Antiarrhythmic Drugs PDF

Dysrhythmias and antidysrhythmic compounds Saturday, December 30, 2023 N.E. EL-reyani 1 Saturday, December 30, 2023 N.E. EL-reyani 2  Arrhythmia Heart condition where disturbances in – Pacemaker impulse formation – Contraction impulse conduction – Combination...

Dysrhythmias and antidysrhythmic compounds Saturday, December 30, 2023 N.E. EL-reyani 1 Saturday, December 30, 2023 N.E. EL-reyani 2  Arrhythmia Heart condition where disturbances in – Pacemaker impulse formation – Contraction impulse conduction – Combination of the two Results in rate and/or timing of contraction of heart muscle that is insufficient to maintain normal cardiac output (CO) To understand how antiarrhythmic drugs work, need to understand electrophysiology of normal contraction of heart Normal heartbeat and atrial arrhythmia Normal rhythm Atrial arrhythmia AV septum  Phases of action potential of cardiac cells Phase 0 rapid depolarisation (inflow of Na+) Phase 1 partial repolarisation (inward Na+ current deactivated, outflow of Phase 1 K+) IV Phase 2 Phase 2 plateau (slow inward calcium0 mV current) Phase 3 repolarisation (calcium Phase 0 I III + current inactivates, K outflow) Phase 3 Phase 4 pacemaker potential (Slow Na+ inflow, slowing of K+ outflow) -80mV Phase 4 ‘autorhythmicity’ II Refractory period (phases 1-3) Saturday, December 30, 2023 N.E. EL-reyani 5  Sinus rhythm Sinoatrial node is cardiac pacemaker Normal sinus rhythm 60- 100 beats/min Depolarisation triggers depolarisation of atrial myocardium (‘forest fire’) Conducts more slowly through AV node Conducts rapidly through His bundles and Purkinje fibres Saturday, December 30, 2023 N.E. EL-reyani 6  Sinus rhythm Sinoatrial rate controlled by autonomic nervous system Parasympathetic system predominates (M2 muscarinic receptors) Sympathetic system (ß1 receptors) – Increased heart rate (positive chronotropic effect) – Increased automaticity – Facilitation of conduction of AV node Saturday, December 30, 2023 N.E. EL-reyani 7  ECG Contraction of ventricles Recording of electrical activity of the heart Net sum of Repolarization depolarisation and Contraction of ventricles repolarisation potentials of atria of all myocardial cells P-QRS-T pattern P - atrial depolarisation QRS - ventricular depolarisation T - ventricular repolarisation Saturday, December 30, 2023 N.E. EL-reyani 8  Definition of arrhythmia Cardiac arrhythmia is an abnormality of the heart rhythm Bradycardia – heart rate slow (100 beats/min) Saturday, December 30, 2023 N.E. EL-reyani 9  Clinical classification of arrhythmias Heart rate (increased/decreased) Heart rhythm (regular/irregular) Site of origin (supraventricular / ventricular) Complexes on ECG (narrow/broad) Saturday, December 30, 2023 N.E. EL-reyani 10  Ventricular Arrhythmia Ventricular arrhythmias are common in most people and are usually not a problem but… VA’s are most common cause of sudden death Majority of sudden death occurs in people with neither a previously known heart disease nor history of VA’s Medications which decrease incidence of VA’s do not decrease (and may increase) the risk of sudden death treatment may be worse then the disease!  Mechanisms of arrhythmias The “Re-Entry” Mechanism of Ectopic Beats & Rhythms  Disorders of Cardiac impulse formation Conduction Tissue or automaticity Fast Conduction Path Slow Conduction Path Slow Recovery Fast Recovery  Abnormalities of impulse conduction 4. On arriving at the top of the fast pathway it finds the  Reentry slow pathway has recovered and therefore the wave of excitation ‘re-enters’ the pathway and continues in a ‘circular’ movement. This creates the re-entry circuit  Triggered activity Saturday, December 30, 2023 N.E. EL-reyani 12  Mechanisms of arrhythmia production Re-entry (refractory tissue The “Re-Entry” Mechanism of Ectopic Beats & Rhythms reactivated due to conduction block, causes abnormal continuous Cardiac Conduction circuit. eg