Antiarrhythmics

Mechanism of arrhythmias and ionic basis of mechanism of action of antiarrhythmics

1. ANTI ARRHYTHMIC DRUGS - I Dr D SUNIL REDDY

2. NORMAL CARDIAC AP

3. IONIC BASIS OF CARDIAC AP

4. Automaticity is the property to initiate an impulse spontaneously, without need for prior stimulation, so that electrical quiescence does not occur. Triggered activity is pacemaker activity that results consequent to a preceding impulse or series of impulses, without which electrical quiescence occurs These are called early afterdepolarizations (EADs), when they arise from a reduced level of membrane potential during phases 2 (type 1) and 3 (type 2) of the cardiac AP L ate or delayed afterdepolarizations (DADs), when they occur after completion of repolarization (phase 4), generally at a more negative membrane potential than that from which EADs arise.

5. EFFECTS OF BLOCKING Na CHANNEL Decrease in conduction velocity ( dromotropy ) manifest as widening of QRS duration ( decreased rentry ) Increase action potential threshold ( decreased automaticity / pacing threshold) Slight decrease in AP duration (QT interval) Negative inotropy ( Lower Na+ permeability through the channel means less Na+ in the cell. More Na/ Ca exchange - less intracellular Ca 2+ and less contractility )

6. Na+ blockers have a greater propensity to bind to channels in the active state, the faster the rate , more the binding and more the anti arrhythmic effect. This is called use dependence, a property of Na+ channel blockers

7. EFFECTS OF BLOCKING K CHANNEL Main effect = Increased APD = increased refractoriness (Decreased reentry ); ( longer QT ) „ Many K+ Ch blockers have a reverse use dependent effect ( binds to resting channels) : AP prolongation is greater at slower rather than at faster rates = EAD Increased risk of triggered activity ( EAD ) leads to proarrhythmias

8. Na blockade Na CHANNEL BLOCKADE K CHANNEL BLOCKADE

9. EFFECTS OF BLOCKING Ca CHANNEL Inhibit the SA & AVN, and tissue with abnormal automaticity dependent on Ca2+channels (e.g . RVOT) Generally little effect on the APD Stops triggered activity ( EAD and DAD ) EADs due to oscillatory depolarisations due to waves of Ca2+ channel reactivation DADs result from Ca 2+ overload of the cell

10. EARLY AFTER DEPOLARISATIONS

11. DELAYED AFTERDEPOLARISATION

12. ANTI ARRHYHTMIC AGENTS Most of the available antiarrhythmic drugs can be classified according to whether they exert blocking actions predominantly on Sodium channels Potassium channels C alcium channels whether they block receptors ( eg . Beta rec.)

13. VAUGHAN WILLIAMS SINGH AND HAUSWIRTH CLASSIFICATION In 1970, Vaughan Williams proposed a classification based on possible ways in which abnormal cardiac rhythms could be corrected or prevented In 1974, Singh and Hauswirth modified the classification , with two major changes . First, lignocaine and Phenytoin were placed in a separate class, because at low concentrations and at low external potassium concentrations, they had little effect upon the AP or cardiac conduction. Secondly , a separate class (now class IV) was introduced to accommodate CCB

14. VAUGHAN-WILLIAMS CLASSIFICATION Class Action Drugs Primary site of action I  Na channel blockade     Ia Q UINIDINE,PROCAINAMIDE, DISOPYRAMIDE HP , A , V    Ib LIDOCAINE, MEXILETINE,PHENYTOIN V    Ic FLECAINIDE, PROPAFENONE, MORICIZINE HP , V II   ß- blockade PROPRANOLOL, METOPROLOL, ESMOLOL, ACEBUTOLOL SAN , AVN III  Potassium channel blockade   SOTALOL, DOFETILIDE, AMIODARONE, BRETYLIUM, IBUTILIDE A , V , AVN , SAN, HP, Acc P IV  CCB   VERAPAMIL, DILTIAZEM AVN

15. DRAWBACKS OF VWSH CLASSIFICATION Over simplification of the effect of these drugs It relies on the effect these agents have on normal tissue and under arbitrary conditions The major effect an agent from one group has, overlaps with the effect of agents from other groups .

16. SICILIAN GAMBIT CLASSIFICATION OF ARRHYTHMOGENIC MECHANISMS Formulated by the European Society of Cardiology working group It seeks the critical mechanisms responsible for arrhythmogenesis to identify a “ vulnerable parameter ” of the arrhythmia concerned Drugs are classed based on their differential effects on ( 1) Channels ( 2) Receptors and ( 3) Transmembrane pumps

17. CLASS I ANTIARRHYTHMICS C lass I drugs predominantly block the fast Na+ channel (may block K+ channels as well) G roup 1 drugs are further subdivided on the basis of their effects on AP duration Group 1A agents - prolong the AP Group 1B drugs - shorten the AP in some cardiac tissues. Group 1C drugs - have no effect on APD

18. The class IC agents have the slowest binding and dissociation from the receptor. The class IB agents have the most rapid binding and dissociation from the receptor. The class IA agents are intermediate in terms of the speed of binding and dissociation from the receptor. Use-dependence is seen most frequently with the class IC agents, less frequently with the class IA drugs, and rarely with the class IB agents 

19. CLASS – I A This class includes drugs that depress phase 0 (sodium-dependent) depolarization, thereby slowing conduction and prolong action potential duration QUINIDINE, PROCAINAMIDE AND DISOPYRAMIDE. Their kinetics of onset and offset in blocking the Na + channel are of intermediate rapidity (less than 5 seconds) compared with class IB and class IC agents These drugs affect both atrial and ventricular arrhythmias . They block I Na , and therefore slow conduction velocity in the atria, Purkinje fibers, and ventricular cells.

