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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
Thank You