1. ANTIARRHYTHMIC DRUGS
Arrhythmia or dysrhythmia means an abnormal or irregular heart beat
Arrhythmias may originate in the atria, SA node or AV node, whereby they are known as supra-ventricular arrhythmias or in the ventricles giving rise to the life-threatening ventricular arrhythmias
Causes of Arrhythmias
Arteriosclerosis
Coronary artery spasm
Heart block (mostly AV block)
Myocardial ischemia

2. Mechnisms of Arrhythmogenesis
I. Abnormal Impulse Generation
II. Abnormal Impulse Conduction
A. Automatic rhythms:
- Enhanced normal automaticity
- Abnormal automaticity
B. Triggered rhythms
Early after-depolarisation
- Delayed after- depolarisation
A. Conduction block
First-, second-, third–degree block
B. Re-entry
- Circus movement
- Reflection

3. ANTIARRHYTHMIC DRUGS Most antiarrhythmic drugs are pro-arrhythmic
Only ß-blockers are proved to reduce mortality in post-myocardial infarction patients
They are classified according to Vaughan William into four classes according to their effects on the cardiac action potential
1. Class I ANTIARRHYTHMIC DRUGS:
Drugs in this class are blockers of voltage-operated Na+ channels in the myocardial membrane
They show (class IA & IB) preferential selectivity to Na+ channels in the open or inactivated closed states
Hence, they have better degree of blockade in tissues that are frequently depolarized or use-dependent or state-dependent
They decrease conduction velocity in non-nodal tissue (atrial and ventricular muscle, purkinje conducting system)

4. Class IA Drugs Quinidine is the prototype of this class
Class IA agents slow the phase 0/reduction of Vmax of the cardiac action potential
They prolong muscle action potential and increase ventricular effective refractory period
They decrease the slope of Phase 4 spontaneous depolarization, tending to suppress enhanced normal automaticity-induced arrhythmias

5. Class IA Drugs
They possess intermediate rate of association and dissociation with sodium channels
Agents of Class IA:
Quinidine
Procainamide
Disopyramide
Uses:
Class IA drugs are used in treatment of both atrial and ventricular arrhytmias

6. Class IA Drugs Toxicity
Quinidine
A-V block at higher plasma levels
At toxic levels, ventricular tachycardia and torsade de pointes ventricular arrhythmia
Increasing digoxin plasma concentration by displacing digoxin from binding sites in addition to decreased digoxin renal clearance
Cinchonism occurs at large dose levels (blurred vision, tinnitus, headache, psychosis and gastrointestinal upset)
Digoxin is administered before quinidine to prevent the conversion of atrial fibrillation or flutter into paradoxical ventricular tachycardia. Quinidine shortens of A-V nodal refractoriness by atropine-like effects
Procainamide
1. At high levels, asystole or induction of ventricular arrhythmias
2. Hypersensitivity reactions including drug fever and rarely agranulocytosis.
3. Systemic lupus erythromatosus (SLE)-like (arthralgia, fever & pleural-pericardial inflammation)
The SLE is dose- and time-dependent, and usually disappears upon drug stop
It is most common in patients with slow hepatic acetylation resulting in higher plasma level of the parent drug
Disopyramide
1. Anticholinergic side-effects
2. Induction of ventricular arrhythmias in patients with prolonged QT interval
3. Similar to quinidine, disopyramide may induce ventricular arrhythmia if used alone in the treatment of fibrillation

7. Class IB Drugs
They shorten Phase 3 repolarisation and decreases the duration of the cardiac action potential
They suppress arrhythmias caused by abnormal automaticity (c.f. quinidine suppresses enhanced normal automaticity-induced arrhythmias)
They show rapid association & dissociation with Na+ channels with appreciable degree of use-dependence

8. Mexiletine and tocainide
Agents of Class IB
Lidocaine
It should be used by intravenous route because of its extensive first-pass metabolism
Lidocaine is the drug of choice in emergency treatment of ventricular arrhythmias
Mexiletine and tocainide
These are the oral analogs of lidocaine
Mexiletine is used for chronic treatment of ventricular arrhythmias associated with previous myocardial infarction
Tocainide is used for ventricular tachyarrhythmias but its use is limited by its pulmonary toxicity that may lead to pulmonary fibrosis
Uses
They are used in the treatment of ventricular arrhythmias arising during myocardial ischemia or due to digoxin toxicity
They have little effect on atrial or AV junction arrhythmias

9. Class IC Drugs They markedly slow Phase 0 fast depolarization
They possess slow rate of association and dissociation with sodium channels
They markedly slow conduction in the myocardial tissue
They only have minor effects on duration of action potential and refractoriness
They reduce automaticity by increasing the threshold potential rather than decreasing the slope of Phase 4 spontaneous depolarization

11. Class IC Drugs Agents of Class IC: Flecainide & propafenone Uses:
They are broad-spectrum but only approved for refractory ventricular arrhythmias
Flecainide is a particularly potent suppressant of premature ventricular contractions
Toxicity and Cautions for Class IC Drugs:
They are severe proarrhythmic drugs causing severe worsening of a preexisting arrhythmia or de novo occurrence of life-threatening ventricular tachycardia
In patients with frequent PVCs following MI, flecainide increased mortality compared to placebo
Notice: Class 1C drugs are particularly of low safety and have shown even to increase mortality when used chronically after MI

