VPT 311: General and Systemic Veterinary Pharmacology (2+1)

ACTIONS OF SODIUM CHANNEL BLOCKERS

• The enhancement of sodium channel block seen in rapidly depolarizing tissue has been termed "use-dependent blockade" and is thought to be responsible for the efficacy of these drugs in slowing and converting tachycardias with minimal effects on conduction in normal tissues stimulated at normal physiological rates.
• A theory to explain use-dependent blockade, termed the modulated receptor theory (MRT), has been proposed and used to explain many characteristics of the sodium channel blockers. 
• This theory is based on a three-state model for the sodium channel originally proposed by Hodgkin and Huxley:
• The three normal channel states are: Resting, Open (or Activated), and Inactive
  • Under normal resting conditions, the sodium channels are predominantly in the Resting state and are nonconducting.
  • When the membrane is depolarized, the sodium channels Open and conduct sodium, resulting in the inward sodium current that makes the major contribution to phase 0 of the action potential
  • The inward sodium current rapidly decays as channels move to the Inactive state
  • The return of the Inactive channel to the Resting state is termed reactivation and is voltage- and time-dependent.
  • The theory assumes that sodium channel blocker drugs bind different channel states with different affinities and that drug binding alters the transition rates between different states.
  • Drug binding results in transitions to R*, O*, and I* channel states. These "*" states have different transition rates between states than the normal channel states.
  • The most clinically useful drugs would have affinity for the Open and/or Inactive state, and thereby exhibit use-dependent blockade.
  • Drugs with high affinity for the Resting state would be toxic.