Antiarrhythmic agents: modulated receptor applications.

IT IS NOW well established that block of transmem-brane ionic channels is frequently time and voltage dependent.' 2 Although the modulated receptor theory has been most extensively studied for sodium and calcium channels in cardiac tissue,3 it may apply to other membrane receptors as well. The present essay is limited to discussion of sodium-channel blockers and how their time-and voltage-dependent block can contribute to antiarrhythmic and arrhythmogenic actions. After a brief description of the modulated receptor theory and the definition of some commonly used but ill-defined terms, these principles will be applied to some clinical conditions. Although the general flavor of the present article should be palatable without studying previous reports describing the modulated receptor hypothesis, full appreciation of all the concepts may require some additional reading.2 4 It is my hope that these considerations will spark some tests in vivo of the modulated receptor concepts that will ultimately benefit the patient suffering from arrhythmias. Basic concepts The modulated receptor hypothesis. According to Hodgkin and Huxley, sodium channels exist in three primary states (figure 1): rested (R, a closed state most prevalent at negative membrane potentials), inactivat-ed (I, a closed state at depolarized membrane potentials), and open or activated (A, the state through which the channels pass upon depolarization when they move from the R to the I state). Applied to cardiac tissue this means that the R state is most prevalent during diastole, the A state during the upstroke, and the I state during the plateau or when the tissue is depolarized (e.g., by ischemia). The modulated receptor theory states that drug affinity for a specific receptor on the channel is modulated by channel state, 514 each sodium-channel blocker has a characteristic association (kR, kA, and k1,) and dissociation (lR 'A, and 1,) rate constant for channels in each of these states. Although drug-associated channels (like drug-free channels) distribute between rested (R'), activated (A'), and inactivated (I') states in a voltage-dependent fashion , they may not conduct sodium and may have altered voltage dependence for their state transitions: they behave as if the membrane potential was less negative. As a result, blocked channels tend to accumulate in the I' state.4 Although at high enough concentrations blockers may bind to the channel receptor in any state, clinically useful agents will block activated channels (e.g., quinidine), inactivated channels (e.g., amiodarone), or both (e.g., lidocaine), but they will usually have a relatively …