© Assoc. Prof. Ivan LambevE-mail: itlambev@mail.bg

ANTIARRHYTHMICDRUGS(Summary)

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

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 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 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 self-

perpetuating “loop” of electricalactivity which acts as a pacemaker.

The re-entry circuit can be localized

within the small area of myocardiumor it can exists as 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 (AAD)

I. AAD used in tachyarrhythmias

The Vaughan WilliamsClassification 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 0of AP by inhibiting fast sodium channels.The class is subdivided according to theeffects of drugs on duration of AP.Ind.: 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

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

Rauwolfia serpentina•Ajmaline•Reserpine

Cinchona succirubra•Quinidine•Chinine

Ventricular fibrillation, characterizedby irregular undulations without clear ventricular complexes.

Treatment: Lidocaine or electrostimulation

Class II (-adrenoceptor antagonists)

Reduce the rateof spontaneous depo-larization of sinusand AV nodal tissueby indirect blockadeof calcium channels.Ind: SV and ventri-cular arrhythmias.

( cAMP)

pindolol, propranololatenolol, esmolol

Atrial flutter with a 4:1 conduction ratio.

Esmolol(short action)

Class IIIThese AAD prolongthe duration of the APand increase the abso-lute refractory period.This is the result ofreduced influx of K+

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

Amiodarone t1/2 5060 days ARs: hypo/hyperthyroidism, pulmonary fibrosis

Sotalol, Bretylium

Class IV (calcium channel antagonists)

Mainly verapamil(22% oral availability)and diltiazem (i.v.) fromcalcium antagonistshave specific actionon the SA and AVnodes. They decreasethe duration of AP.

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

Adenosine inhibits AV conduction. The duration of effect is less than 60 s.•used bolus i.v. in SV tachycardia with narrow QRS complex.•ARs24-h: bradycardia, AV block.

Other drugs used in tachyarrhythmias

Digoxin reduces conduction through AV node and is useful to control atrial flutter and atrial fibrillation.

Atropine is givenby bolus i.v. inj.in sinus brady-cardia and AVblock. It blocksM2-receptors andincreases conductionthrough the AV node.Isoprenalineis used in AV block

II. AAD used in bradyarrhythmias

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Digitalis purpurea(foxglove)

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Digitoxin Digoxin

III. AAD used in Digitalis arrhythmia

PhenytoinPotassium chlorideMagnesium aspartate

PROARRHYTHMIC 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 QT interval which predisposes to develop a polymorphic ventricular tachy-cardia known as “torsades de pointes”.

Polymorphic ventricular tachycardiawith a twisting axis on the ECG

Torsades de Pointes

After overdose of AAD from class IA: