anti-arrhythmic drugs - · pdf fileppt. arrhythmia or asystole ... cinchonism (ha, dizziness,...

ANTI-ARRHYTHMICDRUGS

Mr. D.Raju, M.pharm,Lecturer

ANTI – ARRHYTHMIC DRUGS

Cardiac Arrhythmias:

- 25% treated with digitalis

- 50% anesthetized patients

- 80% patients with AMI

reduced cardiac output

drugs or nonpharmacologic:

- pacemaker, cardioversion, catheter ablation, surgery

ELECTRO-PHYSIOLOGY OF NORMAL CARDIAC RHYTHM

SA node


AV node

ATRIA

His-Purkinje System

VENTRICLES

Transmembrane potential of cardiac cells is determined by the concentrations of the ff. ions:

Sodium, Potassium, CalciumThe movement of these ions produces currents that form the basis of the cardiac action potential


PHASES OF ACTION POTENTIAL

Phase 0>Rapid depolarization>Opening fast Na+channels→ Na+ rushes in

→depolarization


Phase 1>Limited depolarization>Inactivation of fastNa+ channels→ Na+ion conc equalizes>↑ K+ efflux & Cl- influx

Phase 2>Plateau Stage>Cell less permeable to Na+>Ca++ influx through slow

Ca++ channels>K+ begins to leave cell

Phase 3>Rapid repolarization>Na+ gates closed>K+ efflux>Inactivation of slow

Ca++ channels

Phase 4>Resting Membrane Potential>High K+ efflux>Ca++ influx

MECHANISMS OF ARRHYTHMIA

ARRHYTHMIA – absence of rhythmDYSRRHYTHMIA – abnormal rhythm


ARRHYTHMIAS result from:

1. Disturbance in Impulse Formation

2. Disturbance in Impulse ConductionBlock results from severely depressed conductionRe-entry or circus movement / daughter impulse

Supraventricular:- Atrial Tachycardia- Paroxysmal Tachycardia- Multifocal Atrial

Tachycardia- Atrial Fibrillation- Atrial Flutter

Ventricular:- Wolff-Parkinson-White

(preexcitation syndrome)- Ventricular Tachycardia- Ventricular Fibrillation- Premature Ventricular

Contraction

ANTI – ARHYTHMIC DRUGS

ARRHYTHMIAS:

CLASS I: SODIUM CHANNEL BLOCKING DRUGS

IA - lengthen AP duration- Intermediate interaction with Na+ channels- Quinidine, Procainamide, Disopyramide

IB - shorten AP duration- rapid interaction with Na+ channels- Lidocaine, Mexiletene, Tocainide, Phenytoin

IC - no effect or minimal AP duration - slow interaction with Na+ channels- Flecainide, Propafenone, Moricizine


CLASS II: BETA-BLOCKING AGENTS

Increase AV nodal conductionIncrease PR intervalProlong AV refractorinessReduce adrenergic activityPropranolol, Esmolol, Metoprolol, Sotalol


CLASS III: POTASSIUM CHANNEL BLOCKERS

Prolong effective refractory period by prolonging Action Potential

Amiodarone - Ibutilide Bretylium - DofetilideSotalol

ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS

CLASS IV: CALCIUM CHANNEL BLOCKERS


Blocks cardiac calcium currents → slow conduction → increase refractory period

*esp. in Ca++ dependent tissues (i.e. AV node)

Verapamil, Diltiazem, Bepridil


MISCELLANEOUS:

ADENOSINE → inhibits AV conduction & increases AV refractory period

MAGNESIUM → Na+/K+ ATPase, Na+, K+, Ca++ channels

POTASSIUM → normalize K+ gradients


Depress pacemaker rateDepress conduction & excitabilitySlows repolarization & lengthens AP duration → due to K+ channel blockade with reduction of repolarizing outward current → reduce maximum reentry frequency → slows tachycardia(+) alpha adrenergic blocking properties → vasodilatation & reflex ↑ SA node rate

