1. Antiarrhythmic Drugs

2. Drug List Class 1 Sodium Channel Blockers Class 2 Beta-blockers Class 3 Potassium Channel blockers Class 4 Calcium Channel Blockers Others 1aProcainamide Quinidine Metoprolol Propranolol Amiodorone Ibutilide Dofetilide Sotalol Verapamil Diltiazem Adenosine Magnesium Digoxin 1bLidocaine Mexiletine Phenytoin 1cFlecainide More drugs have been mentioned in other slides

3. Physiology Review To function efficiently, heart needs to contract sequentially (atria, then ventricles) and in synchrony Relaxation must occur between contractions Coordination of heartbeat is a result of pacemaker activity of the SA node and transfer of impulses through AV node and the purkinje system

4. Electrophysiology A transmembrane potential is maintained, with the interior of the cell negative with respect to outside the cell Caused by unequal distribution of ions inside vs. outside cell – Na + higher outside than inside cell – Ca + much higher outside than inside cell – K + higher inside cell than outside Maintenance by ion selective channels, active pumps and exchangers

5. ECG (EKG) showing wave segments Contraction of atria Contraction of ventricles Repolarization of ventricles

7. Cardiac Action Potential Divided into five phases (0,1,2,3,4) – Phase 4 - resting phase (resting membrane potential) Addition of current into cardiac muscle (stimulation) causes – Phase 0 – opening of fast Na channels and rapid depolarization – Phase 1 – initial rapid repolarization. Closure of the fast Na + channels – Phase 2 - plateau phase sustained by the inward movement of Ca + – Phase 3 – repolarization, K + channels remain open

8. Arrhythmia A condition where there is a disturbance in – Impulse formation – Impulse conduction – Both Results in change of heart rate or contraction of heart muscle in a way that is insufficient to maintain normal COP Causes of arrhythmias – Cardiac ischemia, Electrolyte disturbance – Exposure to toxic substances – Unknown etiology – Congenital NB: Biggest problem antiarrhythmics can cause arrhythmia!

9. Types of arrhythmias 1. Tachyarrythmias Supraventricular – Atria fibrillation – Atrial flutter – Supraventricular Tachycardia – Sinus Tachycardia Ventricular: – Ventricular Tachycardia Monomorphic VT Polymorphic VT (torsade's de points) – Ventricular fibrillation 2. Bradyarrhythmia

10. Vaughan Williams Classification of Antiarrhythmic Drugs Class I: Sodium channel blockers (membrane-stabilizing agents) 1 a: Block Na + channel and prolong action potential (Quinidine, disopyramide, procainamide) 1 b: Block Na + channel and shorten action potential (Lidocaine, mexiletine) 1 c: Block Na + channel with no effect on action potential (Flecanide, propafenone ) Class II: β- blockers (Atenolol, bisoprolol, metoprolol, I- sotalol ) Class III: Potassium channel blockers (main effect is to prolong the action potential) (Amiodarone ) Class IV: Slow (L-type) calcium channel blockers (Verapamil, diltiazem )

11. 1. Class I; Sodium channel blockers A. Class 1a Drugs They are the oldest group of antiarrhythmic drugs and are still widely used. I. Procainamide (1a) Mechanism of action: Blocks sodium channels, slows the upstroke of the action potential, slows conduction, prolongs the QRS. It also prolongs the action potential duration by blockade of potassium channels. Has direct depressant actions on SA and AV nodes Extracardiac Effects: It has ganglion-blocking properties. This action reduces peripheral vascular resistance and can cause hypotension, particularly with intravenous use.

12. Pharmacokinetics: Absorbed well orally. Metabolized in liver and excreted by kidney. Given IV or oral Therapeutic Use : Supraventricular and ventricular arrhythmias Toxicity : Prolong QT interval and induction of torsade de pointes. New arrhythmias can be precipitated. Lupus erythmatosus, Pleuritis, pericarditis, or parenchymal pulmonary disease. Nausea and diarrhea, rash, fever, hepatitis

13. II. Quinidine (1a) Similar to procainamide. Cardiac effects Negative inotropic effect. Depression of excitability. It suppresses enhanced automaticity. Vasodilatation and hypotension with large doses (block alpha receptors) Effect on the E.C.G: Prolongation of Q-T interval. Prolongation of P-R interval Widening of Q.R.S. complex

14. Adverse effects Anti-muscarinic side effects Blocks α receptors, hypotension Cinchonism: a syndrome of headache, dizziness, and tinnitus. It is observed at toxic drug concentrations. Excessive QT interval prolongation and induction of torsade de pointes arrhythmia. Toxic concentrations cause marked reduction in conduction throughout the heart.

15. Contraindications A.V block with Prolongation of Q.T. interval. Congestive heart failure. Hypotension. Hypersensitivity.

16. B. Class 1b Drugs I. Lidocaine (1b) Block Na + channel and shorten action potential duration. Pharmacokinetics: Extensive first-pass metabolism, must be given parenterally Half-life of 1–2 hours.

