Anti-Arrythmic Drugs Flashcards
what are the 3 goals of anti-arrhythmic therapy?
- decrease automaticity of pacemaker or non-pacemaker cells
- disrupt reentrant pathways
- eliminate triggered activity
why are action potentials slower in the SA and AV node as compared to other regions of the heart?
phase 0 is driven by calcium channels, rather than sodium channels
what is the action of Class 1 vs 2 vs 3 vs 4 antiarrhythmic drugs?
Class 1: sodium channel blockade
- 1A: prolong AP
- 1B: shorten AP, dissociate rapidly
- 1C: minimal AP effects, dissociate slowly
Class 2: sympatholytics (beta blockers)
Class 3: prolong AP by blocking Phase 2 K+ current
Class 4: calcium channel blockade
Drug X is found to block phase 2 potassium current in cardiomyocytes, prolonging the duration of action potential. What class of antiarrhythmic drugs would this fit into?
Class 3: block K+ current in phase 2, prolonging AP
A new drug is developed to treat arrhythmia that works by blocking Na+ channels with minimal effect on the duration of the action potential. Which class of antiarrhythmics does this fit into?
this drug fits in Class 1C - block sodium channels with minimal effect on AP
Class 1: sodium channel blockade
- 1A: prolong AP
- 1B: shorten AP, dissociate quickly
- 1C: minimal AP effects, dissociate slowly
Into which class of antiarrhythmics do verapamil and diltiazem fit?
these are calcium channel blockers
Class 4 antiarrhythmic drugs block calcium current
what is the mechanism of action of Class 1A antiarrhythmic drugs?
Class 1A (Procainamide): bind Na+ and K+ channels with intermediate kinetics and moderate affinity —> slow upstroke of AP to prolong AP duration
prolonged refractory period —> reentrant loop is closed because retrograde pathway has been made unavailable —> termination of arrhythmia
what kind of drug is Procainamide and how does it work?
Class 1A antiarrhythmic: bind Na+ and K+ channels with intermediate kinetics and moderate affinity —> slow upstroke of AP to prolong AP duration
prolonged refractory period —> reentrant loop is closed because retrograde pathway has been made unavailable —> termination of arrhythmia
what toxicities are associated with Procainamide? (1 class associated, 1 specific)
Procainamide: Class 1A antiarrhythmic - blocks sodium channel to prolong AP and refractory period (to block reentrant loop)
however, prolongation of AP increases risk of torsade de pointes, syncope, new arrhythmias
long-term procainamide also causes symptoms resembling lupus erythematosus
what is the mechanism of action of Class 1B antiarrhythmic drugs?
Class 1B (lidocaine): block activated and inactivated Na+ channels —> shorten AP and refractory period —> allows activated K+ channels to repolarize the cell faster
state dependent block - binds cells that are already depolarized (such as ischemic tissue during MI that doesn’t repolarize well)
rapid kinetics ensures the cell recovers before the next AP (drug has no effect on conduction)
preferentially targets cells with long AP - particularly useful for targeting ventricular tissue (slower conduction)
what kind of drug is lidocaine and how does it work?
Class 1B antiarrhythmic: block activated and inactivated Na+ channels —> shorten AP and refractory period —> allows activated K+ channels to repolarize the cell faster
state dependent block - binds cells that are already depolarized (such as ischemic tissue during MI)
rapid kinetics ensures the cell recovers before the next AP (drug has no effect on conduction)
preferentially targets cells with long AP - particularly useful for targeting ventricular tissue (slower conduction)
describe how Class 1B antiarrhythmics such as lidocaine induce “state dependent block”
Class 1B: block activated and inactivated Na+ channels —> shorten AP and refractory period —> allows activated K+ channels to repolarize the cell faster
state dependent block = binding is dependent on the voltage of the cell - binds cells that are already depolarized (like ischemic tissue during MI which doesn’t repolarize well)
preferentially targets cells with long AP - particularly useful for targeting ventricular tissue (slower conduction)
to which cardiac cells do Class 1B antiarrhtymics such as lidocaine target best?
Class 1B: block activated and inactivated Na+ channels —> shorten AP and refractory period —> allows activated K+ channels to repolarize the cell faster
preferentially targets cells with long AP - particularly useful for targeting ventricular tissue (slower conduction), and ineffective for supraventricular tachycardias or atrial fib/flutter
state dependent block - binds cells that are already depolarized
what kind of toxicities are associated with Class 1B antiarrhythmics, such as lidocaine?
Paresthesia (pins&needles), tremor, nausea, lightheaded, slurred speech, convulsions
recall Class 1B antiarrhythmics block activated and inactivated Na+ channels —> shorten AP and refractory period —> allows activated K+ channels to repolarize the cell faster
how are class 1B antiarrhythmics such as lidocaine administered?
