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Antiarrhythmic Drugs Dr. Tom Murray Department of Pharmacology
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Page 1: Antiarrhythmic Drugs Dr. Tom Murray Department of Pharmacology.

Antiarrhythmic Drugs

Dr. Tom MurrayDepartment of Pharmacology

Page 2: Antiarrhythmic Drugs Dr. Tom Murray Department of Pharmacology.

Voltage-gated ion channels

QuickTime™ and aSorenson Video 3 decompressorare needed to see this picture.

Page 3: Antiarrhythmic Drugs Dr. Tom Murray Department of Pharmacology.

Nerbonne, J. M. et al. Physiol. Rev. 85: 1205-1253 2005;doi:10.1152/physrev.00002.2005

Action potential waveforms and underlying ionic currents in adult human and ventricular (left) and atrial (right) myocytes

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Cardiac currents contributing to action potential

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Copyright ©2005 American Society for Clinical Investigation

George, A. L. J. Clin. Invest. 2005;115:1990-1999

Functional properties of NaVChs

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Nerbonne, J. M. et al. Physiol. Rev. 85: 1205-1253 2005;doi:10.1152/physrev.00002.2005

Molecular assembly of cardiac Cav (Nav), Kv, and Kir channels

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Nerbonne, J. M. et al. Physiol. Rev. 85: 1205-1253 2005;doi:10.1152/physrev.00002.2005

Pore-forming ({alpha}) subunits of cardiac Nav (A) and Kv (B and C) channels linked to inherited arrhythmias

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Nerbonne, J. M. et al. Physiol. Rev. 85: 1205-1253 2005;doi:10.1152/physrev.00002.2005

Simulated human ventricular action potentials reveal the impact of gain of function (LQT3) and loss of function (Brugada) mutations in SCN5A

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Loss of function mutation in hERG cause LQT1

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Drugs That May Cause Torsade de Pointes

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Mechanisms of Cardiac Arrhythmias

• Enhanced automaticity• Afterdepolarizations and triggered automaticity

• Re-entry

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Afterdepolarizations and triggered activity

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Reentry circuit in small branches of Purkinje system

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Antiarrhythmic drug actions

• Alter function of ion channels

• Interfere with autonomic control

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Electrophysiological Parameters

Conduction Velocity

Refractory Period

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Curve relating Vmax to the resting membrane potential at the onset of action potential

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ANTIARRHYTHMIC DRUGS• Class I – block Na+ channels

• IA – medium• IB – fast• IC – slow

– IA: quinidine, procainamide (reduce automaticity, delay conduction, increase refractory period)

– IB: lidocaine, mexilitine, tocainide (reduce ectopic automaticity)

– IC: flecainide, propafenone (reduce automaticity, delay conduction)

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• Class II: -Adrenergic receptor blockers (propranolol, esmolol) (reduce automaticity, delay conduction)

• Class III Block K+ channels (amiodarone, ibutilide, sotalol) (delay repolarization, increase refractory period, reduce automaticity)

ANTIARRHYTHMIC DRUGS

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• Class IV: Block Ca2+ channels (verapamil, diltiazem) (reduce conduction velocity, reduce automaticity)

• Adenosine: Stimulates adenosine A1 receptors ( reduces conduction velocity, reduces automaticity)

ANTIARRHYTHMIC DRUGS

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Sites ofAction of

Drugs

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Quinidine

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Background• Discovered from effects of quinine

(from cinchona) - quinidine from same plant

• Beginning in the 1920s, quinidine was used as an antiarrhythmic agent

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Quinidine pharmacological actions

• Inhibits VGSC (open channel blocker)

• Inhibits delayed rectifier K+ channels

• Muscarinic receptor antagonist• Alpha adrenergic receptor antagonist

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Effects• Antimuscarinic – potential increase in AV nodal

transmission of atrial tachycardias• Increased threshold for excitability and

decreased automaticity• Reduces conduction velocity (decreases slope

of phase 0)• Increases duration of QRS (delays conduction)• Increases duration of QT interval (delays

repolarization)• Vasodilation

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Adverse Reactions• Cinchonism: dizziness, tinnitus• Nausea, vomiting and diarrhea• Depressed myocardial contractility• Hypotension and syncope• Ventricular arrhythmia (2-8% of patients

develop torsades de pointes)

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Uses of Quinidine• Maintain sinus rhythm in patients with atrial flutter or

atrial fibrillation prevent recurrence of ventricular tachycardia or ventricular fibrillation

• Prevent recurrence of ventricular tachycardia or ventricular fibrillation

• Use has diminished due to high incidence of proarrhythmias

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Procainamide

•Similar to quinidine in electrophysiological effects – similar to procaine (Novocaine) in structure, weaker antimuscarinic and a-adrenergic effects compared to quinidine.•Blocker of open Na+ channels with an intermediate time constant of recovery from block. Also prolongs cardiac action potentials in most tissues probably by blocking outward K+ current(s).

