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Antiarrhythmic agent

Antiarrhythmic agent

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Antiarrhythmic agent

  1. 1. Antiarrhythmic agents S. Parasuraman, M.Pharm., Ph.D., Senior Lecturer, Faculty of Pharmacy, AIMST University
  2. 2. Antiarrhythmic agents • Antiarrhythmic drugs are used to prevent or treat irregularities of cardiac rhythm. • Arrhythmias are the most important cause of sudden cardiac death.
  3. 3. Mechanisms of cardiac arrhythmias • Enhanced/ectopic pacemaker activity • After-depolarizations • Reentry
  4. 4. Mechanisms of cardiac arrhythmias • Enhanced/ectopic pacemaker activity – Ectopic impulse may also result from current of injury. The slope of phase- 4 depolarization may be increased pathologically in the automatic fibres. • After-depolarizations – Early after-depolarization (EAD) – Delayed after- depolarization (DAD) EAD: Repolarization during phase-3 is interrupted and membrane potential oscillates DAD: After attaining resting membrane potential (RMP) a secondary deflection occurs
  5. 5. Mechanisms of cardiac arrhythmias • Reentry – Primarily due 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. Source of image: https://ecgguru.com/sites/default/files /Reentry%20Fig-Grauer%20%282-2- 2012%29.jpg (Accessed on 25-9-17)
  6. 6. Important cardiac arrhythmias • Extrasystoles (ES) • Paroxysmal supraventricular tachycardia (PSVT) • Atrial flutter (AFI) • Atrial fibrillation (AF) • Ventricular tachycardia (VT) • Torsades de pointes • Ventricular fibrillation (VF) • Atrio-ventricular (A-V) block – First degree A-V block – Second degree A-V block – Third degree A-V block
  7. 7. Important cardiac arrhythmias • Atrial flutter (AFL) [can be regular or irregular] is an abnormality of conduction within the atria. The atria beat more frequently than the ventricles (up to 300 bpm). • Atrial Fibrillation (AF) [always irregular] there is a complete absence of a Sino-Atrial stimulus which would result in a P wave. The atria beat out of coordination ventricle). This leads to a rapid and irregular heart rhythm. In AF, the heart rate ranges from 100 to 175 bpm. Atrial flutter is less common than atrial fibrillation Source of image: https://www.healio.com/cardiology/learn-the-heart/cardiology-review/topic-reviews/atrial-fibrillation (Accessed on 25-9-17)
  8. 8. Antiarrhythmic drugs Class Action Drugs I Membrane stabilizing agents (Na+ channel blockers) 1 (A) Moderately decrease dv/dt of 0 phase Quinidine, Procainamide, Disopyramide 1 (B) Little decrease in dv/dt of 0 phase Lidocaine, Mexiletine 1 (C) Marked decrease in dv/dt of 0 phase Propafenone, Flecainide II Antiadrenergic agents (β blockers) Propranolol, Esmolol, Sotalol (also class III) III Agents widening AP Amiodarone, Dronedarone, Dofetilide, Ibutilide IV Calcium channel blockers Verapamil, Diltiazem For PSVT Adenosine, Digoxin For A-V block Sympathomimetics—Isoprenaline, etc. ; Anticholinergics—Atropine Digitalis is used in AF, AFl and PSVT to control ventricular rate
  9. 9. Class IA antiarrhythmic drugs Membrane stabilizing agents Quinidine: • Dextro isomer of the antimalarial alkaloid quinidine, increases P-R and Q-T intervals and tends to broaden QRS complex. Changes in the shape of T wave may be seen reflecting effect on repolarization. • MOA: Quinidine binds to open and inactivated sodium channels and prevents sodium influx, thus slowing the rapid upstroke during phase 0. It decreases the slope of phase 4 spontaneous depolarization, inhibits potassium channels, and blocks calcium channels.
  10. 10. Class IA antiarrhythmic drugs Membrane stabilizing agents Quinidine: • Quinidine causes fall in BP due to its weak α adrenergic blockade action and direct cardiac depression property. • Quinidine also has mild anticholinergic actions. • Quinidine also decreased skeletal muscle contractility, augmented uterine contractions, vomiting, diarrhoea and neurological effects like ringing in ears, vertigo, deafness, visual disturbances and mental changes (Cinchonism). • Levo isomer of quinidine used as an antimalarial agent, and has been used as a parenteral alternative to quinine for falciparum malaria.
  11. 11. Class IA antiarrhythmic drugs Membrane stabilizing agents Quinidine: • Therapeutic use: – Quinidine effective in many atrial and ventricular arrhythmias, it is rarely used now, because of risk of adverse effects, including that of torsades de pointes, sudden cardiac arrest or Ventricular fibrillation (VF); idiosyncratic angioedema, vascular collapse, thrombocytopenia, etc.
