Anti arrhythmic drugs

Anti arrhythmic drugs

1. ANTI-ARRHYTHMIC DRUGS

2. Cardiac cells undergo depolarization and repolarization to form cardiac action potentials. The shape and duration of each action potential are determined by the activity of ion channel protein complexes in the membranes of individual cells. Arrhythmias can range from incidental, asymptomatic clinical findings to life threatening abnormalities.

3. Anti-arrhythmic drug therapy can have two goals- Termination of an ongoing arrhythmia. Prevention of an arrhythmia. On long term therapy, anti-arrhythmic drugs not only help to control arrhythmias but also can cause them.

4. Physiology of cardiac function Normally, the chambers of the heart contract in a coordinated manner which is achieved by specialized conducting system. Sinus rhythm is characterized by: Impulses arising in the SA node. Conduction through atria, AV node, bundle of His, Purkinje fibers and ventricles.

5. Cardiac cells owe electrical excitability to voltage sensitive plasma membrane channels selective for Na + , K + , and Ca 2+ ions. Electrophysiological features of cardiac muscle: Pacemaker activity Absence of fast Na + current in SA and AV nodes where slow inward Ca 2+ current iniates action potential Long action potential (plateau) and refractory period. Influx of Ca 2+ during the plateau.

6. Cardiac rate and rhythm is controlled by- Intracellular Ca 2+ channels Ryanodine receptors Inositol triphosphate activated calcium channels. Voltage dependent calcium channels in the plasma membrane. Main type of voltage dependent calcium channel is the L-type channel.

7. Phases of cardiac action potential Phase 0  Rapid depolarization Phase 1 Partial reploarisation Phase 2 Plateau Phase 3 Repolarisation Phase 4 Pacemaker potential

8. Phase 0- Rapid Depolarization Occurs when membrane potential reaches a critical firing threshold of about -60mV causing an increase in Na + influx resulting in depolarization. Na + channel proteins change from closed(resting) state to the open(conducting) allowing upto 10 7 ions/sec to enter each cell.

9. This surge lasts only about a millisecond after which the Na + channel protein rapidly moves to an inactivated non conducting state. Once inactivated, cannot reopen until they reassume the closed conformation.

10. Phase 1- Partial Repolarisation Occurs as the Na + current is inactivated. Opening of transient outward channel causing K + efflux. Inactivated rapidly.

11. Phase 2- Plateau Results from an inward Ca 2+ current. These channels show a pattern of voltage sensitive activation and inactivation similar to sodium channels but in a slower time. Assisted by a special property of cardiac muscle membrane- ‘Inward going rectification’ meaning K + conductance falls to a low level when membrane is depolarized.

12. Hence there is little tendency for outward K + current to restore the RMP during the plateau. So a small inward calcium current is sufficient to maintain the plateau.

13. Phase 3- Repolarisation Inactivation of Ca 2+ current and activation of a delayed outwardly rectifying K + current  outward K + current. Augmented by- Another K + activated by high intracellular Ca 2+ Through channels activated by ACh and arachidonic acid.

14. Phase 4- Pacemaker Potential Gradual depolarization during diastole. Caused by a combination of increasing inward currents and declining outward currents during diastole. Normally found only in the nodal and conducting tissue. Usually most rapid in the cells of the SA node, therefore SA node acts as a pacemaker of the whole heart.

15. Cells in the SA node have greater background conductance to Na + than do atrial and ventricular myocytes leading to greater inward current. Inactivation of voltage dependent calcium channels wears off during diastole  increased Ca 2+ current during late diastole. Activation of T-type Ca 2+ channels during late diastole contribute to pacemaker activity in the SA node.

16. Impulse propagation and ECG Normal cardiac impulse originates in the sinus node. Propagates through atria  atrial systole and P wave of surface ECG. At AV node, inward current is slow compared to that in atria, ventricles, subendocardial conducting system propagation slows. Delay atrial contraction propulsion of blood into the ventricle cardiac output optimised.

