ANTI ARRHYTHMIC DRUG THERAPY

Dr.Vinay verma group:512

Normal conduction pathwaySA node Generates

action potential AV node

Delivers the impulse to

purkinje fibersPurkinje fibers

Conduct the impulse to the

ventricles

SAN

AVN

Impulse conductionNormal conduction pathway Impulses originate

regularly at a frequency of 60-100 beat/ min

Normal heartbeat & Arrhythmia

Normal rhythm

Arrhythmia

AV septum

Management of Arrhythmia

Management of Arrhythmia Pharmacological therapy (Antiarrhythmic

Drugs) Cardioversion Pacemaker therapy Surgical therapy e.g. aneurysmal

excision Interventional therapy “ablation”

Antiarrhythmic Drugs

Pharmacologic rationale & Goal The ultimate goal of antiarrhythmic

drug therapy: Restore normal sinus rhythm and

conduction Prevent more serious and possibly lethal

arrhythmias from occurring. Antiarrhythmic drugs are used to:

Decrease conduction velocity Change the duration of the effective

refractory period (ERP) Suppress abnormal automaticityShrivatsa U, Wadhani M, Singh AB; Mechanisms of antiarrhythmic drug action & their

clinical relevance for controlling disorders of cardiac rhythm; Curr Cardiol Rep 2002;4;401

Classification of Antiarrhythmic Drugs

Classified a/c to Vaughan William into four classesClass Mechanis

m Action Notes

INa+

channel blocker

Change the slope of phase 0

Can abolish tachyarrhythmia

caused by reentry circuit

II β blocker ↓heart rate and conduction velocity

Can indirectly alter K and Ca conductance

III K+ channel blocker

1. ↑action potential duration (APD) or

effective refractory period (ERP).

2. Delay repolarization.

Inhibit reentry tachycardia

IVCa++

channel blocker

Slowing the rate of rise in phase 4 of SA node(slide

12)

↓conduction velocity in SA and AV node

Classification of Antiarrhythmic Drugs

Treatment of tachyarrhythmias:

Class I drugs (Membrane stabilizing drugs) : Mechanism: Class I drugs block fast Na+ channels, thereby

Reducing the rate of phase 0 depolarization Prolonging the effective refractory periodIncreasing the threshold of excitability Reducing phase 4 depolarization

These drugs also have local anesthetic properties

Woosely RL. Antiarrhythmic drugs. Hurst’s The Heart (Ed. Fuster V, Alexander RW, O’Rourke RA, et al.) 10th edition.2001;1:899–924

Class IA1. Quinidine Alkaloid – cinchona , dextro isomer of quinine. Blocks sodium channel & potassium channel also Anti-muscarinic and Alpha blocking action Administered orally & is rapidly absorbed from

gastrointestinal tract Hydroxylated in the liver t1/2 of approximately 5—12 hours, longer in

hepatic or renal disease & in heart failure Bitter and irritant Inhibitor of CYP P450 system.

1. Quinidine ↑↑ plasma conc of digoxin by displacing it

from tissue binding sites & decreasing its renal & biliary clearance.

Uses: Atrial fibrillation Ventricular tachycardia

Adverse effects : GIT : Diarrhea, nausea, vomiting and

cinchonism Thrombocytopenia Precipitate torsade de pointes by

prolonging QT interval

1. Quinidine

Drug interactions Increases digoxin plasma levels &risk of

digitalis toxicity t1/2 reduced by agents that induce drug-

metabolizing enzymes (phenobarbital, phenytoin)

May enhance the activity of coumarin anticoagulants & other drugs metabolized by hepatic microsomal enzymes

Cardiotoxic effects exacerbated by hyperkalemia

2. Procainamide Like quinidine, but

Safer to use intravenously Produces fewer adverse GI effects

Acetylated in liver to N-acetylprocainamide (NAPA)