20. They also have moderate potassium channel blocking activity (which tends to slow rate of repolarization and prolong action potential duration [APD]), They also have anticholinergic activity, and tend to depress myocardial contractility. At slower heart rates, when use-dependent blockade of the sodium current is not significant, potassium channel blockade may become predominant (reverse use-dependence), leading to prolongation of the APD and QT interval and increased automaticity.

21. CLASS I B This class of drugs does not reduce rate of rise of AP upstroke and shortens AP duration MEXILETINE, PHENYTOIN, AND LIDOCAINE Their kinetics of onset and offset in blocking the sodium channel are rapid (less than 500 milliseconds).

22. The class IB drugs have less prominent sodium channel blocking activity at rest, but effectively block the sodium channel in depolarized tissues. They tend to bind in the inactivated state (which is induced by depolarization) and dissociate from the sodium channel more rapidly than other class I drugs. As a result, they are more effective with tachyarrhythmias than with slow arrhythmias.

23. CLASS I C This class of drugs can reduce rate of rise of AP upstroke , primarily slow conduction velocity, and prolong refractoriness minimally FLECAINIDE , PROPAFENONE AND MORICIZINE These drugs have slow onset and offset kinetics (10 to 20 seconds).

24. Class IC drugs primarily block open sodium channels and slow conduction. They dissociate slowly from the sodium channels during diastole, resulting in increased effect at more rapid rate (use-dependence). This is the basis for their antiarrhythmic efficacy, especially against supraventricular arrhythmias. Use-dependence may also contribute to the proarrhythmic activity of these drugs, especially in the diseased myocardium, resulting in incessant ventricular tachycardia.

25. GROUP II ( BETA BLOCKERS ) They decrease depresses SA node automaticity and prolong the refractoriness of the AV node Blockers may prevent shortening of refractoriness at all levels in the heart. They also block adrenergic activation of Ca channels. In addition, beta 2 receptors are implicated in ischemia-dependent ventricular fibrillation, which may be prevented by nonselective blockade

26. These agents also act on: I f , important pacemaker current that promotes proarrhythmic depolarization in damaged heart tissue The inward calcium current, which is indirectly inhibited as the level of tissue cAMP falls. Blockers may suppress non sustained ventricular arrhythmias, especially in patients with an underlying adrenergic mechanism. Consequently, they are the drugs of choice in exercise-induced arrhythmias and in patients with long QT syndrome, especially LQT1

27. CLASS III ANTI ARRHYTHMICS The hallmark of group 3 drugs is prolongation of the AP duration. This AP prolongation is caused by blockade of I K  potassium channels ( during phase II and III of AP) that are responsible for the repolarization of the AP leading to an increase in effective refractory period They do not impact conduction

28. MIXED CLASS III – AMIODARONE , SOTALOL PURE CLASS III – IBUTILIDE AND DOFETILIDE

29. CLASS IV (CCB) They are effective in arrhythmias that must traverse Ca -dependent cardiac tissue ( eg , AVN) These agents cause a use-dependent selective depression of calcium current in tissues that require the participation of L-type Ca channels AV conduction velocity is decreased and effective refractory period increased by these drugs. PR interval is consistently increased

30. THANK YOU

31. It is especially important to adhere to the following fundamental principles of drug therapy: Define a benefit for therapy. Define an end point for therapy. Minimize the risks (and ensure that these do not outweigh the expected benefits). Define the need for therapy. Consider alternative therapies.

32. Class IA Slows conduction velocity (less than class IC) and prolongs action potential duration ( APD) Disopyramide Procainamide Quinidine Class IB – They have no effect on conduction velocity and may shorten APD Lidocaine Mexiletine Phenytoin Class IC – Slows conduction and may prolong APD Flecainide Propafenone

33. PROPERTIES FAST RESPONSE TIMES SLOW RESPONSE TIMES Location Atria, specialized infranodal conducting system, ventricles, AV bypass tracts Sinoatrial and atrioventricular nodes, depolarized fast response tissues in which phase 0 depends upon calcium current PASSIVE CELLULAR PROPERTIES Resting Potential -80 to -95 mV -40 to -65 mV ACTIVE CELLULAR PROPERTIES Phase 0 current Sodium Primarily calcium Phase 0 channel kinetics Fast Slow activation; inactivation depends upon voltage and cell calcium concentration Peak overshoot +20 to +40 mV -5 to + 20 mV AP amplitude 90 to 135 mV 30 to 70 mV

34. PROPERTIES DEPENDENT UPON ACTIVE AND PASSIVE PROPERTIES Threshold voltage -60 to -75 mV -40 to -60 mv Conduction velocity 0.5 to 5 m/sec 0.01 to 0.1 m/sec Conducive To reentry Only with inactivation of sodium channels with marked slowing of conduction velocity Present in normal tissue Automaticity Yes Yes