Molecular Mechanisms of Arrhythmias & Anti-Arrhythmin Drugs Flashcards Preview

CVPR: CV Unit I > Molecular Mechanisms of Arrhythmias & Anti-Arrhythmin Drugs > Flashcards

Flashcards in Molecular Mechanisms of Arrhythmias & Anti-Arrhythmin Drugs Deck (18):

Long QT syndrome definition

  • prolongation of the duration of the cardiac action potential that leads to ventricular arrhythmia and sudden death.
  • prolonged plateau phase in ventricular myocytes --> ventricular tachycardia called torsades de pointes --> syncope and sudden cardiac death.


Common gene defects associated w/Long-QT syndrome

  • commonly found in ion channels involved in action potential
  • LQT1=defect in IKs
  • LQT2=defect in IKr
  • LQT3=defect in INa


Molecular mechanisms associated w/Long-QT syndrome

  • mutations @ cardiac K+ channel --> reduced number channels @ plasma membrane --> decreased K+ current that helps terminate the plateau phase and return the membrane to resting potential
  • Mutations @ Na+ channel (INa) --> prevent Na+ channel inactivation (gain of function mutations) --> prolong phase 2 


Class I antiarrhythmic drug targets

  • Na+ channel blockers
  • Ia: Na+ channel blockers; slow the upstroke of the fast response (phase 0), prolong refractory period (phase 4) because depolarization (phase 2) is prolonged.
  • Ib: Na+ channel blockers; slow upstroke (phase 0) mildly, shorten depolarization (phase 2) and prolong refractory period (phase 4).
  • Ic: Na+ channel blockers; pronounced slowing of the upstroke of the fast response (phase 0), mildly prolong depolarization (phase 2).


Class II antiarrhythmic drug targets

  •  beta-adrenergic receptor blockers:
  • Ih, LTCC, and K+ current
  • reduces the rate of diastolic phase 4 depolarization in pacing cells, reduces the upstroke rate and slows repolarization.


Class III antiarrhythmic drug targets

  • K+ channel blockers
  • prolongation of fast response phase 2 and prominent prolongation of refractory period.


Class IV antiarrhythmic drug targets

  • Ca2+ channel blockers
  • slow the Ca2+ -dependent upstroke in slow response tissue (slow rise of action potential), prolong the refractory period (prolonged repolarization).


Afterdepolarization characteristics and types

  • leads to arrhythmia via inappropriate impulse initiation
  • triggered by action potential, mechanism poorly understood
  • early afterdepolarizations (EADs) & delayed afterdepolarizations (DADs)


Early afterdepolarization definition

  • appear during late phase 2 and phase 3 
  • largely dependent upon re-activation of Ca2+ channels in response to elevated [Ca2+]in 
  • prolongation of phase 2 (long QT) contributes to elevated [Ca2+]in 


Delayed afterdepolarization defintion

  • occursduring early phase 4 
  • initiated by elevated [Ca2+]in and, consequently, elevated Na+/Ca2+ exchange 
  • the Na+/Ca2+ exchanger is electrogenic: 3 Na+ move in for 1 Ca2+ moved out (Fig. 5) 
  • net increase in positive charge inside myocytes corresponds to depolarization 
  • this exchanger is called NCX, and the current it generates is INCX 


Causes of re-entry arrhythmia

  • Initiation requires two conditions:
    • Uni-directional conduction block in a functional circuit.
    • Conduction time around the circuit is longer than the refractory period.
  • Reentry occurs when there is a unidirectional block and slowed conduction through the reentry pathway.
  • After slow reentry the previously depolarized tissue has recovered and reentry into it will occur.


Use-dependent block of Na+ channels by class I antiarrhythmics

  • the block of Na+ channels by class I antiarrhythmic drugs is optimized such that Na+ channels in myocytes with abnormally high firing rates or abnormally depolarized membranes will be blocked to a greater degree than Na+ channels in normal, healthy myocytes
  • Channels must open before they can be blocked.

  • The channel must be open for the blocker to enter the pore, bind and thereby block the Na+ channel

  • Mechanism of block of cardiac Na+ channels is identical to local anesthetic block of neuronal Na+channels.


Mechanism of increased Na+ channel refractory period by class I antiarrhythmics

  • drugs have a higher affinity for the inactivated state of the Na+ channel --> these use-dependent blockers stabilize the inactivated state
  • This prolongation of channel inactivation is the fundamental mechanism of prolongation of cellular refractory period.
  • Alternative mechanism: some class I drugs prolong the refractory period by a second, entirely different mechanism. This effect is a class III action exerted by class I drugs, and probably owes to K+ channel block.
    • Prolonging phase 2 means that the myocyte membrane is depolarized for a longer period of time and therefore more Na+ channels become inactivated, making the refractory period longer.



Mechanism of arrhythmia suppression by beta-adrenergic receptor blockers

  • The action of beta-blockers is to reduce Ih current, L-type Ca2+ current, and K+ current. Reduction of Ih, ICa,L and IK reduces the rate of diastolic depolarization in pacing cells, reduces the upstroke rate and slow repolarization.
  • Thus, pacing rate is reduced (¯ automaticity), and in addition, refractory period is prolonged (¯ reentry) in the SA and AV nodal cells.
  • Beta-blockers are used to terminate arrhythmias that involve AV nodal re-entry, and in controlling ventricular rate during atrial fibrillation.


Mechanism of increased refractory period by class III antiarrhythmics

  • These drugs work by blocking cardiac K+ channels. The consequences of which are prolongation of fast response phase 2, and a prominent prolongation of refractory period (¯ reentry). Prolongation of refractory period occurs because the prolonged duration of phase 2 leads to an increased inactivation of Na+ channels.
  • This mechanism of increasing refractoriness is different from the use-dependent block mechanism of all class I drugs, but is similar to the secondary mechanism of increasing refractoriness exhibited by class Ia drugs.


Increased refractory period influence on reentrant arrhythmias

  • Terminating re-entry by slowing conduction velocity --> upstroke rate: A drug-induced reduction in upstroke rate results in a slower conduction velocity. Slower conducting action potentials are more likely to fail to propagate through a depressed region.
    • Unidirectional block can be converted to bi-directional block via this mechanism.
  • Terminating re-entry by prolonging refractory period: Prolonged refractoriness can help suppress re-entrant arrhythmias for the straightforward reason that refractory tissue will not generate an action potential, and so the re-entrant wave of excitation is extinguished.



Mechanism of decreased cardiac automaticy by antiarrbythmics 

  • Some arrhythmias are generated by rogue cardiomyocytes that generate their own action potential without getting “directions” from the action potential propagated by the pacemaker cells of the AV or SA nodes.
  • Decreasing cardiac automaticity, generally by decreasing the rate at which a cell fires, ensures that cells do not generate their own “pacemaking” activity thereby suppressing these arrhythmias.
  • Class II (beta blockers) and Class III (K+ channel blockers) drugs are particularly good at this.


Adenosine suppression of cardiac arrhythmias

  • Adenosine forms its own unclassified category of antiarrhythmic drugs.The action of adenosine is to increase a K+ current, while also decreasing both L-type Ca2+ current and Ih in SA and AV nodes.
    • Similar to beta-blockers.
    • Adenosine is NOT a beta-blocker.
    • adenosine does work via Gi-coupled receptor, which inhibits adenylyl cyclase and cAMP production (thereby ¯cAMP).
  • Adenosine induced changes in membrane currents cause a reduction in SA node and AV node firing rate as well as a reduced conduction rate in the AV node.