ass I (Na + channel blockers) 1A: procainamide, quinidine (no longer recommended) 1B: lidocaine 1C: flecainide, propafenone ass II (-blockers) non-selective: propranolol selective: metoprolol ass III (K + channel blockers) amiodarone, sotalol, dofetilide, ibutilide, (azim ass IV (Ca 2+ channel blockers) verapamil, diltiazem hers: adenosine digoxin magnesium sulfate Arrhythmias and Antiarrhythmic Drugs AJ Davidoff ‘09 atment Guidelines Medical Letters June 2007
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Class I (Na + channel blockers) 1A: procainamide, quinidine (no longer recommended) 1B: lidocaine 1C: flecainide, propafenone Class II ( -blockers) non-selective:
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Class I (Na+ channel blockers)1A: procainamide, quinidine (no longer recommended)1B: lidocaine1C: flecainide, propafenone
Class II (-blockers)non-selective: propranololselective: metoprolol
Class III (K+ channel blockers)amiodarone, sotalol, dofetilide, ibutilide, (azimilide)
Class IV (Ca2+ channel blockers)verapamil, diltiazem
Others:adenosinedigoxinmagnesium sulfate
Arrhythmias and Antiarrhythmic Drugs
AJ Davidoff ‘09Treatment Guidelines Medical Letters June 2007
What happens to QRS interval if conduction through heart is slowed?
What happens to QT interval if APD is prolonged?
What happens to PR interval if AV nodal conduction is prolonged?
ACh M2 ACh receptors
IK+ , ICa2+, If
NE 1-AR
If
ICa2+ (L-type)
Sherwood Fig 9-24
ACh = acetylcholineM-ACh = muscarinic AChNE = norepinephrine-AR = adrenergic receptorI = whole cell current
Nodal cell firing rate control
Fast Action Potentials
FastNa+ current(INa)
IKr
IKs
Outward K+ currents(delayed rectifiers)
ITO = transient outward K+ current
ITO
Nattel and Carlsson 2006 Nature Reviews; Drug Discovery 5:1034-1049
• 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
Boron Fig. 20-14
Afterdepolarizations(due to abnormal intracellular Ca2+ regulation)
EADs prolonged APD
Clinical arrhythmia: e.g., torsades de pointesdue to: long QT syndrome
genetic defects (HERG)diseasedrug-induced
EADsDADs
‘Delayed’
DADs HR or [Ca2+]i
Clinical arrhythmia: e.g., Ca2+ overloaddue to: digoxin or phosphodiesterase (PDE) inhibitor toxicity
Brenner Box 14-1
Boron Fig. 20-15
If afterdepolarization is large can trigger PVCIf 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
RepolarizationClass Phase O Depression
Action Potential Duration
IA Moderate Prolonged Increased
IB Weak Shortened Decreased
IC Strong No effect No effectBrody Table 14-3
Class INa+ channel blockers
“use-dependent block”
Na+ channels inactivated
resting/closed
Vmax APD
Quinidine (oral)prototype Class IArarely used anymore
Procainamide (oral or IV)less (-) on vagus
Class 1A Block Na+ channels and K+ channels
No longer drugs of choiceIndications: (alternative DOC)•Atrial fibrillation or flutter•SVT•Ventricular fib or tachycardia
Toxicity includes:•Prolongs APD too much•Antimuscarinic effects(may inhibit vagus n.)
What might happen?
Brenner Fig 4-2
Class 1B Block inactivated Na+ channels
Indications:•Ventricular tachycardia •V. re-entrant loops? (PVCs)•during surgeryNo effect on atrial cells (with short APD)
Toxicity:•Relatively safe (hemodynamically)but efficacy is relatively low
Rapidly binds to depolarized membranes(e.g., during ischemia)
Rapidly dissociates from resting cells
Vmax
APD
Lidocaine (IV only)
Flecainide mortality after acute MI(CAST; cardiac arrhythmia suppression trial)
Vmax
APD
Class 1C Block open, closed and inactivated Na+ channels
Indications: (alternative drug of choice)Sustained ventricular tachycardiaParoxysmal A. fib or SVTonly with no signs of structural heart disease (e.g., ischemia, hypertrophy)
Very slow off rates, not selective for fast rhythms
Toxicity:•Slows conduction (Vmax) too much•Can cause re-entrant loops(especially v. arrhythmias)
Slow rate of depolarization of phase 4 (pacemaker potential)
Indicated for:Acute/chronic A. Fib and FlutterLong term SVT
IV or PO
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 HRHR, A-V conduction velocity, (may contractility)
Indicated for:Acute/chronic A. Fib and FlutterAcute/chronic SVT
Verapamil (more effect on A-V conduction)
Dihydropyridines (DHPs) have little antiarrhythmic activity
Diltiazem (more effect on SA nodal cells)
Block delayed rectifier channel (IKr)(as well as other channels)
*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 potentialpartially inactivates Na+ channels in fast fibers,
reduces excitability, slows conduction
High affinity to vagus nerve (particularly at the AV node), increases vagal toneslows AV nodal conduction
Binds to, and inhibits Na+/K+ ATPase pumps in other tissues (non-cardiac toxicities include visual distrubances -yellow hues), with highest affinity to cardiac and vagal nerve.
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:AcuteDC 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 arrhythmiasAdenosine (IV only)VerapamilDiltiazemEsmolol (IV only)Ibutilide (IV only)Dofetilide (oral only)
Drug therapy for ventricular arrhythmiasProcainamide (not preferred)Lidocaine (IV only)Flecainide or Propafenone (oral, not approved for IV in US)SotalolAmiodarone