Anti-Arrhythmic Drugs

Question 1

Describe how class I antiarrhythmics increase Na+ channel refractory period, whether or not they prolong phase 2 of the fast response

Answer 1

•	These drugs also have a higher affinity for the inactivated state of the Na+ channel. This means that these use-dependent blockers stabilize the inactivated state. That is, they prolong the time the channel spends in its inactivated state.
•	This prolongation of channel inactivation is the fundamental mechanism of prolongation of cellular refractory period, whether with Na+ channels in non-pacemaker cells or with Ca2+ channels in SA nodal or AV nodal cells.
•	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.
o	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.

Question 2

Describe how beta-adrenergic receptor blockers help suppress arrhythmias

Answer 2

• 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.

Question 3

how class IV antiarrhythmic drugs (Ca2+ channel blockers) reduce re-entry via effects on conduction velocity through the AV node and refractory period of the AV node

Answer 3

These drugs are use-dependent blockers of L-type Ca2+ channels. Their principal effects are exerted via actions on Ca2+ channels in nodal cells, but these drugs also block Ca2+ channels in fast response myocytes. All Ca2+ channel blockers slow the Ca2+-dependent upstroke in slow response tissue (normal or abnormal), which in turn slows conduction velocity, particularly in the AV node. Just as in the case of class I blockers of Na+ channels, class IV Ca2+ channel blockers prolong refractory period and can thereby suppress re-entrant arrhythmias, particularly in the AV node

Question 4

how antiarrhythmic drugs suppress reentrant arrhythmias

Answer 4

• terminating re-entry by slowing conduction velocity leading to decreased upstroke rate
• terminating re-entry by prolonging the refractory period

Question 5

terminating re-entry by slowing conductino velocity -> dec upstroke rate:

Answer 5

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.

Question 6

Terminating re-entry by prolonging refractory period:

Answer 6

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

Question 7

Describe how some antiarrhythmic drugs can suppress arrhythmias by decreasing cardiac automaticity

Answer 7

• 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” activityàthereby suppressing these arrhythmias.
• Class II (beta blockers) and Class III (K+ channel blockers) drugs are particularly good at this.

Question 8

how adenosine can help suppress cardiac arrhythmias

Answer 8

• 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.
o Similar to beta-blockers.
o Adenosine is NOT a beta-blocker. However, 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.