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Adverse reactions• Dose-related nausea is frequent during oral therapy

• Hypotension and marked slowing of conduction are major adverse effects of high concentrations

• Potentially fatal bone marrow aplasia in 0.2% of patients

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Uses• Used in the acute therapy of many supraventricular and ventricular arrhythmias

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Disopyramide•Electrophysiologic effects similar to quinidine•Prominent anticholinergic effects (precipitation of glaucoma, constipation, dry mouth, and urinary retention)•Commonly depresses contractility, which can precipitate heart failure•Used to maintain sinus rhythm in patients with atrial flutter or atrial fibrillation and to prevent recurrence of ventricular tachycardia or ventricular fibrillation

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Lidocaine

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Effects• Blocks both open and inactivated cardiac Na+

channels• Decreases automaticity especially in ectopic

pacemakers• Not useful in atrial arrhythmias possibly

because atrial action potentials are so short that the Na+ channel is in the inactivated state only briefly

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Adverse Reactions• Large intravenous doses of lidocaine administered rapidly may produce seizures

• Tremor, dysarthria, and altered levels of consciousness more common

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Uses•Acute intravenous therapy of ventricular arrhythmias

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Mexilitine

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Mexilitine - Effects• Congener of, and similar to,

lidocaine

• Orally effective

• Used in treatment of ventricular arrhythmias

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Flecainide

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Effects• Reduces conduction velocity (phase 0)

• Very long recovery from Na+ channel block

• Prolongs the duration of PR, QRS, and QT intervals

• Decreases sinus node automaticity

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Adverse Effects• Dose-related blurred vision is the most

common noncardiac adverse effect

• Cardiac risk in patients with recent myocardial infarction – reentrant tachycardia

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Use• Maintenance of sinus rhythm in patients with supraventricular arrhythmias

• In the CAST study, flecainide increased mortality in patients convalescing from myocardial infarction

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Propafenone

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Effects• Depresses inward sodium current

(phase 0) - Reduces conduction velocity

• Reduces automaticity

• S-(+)-propafenone is a -adrenergic receptor antagonist

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Adverse Effects• Contraindicated in severe heart failure,

disorders of conduction, bradycardia

• Increased frequency or severity of episodes of re-entrant ventricular tachycardia

• Adverse effects of -adrenergic blockade, such as sinus bradycardia and bronchospasm

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Indications• Used to maintain sinus rhythm in patients with supraventricular tachycardias

• It also can be used in ventricular arrhythmias

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adrenergic receptor blockers - propanolol

• Effectsblockade• Quinidine-like effect• Reduces automaticity of SA node• Reduces automaticity and

conduction velocity in AV node, His Purkinje and ventricles

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Adverse effects• Reduced myocardial contractility

• Bradycardia

• Angina upon sudden withdrawal

• Bronchospasm

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Uses• Supraventricular tachycardia

• Many studies indicate that, unlike flecainide, blockers provide prominent beneficial effect after myocardial

infarction.

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Esmolol

• Short-acting -adrenergic receptor blocker

• Given IV for a rapid effect

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Amiodarone

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Amiodarone effects• Blocks K+, Na+ and Ca2+ channels and eta

adrenoceptors• Delays repolarization and increases the

refractory period• Decreases automaticity• Slows conduction• A vasodilator• Increased coronary blood flow

Page 55: Antiarrhythmic Drugs Dr. Tom Murray Department of Pharmacology.

Amiodarone (adverse effects)• Conduction abnormalities• Pulmonary fibrosis• Reduced contractility of heart• Thyroid abnormalities • Hypotension with IV use • Skin (photosensitivity), cornea, peripheral neuropathy• Despite the marked QT prolongation and bradycardia typical of chronic amiodarone therapy, torsades de pointes and other drug-induced tachyarrhythmias are unusual.

Page 56: Antiarrhythmic Drugs Dr. Tom Murray Department of Pharmacology.

