1. Antiarrhythmic Drugs

2. Arrhythmias
These are drugs used to prevent or treat irregularities of cardiac rhythm.
Arrhythmias are the most important cause of sudden cardiac death.
Types :
extra beats (extrasystoles):
premature atrial contractions
premature ventricular contractions
supraventricular tachyarrhythmias:
atrial fibrillation (irregular heart rates of 350 to 700  bpm)
atrial flutter( ’flutter waves’ at a regular rate of 240 to 440 bpm)
paroxysmal supraventricular tachycardia ( bpm)
ventricular arrhythmias:
ventricular fibrillation (fatal unless reverted within 2–5 min; the most common cause of sudden cardiac death)
ventricular tachycardia
Torsades de pointes (twisting of points) is a life-threatening form of ventricular tachycardia with rapid asynchronous complexes and an undulating baseline on ECG. It is generally associated with long Q-T interval.
bradyarrhythmias

3. Phases of a cardiac action potential.
The sharp rise in voltage ("0") corresponds to the influx of Na ions
The decay ("1”) corresponds to the Na-channel inactivation, efflux of K+ ions
The plateau ("2") results from the opening of Ca2+channels.
The decay ("3") corresponds to the repolarizing efflux of K+ ions.

4. Phases of a cardiac action potential
Phase-0 - rapid depolarization
Phase-1 – repolarization
phase-2 - plateau phase
Phase-3 - rapid repolarization
Phase-4 – stable phase or resting membrane potential

5. Refractory period
Effective refractory period (ERP) is the minimum interval between two propagating APs or from the beginning of phase 0 until phase 3, during which it is impossible to evoke another action potential.

6. Mechanisms of cardiac arrhythmias
Enhanced/ectopic pacemaker activity
Ectopic impulse may be increased pathologically in the automatic fibres or such activity may appear in ordinary fibres.
Triggered activity
These are secondary depolarizations accompanying a normal or premature action potential (AP).
Early after-depolarization
Repolarization during phase-3 is interrupted and membrane potential oscillates. If the amplitude of oscillations is sufficiently large, neighbouring tissue is activated and a series of impulses are propagated.
Delayed after-depolarization
After attaining resting membrane potential (RMP) a secondary deflection occurs which may reach threshold potential and initiate a single premature AP.

7. Mechanisms of cardiac arrhythmias
C. Re-entry
Due primarily to abnormality of conduction, an impulse may recirculate in the heart and cause repetitive activation without the need for any new impulse to be generated. These are called reentrant arrhythmias.

8. Class I: Fast Na-channel blockers
Class II: Beta blockers(decreases slope of phase 4)
Class III: K-channel blockers(prolongs phase 3)
Class IV: Slow Ca-channel blockers(prolongs phase 2)
Variable mechanism:
Adenosine
Digoxin
Magnesium sulf.

10. CLASS I Class I: Fast Na-channel blockers
Ia -Quinidine, procainamide, disopyramide (depress phase 0, prolonging repolarization)
Ib -Lidocaine, phenytoin, mexiletine (depress phase 0 selectively in abnormal/ischemic tissue, shorten repolarization)
Ic -Flecainide, propafenone, moricizine (markedly depress phase 0, minimal effect on repolarization)

11. See the phase 3 of the curve to apply the mnemonic:
IB antiarrhytmics show the line Before the (normal) face.
IA antiarrhytmics show the line After the (normal) face.
IC antiarrhytmics show the line Cara (spanish world of face), because is the same as normal in phase 3.

12. Clinical uses in cardiologyIa
Ventricular arrhythmias
prevention of paroxysmal recurrent atrial fibrillation (triggered by vagal overactivity)
procainamide in Wolff-Parkinson-White syndrome
Increases QT interval
ADR
Risk of torsades de pointes !!!
neurological effects (ringing in ears, vertigo)
Marked fall in BP
Synergistic cardiac depression with β-blockers, verapamil, K+ salts.

