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

2. ANTI-DYSRHYTHMIC DRUGS
ANTI-ARRHYTHMIC or
ANTI-DYSRHYTHMIC DRUGS

3. 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

4. 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

5. 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

6. 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

7. 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.

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

9. 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

10. 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.

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. -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

19. 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

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

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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. Class IV drug- Diltiazem:
similar antiarrhythmic properties to verapamil

29. 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

30. 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

31. 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

32. 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

33. 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

34. THANK YOU FOR YOUR ATTENTION!