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 AJ Davidoff ‘09 Treatment Guidelines Medical Letters June 2007

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?

Nodal cell firing rate control ACh  M2 ACh receptors IK+ , ICa2+, If NE  1-AR  If  ICa2+ (L-type) Nodal cell firing rate control ACh = acetylcholine M-ACh = muscarinic ACh NE = norepinephrine -AR =  adrenergic receptor I = whole cell current Sherwood Fig 9-24

Fast Action Potentials ITO Fast Action Potentials IKr Outward K+ currents (delayed rectifiers) Fast Na+ current (INa) IKs ITO = transient outward K+ current

Purkinje fiber Optional information inward positive current NCX = sodium/calcium exchanger outward positive current IKACh = ACh K+ current ICaL = L type Ca2+ current INa = Na+ current Purkinje fiber 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

Supraventricular tachycardias? 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 Slow sa or av nodal dep. 2. Slow av conduction 3. Slow ventricular AP duration 4. Slow ventricular conduction/prolong AP duration – depends on where it comes from 5. Prolong 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 Want to protect the ventricle (nodal cell)

Target ventricular muscle cells For V. fib. or V. tach. Target ventricular muscle cells conduction velocity (Vmax) e.g., block Na+ channels (Class I drugs) Vmax is rate of rise. Want to decrease it. Also want to inc AP duration. Keep membrane depolarized longer so it can’t fire again=slows down. AP duration (APD) (refractory period) e.g., block K+ channels (now typically preferred over Class I drugs)

(preventing re-occurrence) 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) Fibrosis = mi, stent, etc.

Cellular models of arrhythmias Increased automaticity:  sympathetic activity (e.g., NE or Epi)  vagal activity (e.g., drug-induced, quinidine) TP = threshold potential MDP = maximum diastolic potential Brenner Box 14-1

G&H Fig 10-1

Ectopic pacemaker activity Often due to partial ischemia, resulting in a more postive resting membrane potential -90mV normal Na+ channels inactivated -60mV -40mV Small cluster of cells that die, the border cells don’t function really well b/c of lack of o2 and nutrients. Cell depolarizes. Dec Vmax b/c of Na channel inactivation. Can start taking on characteristics of nodal cells – ectopic pacemaker. Hyperpolarizing cell can reduce this Vmax Conduction

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

Abnormal Impulse Conduction (hypothetical model) Katzung Fig 14-8 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 Clinical arrhythmia: e.g., torsades de pointes due to: long QT syndrome genetic defects (HERG) disease drug-induced DADs  HR or [Ca2+]i Clinical arrhythmia: e.g., Ca2+ overload due to: digoxin or phosphodiesterase (PDE) inhibitor toxicity EAD’s-occur b/c AP is really long. Second upstroke is slower, not using Na channels but using Ca channels. Have very little Na channel component to it. DAD’s – occur during rapid HR or Ca overload. Brenner Box 14-1

If afterdepolarization is large can trigger PVC 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 “use-dependent block” IA Moderate Na+ channels inactivated “use-dependent block” resting/closed Phase – what it does to Vmax Repolarization Class Phase O Depression Action Potential Duration IA Moderate Prolonged Increased IB Weak Shortened Decreased IC Strong No effect Brody Table 14-3

Class 1A Block Na+ channels and K+ channels No longer drugs of choice Indications: (alternative DOC) Atrial fibrillation or flutter SVT Ventricular fib or tachycardia Vmax APD Toxicity includes: Prolongs APD too much Antimuscarinic effects (may inhibit vagus n.) What might happen? Prolong AP too much get early afterdepolarization. Set up a Torsades Quinidine (oral) prototype Class IA rarely used anymore Procainamide (oral or IV) less (-) on vagus Brenner Fig 4-2

Class 1B Block inactivated Na+ channels Rapidly binds to depolarized membranes (e.g., during ischemia) Rapidly dissociates from resting cells Indications: Ventricular tachycardia V. re-entrant loops? (PVCs) during surgery No effect on atrial cells (with short APD) Vmax APD Does nothing to condu velocity, and reduces APD. Only binds to cells that have a long AP. 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 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)  Vmax APD Toxicity: Slows conduction (Vmax) too much Can cause re-entrant loops (especially v. arrhythmias)  Block Na channels no matter what state they are in = significant effect on Vmax. 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 IV or PO Brenner Fig 4-4 Propranolol (non-selective) 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 can also affect contractility. Used mostly in acute settings now. Diltiazem has less effect on AV nodal cells. For arryth and HTN it is better 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) Indicated for SVT, A. fib, V. fib and V. tach APD Amiodarone (DOC) also Na+, Ca2+ channel blocker and -blocker Sotalol also -blocker (non-selective) Protect Ventricle from a too high rate or rhythm Anything that lengthens AP precipitates torsades. Not amio b/c it also blocks na and ca channels as well. Prolonging AP and reducing risk of prolonged AP. From Opie: Ibutilide good for terminating AF and A flutter, IV only (extensively metabolized by liver) Dofetilite (oral only) indicated for cardioconversion of AF and Flutter, and maintenance of normal sinus rhythm with AF and flutter. Pure Class III blockers Dofetilide (PO only) Ibutilide (IV only) Azimilide (blocks IKr and IKs) risk of torsades de pointes (not with amiodarone)

Others Antiarrhythmic Drugs Digoxin Inhibits 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) Rate Versus Rhythm Control in the Management of Atrial Fibrillation by D. George Wyse, AHA website, last updated 5/08 Discusses the AFFIRM trial and outcomes suggest that patients with A.fib, should be treated with anticoagulant (warfarin) and control heart rate (rather than rhythm , which is muc harder) *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 (non-cardiac toxicities include visual distrubances -yellow hues), with highest affinity to cardiac and vagal nerve. Toxicitity incr with low k

Opens K+ channels  hyperpolarizes membrane 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’ Slows HR by hyperpolarizing membrane. 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  Na/Ca exchange  [Na+]i (3Na+(in): 1Ca2+(out)) (depolarize membrane) Makes NA/Ca exchanger reverse and bring in Na and Ca out. More Na cuases depolarization, etc. Mg blocks Lca to diminsh arrhythmias. Mg2+ (for torsades) Open L-type Ca2+ channels

Reduces action potential duration (APD) Slows conduction 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)

Supraventricular tachycardias? 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 Ca Channel blocker 2. BB or CaB 3. CaB, BB 4. KB

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 NEJM ICD improved survival in CHF patients with stage II and III, with LVEF equal or less than 35%, by 23% over 45 months amiodarone did not improve survival 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