12. Class II ANTIARRHYTHMIC DRUGS (β-adrenergic blockers)
β-Adrenergic blockers produce both negative inotropic & chronotropic effects
They diminish phase 4 spontaneous depolarization suppressing automaticity and prolonging AV conduction
Uses
They are used in treatment of increased sympathetic activity-induced arrhythmias such as stress- and exercise-induced arrhythmias
Treatment of atrial flutter and fibrillation
AV nodal tachycardia

13. Class II ANTIARRHYTHMIC DRUGS
Propranolol: was proved to reduce the incidence of sudden arrhythmatic death after myocardial infarction
Metoprolol & Pindolol
Metoprolol and other selective β1-adrenergic blockers reduce the risk of bronchospasm
Pidolol, having additional partial agonistic activity, may decrease the frequency of cardiac failure
Esmolol:
Esmolol is a very short-acting β1-adrenergic blocker that is used in the by intravenous route in acute arrhythmias occurring during surgery or emergencies

14. Class III ANTIARRHYTHMIC DRUGS
Class III antiarrhythmic drugs prolong phase 3 depolarization, without altering phase 0 upstroke or the resting membrane potential
They prolong both the duration of the action potential and the effective refractory period (ERP)
Their mechanism of action is still not clear but it is thought that they block potassium channels

15. Class III ANTIARRHYTHMIC DRUGS
Drugs of Class III:
Sotalol, bretylium, amiodarone, ibulitide
Uses:
They are used in the treatment of ventricular arrhythmias, especially ventricular fibrillation or tachycardia
Supra-ventricular tachycardia
Amiodarone usage is limited by its wide range of side effects

16. Class III ANTIARRHYTHMIC DRUGS
Sotalol (Sotacor)
Sotalol is a β-adrenergic blocker that also prolongs the duration of action potential and refractoriness in all cardiac tissues
Sotalol suppresses Phase 4 spontaneous depolarization and possibly producing severe sinus bradycardia
The β-adrenergic blockade combined with prolonged action potential duration may of special efficacy in prevention of sustained ventricular tachycardia
It may induce the polymorphic torsade de pointes ventricular tachycardia
Bretylium
It is generally administered parenteraly because of poor GIT absorption
Long-term oral use is associated with painful parotid enlargement as well as severe postural hypotension

17. Class III ANTIARRHYTHMIC DRUGS Amiodarone (Cordarone)
Amiodarone is a drug of multiple actions and not well understood
It is extensively taken up by tissues, especially fatty tissues, and has a half-life of up to 60 days
Amiodarone antiarrhythmic effect is complex comprising class I, II, III, and IV actions
Prolongation of action potential duration and refractoriness is the main
It slows cardiac conduction, works as Ca2+ channel blocker, and as a weak β-adrenergic blocker
Amiodarone Toxicity
Amiodarone has wide-spectrum toxicity
Most common include GI intolerance, tremors, ataxia, dizziness, hyper-or hypothyrodism
Corneal microdeposits may be accompanied with disturbed night vision
Other common side effects include liver toxicity, photosensitivity, gray facial discoloration, neuropathy, muscle weakness, and weight loss
The most dangerous side effect is pulmonary fibrosis which occurs in 2-5% of the patients

18. Class IV ANTIARRHYTHMIC DRUGS (Calcium Channel Blockers)
Calcium channel blockers decrease inward Ca2+ currents resulting in a decrease of phase 4 spontaneous depolarization
They slow conduction in Ca2+ current-dependent tissues like AV node
Verapamil and diltiazem, but not nifedipine (or the other dihydropyridine Ca2+ antagonists), are representative of this class being more effective on the heart than blood vessels

19. Class IV ANTIARRHYTHMIC DRUGS
Verapamil and diltiazem bind only to open depolarized voltage-operated Ca2+ channels, and hence preventing re-polarization until the drug dissociates from the channels.
Therefore, they are use-dependent blocking rapidly beating heart since in a normally-paced heart, Ca2+ channels have enough time to repolarize and the drug to dissociate from the channel before the next conduction cycle
Verapamil and diltiazem slow conduction and prolong effective refractory period in Ca2+ current-dependent tissues like AV node

20. Class IV ANTIARRHYTHMIC DRUGS
Verapamil & diltiazem are more effective in treatment of atrial than ventricular arrhythmias.
They are used in treatment of supra-ventricular tachycardia preventing the occurrence of ventricular arrhythmias
They are used in treatment of atrial flutter and fibrillation
Both drugs are contraindicated patients with pre-existing depressed heart function because of their negative inotropic activity
Both drugs may cause bradycardia, and asystole especially when given in combination with β-adrenergic blockers

21. Miscellaneous Antiarrhythmic Drugs
Adenosine
Adenosine activates A1-purinergic receptors decreasing the SA nodal firing and automaticity, reducing conduction velocity, prolonging effective refractory period, and depressing AV nodal conductivity
It is the drug of choice in treatment of supra-ventricular tachycardia
It is used only by intravenous route
It has only low-profile toxicity being ultra-short acting of 15 seconds duration

22. Sodium-channel blockade:    IC > IA > IB
Increasing the ERP: IA>IC>IB (lowered)