Arrhythmias and Antiarrhythmic Drugs
Class I (Na+ channel blockers)
1A: procainamide, quinidine (no longer recommended)
1B: lidocaine
1C: flecainide, propafenone
Class II (-blockers)
non-selective: propranolol
selective: metoprolol
Class III (K+ channel blockers)
amiodarone, sotalol, dofetilide, ibutilide, (azimilide)
Class IV (Ca2+ channel blockers)
verapamil, diltiazem
Others:
adenosine
digoxin
magnesium sulfate
Treatment Guidelines Medical Letters June 2007
AJ Davidoff ‘09
What happens to PR
interval if AV nodal
conduction is prolonged?
What happens to QRS
interval if conduction
through heart is slowed?
What happens to QT
interval if APD is
prolonged?
ACh  M2 ACh receptors
IK+ , ICa2+, If
NE  1-AR
 If
 ICa2+ (L-type)
Nodal cell firing
rate control
Sherwood Fig 9-24
ACh = acetylcholine
M-ACh = muscarinic ACh
NE = norepinephrine
-AR =  adrenergic receptor
I = whole cell current
ITO
Fast Action Potentials
IKr
Fast
Na+ current
(INa)
ITO = transient outward
K+ current
Outward K+ currents
(delayed rectifiers)
IKs
Optional information
inward positive current
NCX = sodium/calcium exchanger
outward positive current
IKACh = ACh K+ current
ICaL = L type Ca2+ current
INa = Na+ current
transient outward K+ current
ultra rapid K+ current
current activation
rapid K+ current
slow K+ current
‘funny’ current
Nattel and Carlsson 2006 Nature Reviews; Drug Discovery 5:1034-1049
Most arrhythmias result from altered conduction
and/or automaticity
Conduction abnormalities
Typically arise from partial depolarization due to injury (e.g.,
over stretch, ischemia) or abnormal anatomy
Partial or complete block
Accessory conduction pathways
e.g., Wolff-Parkinson-White (WPW) Syndrome
Re-entry
Fibrillation (multi-re-entry loops)
Automaticity abnormalities
Originating from nodal cells or ectopic loci
Depolarization-dependent automaticity:
• Changes in sinus node firing rate
• Prolonged action potential duration (APD)
• Early afterdepolarizations
may lead to premature ventricular contractions (PVCs)
or multiple extrasystoles
• Long QT syndrome
may lead to Torsades de Pointes
In terms of cellular target and
action potential (AP) duration, what
strategy would you use for:
Rapid nodal firing?
Supraventricular tachycardias?
Premature ventricular contractions
(PVCs)?
Ectopic ventricular arrhythmias?
Ventricular tachycardias?
• Slow SA or AV nodal
depolarizations
• Slow atrial cell
conduction
• Slow AV conduction
• Slow ventricular
conduction
• Prolong ventricular
AP duration
• Shorten ventricular
AP duration
Strategies to convert fibrillation/tachycardia
For acute atrial fibrillation or supraventricular tach.
Target atrial muscle cells or AV nodal tissue
hyperpolarize membrane
 conduction velocity AV node
Drugs  adenosine
Ca2+ channels
-blockers
digoxin
(nodal cell)
For V. fib. or V. tach.
Target ventricular muscle cells
conduction velocity
(Vmax)
e.g., block Na+ channels
(Class I drugs)
AP duration (APD)
(refractory period)
e.g., block K+ channels
(now typically preferred over Class I drugs)
For Maintenance
(preventing re-occurrence)
Slow AV nodal conduction or frequency of firing
Drugs:
digoxin
Ca2+ channel blockers
-blockers
Na+ channel blockers are contraindicated for:
•long-term therapy
•patients with structural defects (e.g., fibrosis, WPW)
Cellular models of arrhythmias
Increased automaticity:
 sympathetic activity (e.g., NE or Epi)
 vagal activity (e.g., drug-induced, quinidine)
Brenner Box 14-1
TP = threshold potential
MDP = maximum diastolic potential
G&H Fig 10-1
Ectopic pacemaker activity
Often due to partial ischemia,
resulting in a more postive resting membrane potential
normal
Na+ channels inactivated
-40mV
-60mV
-90mV
Vmax
Conduction
Closed
Open
Closed
(ready to open)
Resting potential
(-90 mV)
Threshold and
activation potentials
(-50 mV to +30mV)
(unable to open)
Inactivation potentials
(+30 mV to -90mV)
Sherwood Fig 4-7
see also Katzung Fig 14-2
Abnormal Impulse Conduction
Katzung Fig 14-8
(hypothetical model)
Normal conduction
Ischemia
Unidirectional block
Re-entry loop
Abnormal Impulse Conduction
• Ischemic or fibrotic areas slow conduction
• Ischemia partially depolarizes resting membrane
potential, inactivates some Na+ channels
• Slow rate of phase 0 (i.e., rapid depolarization phase)
results in slow conduction through heart
