Several hypotheses of antiarrhythmic drug action have been proposed, but none provide a detailed quantitative description of drug effects on the cardiac sodium channel. The most widely accepted of these hypotheses is the modulated receptor hypothesis which states drug binds with different affinities to the resting, activated, and inactivated channel states. Using this hypothesis, we built a quantitative model of drug action on the cardiac sodium channel patterned after that of Hondeghem and Katzung (Biochim. Biophys. Acta 472: 373--98). The model is unable to reproduce experimental data at multiple drug concentrations including the dose-response curve. We suggest that the model fails because it seeks only to represent phenomenologically a drug's effect instead of the mechanism by which the effect is generated.
A better model of antiarrhythmic drug action on the cardiac sodium channel would be more biophysically-detailed and would describe how drug binds to the channel and interacts with its gates. Building such a drug model requires the development of a biophysically-detailed cardiac sodium channel model. We have constructed a new Markov model of the cardiac sodium channel that not only is an improvement over existing Markov models, but is an improvement over existing Hodgkin-Huxley models as well. This model forms the basis of a model of lidocaine's action. Drug effect is the result of non-drug-bound channels gating as above and drug-bound channels gating with modified kinetics.