Eliminated by the kidney (t ½ -3 – 5 hrs) More likely than quinidine to produce

severe or irreversible heart failure Adverse effects

SLE like syndrome consisting of arthralgia and arthritis specially in slow acetylators

Class IB1. Lidocaine: Least cardiotoxic : (t ½ - 1.5 - 2 hrs) Block inactivated Na channels : preferred

for partially depolarized cells in ischemic area

High first pass metabolism – not given orally

Used in: Ventricular arrhythmia Digoxin induced arrhythmia

Main toxicity:Neurological – drowsiness, nystagmus &

seizures

2. Mexiletine and Tocainide Similar in action to lidocaine Can be administered orally T ½ - Mexiletine – 10-12 hrs - Tocanide – 11-23 hrs Used for long-term treatment of

ventricular arrhythmias associated with previous Myocardial Infarction

Adverse events: Mexiletine : Ataxia, dizziness, tremors Tocainide : Blood dyscrasias, pulmonary

fibrosis, GI and neurological symptoms

Class IC Class of potent Na channel blocker Drugs of this class have negative inotropic

effect High pro-arrhythmogenic potential –

sudden death

Class IC1.Flecainide

Orally active antiarrhythmic Metabolized by microsomal enzymes (t ½ - 20

hrs) Used for ventricular tachyarrhythmias &

maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation and/or atrial flutter & WPW

C/I in pts with structural heart disease Adverse events :

Heart failure, dizziness, headache , Blurred vision

2. Propafenone Spectrum of action similar to that of quinidine Possesses β-adrenoceptor antagonist activity Metabolized by hepatic microsomal enzymes T ½ - 2 – 10 hrs Approved for treatment of supraventricular

arrhythmias and suppression of life-threatening ventricular arrhythmias

C/I in structural heart disease Adverse events:

Nausea, Vomitting, altered taste

Class II They Are β-adrenoceptor antagonists,

including propranolol Act by reducing sympathetic stimulation Inhibit phase 4 depolarization Depress automaticity Prolong AV conduction Decrease

Heart rate Contractility

Class II Major drugs

Propranolol, a nonselective β-adrenoceptor antagonist

Acebutolol & esmolol, more selective β1-adrenoceptor antagonists

Used to treat ventricular arrhythmiasPropranolol, metoprolol, nadolol, and timolol frequently used to prevent recurrent MI

Class II Absorption and elimination:

Propranolol: oral, iv Esmolol: iv only (very short acting T½, 9

min) Cardiac effects

APD and refractory period in AV node to slow AV conduction velocity

decrease phase 4 depolarization (catecholamine dependent)

Class II Uses:

Treating sinus and catecholamine dependent tachyarrhythmias

Converting reentrant arrhythmias in AV Protecting the ventricles from high atrial

rates Side effects:

Bronchospasm Hypotension  Don’t use in partial AV block or

ventricular failure

Class III Class III drugs:

Prolong action potential duration Prolong effective refractory period

Act by: interfering with outward K+

currents or slow inward Na+ currents

1. Amiodarone Structurally related to thyroxine. Net effect:

Increases refractoriness Depresses sinus node automaticity Slows conduction.

Long half-life (14—100 days) ↑ risk of toxicity Plasma conc not well correlated with its effects After parenteral administration:

Electrophysiologic effects →within hours Effects on abnormal rhythms may not be seen

for several days

1. Amiodarone Antiarrhythmic effects may last for weeks

or months after the drug is discontinued Uses:

Refractory life-threatening ventricular arrhythmias in preference to lidocaine

T/t of atrial and/or ventricular arrhythmias

Adverse effects Pulmonary fibrosis Skin pigmentation Corneal deposits Interferes with the thyroid function

Class IV Mechanism

Class IV drugs selectively block L-type calcium channels.

These drugs prolong nodal conduction and effective refractory period and have predominate actions in nodal tissues

Class IV

Verapamil Phenylalkylamine that blocks both

activated and inactivated slow calcium channels.

