CARDIAC ARRHYTHMIAS & ANTI-ARRHYTHMIC DRUGS PART II 16th Feb 2017

ANTI-DYSRHYTHMIC DRUGS ANTI-ARRHYTHMIC or ANTI-DYSRHYTHMIC DRUGS

Antidysrhythmic Drugs A classification of antidysrhythmic drugs based on their electrophysiological effects was proposed by Vaughan Williams in 1970. It provides a good starting point for discussing mechanisms, although many useful drugs do not fit neatly into this classification. Furthermore, emergency treatment of serious dysrhythmias is usually by physical means (e.g. pacing or electrical cardioversion by applying a direct current shock to the chest or via an implanted device) rather than drugs

Antidysrhythmic Drugs- Classification There are 4 classes: Class I: Inhibitors of Na+ influx (voltage sensitive Na)- subdivided into Ia, Ib and Ic Class II: ß-adrenoceptor antagonists Class III: Drugs that substantially prolong the cardiac action potential Class IV: Calcium antagonists 4

Class I Drugs-Inhibitors of Na+ Influx Inhibit the fast Na+ channels also block the slow Ca2+ - Na+ channels reduce intracellular Ca2+ leading to a -ve inotropic effect must be used with care where heart failure is suspected

inhibition of Na+ channels leads to either: - (a) slowing of conduction - (b) increase in refractory period Drugs under this class have local anaesthetic or membrane stabilizing effect 6

Class I subgroups: Ia, Ib and Ic The reason for subdivision is that the earliest examples, quinidine and procainamide (Class Ia) have different effects from many of the more recently developed drugs, even though all share the same basic mechanism of action. A partial explanation for these functional differences comes from electrophysiological studies of the characteristics of the sodium channel block produced by different class I drugs.

Class Ia: suitable for ventricular & supraventricular arrhythmias include: quinidine procainamide Disopyramide Lorcainide 8

Class Ia … In the therapeutic concentrations they: raise the threshold for excitation (lengthen AP duration) cause minor slowing of intra-cardiac conduction widen the QRS complex they prolong the AP and lengthen the effective refractory period (probably results from K+ channel blockade) of atrial, ventricular & purkinje fibres. 9

NB: QRS Complex is a name for the combination of three of the graphical deflections seen on a typical electrocardiogram {ECG –a record or display of a person’s heart beat produced by electrocardiography} It is usually the central and most visually obvious part of the tracing, It corresponds to the depolarization of the right and left ventricles of the human heart.

Class Ia… Quinidine, procainamide & disopyramide have a low therapeutic index their -ve inotropic effects extend to skeletal muscle (aggrevation of myasthenia gravis) and vascular smooth muscle (hypotension) -varying degree of atropine-like effect. 11

Class Ib suitable for suppression of ventricular arrhythmias after myocardial infarction include: Lignocaine, Phenytoin, Mexiletene and tocainide Properties: -they shorten AP duration & effective refractory period - have no effect on intra-cardiac conduction or QRS complex 12

Class Ib…: Lignocaine/lidocaine Has a rapid onset of action and a short half-life (approx. 1h) given i/v as the 1st line drug in the treatment of ventricular arrhythmias after myocardial infarction and surgery inactive orally also an antagonist at muscarinic acetylcholine receptors and may evoke mild tachycardia by removing the effect of vagal tone on the SA node SE: confusion, fits, sweating and drowsiness 13

Class Ib: Phenytoin used almost exclusively in digitalis-induced ventricular arrhythmias Its general anti arrhythmic effectiveness is less than that of lignocaine Side Effects: hypotension

Class Ib:… Tocainide: -analogue of lignocaine -active orally and i/v -has similar electrophysiological & haemodynamic properties to lignocaine. -longer acting Mexiletene: -similar electrophysiological properties to lignocaine - active orally and i/v 15

Class Ic Drugs in this group have 2 effects: (a) slow intra-cardiac conduction (b) widen the QRS complex They do not so much affect the threshold of excitation Include: Flecainide, Encainide, and Propafenone 16

Class Ic; Flecainide Slows conduction in atria, His-purkinje system, accessory pathways & ventricles in therapeutic concentrations it causes lengthening of the PR & QRS intervals it is a powerful broad spectrum antiarrhythmic effective vs atrial arrhythmias, tachycardia involving accessory pathways (Wolff-Parkinson-White syndrome) & ventricular arrhythmias 17