Class 1B: block activated and inactivated Na+ channels —> shorten AP and refractory period —> allows activated K+ channels to repolarize the cell faster
extensive first-pass hepatic metabolism, given by IV (short t1/2 of 1-2 hours)
how are class 1B antiarrhythmics such as lidocaine used? (3)
Class 1B: block activated and inactivated Na+ channels —> shorten AP and refractory period —> allows activated K+ channels to repolarize the cell faster
exhibit state-dependent block for cells already depolarized - therefore, used to treat arrhythmias caused by acute MI (recall ischemic tissue will continue to depolarize)
also preferentially targets cells with long AP - therefore, useful for termination of ventricular tachycardia/prevention of ventricular fibrillation (slower conducting)
also used for digitalis-induced arrhythmias
what is meant by “use-dependent” or “state-dependent” drugs? (antiarrhythmics)
drugs that are “use/state” dependent readily bind to activated channels (phase 0) or inactivated channels (phase 2) but poorly to rested channels
these drugs block electrical activity when there is either fast tachycardia or significant loss of resting potential
channels in normal cells will lose the drug during the resting portion of the cycle, but cells that are chronically depolarized will recover from the block very slowly if at all —> allows drug to target abnormal activity (such as ectopic pacemaker)
ex: Lidocaine (Class 1B)
compare how Class 1A, 1B, and 1C antiarrhythmic drugs affect sodium channels and the duration of the AP
Class 1B: mild Na+ channel block, shorten AP (state/use dependent)
Class 1A: moderate Na+ channel block, prolong AP (prolong repolarization/ increase effective refractory period)
Class 1C: marked Na+ channel block, doesn’t alter duration of AP
what is the mechanism of action of Class 1C antiarrhythmic drugs?
Class 1C (flecainide): block Na+ channels with slow dissociation (unblocking) kinetics - slowww depolarization
do not alter duration of AP except in AV node and bypass tracts
what kind of drug is flecainide, and what is its mechanism of action?
Class 1C antiarrhythmic (flecainide): block Na+ channels with slow dissociation (unblocking) kinetics - slowww depolarization
do not alter duration of AP except in AV node and bypass tracts
what toxicity is associated with Class 1C antiarrhythmic drugs such as flecainide?
Class 1C: block Na+ channels with slow dissociation kinetics, do not alter duration of AP except in AV node and bypass tracts
toxicity provokes/exacerbates arrhythmias - acceleration of ventricular rate in patients with atrial flutter, increased frequency of episodes of re-entrant v-tach, etc
can cause heart failure in patients with heart abnormalities, not preferred for patients with MI (may increase mortality)
what is the therapeutic use of Class 1C antiarrhythmic drugs such as flecainide?
Class 1C: block Na+ channels with slow dissociation kinetics, do not alter duration of AP except in AV node and bypass tracts
useful for treating supraventricular arrhythmias and pharmacological conversion of atrial flutter
beta blockers decrease the slop of phase ___ depolarization by blocking the ____current
beta blockers decrease the slope of phase 4 depolarization by blocking the funny (slow Na+) current
what is the mechanism of action of propranolol and esmolol?
“-olol” = beta blocker (Class 2 antiarrhythmics)
lower cAMP —> reduced Na+ (funny current) and Ca2+ currents —> slower depolarization —> decreased oxygen demand
this can suppress abnormal pacemakers, especially in the AV node
to what class of antiarrhythmic drugs do propranolol and esmolol belong to? how do they differ in their binding preferences?
Class 2 antiarrhythmic beta-blockers
propranolol: non-selective, also exhibits Na+-channel blocking
esmolol: beta1-selective with very short t1/2 - effective for controlling ventricular rate in atrial flutter/fib
This beta-blocker (Class 2 antiarrhythmic) is selective for beta1 adrenergic receptors, and has a very short half life (~9min). Therefore, it is very effective in controlling ventricular rate during atrial flutter or fibrillation, particularly following cardiac surgery. What is?
esmolol
what is the mechanism of Ivabradine?
