Valheart Mechanism of Action

Pharmacology: Pharmacodynamics: Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocking agent that reduces the spontaneous pacemaker activity of the cardiac sinus node by selectively inhibiting the I_f current, resulting in heart rate reduction with no effect on ventricular repolarization or myocardial contractility.
Ivabradine causes a dose-dependent reduction in heart rate. Analysis of heart rate reduction with doses up to 20 mg twice daily indicates a trend towards a plateau effect. At recommended doses, heart rate reduction is approximately 10 beats per minute (bpm) at rest and during exercise. Ivabradine does not influence intracardiac conduction, contractility (no negative inotropic effect) or ventricular repolarization.
In clinical studies, ivabradine has reduced heart rate, improved exercise capacity, and decreased the number of anginal attacks in patients with chronic stable angina.
Ivabradine can also inhibit the retinal I_h current. The I_h current, closely resembling the cardiac I_f current, is involved in temporally inhibiting retinal responses to bright light stimuli. Under triggering circumstances (e.g., rapid changes in luminosity), partial blockade of I_h by ivabradine may underlie the luminous phenomena experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field (see Adverse Reactions).
Pharmacokinetics: Ivabradine is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration. Peak plasma concentrations (C_max) are reached within 1 hour under fasting conditions. The absolute oral bioavailability of ivabradine is about 40% due to first-pass metabolism. Ivabradine exhibits linear pharmacokinetics over an oral dose range of 0.5 to 24 mg. Food delays the absorption of ivabradine by approximately 1 hour and increases plasma exposure by 20 to 40%. Ivabradine should be taken with food to reduce individual variability in systemic exposure.
Ivabradine is approximately 70% bound to plasma proteins and the volume of distribution at steady state is about 100 L.
Ivabradine is extensively metabolized in the liver and intestines by oxidation through the cytochrome P450 (CYP) 3A4. The major metabolite is the N-desmethylated derivative (S 18982), which is equipotent to ivabradine and circulates at concentrations of approximately 40% that of ivabradine and is also metabolized by CVP3A4. Ivabradine has low affinity for CYP3A4 and does not modify CYP3A4 substrate metabolism or plasma concentrations. Conversely, potent inhibitors or inducers of CYP3A4 may have a significant effect on plasma concentrations of ivabradine.
Ivabradine plasma concentrations decline with a distribution half-life of 2 hours and an effective half-life of approximately 6 hours.
The total clearance of ivabradine is 24 L/hour and the renal clearance is approximately 4.2 L/hour. About 4% of an oral dose is excreted unchanged in urine. The excretion of metabolites occurs to similar extents via feces and urine.