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

ultra rapid K+ current

rapid K+ currentslow K+ current

transient outward K+ current

‘funny’ current

inward positive current

outward positive currentNCX = sodium/calcium exchanger

IKACh = ACh K+ current

ICaL = L type Ca2+ currentINa = Na+ current

current activation

Optional information

Pur

k in j

e fib

er

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 blockAccessory conduction pathways

e.g., Wolff-Parkinson-White (WPW) Syndrome

Re-entryFibrillation (multi-re-entry loops)

Automaticity abnormalitiesOriginating 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 adenosineCa2+ channels-blockersdigoxin

(nodal cell)

For V. fib. or V. tach.Target ventricular muscle cells

AP duration (APD) (refractory period) e.g., block K+ channels

(now typically preferred over Class I drugs)

conduction velocity (Vmax) e.g., block Na+ channels

(Class I drugs)

For Maintenance(preventing re-occurrence)

Slow AV nodal conduction or frequency of firingDrugs: 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 potentialMDP = maximum diastolic potential

G&H Fig 10-1

Na+ channels inactivated

-60mV -40mV

Ectopic pacemaker activity

-90mV

normal

Often due to partial ischemia, resulting in a more postive resting membrane potential

VmaxConduction

Sherwood Fig 4-7 see also Katzung Fig 14-2

Closed

(ready to open)Resting potential

(-90 mV)

Open

Threshold and activation potentials(-50 mV to +30mV)

Closed

(unable to open)Inactivation potentials

(+30 mV to -90mV)

Normal conduction

Re-entry loopUnidirectional block

Ischemia

Katzung Fig 14-8Abnormal Impulse Conduction(hypothetical model)

A model for unidirectional block

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

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)

FlecainidePropafenone (also ~-blocker)

Class II (-blockers)

Some may be cardioprotective after acute MI

Propranolol (non-selective)Metoprolol (1 selective)

Brenner Fig 4-4

Block -AR on nodal and muscle cells:

HRA-V conduction(may contractility)

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)

APD

Class III (K+ channel blockers)

Amiodarone (DOC)also Na+, Ca2+ channel blockerand -blocker

Sotalolalso -blocker (non-selective)

Indicated for SVT, A. fib, V. fib and V. tach

Pure Class III blockersDofetilide (PO only)Ibutilide (IV only)Azimilide (blocks IKr and IKs)

risk of torsades de pointes (not with amiodarone)

Others Antiarrhythmic Drugs

DigoxinInhibits Na/K ATPase Slows A-V conduction (through increasing vagal tone)Increases refractory period

Indicated for: A. Fib with fast ventricular rate* (and CHF)

Toxicity: 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 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.

AdenosineOpens K+ channels hyperpolarizes membrane

(also blocks Ca2+ channels)Selective for coronary arteries and atrial muscle cells

(not ventricular myocytes)Slows SA nodal firingSlows A-V conduction

Very short T1/2 (seconds)Indicated for ‘cardioconversion’

MagnesiumInhibits Ca2+ influx through L-type Ca2+ channelsIndicated for:

Drug-induced torsadesDigoxin-induced ventricular arrhythmias

Triggered activity due too much intracellular Ca2+

[Ca2+]i Na/Ca exchange [Na+]i

(3Na+(in): 1Ca2+(out)) (depolarize membrane)

Open L-type Ca2+ channelsMg2+

(for torsades)

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

RanolazineRecently approved for chronic stable anginaProlongs QT interval (maybe by inhibiting late Na+ current or delayed K+ rectifier

current)

Katzung 2009 p. 228

In terms of cellular target and action potential duration, what strategy would you use for:

Rapid nodal firing?

Supraventricular tachycardias?

Premature ventricular contractions (PVCs)?

Ventricular tachycardias?

Na+ channel blockers

-blockers

K+ channel blockers

Ca2+ channel blockers

Atrial fibrillation or flutter:Acute •Rate control: (IV) verapamil, diltiazem, -blockers, digoxinChronic•Rate control: verapamil, diltiazem, -blockers, digoxin•Maintenance of sinus rhythm: amiodarone, sotalol, flecainide, propafenone, dofetilide

According to Treatment Guidelines, Medical Letters 2007

Other SVTs:Acute• (vagotonic maneuvers, e.g., carotid sinus massage)• (IV) adenosine, verapamil, diltiazemChronic-blockers, verapamil, diltiazem, flecainide, propafenone, amirodarone, sotalol, digoxin

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

LH Opie 2004