Use(Rate)-Dependent Blockade by Channel Blockers

• An ideal antiarrhythmic drug should target ectopic pacemakers and rapidly depolarizing tissue to a greater extent than normal tissues of the heart

• Many of the sodium (Class I) and calcium (Class IV) channel blockers have this property because they preferentially block sodium and calcium channels in depolarized tissues

• Enhanced sodium or calcium channel blockade in rapidly depolarizing tissue has been termed "use-dependent blockade" and is thought to be responsible for increased efficacy in slowing and converting tachycardias with minimal effects on tissues depolarizing at normal (sinus) rates

• Many of the drugs that prolong repolarization (Class III drugs, potassium channel blockers) exhibit negative or reverse rate-dependence

  • These drugs have little effect on prolonging repolarization in rapidly depolarizing tissue

  • These drugs can cause prolongation of repolarization in slowly depolarizing tissue or following a long compensatory pause, leading to repolarization disturbances and torsades de pointes

Modulated Receptor Theory (MRT)

• 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 and calcium channel blockers

• The 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 (polarized) 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 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 which 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

  • Additive and synergistic interactions between drugs that prolong action potential duration and those that have high affinity for the Inactive state have been predicted (e.g.- lidocaine and quinidine); combination therapy in experimental settings using low doses of each drug has indicated greater efficacy and fewer side effects than high doses of the individual drugs

Guarded Receptor Theory

• An alternative theory for channel blockers is termed the "guarded receptor" model and it assumes that drug binding to different channel states is regulated by access or egress of drug to drug binding sites on the channel

• This theory may be more useful in analyzing the properties of ionizable channel blockers whose access to the intracellular drug-binding sites is pH-dependent

• Other potentially useful models to predict the actions of channel blockers are based on the size, pK, and solubility of drugs

Examples of Channel Blockers Showing Use-Dependent Blockade

• Quinidine, procainamide, and disopyramide preferentially bind to the Active state of the sodium channel

• Amiodarone binds almost exclusively to the Inactive state of the sodium channel

• Lidocaine binds Active and Inactive states of the sodium channel

• Verapamil and diltiazem bind Active and Inactive states of the calcium channel

• Quinidine, bretylium, and sotalol show reverse use-dependence towards potassium channel blockade

Category: Pharmacology Notes , Physiology Notes