Antiarrhythmic drugs By Dr/Azza Baraka Professor of Clinical Pharmacology

Phases of action potential of cardiac cells

Phase 0 rapid depolarisation

(inflow of Na+) Phase 1 Phase 1 partial repolarisation (inward Na+ current deactivated, 0 mV outflow of K+) Phase 2 plateau (slow inward Phase 0 calcium current) I Phase 3 repolarisation (calcium current inactivates, K+ outflow) -80mV Phase 4 pacemaker potential Phase 4 II (Slow Na+ inflow, slowing of K+ outflow) autorhythmicity Refractory period (phases 1-3)

IV
Phase 2

III
Phase 3

ECG

P - atrial depolarisation QRS - ventricular depolarisation T - ventricular repolarisation

Definition of dysrrhythmia

Cardiac dysrrhythmia is an abnormality of the heart rhythm

Mechanisms of dysrrhythmia production

Abnormal impulse formation: 2. 2. Abnormal impulse conduction: Re-entry
1.

Mechanism of Reentry

Therapeutic Objectives of AADs

1.

2.

3.

Terminate and prevent arrhythmia (rhythm control) In case of supraventricular arrhythmias: Protect ventricle , i.e. decrease conduction of impulse from atrium to ventricle through AV node( rate control) Reduce mortality. However, toxicity is

common with AADs.

Class I: block sodium channels Vaughanprocainamide,) Williams classification of AADs Ia (quinidine, Ib (lignocaine) Ic (flecainide) Class II: -adrenoceptor Phase 1 antagonists (atenolol) IV Class III: prolong action Phase 2 0 mV potential and prolong refractory period ( e.g.amiodarone ) III Phase 0 I Phase 3 Class IV: Calcium channel antagonists. Impair impulse -80mV Phase 4 propagation in nodal and II damaged areas (verapamil) Class V: others, e.g. digitalis,

Properties of an ideal antiarrhythmic drug

1-

Treats both supraventricular & ventricular tachycardia: All used in both EXCEPT: Class Ia & Ic , II & III are used for both Class Ib used for Ventricular only Class IV , & V used for supra only. 2-No depression of cardiac contractility: All depress EXCEPT: Digoxin, Amiodarone, Lignocaine. 3-Decresae mortality: All are neutral EXCEPT: Beta blockers , and amiodarone( mortality in MI), and Class Ic( mortality in pts with MI)

Properties of an ideal antiarrhythmic drug 4-No proarrhythmia All can initiate new arrhythmia and the least are Class II and Class Ib.

Effect of Na channelautomaticity in fast blockade Conduction velocity (CV) ,

response tissue( i.e. Na dependent cardiac tissue). Negative inotropy -Lower Na+ permeability through the channel means less Na+ in the cell. Less Na+ in the cell means more driving force for the Na/Ca exchanger. More Na/Ca exchange means less intracellular Ca2+and less contractility.

The extent of Na channel blockade depends on: 1- Heart rate 2-membrane potential 3-Drug specific kinetics of interaction with Na channel.

Na channel blockers
1.

2.
3.

4. 5.

All reduce the maximal rate of depolarization of the AP and thereby slow conduction (QRS prolongation). Use dependent drugs Very effective AADs, but, to a varying degree, depress left ventricular contractility. All have been associated with proarrhythmia. They are subclassified based on the kinetics of interaction with sodium channels into classes Ia, Ib and Ic.

Use dependence Class I AADs are characterized by the fact that they bind and thus block Na channels when these channels are only in the activated state , or in the inactivated, and they unbind from the channels when these channels are in the resting closed state. Thus, at fast heart rate, Class I AADs have no enough time to unbind from Na channels because when heart rate increases the time available for dissociation of the AAD from the channel decreases and Na channel block increases.. Thus the more the channels are used the more these channels are blocked by Class I

Ia:
1.

Na channel subclasses
intermediate kinetics of interaction with Na channels prolong APD due to additional blockade of K channels. rapid kinetics no effect on APD Slow kinetics do not affect APD

2.

Ib:
1. 2.

Ic:
1.

2.

Examples quinidine 1. Intermediate kinetics of interaction with Na channels . 2. Slows conduction velocity and thus widens QRS complex . 3. Prolongs APD due to blocking of K channels thus can prolong QT interval. 4. Depress left ventricular contractility 5. Indications for supraventricular and ventricular tachycardia.

Class Ia

Adverse effects of Class Ia: Proarrhythmia:Torsade de pointes (also called polymorphic ventricular tachycardia) is a proarrhythmic side effect that can occur due to-induced QT prolongation.

Class Ib

Examples lignocaine(lidocaine). 1. Rapid kinetics of interaction with Na channels. 2. Thus widening of QRS complex only appears at rapid heart rates. 3. Does not block K channels. No effect on APD. 4. Indications for ventricular tachycardia only, drug of choice for treatment of post MI ventricular tachycardia. 5. Extensive first-pass effect that requires IV administration. Toxicity: mainly CNS, e.g. convulsions.

Why lidocaine is only effective in ventricular tacchycardia not supraventricular???

Increased action potential duration increases the time spent for Na channels in the inactivated state which increases block by lidocaine (known to bind to inactivated Na channels). Ventricular tissue has a longer APD compared to atrial tissue.

The most potent sodium channel blocking agents (prolong QRS interval >25%), have been associated with a significant risk of proarrhythmia (monomorphic ventricular tachycardia) and depression of cardiac contractility These adverse effects are uncommon in patients with normal hearts, but important in patients with extensive cardiac damage, e.g.MI, who might be subject to life-threatening ventricular tachyarrhythmias if received class Ic.

Class Ic, e.g. Flecainide

Ia

Ib

Ic

Kinetics of interaction with Na channels

K channel block QT interval QRS

Intermediate
+(but variable among individual drugs) Prolonged Moderate Widening ++

Rapid
No effect Widening only in the presence of tachycardia+ _ Least Least

Slow
No effect Marked widening ++++ _ ++++ Monomorphic ventricular tachycardia especially in presence of structural heart disease e.g. MI
Supraventricular & ventricular tachyarrhythmia in structurally normal heart

Atropine like action Negative inotropism Proarrhythmia

With some drugs Variable between groups Torsades de pointes due to K channel blockade

Therapeutic uses

Supraventricular & ventricular tachyarrhythmia

Only ventricular

Block K channels. Prolong APD. Prolong QT interval. Prolong refractoriness. Amiodarone is a class III drughowever, g has Class I, II& IV Indications for treatment of supraventricular and ventricular tachycardia. Elimination half life of amiodarone is long ( about 58 days) due to accumulation in the tissues.

Class III

Amiodarone side effects

Bradycardia and heart block

Extracardiac
Due to the wide tissue distribution and concentration of the drug
1.
2. 3.

4.

Pulmonary fibrosis Skin deposits and photodermatitis Hypothyroidism or hyperthyroidism Liver toxicity