.