ANTI – ARRHYTHMIC DRUGSANTI – ARRHYTHMIC DRUGS

CLASS I: Sodium Channel Blocking Drugs

CLASS IA: QUINIDINE

CLASS I: SODIUM CHANNEL BLOCKERS

Pharmacokinetics:Oral → rapid GI absorption 80% plasma protein binding 20% excreted unchanged in the urine → enhanced by acidityt½ = 6 hoursParenteral → hypotension

Dosage: 0.2 to 0.6 gm 2-4X a day


CLASS IA: QUINIDINE


Therapeutic Uses:– Atrial flutter & fibrillation– Ventricular tachycardia– IV treatment of malaria

Drug Interaction:– Increases digoxin plasma levels


CLASS IA: QUINIDINE


Toxicity:– Antimuscarinic actions → inh. vagal effects– Quinidine syncope (lightheadedness, fainting)– Ppt. arrhythmia or asystole– Depress contractility & ↓ BP– Widening QRS duration– Diarrhea, nausea, vomiting– Cinchonism (HA, dizziness, tinnitus)– Rare: rashes, fever, hepatitis, thrombocytopenia,etc


CLASS IA: QUINIDINE

↑ AV nodal conduction time (↑ PR interval)Prolong AV nodal refractoriness

Useful in terminating reentrant arrhythmias that involve the AV node & in controlling ventricular response in AF & A.fib.

Depresses phase 4 → slows recovery of cells, slows conduction & decrease automaticityReduces HR, decrease IC Ca2+ overload & inhibit after depolarization automaticityPrevent recurrent infarction & sudden death in patients recovering from AMI


CLASS II: BETA ADRENOCEPTOR BLOCKERS

“membrane stabilizing effect”Exert Na+ channel blocking effect at high dosesAcebutolol, metoprolol, propranolol, labetalol, pindolol

“intrinsic sympathetic activity”Less antiarrhythmic effectAcebutolol, celiprolol, carteolol, labetalol, pindolol

Therapeutic indications:Supraventricular & ventricular arrhythmiashypertension



Propranolol – (+) MSAAcebutolol – as effective as quinidine in

suppressing ventricular ectopic beats

Esmolol - short acting hence used primarily for intra-operative & other acute arrhythmias

Sotalol – has K+ channel blocking actions (class III)



Specific agents:

Drugs that prolong effective refractory period by prolonging action potentialProlong AP by blocking K+ channels in cardiac muscle (↑ inward current through Na+ & Ca++ channels)Quinidine & Amiodarone → prolong AP durationBretylium & Sotalol → prolong AP duration & refractory periodIbutilide & Dofetilide → “pure” class III agentsReverse use-dependence



Nonselective beta-blocker that also slows repolarization & prolongs AP durationEffective antiarrhythmic agentUsed in supraventricular & ventricular arrhythmias in pediatric age groupRenal excretionDosage: 80 – 320 mg bidToxicity: torsades de pointes

beta-blockade symptoms



SOTALOL

Blocks both activated & inactivated calcium channelsProlongs AV nodal conduction & effective refractory periodSuppress both early & delayed afterdepolarizationsMay antagonize slow responses in severely depolarized tissuesPeripheral vasodilatation → HPN & vasospastic disorders



VERAPAMIL

Oral administration → 20% bioavailabilityt½ = 7 hrsLiver metabolismDosage: IV: 5-10 mg every 4-6 hrs or infusion of 0.4 ug/kg/minOral: 120-640 mg daily, divided in 3-4 dosesTptic use: SVT, AF, atrial fib, ventricular arrhythmiasToxicity: AV block, can ppt. sinus arrest

constipation, lassitude, nervousness, peripheral edema



VERAPAMIL

Indirectly alters autonomic outflow by increasing parasympathetic tone & decreasing sympathetic tone Results in decreased conduction time & increased refractory period in the AV node


MISCELLANEOUS ANTIARRHYTHMIC AGENTS:

DIGITALIS

anti-arrhythmic drugs - · pdf fileppt. arrhythmia or asystole ... cinchonism (ha, dizziness,...

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