Assoc. Prof. Ivan Lambevwww.medpharm-sofia.eu

Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology

ANTIARRHYTHMICANTIARRHYTHMICDRUGSDRUGS(Summary)(Summary)

Myocardial cells maintain transmembraneion gradients by movement of the Na+, Ca2+

and K+ through membrane channels.

The resting potential of a cardiac cell is– 85 mV compared to the extracellular environment.

Depolarization is initiated by a rapid influxof Na+ (phase 0).

BASIC ELECTROPHYSIOLOGYBASIC ELECTROPHYSIOLOGY

Depolarization

Rapid repolarization

Final repolarization

Plateau

Resting potential Spontaneousdepolarization

In the AV node depolarization isdue to the slower influx of calcium ions.This results in slower conduction of the impulse through the AV node than in other parts of the heart.

During the period between phase 0 and theend of phase 2, the cell is refractory to thefurther depolarization (absolute refractoryperiod) since the sodium channels are inactivated.

During phase 3, a sufficiently large stimuluscan open enough sodium channels to over-come the potassium efflux. This is therelative refractory period.

Rapid repolarization

Plateau

Depolarization

Final repolarization

Spontaneous depolarization

Absoluterefractory periodRelative refractory period

Threshold potential

Resting membrane potential

The cardiac action potential

MECHANISMS OF ARRHYTHMOGENESISMECHANISMS OF ARRHYTHMOGENESIS

Arrhythmias can arise as the result ofabnormal impulse generation or abnormalimpulse conduction. The main mechanisms:

•RE-ENTRY (the most frequently): if animpulse arrives at an area of tissue whenit is refractory to the stimulus, this impulsewill be conducted by an alternative route.

If the impulse again reaches the “blocked”tissue distally when it has had sufficienttime to recover, the same impulse will beconducted retrogradely (re-entry).

This retrogradeconductionis slow, becauseto initiate a circuitof electrical acti-vity, the healthy tissue has to be given timeto repolarize.

Such a mechanism can initiate a selfperpetuating “loop” of electricalactivity which acts as a pacemaker.

The re-entry circuit can be localized within small a area of the myocardiumor it can exist as a large circuit, for example between the atria and ventricles.

•AUTOMATICITY Subsidiary (or ectopic) pacemakers may develop when a sitein the myocardiumdevelops a more rapid phase 4 depolarizationthan the SA node, e.g. as a result of ischaemia.

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Threshold potential

ANTIARRHYTHMIC DRUGS ANTIARRHYTHMIC DRUGS (AAD)(AAD)

I. AAD used in tachyarrhythmias

The Vaughan William’sClassification of AAD

is based on their effects on the cardiac action potential (AP).

Class I (membrane stabilizers)These AAD slow the rate of raise of phase 0 of AP by inhibiting fast sodium channels. The class is subdivided according to the effects of drugs on the duration of AP.Indications: SV and ventricular arrhythmias.

IA IB ICIncreasethe duration of AP

Decreasethe duration

No effect onthe duration

IA IB IC

DisopyramideProcainamideAjmaline- weak negative inotropic effectQuinidine

LidocaineMexiletinePhenytoin

PropafenoneFlecainide

ADRs: Bradycardia, AV block, (–) inotropiceffect, disturbances of GIT, rashes

Rauwolfia serpentina•Ajmaline•Reserpine

Cinchona succirubra•Quinidine•Chinine

Treatment: Lidocaine, Ajmaline

Ventricular fibrillationVentricular fibrillation, characterizedby irregular undulations without clear ventricular complexes.

Treatment: Lidocaine or electrical defibrillation

Ventricular Ventricular flutterflutter

Class II (-adrenoceptor antagonists)

Reduce the rate of spontaneous depo- larization of sinus and AV nodal tissue by indirect blockade of calcium channels.Indications: SV and ventricular arrhythmias.

( cAMP)( cAMP)

Pindolol, PropranololAtenolol, Esmolol

Atrial flutter with a 4:1 conduction ratio.

Esmolol(short action)

Class III

These AAD prolong the duration of the AP and increase the abso- lute refractory period. This is the result of reduced influx of K+

into the cell. Ind: SV and ventri- cular arrhythmias.

Amiodarone (p.o.; i.v. inf.) t1/2 20–100 days ADRs: bradycardia, hypo/hyper thyreoidism, corneal micro-deposits under pupil, neuritis n. opticus, pulmonary fibrosis.Dronedarone (contains no iodine but has hepatotoxic effect)Sotalol, Bretylium

Class IV (calcium channel antagonists)

Mainly Verapamil (22% oral availability) and Diltiazem (i.v.) from calcium antagonists have specific action on the SA and AV nodes. They decrease the duration of AP.

Ind: SV arrhythmias.ADRs: headache, edema,bradycardia, AV block

Atrial fibrillationAtrial fibrillation

AdenosineAdenosine inhibits AV conduction. The duration of effect is less than 60 s.•used as an i.v. bolus in SV tachycardia with SV tachycardia with narrow QRS complexnarrow QRS complex.•ADRs: bradycardia, AV block.

Other drugs used in tachyarrhythmias

Digoxin reduces conduction through the AV node and is useful in the control of atrial flutter and atrial fibrillation.

Atropine is given by bolus i.v. inj. in sinus brady- cardia and AV block. It blocks M2-receptors and increases conduction through the AV node.Isoprenaline is used in AV block

II. AAD used in bradyarrhythmiasII. AAD used in bradyarrhythmias

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Pacemaker

Digitalis purpurea(foxglove)

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Digitoxin Digoxin

PhenytoinPotassium chlorideMagnesium aspartate•Digoxin- specific FAB (Fragment AntiBody): Digibind®

(38 mg connect 0,5 mg Digoxin)

III. AAD used in Digitalis arrhythmiaIII. AAD used in Digitalis arrhythmia

PROARRHYTHMIC ACTIVITY OF AADPROARRHYTHMIC ACTIVITY OF AAD

All AAD have the potential to precipitateserious arrhythmias, particularly ventri-cular tachycardia or fibrillation.

Mainly the AAD from class IA prolong the Q–T interval which predisposes to the development of a polymorphic ventricular tachycardia known as “torsades de pointes”.

Polymorphic ventricular tachycardiawith a twisting axis on the ECG

Torsades de PointesTorsades de Pointes

Treat hypokalemia if it is the precipitating factor and administermagnesium sulfate in a dose of 2–4 g i.v. initially. Magnesium is usually very effective, even in the patient with anormal magnesium level. If this fails, repeat the initial dose, but because of the danger of hypermagnesemia (depression ofneuromuscular function) the patient requires close monitoring. Other therapies include overdrive pacing and isoprenaline infusion.Most (75–82%) torsade de pointes rhythms are started by apause. Pacing at rates up to 140 bpm may prevent the ventricularpauses that allow torsade de pointes to originate. The patient with torsade who is in extremis should be treated with electrical cardioversion or defibrillationelectrical cardioversion or defibrillation.

See: http://emedicine.medscape.com/article/760667-treatment

Torsades de Pointes: TreatmentTorsades de Pointes: Treatment