17. Once impulses exit AV node, they enter the conducting system  spreads throughout the ventricles ventricular contraction Manifests as QRS complex on ECG. T wave on ECG ventricular repolarisation

18. ECG used to guide properties of cardiac tissues- Heart rate SA node automaticity PR interval duration  AV nodal conduction time QRS duration conduction time in the ventricle QT interval measure of ventricular APD

19. Mechanism of Cardiac Arrhythmias Arrhythmia  Disturbance in the normal sequence of impulse initiation and propagation. Classified according to: Site of origin of abnormality- atrial/ junctional /ventricular Heart rate- increased or decreased. Diagnosis mainly depends on surface ECG.

20. Three major mechanisms: Enhanced automaticity Triggered automaticity Reentry

21. Enhanced Automaticity Occurs in the cells that display diastolic depolarization. Increase in the phase 4 slope and pacemaker rate caused by: β- adrenergic stimulation Hypokalemia Mechanical stretch of cardiac muscle cell Reduced by acetylcholine.

22. Automatic behavior also occurs in sites lacking spontaneous pacemaker activity  ‘Abnormal automaticity’. Impulse propagate from region of enhanced normal /abnormal automaticity induction of functional reentry complex arrhythmias.

23. Triggered Automaticity & Afterdepolarisations Pathophysiological condition  Normal cardiac action potential Interrupted/ followed by abnormal depolarization Abnormal rhythms (Triggered rhythms) In the first form, there is intracellular/sarcoplasmic reticulum Ca 2+ overload. A normal action potential is followed by a Delayed afterdepolarisation. Also responsible for exercise induced ventricular tachycardia.

24. In the second type  marked prolongation of action potential interruption in Phase 3 repolarisation by an early afterdepolarisation. More readily induced in Purkinje cells. Activity is more when heart rate is slow and extracellular K + is low. Prolonged cardiac repolarisation  polymorphic ventricular tachycardia with long QT interval ( torsades de pointes syndrome)

25. Re-entry Occurs when a cardiac impulse travels in a path such as to return to its original site and self perpetuate rapid activation independent of normal sinus conduction. Requires anisotropic conduction slowing due to either an anatomic/functional barrier.

26. Anatomically defined reentry: Occurs when impulses propagate by more than one pathway between 2 points in the heart. Commonly occurs in the AV node(AV nodal reentrant tachycardia) and atria (atrial flutter)

27. Functionally defined reentry: May occur in the absence of an anatomically defined pathway . Eg : Atrial/ ventricular fibrillation Cells are re-excited as soon as they are repolarised sufficiently to allow enough Na + channels to recover from inactivation.

28. Types of Cardiac Arrhythmias Extrasystoles (ES): Premature beats due to abnormal automaticity or after depolarisation arising from an ectopic focus in the atrium, AV node or ventricle. Paroxysmal Supraventricular Tachycardia(PSVT): Sudden onset episodes of atrial tachycardia(150-200/min) Atrial Flutter: Atria beat at a rate of 200-350/min A physiological 2:1 to 4:1 or higher AV block

29. Atrial Fibrillation: Atrial fibres are activated asynchronously at a rate of 350-550/min associated with irregular and fast ventricular response (100-160/min) Torsades de pointes : A life threatening form of polymorphic ventricular tachycardia Associated with long Q-T interval

30. Antiarrhythmic Drugs

31. Class 1- Sodium Channel Blockers Action is sodium channel blockade. Subclasses  Effects on action potential duration (APD) and kinetics of sodium channel blockade. Class 1A  Prolong APD; Dissociates from channel with intermediate kinetics Class 1B  Shortens APD; Dissociates with rapid kinetics Class 1C  Minimal effects on APD; Dissociates with slow kinetics.

32. Drugs of Class 1A PROCAINAMIDE: Analog of procaine. Acts by blocking sodium as well as potassium channels  slows upstroke of action potential; prolongs QRS of ECG. Pharmacokinetics: Well absorbed orally, IM/IV safely administered Hepatic metabolism; N-acetyl procainamide (NAPA) Renal excretion; t 1/2 : 2-4 hrs

33. Use- Drug of 2 nd or 3 rd choice against most atrial /ventricular arrhythmias. Dose: Loading dose: Upto 12mg/kg at a rate of 0.3mg/kg/min Maintainance dose: 2-5mg/min ADR Hypotension, Lupus erythematosus , arthralgia , arthritis, pleuritis , pericarditis or parenchymal pulmonary disease.