Amiodarone (uses)• Recurrent ventricular tachycardia or fibrillation resistant to other drugs

• Maintaining sinus rhythm in patients with atrial fibrillation

• IV dosage form supplanting lidocaine as first-line therapy for out-of-

hospital cardiac arrest

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Sotalol• A Class III drug• Prolongs cardiac action potentials by inhibiting delayed rectifier and possibly other K+ currents

• l-enantiomer is a much more potent -adrenergic receptor antagonist than the d-enantiomer, but the two are equipotent as K+ channel blockers

• Used in patients with both ventricular tachyarrhythmias and atrial fibrillation or flutter

• Torsades de pointes is the major toxicity with sotalol overdose

Page 58: Antiarrhythmic Drugs Dr. Tom Murray Department of Pharmacology.

Ibutilide

• An IKr blocker that in some systems also activates an inward Na+ current

• Administered as a rapid infusion (1 mg over 10 minutes) for the immediate conversion of atrial fibrillation or flutter to sinus rhythm

• Major toxicity with ibutilide is torsades de pointes, which occurs in up to 6% of patients

Page 59: Antiarrhythmic Drugs Dr. Tom Murray Department of Pharmacology.

Calcium channel blockers –Verapamil, Diltiazem

• Block slow inward Ca2+ current• Reduce automaticity• Increase refractory period and decrease

conduction velocity of AV Node• Inhibit contractility• Vasodilatation

Page 60: Antiarrhythmic Drugs Dr. Tom Murray Department of Pharmacology.

Calcium channel blockers (adverse effects)

• Flushing etc.• Reduced contractility of the heart• AV node conduction defects• Constipation

Use• Supraventricular arrhythmias

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Adenosine

• Adenosine released by most cells

• Normal plasma levels ~300 nM• Can reach micromolar levels in ischemic tissue

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Adenosine Metabolism

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Adenosine Receptors

• Four receptor subtypes have been classified:– A1, A2A, A2B, A3 (Fredholm, 1993)

• All four subtypes are G-protein coupled receptors

• Methylxanthines such as caffeine and theophylline are competitive antagonists

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Adenosine receptors

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G-Protein Coupled Receptors

• Seven-spanning transmembrane proteins

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Adenosine (effects)

• Stimulates adenosine receptors (A1 receptors in the heart)

• Increases K+ conductance

• Inhibits opening of Ca2+ channels

• Reduces norepinephrine release

• Reduces automaticity and AV nodal conduction

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Adenosine (adverse effects)

• Flushing

• Asthma – dyspnea – chest pain

• SA nodal arrest, AV nodal block

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Other Drugs• Dofetilide

– A “pure” class III antiarrhythmic – Potent and "pure" IKr blocker– Can prolong the QT interval– Maintenance of sinus rhythm in patients with atrial

fibrillation

• Moricizine– A class IC antiarrhythmic– A phenothiazine– Used for ventricular arrhythmias– Has active metabolites

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Appendix

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Nerbonne, J. M. et al. Physiol. Rev. 85: 1205-1253 2005;doi:10.1152/physrev.00002.2005

Electrical activity in the myocardium

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Diversity of inward rectifying potassium channels

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Control of membrane potential

* if the membrane potential (Em) equals Nernst potential for an ion (Eion), there will be no net flux of that ion across the membrane * illustration: * vary membrane potential of cell (Em) while measuring flux of K+ * when Em = EK, no flux * when Em is more negative (-65 mV) than EK (-55 mV) as in hyperkalemia, influx of K+ (K+ flows into of cell) * influx of K+ makes the membrane potential less negative = depolarization * when Em (-65 mV) is more positive than EK (-90 mV), efflux of K+ (K+ flows out of cell) * efflux of K+ makes the membrane potential more negative = hyperpolarization

* thus, when the the equilibrium potential for a permeant ion differs from the membrane potential, that ion will tend to flow across membrane so as to draw the membrane potential closer to its equilibrium potential

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Ionic currents• Each current is distinguished by ion selectivity, time course and voltage dependence

• Properties conferred by transmembrane proteins: ion channels

• Ion channels permit passage of 100,000 ions per second per channel due to passive movement of ions down their concentration gradient

• When ion channels open they bias membrane potential towards the equilibrium potential for that ion (eg. K+ channels -90 mV; Na+ channels +60)

• Channels are gated by voltage and may display rapid inactivation (eg. Na+ channels)

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Diversity of voltage-gated sodium channels

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Voltage-

gated sodium channe

l

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Cardiac ion

channels

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Differences in responses of fast- and slow-response tissues to

premature stimuli

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Requirements for induction of reentryRequirements for induction of reentry

trigger unidirectional block excitable gap

exctitable gap(non-refractory tissue)

unidirectional block(prevents wavefronts collision)

trigger

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Influence of hyperkalemia on cardiac action

potential