pKa does not predict pH potentiation of sodium channel blockade by lidocaine and W6211 in guinea pig ventricular myocardium.

During diastole, tertiary amine local anesthetic molecules may exit cardiac sodium channels quickly through the membrane if they are neutral, or more slowly through the aqueous channel pore if they are charged. Extracellular acidosis potentiates sodium channel blockade by these drugs, and drug pKa should be a potent predictor of the degree of response of drug dissociation kinetics to changes in extracellular pH. To test this hypothesis, we measured kinetics of recovery from drug-induced channel blockade in guinea pig papillary muscle exposed to lidocaine (pKa 7.86) and to W6211 (pKa 6.29) using Vmax as a measure of peak sodium current. Both compounds, which are physicochemically very similar in respects other than pKa, delayed Vmax recovery in a pH-dependent fashion. As pH was lowered from 7.9 to 6.5, the recovery time constant rose from 86 to 230 msec for lidocaine and from 53 to 154 msec for W6211. We revised an earlier kinetic scheme of drug-channel interaction to incorporate newer concepts of drug trapping and ionization within the channel, and the resulting analytic expressions fit the data well. Important implications of the new scheme are that the pKa of the drug-receptor complex may differ from the drug pKa, and that deprotonation of channel-bound charged drug molecules may be a rate-limiting process.

Duke Scholars

Author Charles Franklin Starmer Computer Science