Re-entry loops
A model for unidirectional block
Boron Fig. 20-14
Afterdepolarizations
(due to abnormal intracellular Ca2+ regulation)
‘Delayed’
EADs
DADs
EADs  prolonged APD
DADs  HR or [Ca2+]i
Clinical arrhythmia:
e.g., torsades de pointes
due to: long QT syndrome
genetic defects (HERG)
disease
drug-induced
Clinical arrhythmia:
e.g., Ca2+ overload
due to: digoxin or
phosphodiesterase (PDE)
inhibitor toxicity
Brenner Box 14-1
Boron Fig. 20-15
If afterdepolarization is large can trigger PVC
If sustained, can trigger “run” of extra systoles
Nature of Antiarrhythmic Drugs
• All have potential of being pro-arrhythmic:
Toxicity may  depress automaticity or
depress conduction velocity
Many are metabolized by cytochrome P450 enzymes
(induced/inhibited, “poor metabolizers”)
Most have a low TI
(especially Na+ channel blockers)
• Most show ‘use- (or frequency-) dependent block’
higher affinity for membranes depolarizing frequently
Advantage, because drugs may be selective for abnormally
fast rhythms
Generally classified based on primary mechanism of action
Class I
Na+ channel
blockers
Na+ channels inactivated
“use-dependent block”
resting/closed
Class
Phase O
Depression
Repolarization
Action Potential
Duration
IA
IB
IC
Moderate
Weak
Strong
Prolonged
Shortened
No effect
Increased
Decreased
No effect
Brody Table 14-3
Class 1A Block Na+ channels and K+ channels
Vmax
APD
No longer drugs of choice
Indications: (alternative DOC)
•Atrial fibrillation or flutter
•SVT
•Ventricular fib or tachycardia
What might happen?
Toxicity includes:
•Prolongs APD too much
•Antimuscarinic effects
(may inhibit vagus n.)
Quinidine (oral)
prototype Class IA
rarely used anymore
Brenner Fig 4-2
Procainamide (oral or IV)
less (-) on vagus
Class 1B Block inactivated Na+ channels
Rapidly binds to depolarized membranes
(e.g., during ischemia)
Rapidly dissociates from resting cells
Vmax
APD
Indications:
•Ventricular tachycardia
•V. re-entrant loops? (PVCs)
•during surgery
No effect on atrial cells
(with short APD)
Toxicity:
•Relatively safe (hemodynamically)
but efficacy is relatively low
Lidocaine (IV only)
Class 1C Block open, closed and inactivated Na+ channels
Very slow off rates, not selective for fast rhythms

Vmax
APD

Indications: (alternative drug of choice)
Sustained ventricular tachycardia
Paroxysmal A. fib or SVT
only with no signs of structural heart
disease (e.g., ischemia, hypertrophy)
Toxicity:
•Slows conduction (Vmax) too much
•Can cause re-entrant loops
(especially v. arrhythmias)
Flecainide
Propafenone (also ~-blocker)
Flecainide   mortality after acute MI
(CAST; cardiac arrhythmia suppression trial)
Class II (-blockers)
Block -AR on nodal and muscle
cells:
HR
A-V conduction
(may contractility)
Slow rate of depolarization of
phase 4 (pacemaker potential)
Indicated for:
Acute/chronic A. Fib and Flutter
Long term SVT
Brenner Fig 4-4
Propranolol (non-selective)
IV or PO
Metoprolol (1 selective)
Some may be cardioprotective after acute MI
Class IV (Ca2+ channel blockers: cardioselective)
• Inhibit L-type Ca2+ channels
• Effectively raise threshold potential to fire an AP
• Use-dependent block, therefore more effective with fast HR
• HR, A-V conduction velocity, (may contractility)
Indicated for:
Acute/chronic A. Fib and Flutter
Acute/chronic SVT
Verapamil (more effect on A-V conduction)
Diltiazem (more effect on SA nodal cells)
Dihydropyridines (DHPs) have little antiarrhythmic activity
Class III (K+ channel blockers)
Block delayed rectifier channel (IKr)
(as well as other channels)
APD
Indicated for SVT, A. fib, V. fib and
V. tach
Amiodarone (DOC)
also Na+, Ca2+ channel blocker
and -blocker
Sotalol
also -blocker (non-selective)
Pure Class III blockers
Dofetilide (PO only)
risk of torsades de pointes Ibutilide (IV only)
(not with amiodarone)
Azimilide (blocks IKr and IKs)
Others Antiarrhythmic Drugs
Digoxin
Inhibits Na/K ATPase
Slows A-V conduction (through increasing vagal tone)
Increases refractory period
Indicated for:
Toxicity:
A. Fib with fast ventricular rate* (and CHF)
complete heart block (narrow TI)
may precipitate Ca2+ overload (e.g., torsades)
*approaches are now focusing on controling heart rate (with warfarin),
rather than rhythm (G. Wyse, AHA website updated 5/08). Thus digoxin is
used much less frequently now.
