ANTIARRHYTHMIC DRUGS

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INTRODUCTION• The heart contains specialized cells that exhibit

automaticity; that is, they can generate rhythmic action potentials in the absence of external stimuli

• This phenomenon of automaticity is carried out by the “pacemaker” cell that spreads the depolarization from the SA node → AV node → Bundle of His → Purkinje cells

• Dysfunction of impulse generation or conduction at any level in the heart can cause an abnormality in cardiac rhythm called Arrhythmia

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Types OF Arrhythmia

• Altered Rate• Premature beats• Altered Conduction

• http://www.cvpharmacology.com/clinical%20topics/arrhythmias-2

• http://www.skillstat.com/tools/ecg-simulator

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Reentry

For reentry to occur, certain conditions must be met that are related to the following:

1)the presence of a unidirectional block within a conducting pathway

2) critical timing

3) the length of the effective refractory period of the normal tissue

CONSEQUENCES OF ARRHYTHMIA

• Cause the heart to beat too slowly• To beat too rapidly (vent tachycardia, atrial

flutter• To respond to impulses originating from sites

other than the SA node• To respond to impulses traveling along

accessory pathways that lead to deviant depolarization

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Action Potential in cardiac &His-Purkinje system

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- 80 mV

Resting Membrane Potential

Plateau Phase (Opening of Ca-Na Channels and Decrease K permeability)

Repolarization Phase(Opening of K Channels)

Depolarization Phase(Opening of Fast Na Channels)

+ 20 mV

0.2 to 0.3 sec

PHASES OF AP in Fast fibers• Phase 0 - depolarization - opening of Na

channels( fast sodium current)• Blocked by class I drugs• phase 1 – Inactivation of Na channels, • phase 2 – Plateau phase -- slow but prolonged

opening of Ca channels balanced by late outward K⁺ current.

• Phase 3 – Final repolarization – closure of Ca channels and rapid K efflux.

• Blocked by class III drugs• Phase 4 ---- return of membrane to resting potential

by the activity of Na⁺/K⁺-ATPase

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Three ion channel mechanisms contribute to the pacemaker potential –

The first is a progressive reduction in potassium permeability.

Second is presence of funny channels.

Third is presence of T-type calcium channels (T transient).

ANS Regulation of Heart Rate

• SA & AV nodes are innervated by both PANS & SANS fibers activating M2 & b1 receptors respectively.

• Phase 4 slope increased by increase cAMP (b1 activation) & slowed by decrease cAMP (M2 activation).

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CLASSES OF DRUGS

• CLASS I ANTIARRHYTHMIC DRUGS

• CLASS II ANTIARRHYTHMIC DRUGS

• CLASS III ANTIARRHYTHMIC DRUGS

• CLASS IV ANTIARRHYTHMIC DRUGS

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Class I – (Na CHANNEL BLOCKERS)

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Effects on depolarization

Effects on repolarization

Effects on automaticity

Indirect vagal effects

Na+ Channel Blockers - Class IA

• Decrease Vmax(phase 0) via block of fast Na channels in the open or activated state

• Increase APD & Effective Refractory Period (ERP)

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QUINIDINE• Increase HR & AV conduction due to

its muscarinic blockade• Vasodilation due to blockade of alpha

receptor → hypotension• orally effective

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THERAPEUTIC USES

• WIDE RANGE• A-Fib, Ventricular tachyarrhythmias• MAINTAIN NORMAL RHYTHM AFTER

CARDIOVERSION

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Adverse effects• nausea & vomiting,• cinchonism (GI, tinnitus, ocular dysfunction,

CNS excitation), • syncope due to prolongation of QT interval

(torsades), AV & SA block • At toxic doses: ventricular tachycardia.

• Interactions: hyperkalemia increases its cardiotoxicity; enhances digoxin toxicity; Decrease effects of AChE inhibitors in myasthenia.

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PROCAINAMIDE

• CLASS 1A• DERIVATIVE OF LOCAL ANAESTHETICPROCAINE• ADVANTAGES• LESS ANTIMUSCARINIC EFFECTS

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Pharmacokinetics

• Well absorbed via oral route• Short half-life• Metabolized via N-acetyltransferase to N-

acetyl procainamide (NAPA), an active metabolite

• NAPA is eliminated via the kidney

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SIDE EFFECTS

• SLE LIKE SYNDROME, Hematotoxic

• CNS effect: DEPRESSION, HALLUCINATIONS, & PSYCHOSIS.

