Mechanisms Of Action Of Antiarrhythmic Drugs

An arrhythmia may be controlled either by slowing the primary mechanism or, in the case of supraventricular arrhythmias, by reducing the proportion of impulses transmitted through the AV node to the ventricular conducting system. The cardiac action potential may be pharmacologically manipulated in three ways:

• The automaticity (tendency to spontaneous discharge) of cells may be reduced. This result can be achieved by reducing the rate of leakage of sodium (reducing the slope of phase 4), by increasing the electronegativity of the resulting membrane potential or by decreasing the electronegativity of the threshold potential.

• The speed of conduction of the action potential may be suppressed as reflected by a lowering of the height and slope of the phase 0 discharge. A reduction in the electronegativity of the membrane potential at the onset of phase 0 reduces both the amplitude and the slope of the phase 0 depolarization. This situation occurs if the cell discharges before it has been completely repolarized.

• The rate of repolarization may be reduced, which prolongs the refractory period of the discharging cell.

All antiarrhythmic drugs may themselves induce arrhythmias. Many (particularly class 1 antiarrhythmics) have a narrow therapeutic index and some have been associated with no benefit or even an increase in mortality in large-scale studies. In addition, non-pharmacological techniques (e.g. DC cardioversion, implantable pacemakers or cardioverter defibrillators, and radiofrequency ablation) have become more widespread. Consequently, the use of antiarrhythmic drugs for chronic therapy has declined in recent years. However, owing to the frequency of arrhythmias during anaesthesia, knowledge of the available drugs and their interactions is important for the anaesthetist.

Antiarrhythmic agents may be classified empirically on the basis of their effectiveness in supraventricular tachycardias (e.g. digoxin, p-blockers and verapamil) or in ventricular arrhythmias (lidocaine, mexiletine, tocainide, phenytoin and bretylium). Many agents (disopyramide, amiodarone, quinidine and procainamide) are effective in both supraventricular and ventricular arrhythmias. The Vaughan Williams classification (Table 7.13) is based on electrophysiological mechanisms. Although this classification has limitations (some drugs belong to more than one class, some arrhythmias may be caused by several mechanisms, some drugs, e.g. digoxin, adenosine, do not fit into the classification) it remains in common use, and is therefore described below.

Class 1 drugs inhibit the fast sodium influx during depolarization; they inhibit arrhythmias caused by abnormal automaticity or re-entry. All class 1 antiarrhythmics decrease the maximum rate of rise of phase 0, and decrease conduction velocity, excitability and automaticity to varying degrees. In addition to these local anaes-

Table 7.13 Vaughan Williams classification of ami-arrhythmic drugs

Class Examples



Indication la Quinidinc Na+ channel blockade (moderate) Disopyramide J Conduction velocity

Prolonged duration of action potential lb Lidocaine Na* channel blockade (mild) Bretvlium 1 Conduction velocity

Shortened repolarization lc Flecainide Na* channel blockade (marked) Propafenone I Conduction velocity

No change in repolarization

2 p-Blockers ^-Adrenergic receptor blockade

Amiod arone




Inhibition of inward K+ current

Calcium channel blockade

Moderate J I'max t Action potential duration Î Refractory period QRS widened Mild A VMAX

i Action potential duration J Refractory period QRS tin changed Marked ; l'MAX

Minimal change in action potential duration and refractory period QRS widened Decreased auto m ati city (SA and AVnodes)

Markedly prolonged repolarization t Action potential duration t Refractory period QRS unchanged i Depolarization and i'max of slow response cells in SA and AV nodes I Action potential duration | Refractory period of AV node

Prevention of SVT, VT, atrial tachycardia WPW

Prevention ofVT/VF during ischacmia

Prevention of sympathetic-induced tachyarrhythmias, rate control in AH, 2" prevention after Ml, prevention of AV node re-entrant tachycardia Prevention of SVT/VT/VF

Rate control in AF Prevention of AV7 node re-entrant tachycardia thetic properties, some have membrane-stabilizing effects. Class la drugs antagonize primarily the fast influx of sodium ions and so reduce conduction velocity through the AV node and His-Purkinje system, whilst prolonging the duration of the action potential and the refractory period. They also have antimuscarinic and sympathomimetic effects, to varying degrees. Class lb drugs have much less effect on conduction velocity in usual therapeutic doses and they shorten the refractory period. Agents in class lc affect conduction profoundly without altering the refractory period.

P-Blockers (class 2) depress automaticity in the SA and AV nodes, and attenuate the effects of catecholamines on automaticity and conduction velocity in the sinus and AV nodes. Class 3 drugs prolong the action potential and so lengthen the refractory period. Verapamil (class 4) also prolongs the action potential, in addition to depressing automaticity (especially in the AV node) (see Tables 7.14 and 7.15).

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