Vernakalant Hydrochloride

Vernakalant Hydrochloride (CAS No. 748810-28-8) is an atrial-selective antiarrhythmic agent whose core bioactivity is the rapid conversion of atrial fibrillation (AF) to sinus rhythm. Its targets include atrial-specific ion channels (IK, Ito, IKr, IKACh), sodium channels (INa, with frequency/voltage/concentration-dependent block), and Kv1.5, Kv4.3, hERG, Nav1.5 channels. It acts by prolonging atrial refractoriness and inhibiting atrial electrical remodeling, with minimal effects on the ventricles. Regarding IC50, the parent drug shows values of 5–45 μM for the above ion channels, while the metabolites RSD1385 and RSD1390 show values of 15–80 μM. It exhibits no significant inhibition of hKCa2.2/2.3 channels (IC50 far above therapeutic concentrations). In PK/PD models, the EC50 related to QTcF is 2276 ng/ml (non-converted AF) and 4222 ng/ml (converted AF), and the EC50 related to systolic blood pressure (SBP) is 1141 ng/ml. Commonly used application concentrations: in vitro cell experiments (HEK293 expressing ion channels) use test concentrations of 0.1–300 μM; in animal experiments (canine AF model) it selectively prolongs atrial refractoriness and terminates AF. Clinical concentrations are based on an intravenous infusion regimen (initial 3 mg/kg, 10-minute infusion; if not converted, an additional 2 mg/kg 10-minute infusion 15 minutes later). A single 3 mg/kg dose yields a peak plasma concentration of about 3.9 μg/ml, and about 4.3 μg/ml after two doses. The effective therapeutic free plasma concentration is 1000–10000 nmol/L. For short-duration AF (3 hours–7 days), the conversion rate reaches 51.7%, with a median conversion time of 8–12 minutes. Tolerability is good; common transient adverse reactions include dysgeusia and sneezing, with no clear risk of torsade de pointes.

References:

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