arrhythmia mech 3 Flashcards
The plateau of the fast response can be prolonged either by
- increased inward current during this time (e.g., incomplete Na+ channel inactivation in LQT3) or
- by decreased outward current (e.g., smaller K+ current in LQT1, LQT2).
Ca2+ entry during the resulting prolonged QT interval can result in
- EADs (via Ca2+ channel reactivation) or
2. DADs (via NCX-dependent depolarization)
Increased sympathetic tone (startled, excited) increases the likelihood of
triggered afterdepolarizations because Ca2+ influx is enhanced by β-adrenergic receptor activity.
An EAD or DAD may be able to initiate
re-entry, resulting in torsades de pointes which can degenerate into ventricular fibrillation (disorganized contraction of ventricular muscle, poor ejection fraction) and sudden cardiac death.
Re-entry can develop from many other insults, such as:
myocardial infarction, or drugs that block K+ channels.
All class I drugs act primarily by
blocking voltage-gated Na+ channels.
class I primary action
is on fast- response cells, but they also affect slow response cells (this latter effect probably occurs because these drugs also block, less effectively, L-type Ca2+ channels).
All Na+ channel blockers
decrease conduction rate and nearly all increase refractory period; these effects underlie the clinical efficacy of the Na+ channel blockers.
Class I action results in ___ upstroke.
slowed
Class Ib drugs exhibit
- pure class I action,
- slowing upstroke and also
- decreasing action potential duration
class Ia and class Ic drugs
delay phase 3 onset by virtue of their block of K+ channels.
Na+ current block:
- lessens depolarization
- decreases phase 2 Ca2+ current
- hastens phase 3 repolarization.
K+ channel blocking action of class Ia and Ic drugs is more effective in
prolonging phase 2 than is their Na+ channel blocking action in shortening phase 2.
Class Ia Na+ channel blockers
Drugs:
- quinidine
- procainamide
- disopyramide
All class Ia drugs function to
1. slow the upstroke of the fast response (from block of Na+ channels (class I action)) 2. delay the onset of repolarization (from K+ channel block (a class III effect))
Class Ia drugs prolong refractory period, via two processes:
- via classic, use-dependent mechanism, similar to local anesthetics in action
- because depolarization (phase 2 duration) is prolonged
Quinidine
- has important effects not related to Na+ channel block
- blocks K+ channels, thereby prolonging action potential duration
- it is a vagal inhibitor (anti-cholinergic)
- it is an α-adrenergic receptor antagonist
5. these effects underscore the non-selectivity of action for antiarrhythmic drugs
Class Ib Na+ channel blockers
Drugs:
- lidocaine
- mexiletine
- phenytoin
Class Ib Na+ channel blockers
- use-dependent blockers of voltage-gated Na+ channels.
- slow upstroke (more mildly than class Ia or Ic)
- prolong refractory period
- do not prolong phase 2 of the action potential despite shortened duration of phase 2,
- refractory period increased
- fast response
- In treating arrhythmias, lidocaine is the most important of the Class Ib drugs.
Class Ic Na+ channel blockers
Drugs:
- propafenone
- flecainide
- encainide
Class Ic Na+ channel blockers
- use-dependent blockers of INa
- produce the most pronounced slowing of upstroke rate,
- mildly prolong phase 2
- net effect is powerful prolongation of tissue refractory period
- Encainide is no longer marketed: the 1989 CAST study showed increased mortality with encainide
The block of Na+ channels by class I antiarrhythmic drugs is optimized so that
Na+ channels in myocytes with abnormally high firing rates or abnormally depolarized membranes will be blocked to a greater degree than are Na+ channels in normal, healthy myocytes.
“use-dependent block”
preferentially target
(1) over-active cells or
(2) cells that have abnormally depolarized resting potentials
mechanism of use-dependent ion channel block
(1) use-dependent channel block = channel must open (be used, or activated) before it can be blocked
(2) the channel must be open for the blocker to enter the pore, bind and thereby block the Na+ channel
(3) mechanism of block of cardiac Na+ channels is identical to local anesthetic block of neuronal Na+
channels.
Mechanism of local anesthetic block of Na+ channels.
- Charged, hydrophilic drug may enter and exit the channel when the channel is in the open state, and not when the channel is either closed or inactivated.
- Neutral, hydrophobic drug, at a much slower rate, can reach the local anesthetic site even when the channel is closed or inactivated.
Use-dependent blockers include
- class I Na+ channel blockers
2. class IV Ca2+ channel blockers.
