Drugs used in cardiac arrhythmias

Drugs used in cardiac arrhythmias

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  Drugs used inCardiac Arrhythmias Dr. Pravin Prasad MBBS, MD Clinical Pharmacology Assistant Professor, Department of Clinical Pharmacology Maharajgunj Medical Campus, Kathmandu 12 November 2021 (26 Kartik 2078), Friday
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  By the endof this class, BDS 2nd year students will be able to: • Define the term arrhythmia • Explain the basic mechanism of arrhythmias • Classify the drugs used for treatment of arrhythmias • Explain the pharmacology of Class IA antiarrhythmic agents
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  Introduction • Arrhythmia isloss of cardiac rhythm, especially irregularity of heartbeat • Can be physiological as well as pathological • Arrhythmias may require treatment if: • Rhythms that are too rapid, too slow, or asynchronous leading to reduced cardiac output • Has potential to precipitate more serious or even lethal rhythm disturbances • Asymptomatic or minimally symptomatic arrhythmias should not be treated with drugs • Anti-arrhythmic drugs can precipitate lethal arrhythmias
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  The normal conductionpathway
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  Action Potentials 5 INa+ ICa++ ICa++ OK+ Pacemaker potentialCardiac action potential
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  Arrhythmias: abnormal impulseformation • Enhanced/ectopic pacemaker activity • Damaged tissue of heart • From the automatic fibres of heart
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  Arrhythmias: abnormal impulseformation • After-depolarizations • Secondary depolarizations accompanying a normal or premature action potential • Early after-depolarization (EAD) • Large impulse is generated during repolarization that gets propagated
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  Arrhythmias: abnormal impulseformation • After-depolarizations • Secondary depolarizations accompanying a normal or premature action potential • Delayed after-depolarization (DAD): • Secondary deflection after reaching RMP • Generally results from Ca2+ overload (digitalis toxicity, ischaemia-reperfusion).
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  Arrhythmias: Abnormal impulsetransmission • Reentry • Primarily due to abnormality of conduction • Impulse recirculate and cause repetitive activation • Are called reentrant arrhythmias • Of several types: • Circus movement entry • Functional re-entry • Fractionation of impulse
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  Classification Vaughan Williams Classificationof anti-dysrhythmic drugs Class Actions Drugs I Membrane Stabilizing Agents (Na+ channel blockers) IA. Moderately decrease dv/dt of phase 0 Quinidine, Procainamide, Disopyramide IB. Little decrease in dv/dt of phase 0 Lidocaine, Mexiletine IC. Marked decrease in dv/dt of phase 0 Propafenone, Flecainide II Antiadrenergic agents (β blockers) Propanolol, Esmolol, Sotalol (also class III) III Agents widening Action Potential (prolong repolarization and Effective refractory period) Amiodarone, Dronedarone, Dofetilide, Ibutilide IV Calcium channel blockers Verapamil, Diltiazem
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  Other Anti-dysrhythmic drugs Drugsnot classified by Williams Drugs Use Atropine Sinus bradycardia Adrenaline Cardiac Arrest Isoprenaline Heart block Digoxin Rapid atrial fibrillation Adenosine Supraventricular tachycardia Calcium chloride Ventricular tachycardia due to hyperkalemia Magnesium chloride Ventricular fibrillation, digoxin toxicity
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  Clinical Classification: Anti-dysrhythmicdrugs Supraventricular arrhythmias only Supraventricular and ventricular arrhythmias Ventricular arrhythmias only • Adenosine • Verapamil, Diltiazem • Dronedarone • Digoxin • Amiodarone • β – blockers • Sotalol • Propranolol • Esmolol • Procainamide • Disopyramide • Quinidine • Flecainide • Propafenone • Lidocaine • Mexiletine
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  Mechanism of Action:Class I agents • 3 distinct functional states of Na+ channels: resting, open and inactivated • Resting • Open (activation) • Inactivated • Class I drugs binds most strongly to Na+ channels in open or inactivated state • Use dependent blockade