• CVS: TORSADES

• Toxic dose: ASYSTOLE, ventricular arrhythmia

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DISOPYRAMIDE• CLASS I A• NEGATIVE IONOTROPIC• ANTI MUSCARINIC EFFECT – GREATER

• SIDE EFFECTS• ANTICHOLINERGIC EFFECTS

• NOT FIRST LINE DRUG. USED AS AN ALTERNATIVE TO OTHER CLASS 1A DRUGS

• CI: in patients with heart failure

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Na+ Channel Blockers - Class IB

• Decrease Vmax – • block fast Na+ channels in the

inactivated state - preference for tissues partly depolarized (ischemic or hypoxic tissues)

• Decrease APD( blockade of slow Na⁺ window current in the plateau)

• (SHORTENS PHASE 3 REPOLARISATION)

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• ROUTE – I.V.• EXTENSIVE FIRST PASS METABOLISM preclude

oral use. • USES : arrhythmias during an MI, & DOC (Drug

Of Choice) for arrhythmias following attempted cardioversion.

• MC : VENTRICULAR ARRHYTHMIAS• Digoxin toxicity

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Lidocaine

• Adverse effects: CNS toxicity culminating in seizures.

• Least cardiotoxic of conventional antiarrhythmics.

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OTHER CLASS 1 B

• MEXILETINE• TREATMENT OF VEN. ARRHY. MOSTLY WITH

PAST H/O OF MI.• Side effects: • Epigastric burning: • nausea (common) • Neurologic side effects:

– diplopia, vertigo, slurred speech, tremor

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CLASS 1B

• TOCAINIDE - VTA

• SIDE EFFECTS• fatal bone marrow aplasia • pulmonary fibrosis.

• RARELY USED

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Na+ Channel Blockers - Class IC

• Decrease Vmax - block fast Na+ channels in all states

• No effect on APD

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CLASS 1 C - FLECAINIDE• Na channel blocker at all states• SLOWS PHASE O • NEGATIVE IONOTROPIC EFFECT• CI : HEART FAILURE-CAN INDUCE V TAC (proarrhythmic) • SIDE EFFECTS : DIZZINESS, BLURRED VISION

• USES : reserved for management of life-threatening arrhythmias or refractory VA

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CLASS II ( BETA BLOCKERS)

• Decrease SA & AV nodal activity • Decrease slope of phase 4 (diastolic currents)

of AP in pacemakers • prevent b1 adrenoceptors activation which

would normally increase cAMP

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• Propranolol (non-selective) &

• cardioselective drugs – acebutolol, metoprolol esmolol

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• Rx uses:• prophylaxis post-MI & in SVTs & Atrial

arrhythmias; • esmolol (IV) is used in acute SVTs.

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Class III (K+ Channel Blockers)

• Increase APD & ERP especially in Purkinje & ventricular tissues

• Decrease IK (delayed rectifier current) slowing phase 3 of AP.

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CLASS III ( K CHANNEL BLOCKERS)

• AMIODARONE• Dofetilide• SOTALOL

• PROLONGS PHASE 3 REPOLARIZATION• BLOCKS K OUTLFOW, ↑ APD & ERP

• All class III drugs prolong QT-interval except Amiodarone

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SOTALOL• β₁ blocker but acts as a K⁺ channel blocker

• USES:• Treatment of life threatening arrhythmia• SUPPRESS ECTOPIC BEATS• DECREASES rate of sudden death following

an acute MI & IN PTS with SUSTAINTED VENT. TACHYCARDIA.

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AMIODARONE• Both antianginal & antiarrhythmic activity. • Shows actions of class I, II, III, IV .• Does not prolong the QT-interval

• Use:• in treatment of severe refractory Supraventricular and

VTA.

• SE: GI intolerance , photosensitivity, ataxia, blue skin discoloration, tremor, dizziness, liver toxicity, pul. Fibrosis hepatotoxicity, hypo/hyperthyroidism.

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CLASS IV (Ca Channel blockers)

• Verapamil• Diltiazem• Decrease the influx of Ca²⁺ – decrease the

rate of phase 0 depolarization and phase 4 spontaneous depolarization

• Decrease conduction velocity

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USES

• Used in treatment of atria than ventricular arrhythmia

• SVTs of nodal arrhythmias• They also have effect on the vascular smooth

muscle and the heart.• So can be used in treatment of hypertension

also.• CI: in pts with depressed heart function

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SE:• GI distress: CONSTIPATION• dizziness• flushing• Hypotension• AV block

• Interaction: Verapamil displaces digoxin from binding sites

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Other drugs: ADENOSINE

1. Activates adenosine receptor2. Gi-coupled decreasing cAMP • Decrease SA and AV nodal activity

• USES: • Used mainly for the abolishing paroxysmal

Supraventricular tachycardia( IV route )• AV nodal arrhythmia

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• Possible side effects - flushing, sedation & dyspnea , bronchospasm

• Antagonized by theophylline.

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• DIGOXIN• Prolongs ERP• Diminishes conduction velocity in purkinje

fibers.• Can be used in atrial fib and flutter.

• Toxic dose: results in ventricular tachycardia

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