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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

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ANTIARRHYTHMIC DRUGS

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  1. 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 ANTIARRHYTHMIC DRUGS

  2. Mechnisms of Arrhythmogenesis

  3. 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) ANTIARRHYTHMIC DRUGS

  4. Class IA Drugs • Quinidineis the prototype of this class • Class IA agents slow the phase 0/reduction of Vmaxof 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. 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 Class IA Drugs Toxicity

  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. 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 Agents of Class IB • 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

  10. 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

  11. 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 Class II ANTIARRHYTHMIC DRUGS(β-adrenergic blockers)

  12. 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

  13. 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

  14. 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

  15. 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

  16. Class III ANTIARRHYTHMIC DRUGSAmiodarone (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

  17. 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 • Verapamiland diltiazem, but not nifedipine (or the other dihydropyridine Ca2+ antagonists), are representative of this class being more effective on the heart than blood vessels

  18. Class IV ANTIARRHYTHMIC DRUGS • Verapamiland 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 • Verapamiland diltiazem slow conduction and prolong effective refractory period in Ca2+ current-dependent tissues like AV node

  19. 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

  20. 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

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

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