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  Mechanism of Action:Class I • Blocks Na+ channels • Limit the conductance of Na+ across cell membrane • Decrease the slope of phase 0 • Reduces maximum rate of depolarization • Blocks only high frequency excitation of myocardial cells • Conducting tissues: • Reduce rate of phase 4 depolarization  reduced automaticity • Further divided into Ia, Ib, Ic: • Characteristics of the sodium-channel block
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  Mechanism of action:Class I • Class Ia (quinine, procainamide, disopyramide): • Open state Na+ channel blocker: Intermediate association and dissociation • Greater at higher frequency (premature ectopics affected more) • Useful in triggered arrhythmias due to ectopic pacemakers • Abolishes re-entry by converting unidirectional to bidirectional block • Prolongs recovery: prolongs repolarization • Supresses A-V conduction: prolonged refractoriness
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  Subclass Ia: Quinidine •Acts by prolonging atrial effective refractory period • A-V node: inconsistent effect • Depresses myocardial contractility • May precipitate failure in damaged heart • ECG changes • Broad QRS, increased PR, QT intervals, T wave changes
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  Subclass Ia: Quinidine •Mechanism of Action: • Blocks myocardial Na+ channels in open state • Reduced automaticity • Reduced maximal rate of phase 0 depolarization • Blocks K+ channels • Prolonged action potential duration (APD) • Delayed recovery of Na+ and K+ channels • Prolonged Effective Refractory Period (ERP)
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  Subclass Ia: Quinidine •Side Effects: • Torsades de pointes (TdP) • Sudden cardiac arrest • Ventricular Fibrillation (VF) • Idiosyncratic angioedema • Vascular collapse • Thrombocytopenia • Use: • Atrial and ventricular arrhythmia • To maintain sinus rhythm after termination of Atrial Fibrillation (AF) or Atrial Flutter (AFl)
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  Subclass Ia: Procainamide •Orally active amide derivative of procaine • Action similar to quinidine: • Slowing of phase 0 depolarization and impulse conduction • Prolonged APD, ERP • Broad QRS, prolonged QT interval • Difference form quinidine: • Less effective in suppressing ectopic automaticity • Less marked depression of contractility and A-V conduction • No anti-vagal action • Less fall in BP (no α blockade; ganglion blockade at high doses)
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  Subclass Ia: Procainamide •Use: • Occasionally used i.v. to terminate monomorphic VT and SVTs • WPW reciprocal VTs • Prevent recurrences of VF • Not suitable for prolonged long term oral thrapy: • Poor efficacy • High risk of lupus
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  Subclass Ia: Procainamide •Adverse Effects • GI intolerance: nausea/vomiting (lesser than quinidine) • CNS: weakness, mental confusion, hallucination (higher doses) • Cardiac toxicity: potential to cause TdP • Hypersensitivity reaction: rashes, fever, angioedema, agranulocytosis and anaemia (rare) • Long term high dose: SLE in slow acetylators
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  Subclass Ia: Disopyramide •Prominent cardiac depressant and anticholinergic activity; no α blocking property • No effect on sinus rate • Prolonged PR and QRS broadening: less marked • Use: • Second line drug for prevention of recurrences of VT • Maintenance therapy after cardioversion of AF or AFl
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  Subclass Ia: Disopyramide •Adverse Effects: • Less GI effects • Anticholinergics side effects • Depression of cardiac contractility: cardiac decompensation, hypotension • Contra-indications: • Sick sinus • Cardiac failure • Prostate hypertrophy
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  Drugs used inCardiac Arrhythmias-II Dr. Pravin Prasad MBBS, MD Clinical Pharmacology Assistant Professor, Department of Clinical Pharmacology Maharajgunj Medical Campus, Kathmandu 15 November 2021 (29 Kartik 2078), Monday