  12. 12. Class IA antiarrhythmic drugs Membrane stabilizing agents Procainamide and disopyramide: • Therapeutic use: – Procainamide is available in an intravenous formulation only and may be used to treat acute atrial and ventricular arrhythmias. – Disopyramide is used in the treatment of ventricular arrhythmias as an alternative to procainamide or quinidine and may also be used for maintenance of sinus rhythm in atrial fibrillation or flutter.
  13. 13. Class IB antiarrhythmic drugs Membrane stabilizing agents Lidocaine and mexiletine: • The most prominent cardiac action of lidocaine is suppression of automaticity in ectopic foci. • Mechanism of action: Lidocaine is a blocker of inactivated Na+ channels more than that of open state. In addition to sodium channel blockade, lidocaine and mexiletine shorten phase 3 repolarization and decrease the duration of the action potential.
  14. 14. Class IB antiarrhythmic drugs Membrane stabilizing agents Lidocaine and mexiletine: • Lidocaine has minimal effect on normal ECG; QT interval may decrease. It causes little depression of cardiac contractility or arterial BP. • Adverse effects: – Lidocaine has a fairly wide therapeutic index. It shows little impairment of left ventricular function and has no negative inotropic effect. – Lidocaine has practically no proarrhythmic potential and is the least cardiotoxic antiarrhythmic. – Drowsiness, nausea, paresthesias, blurred vision, disorientation, nystagmus, twitchings and fits.
  15. 15. Class IC antiarrhythmic drugs Membrane stabilizing agents Flecainide and propafenone: • These are the most potent Na+ channel blockers with more prominent action on open state and the longest recovery times They markedly delay conduction, prolong P-R interval, broaden QRS complex, but have variable effect on Action Potential Duration (APD).
  16. 16. Class IC antiarrhythmic drugs Membrane stabilizing agents Flecainide and propafenone: • Flecainide suppresses phase 0 upstroke in Purkinje and myocardial fibers. This causes marked slowing of conduction in all cardiac tissue, with a minor effect on the duration of the action potential and refractoriness. • Flecainide also blocks potassium channels leading to increased action potential duration, even more so than propafenone. • Propafenone blocking Na+ channels propafenone considerably depresses impulse transmission and has profound effect on His-Purkinje as well as accessory pathway conduction.
  17. 17. Class II Antiarrhythmic Drugs Antiadrenergic agents (β blockers) Propranolol, Sotalol, Esmolol: • Class II agents are β-adrenergic antagonists, or β- blockers. • These drugs diminish phase 4 depolarization and, thus, depress automaticity, prolong AV conduction, and decrease heart rate and contractility. • Class II agents are useful in treating tachyarrhythmias caused by increased sympathetic activity. • They are also used for atrial flutter and fibrillation and for AV nodal reentrant tachycardia.
  18. 18. Class II Antiarrhythmic Drugs Antiadrenergic agents (β blockers) • In addition, β-blockers prevent life-threatening ventricular arrhythmias following a myocardial infarction. • Propranolol
  19. 19. Class III antiarrhythmic drugs Membrane stabilizing agents Amiodarone, Dronedarone, Dofetilide, Ibutilide: • Class III agents block potassium channels and, thus, diminish the outward potassium current during repolarization of cardiac cells. • These agents prolong the duration of the action potential without altering phase 0 of depolarization or the resting membrane potential.
  20. 20. Class III antiarrhythmic drugs Membrane stabilizing agents Amiodarone, Dronedarone, Dofetilide, Ibutilide: • Class III agents block potassium channels and, thus, diminish the outward potassium current during repolarization of cardiac cells. These agents prolong the duration of the action potential without altering phase 0 of depolarization or the resting membrane potential.
  21. 21. Class III antiarrhythmic drugs Membrane stabilizing agents Amiodarone: • Amiodarone unusual iodine containing highly lipophilic long-acting antiarrhythmic drug exerts multiple Actions • Prolongs APD and Q-T interval attributable to block of myocardial delayed rectifier K+ channels. • Preferentially blocks inactivated Na+ channels with relatively. • Partially inhibits myocardial Ca2+ channels, has noncompetitive β adrenergic blocking property and alters thyroid function.
  22. 22. Class III antiarrhythmic drugs Membrane stabilizing agents Amiodarone: • Interactions: – Amiodarone can increase digoxin and warfarin levels by reducing their renal clearance. – Additive A-V block can occur in patients receiving β blockers or calcium channel blockers. • Adverse effects: • Amiodarone shows a variety of toxic effects, including pulmonary fibrosis, neuropathy, hepatotoxicity, corneal deposits, optic neuritis, blue-gray skin discoloration, and hypo- or hyperthyroidism.
  23. 23. Class III antiarrhythmic drugs Membrane stabilizing agents Dronedarone: • Dronedarone is a noniodinated congener of amiodarone, less toxic, but also less effective class III antiarrhythmic. The drug is contraindicated in those with symptomatic heart failure or permanent atrial fibrillation due to an increased risk of death.