34. QUINIDINE : A diastereomer of antimalarial quinine extracted from the bark of cinchona plant. Actions same as that of procainamide . Used to maintain sinus rhythm in patients with atrial flutter/fibrillation. To prevent recurrence of ventricular tachycardia/VF

35. ADR- Immunologic reactions- Thrombocytopenia ‘ Cinchonism ’: Related to elevated plasma quinidine concentration Includes headache, dizziness and tinnitus Managed by dose reduction.

36. Drugs of Class 1B LIDOCAINE A local anaesthetic ; agent of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation. Blocks both open and inactivated sodium channels with rapid kinetics. Has greater effects on cells with long action potential (Purkinje cells & ventricular cells) No significant effect on PR or QRS duration.

37. ADR- Nystagmus is the early sign of lignocaine toxicity. Neurlogic effects like paresthesias , tremor, nausea, lightheadedness, hearing disturbances, slurred speech, convulsions . May cause hypotension in patient with preexisting heart failure.

38. Pharmacokinetics: Undergoes extensive first pass metabolism; 3% of the oral drug appears in the plasma. T 1/2 - 1-2hrs Dose- Loading dose- 150-200mg for 15 minutes Maintainance dose- 2-4mg/min

39. Drugs of Class 1C FLECAINIDE A potent blocker of sodium and potassium channels with slow unblocking kinetics. Effective in suppressing premature ventricular contractions. Normal dose may cause exacerbation of arrhythmia when administered in patients with preexisting ventricular tachyarrhytmia - demonstrated in Cardiac Arrhythmia Suppression Trial (CAST)

40. Well absorbed; t 1/2 - 20 hrs Elimination by hepatic metabolism and by the kidney. Dose- 100-200mg BD

41. Class 2: β Adrenergic Blockers Actions: Reduce the heart rate. Decrease intracellular Ca 2+ overload Inhibit afterdepolarisation mediated automaticity. Increase AV nodal conduction time and prolong AV nodal refractoriness. Adverse effects: Fatigue, bronchospasm, hypotension, impotence, depression, worsening of symptoms.

42. ESMOLOL: A β 1 selective agent, metabolised by erythrocyte esterases . Very short elimination, t 1/2 - 9min IV esmolol is useful in situations in which immediate β adrenergic blockade is desired. Eg : for rate control of rapidly conducted atrial fibrillation.

43. SOTALOL Non selective β adrenergic receptor antagonist. Prolongs QT interval, decreases automaticity, slows AV nodal conduction, prolongs AV refractoriness by blocking both K + channels and β adrenergic receptors. Causes EADs and triggered activity in vitro and can cause torsade de pointes

44. Class 3- Potassium Channel Blockers Prolong action potential by blocking potassium channels in cardiac muscles. Action potential prolongation  “Reverse use dependence” action potential prolongation is least marked at fast rates and most marked at slow rates risk of torsade de pointes. Also evokes QT prolongation.

45. AMIODARONE A structural analog of thyroid hormone. Highly lipophilic ; concentrated in the tissues; eliminated extremely slowly. Prolongs action potential and QT intervals. Also has weak adrenergic and calcium channel blocking actions  Slowing of heart rate and AV node conduction. Oral amiodarone is effective in maintaining sinus rhythm in patients with atrial fibrillation.

46. ADR- Symptomatic bradycardia and heart block in patients with sinus or AV node disease. Dose related pulmonary toxicity  fatal pulmonary fibrosis even on low dose of 200mg/d Abnormal liver function tests & hypersensitivity hepatitis.