13. Clinical uses Ib
only for ventricular tachycardia (VT) (inefficacy in atrial arrhythmias)
treatment and prevention VT during and immediately after myocardial infarction
ADR
Proarrhythmic potential !!!
neurological effects(paresthesias, blurred vision)

14. Clinical uses Ic prevents paroxysmal atrial fibrillation
treats recurrent tachyarrhythmias of abnormal conduction system.
contraindicated immediately post-myocardial infarction.
ADR
High proarrhythmic potential
Sudden deaths

15. CLASS II Class II agents include: They act by: Atenolol
Esmolol
Propranolol
Metoprolol
Uses
prevent and treatment of supraventricular tachyarrhythmias
decrease myocardial infarction mortality
They act by:
blocking the β1-adrenergic receptors,
decreasing sympathetic activity on the heart.
decrease conduction through the AV node.

16. CLASS III Class III: Potassium (K) channel blockers
Amiodarone (prolongs phase 3; also acts on phases 1, 2, and 4)
Sotalol (prolongs phase 3, decreases slope of phase 4)
Ibutilide (prolongs phase 3)
Dofetilide (prolongs phase 3)
The characteristic action of this class is:
prolongation of repolarization (phase-3);
AP is widened
ERP is increased.

17. Amiodarone
Iodine containing highly lipophilic long-acting antiarrhythmic drug exerts multiple actions: Amiodarone has Class I, II, III & IV activity
It accumulates in muscle and fat.
The duration of action is exceptionally long: t½ 3–8 weeks
It is useful both in supraventricular arrhythmias and ventricular arrhythmias (e.g. ventricular fibrillation, ventricular tachycardia, atrial fibrillation)
Side effects:
Pulmonary fibrosis
Hypothyroidism
Hyperthyroidism
Corneal micro-deposits
Blue-grey discoloration of the skin
Photosensitization
Peripheral neuropathies
Possible association between amiodarone and an increased risk of cancer
Fall in BP
Bradycardia
Myocardial depression

19. CLASS IV Calcium (Ca) channel blockers Verapamil (prolongs phase 2)
Diltiazem (prolongs phase 2)
They decrease conduction through the AV node
They thus reduce the contractility of the heart, so may be inappropriate in heart failure.
Poor /no efficacy in ventricular arrhythmias
Uses:
paroxysmal supraventricular tachycardia
reduce ventricular rate in patients with atrial fibrillation.
ADR
bradycardia, A-V block, cardiac arrest and hypotension

20. Class V / Other agents Digoxin
decreases conduction of electrical impulses through the AV node and increases vagal activity.
Adenosine
Is used intravenously for terminating supraventricular tachycardias (PSVT).
Magnesium sulfate
an antiarrhythmic drug, but only against very specific arrhythmias which has been used for torsades de pointes.

21. Adenosine Very short t½ ~ 10 sec Uses : Termination of attack of PSVT
Advantages of adenosine:
Efficacy equivalent to or better than verapamil.
Action lasts < 1 min adverse effects are transient.
Can be given to patients with hypotension, CHF or those receiving β blockers. Verapamil is contraindicated in these situations.
Effective in patients not responding to verapamil.
ADR
Transient dyspnoea, chest pain, fall in BP, cardiac arrest

22. Digoxin Indications: atrial fibrillation atrial flutter
By slowing down the conduction in the AV node and increasing its refractory period, digoxin can reduce the ventricular rate.
The arrhythmia itself is not affected, but the pumping function of the heart improves, owing to improved filling.

23. Clinical classification of antiarrhythmic drugs

24. Bradyarrhythmias and A-V Block
Treatment of chronic heart block - implanted cardiac pacemaker.
For acute/transient A-V block :
Atropine
Atropine abbreviates A-V node ERP and increases conduction velocity in bundle of His.
Adrenomimetics (Adr, isoprenaline)
These drugs may overcome partial heart block by facilitating A-V conduction and shortening ERP of conducting tissues.
They may also be used in complete heart block to maintain a sufficient idioventricular rate (by increasing automaticity of ventricular pacemakers) till external pacemaker can be implanted.