  24. 24. Class III antiarrhythmic drugs Membrane stabilizing agents (new drug) Dofetilide: • It is a pure class III antiarrhythmic (pure potassium channel blocker). • Dofetilide prolongs APD and ERP by selectively blocking rapid component of delayed rectifier K+ current without affecting other channels or receptors Ibutilide: • is a potassium channel blocker that also activates the inward sodium current (mixed class III and IA action). • Ibutilide is used i.v. for pharmacological conversion of AFl and AF to sinus rhythm. • Induction of Torsades de pointes is a risk.
  25. 25. Class IV antiarrhythmic drugs Membrane stabilizing agents (new drug) Verapamil, Diltiazem: • Class IV drugs are the nondihydropyridine calcium channel blockers. • Verapamil shows greater action on the heart than on vascular smooth muscle, and diltiazem is intermediate in its actions. • In the heart, verapamil and diltiazem bind only to open depolarized voltage-sensitive channels, thus decreasing the inward current carried by calcium.
  26. 26. Class IV antiarrhythmic drugs Membrane stabilizing agents (new drug) Electrophysiological actions of calcium channel blockers. ↑ : increase; ↓ : decrease; —: no change Verapamil Diltiazem SA node automaticity ↓ ↓, — Ventricular automaticity ↓, — — ERP atrial -- — AV nodal ↑↑ ↑ ventricular — — bypass tract ↑↓ ↑↓ ECG RR interval ↑ ↑↓ PR interval ↑ ↑
  27. 27. Other antiarrhythmic drugs Digoxin: • Digoxin inhibits the Na+/K+-ATPase pump, and shortening the refractory period in atrial and ventricular myocardial cells while prolonging the effective refractory period and diminishing conduction velocity in the AV node. Digoxin is used to control ventricular response rate in atrial fibrillation and flutter. • Intravenous magnesium sulfate is the salt used to treat arrhythmias, as oral magnesium is not effective in the setting of arrhythmia.
  28. 28. Other antiarrhythmic drugs Magnesium sulfate: • Magnesium is necessary for the transport of sodium, calcium, and potassium across cell membranes. It slows the rate of SA node impulse formation and prolongs conduction time along the myocardial tissue.
  29. 29. Other antiarrhythmic drugs Adenosine: • Adenosine is a naturally occurring nucleoside. In high doses, adenosine decreases conduction velocity, prolongs the refractory period, and decreases automaticity in the AV node. • Intravenous adenosine is the drug of choice for abolishing acute supraventricular tachycardia. • It has low toxicity but causes flushing, chest pain, and hypotension. • Adenosine has an extremely short duration of action (appro. 10 - 15 sec.) due to rapid uptake by erythrocytes and endothelial cells where it is converted to 5-AMP and inosine.
  30. 30. Other antiarrhythmic drugs Adenosine: • Advantages of adenosine for termination of PSVT – efficacy equivalent to or better than verapamil. – action lasts < 1 min; adverse effects (even cardiac arrest, if it occurs) are transient. – No haemodynamic deterioration; can be given to patients with hypotension, CHF or those receiving β blockers. Verapamil is contraindicated in these situations. – Safe in wide QRS tachycardia (verapamil is unsafe). – Effective in patients not responding to verapamil.
  31. 31. Drugs for Paroxysmal supraventricular tachycardia (PSVT) • An attack of PSVT can be terminated by reflex vagal stimulation through Valsalva maneuver, splashing ice cold water on face, hyperflexion (head between knees), etc. • Drug of choice: Adenosine (i.v.) or verapamil/ diltiazem/esmolol (i.v.) • To prevent recurrences, oral therapy with verapamil, diltiazem or propranolol alone or combined with digoxin may be prescribed. Termination of PSVT following adenosine administration Source of image: https://en.wikipedia.org/wiki/Paroxysmal_supraventricular_tachycardia (Accessed on 25-09-2017)
  32. 32. Drugs for Drugs for A-V Block • The definitive treatment of chronic heart block is pacing with an implanted cardiac pacemaker. • Drugs such as atropine, sympathomimetics (Adr, isoprenaline) are of value only for acute/transient A-V block and as an interim measure.
  33. 33. Risk factor framework and the progression of cardiovascular disease Ref: Franklin BA, Cushman M. Recent advances in preventive cardiology and lifestyle medicine: a themed series. Circulation. 2011;24;123(20):2274-83.
  34. 34. References • Brunton L, Knollman B, Hilal-Dandan R. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Ed, New York: McGraw-Hill Education, 2011. • Tripathi KD. Essentials of Medical Pharmacology, 7th Ed, New Delhi: Jaypee Brothers Medical Publisher (P) Ltd, 2013. • Whalen K, Finkel R, Panavelil T. Lippincott Illustrated Reviews in Pharmacology, 7th Ed, Philadelphia: Wolters Kluwer, 2015. • Katzung B, Trevor A. Basic and Clinical Pharmacology, 13th Ed, New York: McGraw-Hill Education, 2017.

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