47. Photodermatitis ; Gray-blue skin discolorations in sun exposed areas. May result in hypothyroidism or hyperthyroidism. Pharmacokinetics: Bioavailability: 35-65% Undergoes hepatic metabolism; Desethylamiodarone

48. Dose: Loading dose: 10g achieved with 0.8-1.2g daily Maintainence dose: 200-400mg daily. Uses: Low doses (100-200mg/d)- maintains normal sinus rhythm in patients with atrial fibrillation Effective in prevention of recurrence of ventricular tachycardia. Dronedarone - a derivative of amiodarone is approved for the treatment of atrial fibrillation and atrial flutter.

49. DOFETILIDE Prolongs action potential by dose dependent blockade of the rapid component of the delayed rectifier potassium current. Bioavailability- 100% 80% of oral dose is excreted unchanged; remaining eliminated in the urine as inactive metabolites. QT prolonging effect and ventricular proarrhythmia , directly related to plasma concentration.

50. Contraindications for treatment with Dofetilide : Baseline QT c more than 450ms Bradycardia , <50bpm Hypokalemia Used for maintaining normal sinus rhythm in patients with atrial fibrillation.

51. Class 4- Calcium Channel Blockers VERAPAMIL Blocks both activated and inactivated L-type calcium channels. Effect is more marked in SA and AV node. Can suppress both early and delayed afterdepolarizations . ADR- induces AV block when used in large doses or in patients with AV nodal disease. Constipation, nervousness, peripheral edema

52. Pharmacokinetics: Half life is 7 hrs. Bioavailability is 20% after oral absorption Extensively metabolised by the liver. Dose: Initial bolus of 5mg for 2-5min followed by second 5mg bolus if needed. Thereafter, 5-10mg can be administered every 4-6hrs or a constant infusion of 0.4mcg/kg/min.

53. Uses: Supraventricular tachycardia To reduce ventricular rate in atrial fibrillation or atrial flutter. Diltiazem : Similar to verapamil in the management of supraventricular arrhythmias, including rate control in atrial fibrillation.

54. Miscellaneous Agents ADENOSINE Natural nucleoside; drug of choice for conversion of PSVT to sinus rhythm. Short duration of action; t 1/2 <10s Dose- 6mg bolus followed by 12mg ADR- Flushing(20%), shortness of breath, chest burning(10%). Less common- headache, hypotension, nausea, paraesthesias .

55. Mechanism of action: When given as bolus dose, directly inhibits AV nodal conduction and increases AV nodal refractory period. Activation of inward K+ current Inhibition of calcium current Hyperpolarisation Suppression of calcium dependent action potentials

56. MAGNESIUM Known to influence Na + , K + ATPase, Na + channels, certain K + and Ca 2+ channels. Indications: Digitalis induced arrhythmia if hypomagnesaemia is present Torsade de pointes Dose- 1g IV over 20 min. Repeated if necessary.

57. POTASSIUM Hypokalaemia  increased risk of EAD & DAD. Hyperkalaemia  suppresses SA node and slows conduction. Both insufficient and excess potassium is arrhythmogenic. Hence potassium therapy is directed toward normalising potassium gradients in the body.

58. Principles in the Clinical Use of Antiarrhythmic Agents Pre-treatment evaluation: Eliminate the cause Make a firm diagnosis Determine the baseline condition Question the need for therapy Benefits: Reduction of arrhythmia-related symptoms (palpitations, syncope, cardiac arrest) Reduction in long term mortality in asymptomatic patients.

59. Risks: Related to high dose/plasma concentration Combination of drug therapy Underlying heart disease Drugs like Quinidine, Dofetilide  slow repolarisation & prolong action potential QT prolongation & Torsades de pointes. R x - recognition, withdrawal of offending agent, correction of hypokalaemia, treatment with manoeuvres to increase heart rate.

60. Conduct of Antiarrhythmic Therapy: Urgency of clinical situation determines the route and rate of drug initiation. For immediate drug action  IV route Therapeutic drug levels multiple slow IV bolus Drug therapy effective target arrhythmia suppressed and toxicities are absent. Managing plasma drug concentrations

61. References Goodman and Gilman’s Pharmacological Basis of Therapeutics Rang and Dales pharmacology . Basic and clinical pharmacology – Katzung . KD Tripathi

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