Dronedarone HCl is a multichannel blocker targeting potassium channel,sodium channel and calcium channel, used as an antiarrhythmic drug for treatment of atrial fibrillation (AF).
Dronedarone hHydrochloride, is a non-iodinated amiodarone derivative that inhibits Na+, K+ and Ca2+ currents. It is a potent inhibitor of the acetylcholine-activated K+ current from atrial and sinoatrial nodal tissue, and inhibits the rapid delayed rectifier more potently than slow and inward rectifier K+ currents and inhibits L-type calcium current. Dronedarone is an antagonist at alpha- and beta-adrenoceptors and unlike amiodarone, has little effect at thyroid receptors[3]. Intravenous administration of dronedarone hydrochloride in doses of 0.3 and 3 mg/kg over 30s attained the peak plasma concentrations of 61 and 1248 ng/mL, respectively, reflecting sub- to supra-therapeutic ones. The low dose decreased the left ventricular contraction and mean blood pressure, which were enhanced at the high dose. The high dose also decreased the heart rate and cardiac output, but increased the total peripheral resistance and left ventricular end-diastolic pressure, showing its potent cardiodepressive profile. Dronedarone significantly prolonged the T(peak)-T(end) in a dose-related manner with a tendency to prolong the terminal repolarization period and J-Tpeakc, indicating considerable risk to induce torsade de pointes[4]. Improved oral bioavailability of dronedarone could be provided by an optimized proliposomal formulation with enhanced solubility, permeability, and oral absorption[5]. In guinea pig ventricular myocytes, dronedarone exhibited a state-dependent inhibition of the fast Na(+) channel current with an IC(50) of 0.7 ± 0.1 μM, when the holding potential (V (hold)) was -80 mV. The maximal block at the highest concentration used was 77 ± 8%. In contrast, when V (hold) was -100 mV, inhibition with 10 μM dronedarone was only 9 ± 3% (n = 7). Dronedarone blocked Ca(2+) currents elicited by rectangular pulses at V (hold) = -40 mV with an IC(50) value of 0.4 ± 0.1 μM (maximal block by 10 μM dronedarone, 80 ± 6%), whereas at V (hold) = -80 mV, 10 μM dronedarone blocked only 20 ± 6% (n = 4) of the current. Inhibition of fast Na+ and Ca2+ channels by dronedarone depends on the cell’s resting membrane potential (state-dependent block) favouring an atrialselective mode of action. Besides fast Na+ and Ca2+ channels, dronedarone also inhibits HCN4 currents. This might contribute to the clinically observed reduction in heart rate seen in patients in sinus rhythm after dronedarone treatment[6].
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