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  Mechanism of Action:Class I • Class Ib: • Associate and dissociate rapidly within the timeframe of the normal heartbeat • Association: • Binds to open channels during phase 0 of the action potential • Leaves many of the channels blocked by the time AP reaches peak • Dissociation: • Occurs in time for the next AP • Ectopics / premature beats blocked • Further selectivity for inactivated channels: blocks arrhythmia during ischaemia
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  Subclass Ib: Lidocaine •Acts by: • Blocks inactivated Na+ channels preferentially • Relatively selective for partially depolarized cells, with longer APD • Supresses automaticity in ectopic foci (phase 4) • Automaticity/After depolarization of Purkinje Fibres (PF) antagonised • Can suppress re-entrant ventricular arrhythmia by: • Abolishing one way block • Producing two way block
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  Subclass Ib: Lidocaine •Intravenous doses lasts only for 10-20 mins • Initial t1/2 8 hrs, later 2 hrs • Adverse Effects: • Dose related neurological effects: drowsiness, paresthesia, nausea, blurred vision, disorientation, nystagmus, twitching and fits • NO anti-arrhythmic potential, least cardiotoxic • Use: (slow i.v. injection) • Supress VT, prevent VF • Supress VT due to digitalis toxicity
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  Class II: Propanolol •Acts by: • Blocking cardiac adrenergic stimulation • Marked decrease in the slope of phase 4 depolarization and automaticity in SA node, PF and other ectopic foci • Better action when higher adrenergic tone on heart present • Prolong ERP of A-V node: • Impedes A-V conduction • No paradoxical tachycardia when rate reduced in AF or AFl
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  Class II: Propanolol •Use: • Inappropriate sinus tachycardia (esp. emotionally/exercise provoked) • ONLY IF symptomatic and disturbing • Prevent recurrences of PSVT • Control ventricular rate in AF or AFl • Arrhythmias due to pheochromocytoma, during anaesthesia with halothane • Digitalis induced tachyarrhythmia • Non-sustained VT, prevent recurrence of VT • Prophylactic treatment in post-MI patients • Terminate torsades de pointes • WPW reciprocal rhythms
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  Class II: Atenolol •Cardioselective beta blocker • Lower propensity to cause bronchospasm • Lesser metabolic derangements • No/ less deleterious effect o n blood lipid profile • Less chances of precipitating Raynaud's phenomenon • Less liable to impair exercise capacity • Less lipid soluble • Less likely to produce CNS side effects • Favourable pharmacokinetic profile • Uses: • Atrial fibrillation/flutter • Supraventricular tachycardia • Maintenance of ventricular rate control • Ventricular arrhythmia, VPCs
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  Class IV: Verapamil •Acts by blocking as well as delaying recovery of L-type Ca2+ channels: • Depresses Ca2+ mediated depolarization • Suppressed automaticity and re-entry dependent on slow channel response • Reduced phase 4 depolarization in SA node: • Bradycardia • Prolonged A-V nodal ERP: • Re-entry involving AVN terminated • Dampens delayed after depolarization in PFs • Negative inotropic action
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  Class IV: Verapamil •Uses and precaution: • PSVT-to terminate attacks, prevent recurrences • DO NOT USE if PSVT accompanied with hypotension or CHF • Control ventricular rate in AF or AFl: first line of drug • Contraindicated in: • Broad QRS complex WPW syndrome • Myocardial Infarction • Digitalis toxicity • Partial Heart block and sick sinus
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  Drugs for AVblock • Sympathomimetics (Isoprenaline): • Acts by: • Stimulates beta-1 receptors of heart • Also stimulates beta-2 and beta-3 receptors • Facilitating AV conduction • Shortening of ERP of conducting tissues • Use: • To maintain idioventricular rate in complete heart block till external pacemaker can be implanted
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  In Summary… Supraventricular arrhythmias only Supraventricularand ventricular arrhythmias Ventricular arrhythmias only • Adenosine • Verapamil, Diltiazem • Dronedarone • Digoxin • Amiodarone • β – blockers • Sotalol • Propranolol • Esmolol • Procainamide • Disopyramide • Quinidine • Flecainide • Propafenone • Lidocaine • Mexiletine 37
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  PLEASE READ!! • Questions?? •Thank you!