17. Adverse effects: Lidocaine is one of the least cardiotoxic in this group Paresthesias, nausea of central origin, lightheadedness, hearing disturbances. In preexisting heart failure, lidocaine may cause hypotension Therapeutic Use: Lidocaine is the agent of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia (Myocardial infarction) In digitalis induced arrhythmias

18. II. Mexiletine (1b) Its electrophysiologic and antiarrhythmic actions are similar to those of lidocaine. Mexiletine is given orally. Therapeutic use: Treatment of ventricular arrhythmias. Pain due to diabetic neuropathy and nerve injury. Adverse effects: Tremor, blurred vision, and lethargy. Nausea

19. C. Class 1c Drugs Flecainide (1c) Blocks Na + channel with no effect on action potential. Flecainide is a potent blocker of sodium and potassium channels. (Note that although it does block certain potassium channels, it does not prolong the action potential or the QT interval). It has no anti-muscarinic effects. Pharmacokinetics: It is well absorbed, half-life 20 hours. Elimination is both by liver and kidney Therapeutic Uses: Premature ventricular contractions. Atrial fibrillation (AF), Wolf Parkinson White (WPW) syndrome Toxicity: Arrhythmia

20. 2. Class II; Beta Blockers Their antiarrhythmic properties is due to β receptor blocking action 1.Non selective: propranolol, Sotalol (Sotalol prolongs action potential). 2.Selective B1 blockers; e.g. metoprolol, Esmolol 3.Intrinsic sympathomimetic activity e.g. pindolol. These agents can prevent recurrent infarction and sudden death in patients recovering from acute myocardial infarction. Therapeutic Uses: Sinus tachycardia, Supraventricular arrhythmias Atrialextrasystole. Pheochromacytoma. Arrhythmia due to digitalis.

21. 3. Class III Antiarrhythmic Drugs Amiodarone Pharmacological effects Amiodarone markedly prolongs the action potential duration (and the QT interval on the ECG) It blocks Potassium Channel Amiodarone also significantly blocks inactivated sodium channels. Amiodarone also has weak anti-adrenergic and calcium channel blocking actions Extracardiac Effects: causes peripheral vasodilation.

22. Pharmacokinetics Incompletely and slowly absorbed orally. It undergoes hepatic metabolism to active metabolite The elimination half-life is complex. The drug accumulates in many tissues, including the heart (10– 50 times more so than in plasma), lung, liver, and skin, and is concentrated in tears Therapeutic Use: Works on both supraventricular and ventricular arrhythmias.

23. Adverse effects Fatal pulmonary fibrosis Abnormal liver function tests and hepatitis Photodermatitis and a gray-blue skin discoloration in sun-exposed areas (smurf skin) Corneal micro-deposits and discoloration Optic neuritis: Halos develop in the peripheral visual fields, may progress to blindness Hypothyroidism or hyperthyroidism Bradycardia and heart block

25. 4. Class VI; Calcium Channel Blockers Verapamil: Verapamil blocks L-type calcium channels. AV nodal conduction time and effective refractory period are prolonged. Slows the SA node by its direct action Extracardiac Effects include; Peripheral vasodilation (Less than nifedipine) Therapeutic Use. Supraventricular tachycardia. Atrial fibrillation and flutter

26. Miscellaneous Antiarrhythmic Agents These include 1.Digitalis 2.Adenosine 3.Magnesium

27. 1. Adenosine Adenosine is a nucleoside that occurs naturally in body. Its half-life in the blood is less than 10 seconds. Mechanism of action: Act by activation of K + channels and inhibition of ca current. Slows the AV nodal conduction and prolong nodal refractory period. Therapeutic use: It is drug of choice (DOC) for conversion of paroxysmal supraventricular tachycardia to sinus rhythm. High efficacy (90–95%) and very short duration of action.

28. Adverse effects: Flushing shortness of breath or chest burning high-grade atrioventricular block. Atrial fibrillation may occur. Headache, hypotension, nausea & paresthesias

29. 2. Magnesium Mechanism of action is not known. Therapeutic uses Digitalis -induced arrhythmias. Torsade de pointes even if serum magnesium is normal.

30. 3. Digoxin Digoxin is used to control the ventricular response rate in atrial fibrillation and flutter.

31. Pacemakers Surgical implantation of electrical leads attached to a pulse generator 1)Leads are inserted via subclavian vein and advanced to the right side of the heart 2)Two leads used, one for right atrium, other for right ventricle 3)Pulse generator containing micro-circuitry and battery are attached to leads and placed into a “ pocket ” under the skin near the clavicle 4)Pulse generator sends signal down leads in programmed sequence to contract atria, then ventricles

32. Pulse generator can sense electrical activity generated by the heart and only deliver electrical impulses when needed. Pacemakers can only speed up a heart experiencing bradycardia, they cannot alter a condition of tachycardia

34. Torsades de pointes

35. PVC

36. WPW

37. SVT

38. AFib

39. Good luck