Ivabradine: blocks funny Na+ current (phase 4 depolarization) in SA node to reduce HR without affecting myocardial contractility
use-dependent drug: binds when channels are active or inactive, not while they are resting
good for patients with low ejection fraction heart failure
side effects: A-fib, bradycardia, conduction defects
IVA[bradine] was a FUNNY comedian but was BLOCKED by a Serious Audience
what is the mechanism of action of Class 3 antiarrhythmics?
class 3: block K+ channels (phase 3) to prolong AP —> increased refractory period
most are reverse use-dependent: AP prolongation occurs most at slow rates —> increased risk of torsade de pointes
to what class of antiarrhythmic drugs do sotalol and ibutilide belong?
class 3: block K+ channels (phase 3) to prolong AP —> increased refractory period
reverse use-dependent: AP prolongation occurs most at slow rates —> increased risk of torsade de pointes
why is amiodarone usually preferred over other Class 3 antiarrhythmics such as sotalol and ibutilide?
class 3: block K+ channels (phase 3) to prolong AP —> increased refractory period
most are reverse use-dependent: AP prolongation occurs most at slow rates —> increased risk of torsade de pointes
EXCEPT amiodarone - NOT reverse use-dependent, therefore safer drug
why are Class 3 antiarrhtyhmic drugs (sotalol, ibutilide) not usually preferred? (what danger is associated with them?)
class 3: block K+ channels (phase 3) to prolong AP —> increased refractory period
most are reverse use-dependent: AP prolongation occurs most at slow rates —> increased risk of torsade de pointes, early afterdepolarizations (EADs), long QT syndrome
[amiodarone does not exhibit this binding phenomenon - considered much safer]
which antiarrhythmic drug is considered most efficacious, and to what does it bind/block?
amiodarone: classified as Class 3 (phase 3 K+ channel blocker —> prolonged AP), but also blocks Na+ and Ca2+ channels and beta adrenoreceptors (decrease phase 4 depolarization slope —> reduced automaticity)
prolongs duration of AP over wide range of heart rates (NOT reverse-use dependent like other Class 3), prolongs QT interval
slows HR and AV conduction via adrenergic/calcium blockage
because of wide blocking effects, there is very low risk of causing new arrhythmias
what toxicities are associated with amiodarone? (3)
amiodarone: classified as Class 3 (phase 3 K+ channel blocker), but also blocks Na+ and Ca2+ channels and beta adrenoreceptors —> prolongs duration of AP over wide range of heart rates
wide blocking effects reduce risk of inducing new arrhythmias, but there are several other toxicities:
1. pulmonary fibrosis
2. microcrystalline deposits in cornea and skin
3. thyroid dysfunction - inhibits conversion to T4 to T3 (contains iodine - amIODarone)
*also interacts with warfarin and digoxin
which Class 3 antiarrhythmic drug can reduce reentry AND automaticity?
amiodarone: classified as Class 3 (phase 3 K+ channel blocker —> prolonged AP), but also blocks Na+ and Ca2+ channels and beta adrenoreceptors (decrease phase 4 depolarization slope —> reduced automaticity)
to what class of antiarrhythmic drugs do verapamil and diltiazem belong, and how do they work?
Class 4: block both activated and inactivated L-type Ca2+ channels
decreased phase 4 depolarization slope —> decreased automaticity
decreased phase 0 slope —> decreased conduction velocity, increased effective refractory period
Verapamil and diltiazem also cause peripheral vasodilation
what is the mechanism of Class 4 antiarrhythmic drugs?
Class 4: block both activated and inactivated L-type Ca2+ channels
decreased phase 4 depolarization slope —> decreased automaticity
decreased phase 0 slope —> decreased conduction velocity, increased effective refractory period
Verapamil and diltiazem also cause peripheral vasodilation
what is the therapeutic use of Class 4 antiarrhythmic drugs (verapamil, diltizem)? what are the associated toxicities?
Class 4: block both activated and inactivated L-type Ca2+ channels —> decreased automaticity, decreased conduction velocity, increased effective refractory period
prevent AVNRT
toxicities: atrioventricular block, hypotension, constipation, peripheral edema (Verapamil and diltiazem also cause peripheral vasodilation)
contraindicated for use with beta blockers (higher risk of heart failure) and patients with Wolff-Parkinson-White syndrome
what is the mechanism of action of adenosine?
adenosine: nucleoside with VERY fast t1/2 (<10s)
- activates inward rectifier K+ current
- inhibits Ca2+ and funny (Na+) current
—> hyperpolarization, inhibited AV node conduction/ increased AV node refractory period
when is adenosine used therapeutically?
adenosine (nucleoside): activates inward rectifier K+ current, inhibits Ca2+ and funny (Na+) current —> hyperpolarization, inhibited AV node conduction/ increased AV node refractory period
DOC for conversion of paroxysmal supraventricular tachycardia to sinus rhythm
VERY fast t1/2 (<10s)
how can magnesium be used in anti-arrhythmic therapy?
Mg2+: co-factor for Na+/K+ ATPase and natural antagonist of Ca2+ channels
hypo-magnesium can therefore contribute to arrhythmia
can be used for digitalis-induced arrhythmias, supraventricular arrhythmias, Torsade de Pointe