Digoxin:
Cardiac effects:
Increases intracellular [Na+], increases in Ca2+ (via NCX)
more Ca2+ to trigger SR Ca2+ release,
increases contraction (positive inotropic effects, discussed in heart
failure lecture)
Decreases intracellular [K+], depolarizes membrane potential
partially inactivates Na+ channels in fast fibers,
reduces excitability, slows conduction
High affinity to vagus nerve (particularly at the AV node),
increases vagal tone
slows AV nodal conduction
Binds to, and inhibits Na+/K+ ATPase pumps in other tissues (noncardiac toxicities include visual distrubances -yellow hues), with
highest affinity to cardiac and vagal nerve.
Adenosine
Opens K+ channels  hyperpolarizes membrane
(also blocks Ca2+ channels)
Selective for coronary arteries and atrial muscle cells
(not ventricular myocytes)
Slows SA nodal firing
Slows A-V conduction
Very short T1/2 (seconds)
Indicated for ‘cardioconversion’
Magnesium
Inhibits Ca2+ influx through L-type Ca2+ channels
Indicated for:
Drug-induced torsades
Digoxin-induced ventricular arrhythmias
Triggered activity due too much intracellular Ca2+
[Ca2+]i 
Mg2+
(for torsades)
Na/Ca exchange

(3Na+(in): 1Ca2+(out))
Open L-type Ca2+ channels
[Na+]i
(depolarize membrane)
Effects of serum potassium appear paradoxical: contrary to what
would be predicted by changes in electrochemical gradient
Hyperkalemia
• Reduces action potential duration (APD)
• Slows conduction
• Decreases pacemaker rate and arrhythmogenesis
(leading to bradiacardia and perhaps asytole)
Hypokalemia (more detrimental than hyperkalemia)
• Prolongs APD
• Increases pacemaker rate and arrhythmogenesis
(increasing risk of ventricular fibrillations)
• Increases sensitivity to K+ channel blockers
resulting in accentuated APD prolongation with risk of
Torsades de Pointes
Katzung 2009 p. 228
Ranolazine
Recently approved for chronic stable angina
Prolongs QT interval
(maybe by inhibiting late Na+ current or delayed K+ rectifier current)
In terms of cellular target and
action potential duration, what
strategy would you use for:
Rapid nodal firing?
Na+ channel blockers
-blockers
K+ channel blockers
Ca2+ channel blockers
Supraventricular tachycardias?
Premature ventricular contractions
(PVCs)?
Ventricular tachycardias?
Atrial fibrillation or flutter:
Acute
•Rate control: (IV) verapamil, diltiazem, -blockers, digoxin
Chronic
•Rate control: verapamil, diltiazem, -blockers, digoxin
•Maintenance of sinus rhythm:
amiodarone, sotalol, flecainide, propafenone, dofetilide
Other SVTs:
Acute
• (vagotonic maneuvers, e.g., carotid sinus massage)
• (IV) adenosine, verapamil, diltiazem
Chronic
•-blockers, verapamil, diltiazem, flecainide, propafenone,
amirodarone, sotalol, digoxin
According to Treatment Guidelines, Medical Letters 2007
PVCs or non-sustained V. tach:
Asymptomatic
• no therapy
Symptomatic (flecainide is contraindicated post-MI)
• -blockers (post MI improves mortality rates)
Sustained V. tach. or V. fib:
Acute
DC cardioversion is safest
• amiodarone
Chronic
• Implantable cardiac defribillator (ICD) (NEJM Jan 20, 2005)
• amiodarone, plus a -blocker
According to Medical Letters
Alternative Classification based on target
Drug therapy for supraventricular arrhythmias
Adenosine (IV only)
Verapamil
Diltiazem
Esmolol (IV only)
Ibutilide (IV only)
Dofetilide (oral only)
Drug therapy for ventricular arrhythmias
Procainamide (not preferred)
Lidocaine (IV only)
Flecainide or Propafenone (oral, not approved for IV in US)
Sotalol
Amiodarone
LH Opie 2004