-similar antiarrhythmic spectrum to flecainide Class Ic: Propafenone: Class Ic:Encainide: -similar antiarrhythmic spectrum to flecainide Class Ic: Propafenone: -has additional minor ß-blocking and calcium channel antagonist properties -effective against supraventricular and ventricular arrhythmias 18

Class II: ß-adrenoceptor antagonists effective in arrhythmias associated with sympathetic overactivity or increased circulating catecholamines E.g. Myocardial infarction, emotion, exercise, anaesthesia they reduce automaticity (ectopic pacemaker) 19

Class II: ß-adrenoceptor antagonists … increase effective refractory period decrease conduction velocity Include: Propranolol Atenolol Metoprolol Acebutolol Timolol 20

Class II Bretylium: has adrenergic neurone blocking activity suppresses release of NA It is both Class II & III 21

Drugs That Prolong Both the Action Potential and Refractory Period Class III Drugs That Prolong Both the Action Potential and Refractory Period Also called slow repolarizers they block K+-channels prolong the duration of the plateau region of cardiac AP lengthen effective refractory period 22

Drugs: Amiodarone, bretylium, sotalol Amiodarone: blocks K+ & Na+ - channels it is a non-competitive antagonist at alpha & ß-adrenoceptors (Class I and class II effects) effective against many arrhythmias including Wolff-Parkinson-White syndrome) due to side effects it is only used when other drugs can not be used 23

it causes neuropathy & pulmonary alveolitis Sotalol: It causes irreversible liver damage, thyroid disorders (its molecule contains iodine) it causes neuropathy & pulmonary alveolitis Sotalol: it is a non-selective beta-blocker also has class III activity prolongs atrial & ventricular action potential duration prolongs refractory period 24

Inhibitors Of Calcium Influx (Calcium antagonists) Class IV Inhibitors Of Calcium Influx (Calcium antagonists) Inhibit the slow inward Ca2+ - current which result in: (1) slowed conduction (2) prolonged refractoriness in the AV node useful for supraventricular tachycardia involving the AV node. Blocks intranodal re-entry circuits 25

Not effective in Wolff-Parkinson-White syndrome effective in some types of re-entry tachycardia in which the AV node is involved Not effective in Wolff-Parkinson-White syndrome 26

Class IV drug-Verapamil effective when the Ca2+ channels are either activated or inactivated (occurs when frequency of AP is high) [use-dependent] It is the main drug Used to prevent recurrence of paroxysmal supraventricular tachycardia And to reduce the ventricular rate in patients with atrial fibrillation (especially if inadequately controlled with digoxin), provided they do not have Wolff-Parkinson-White or related disorder

Class IV drug- Diltiazem: similar antiarrhythmic properties to verapamil

Nifedipine: not anti-arrhythmic. It does not exhibit use-dependence it also blocks the slow Ca2+ channels but it is only effective when the channels are in the activated state 29

Not Classified DIGOXIN: slows conduction and prolongs the refractory period in the AV node and bundle of His used in atrial fibrillation which it does not stop but it slows & strengthens the ventricular beat reduces the frequency at which impulses pass along the conducting tissue Principal indication: CHF associated with atrial fibrillation 30

Adenine nucleotides Adenosine & ATP used as substitutes for verapamil in the treatment of supraventricular tachycardias (adenosine is safer than verapamil) they act via purinergic receptors situated in the SA & AV nodes stimulation of these receptors hyperpolarizes cells resulting in suppression of automaticity and conduction 31

Interrupt re-entry circuits in AV nodal tachycardia, and AV tachycardia involving an accessory pathway (Wolff-parkinson-White syndrome). ALTERNATIVE TO DRUGS use of pacemakers DC shock - if atrial size is normal it causes reversion to normal rhythm in most patients with atrial fibrillation (relapse 60% within 1 yr) surgical ablation of ectopic focus or bundle of His to control supraventricular arrhythmias - pacemaker 32

References Lecture notes on clinical pharmacology 4th Ed. John L. Reid, Peter C. Rubin & Brian Whiting Basic Pharmacology 4th Ed by R.W. Foster Pharmacology 5th ed by Rang & Dale et al Medical Pharmacology at a glance by M.J. Neal The Physiology of excitable cells 3rd ed by David J. Aidley pg 313 Textbook of Medical physiology 7th ed. By Arthur C. Guyton Pharmacology by Rang & Dale, 7th edition, chapter 21 33

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