Tissues that depend on L-type calcium channels are most affected

Has equipotent activity on the AV and SA nodes and in cardiac and vascular muscle tissues

Useful in: Supraventricular tachycardia Atrial flutter and fibrillation

Verapamil Adverse effects:

Negative inotropic action that limits its use in damaged hearts;

Can lead to AV block when given in large doses or in patients with partial blockage.

Can precipitate sinus arrest in diseased patients

Causes peripheral vasodilation.

Miscellaneous Antiarrhythmic Drugs Adenosine

Acts through specific purinergic (P1) receptors.

Causes an increase in potassium efflux and decreases calcium influx.

This hyperpolarizes cardiac cells and decreases the calcium-dependent portion of the action potential.

Drug of choice for the treatment of paroxysmal supraventricular tachycardia, including those associated with Wolff-Parkinson-White syndrome

Digoxin Mode of action:

Na-K ATPase inhibition Positive inotrope Vagotonic

T ½ - Premature (61hrs), Neonate (35hrs), Infant (18hrs), Child (37hrs), Adult (35-48hrs )

Uses: Supraventricular Tachycardia

Digoxin Interactions:

Coumadin- ↑ PT ↑ Digoxin level Quinidine, amiodarone, verapamil ↓ renal function/renal tubular excretion

(Spironolactone) Worse with ↓ K+, ↓ Ca++

Investigational Drugs Analogs of Amiodarone are being developed

such as: ATI-2001 Dronedarone SR-33589

Dronedarone: Resonable safety profile Well characterized pharmacokinetic &

pharmacodynamic profile Effective in doses lower than 2000 mg/dayWolbrette D et al ; Dronedarone for the treatment of atrial fibrillation and atrial flutter: Approval and efficacy ; Vasc Health Risk Manage 2010;6;517

Investigational Drugs Azimilide :

Potassium-channel blocking properties Prolongs cardiac AP & refractory periods Found to be effective in patients with

symptomatic tachyarrhythmias and ICDs therapies in recent studies

Other drugs, such as Ambasilide, are also in clinical development

Chromanol 293B is in preclinical testingReynolds RM, Josephson ME. Sustained ventricular tachycardiain ischemic cardiomyopathy : current management. ACC Current Journal Review 2005;14:63-71

Treatment of bradyarrhythmias Atropine

Blocks the effects of acetylcholine. Elevates sinus rate and AV nodal and

sinoatrial (SA) conduction velocity, & decreases refractory period

Used to treat bradyarrhythmias that accompany MI

Adverse effects: Dry mouth, mydriasis, and cycloplegia; May induce arrhythmias.

T/t of Atrial Flutter/Fibrillation1. Reduce thrombus formation by using

anticoagulant warfarin2. Prevent the arrhythmia from converting to

ventricular arrhythmia First choice: class II drugs:

After MI or surgery Avoid in case of heart failure

Second choice: class IV drugs Third choice: digoxin

Only in heart failure of left ventricular dysfunction

T/t of Atrial Flutter/Fibrillation3. Conversion of the arrhythmia into normal

sinus rhythm Class III: IV ibutilide, IV/oral amiodarone, or oral sotalol Class IA: Oral quinidine + digoxin (or any drug from the

2nd step) Class IC: Oral propaphenone or IV/oral flecainide Use direct current in case of unstable

hemodynamic patient Fuster V et al; ACC/AHA/ESC Guidelines for the management of patients with atrial fibrillation. Circulation 2006;114;700

T/t of Ventricular Arrhythmia Premature ventricular beat (PVB) First choice: class II

IV followed by oral Early after MI

Second choice: amiodarone Avoid using class IC after MI ↑ mortality

T/t of Ventricular Tachycardia First choice: Lidocaine IV

Repeat injection if needed Second choice: procainamide IV

Adjust the dose in case of renal failure Third choice: class III drugs

Especially amiodarone and sotalol

Grant AO, Recent advances in the treatment of arrhythmia. Circ J 2003;67;651

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