accessory pathways Tissue linking atria and ventricles in Fast Conduction Path Slow Conduction Path Slow Recovery Fast Recovery Wolff-Parkinson-White syndrome) Abnormal pacemaker activity in non-conducting/conducting tissue (eg ischaemia) 4. On arriving at the top of the fast pathway it finds the Delayed after-depolarisation slow pathway has recovered and therefore the wave of excitation ‘re-enters’ the pathway and continues in a (automatic depolarisation of ‘circular’ movement. This creates the re-entry circuit cardiac cell triggers ectopic beats, can be caused by drugs eg digoxin) Saturday, December 30, 2023 N.E. EL-reyani 13  Vaughan Williams classification of antiarrhythmic drugs Class I: block sodium channels – Ia (quinidine, procainamide, disopyramide, Moricizine) AP – Ib (Lidocaine, Mexiletine, Phenytoin ) AP Phase 1 IV – Ic (flecainide, Propafenone) Phase 2 AP 0 mV Class II: ß-adrenoceptor antagonists (atenolol, sotalol) Phase 0 I III Phase 3 Class III: prolong action potential and prolong refractory period (suppress re-entrant rhythms) -80mV Phase 4 (amiodarone, sotalol) II Class IV: Calcium channel antagonists. Impair impulse propagation in nodal and damaged areas (verapamil) Saturday, December 30, 2023 N.E. EL-reyani 14  Management of arrhythmias Acute management (clinical assessment of patient and diagnosis) Prophylaxis Non-pharmacological Pharmacological (some antiarrhythmics are also proarrhythmic) Saturday, December 30, 2023 N.E. EL-reyani 15  Non-pharmacological treatment Acute – Vagal manoeuvres – DC cardioversion Prophylaxis – Radiofrequency ablation – Implantable defibrillator Pacing (external, temporary, permanent) Saturday, December 30, 2023 N.E. EL-reyani 16  Pharmacological treatment – Subclass IA Cause moderate Phase 0 depression Prolong repolarization Increased duration of action potential Includes – Quinidine – 1st antiarrhythmic used, treat both atrial and ventricular arrhythmias, increases refractory period – Procainamide - increases refractory period but side effects – Disopyramide – extended duration of action, used only for treating ventricular arrthymias Saturday, December 30, 2023 N.E. EL-reyani 17  Pharmacological treatment- Lignocaine (Lidocaine), Mexiletine, Phenytoin – Class Ib; shortens APD; they DO NOT affect conduction or refractoriness. – Ventricular arrhythmias (acute Rx), prevention of VF, symptomatic ventricular beats. – IV infusion only (2 hour half life, high first pass metabolism) – Hepatic metabolism (inhibited by cimetidine, propranolol) – SE mainly CNS - drowsiness, disorientation, convulsions, hypotension Saturday, December 30, 2023 N.E. EL-reyani 18  Pharmacological treatment Flecainide, Propafenone – Class Ic; more than Class Ia (block Na+ channels, no change to AP) – Slows conduction in all cardiac cells – Acute Rx /prophylaxis – Supraventricular tachycardias – Paroxysmal atrial fibrillation – Ventricular tachycardias – Oral/IV – Long acting (T1/2 14 hours) – Hepatic metabolism, urinary elimination Saturday, December 30, 2023 N.E. EL-reyani 19  Flecainide CAST (Cardiac Arrhythmia Suppression Trial) 1989 – increased mortality post MI (VF arrest) SE- cardiac failure, ventricular arrhythmias, blurred vision, abdominal discomfort, nausea, paraesthesia, dizzyness, tremor, metallic taste Saturday, December 30, 2023 N.E. EL-reyani 20  Class II; β-blockers Class II; β–adrenergic blockers – Based on two major actions 1) Blockade of myocardial β–adrenergic receptors 2) Direct membrane-stabilizing effects related to Na+ channel blockade – It includes the following drugs; Propranolol – causes both myocardial β–adrenergic blockade and membrane-stabilizing effects – Slows SA node and ectopic pacemaking – Can block arrhythmias induced by exercise or apprehension – Other β–adrenergic blockers have similar therapeutic effect Metoprolol Nadolol Atenolol Acebutolol Pindolol Sotalol Timolol Esmolol Saturday, December 30, 2023 N.E. EL-reyani 21  Class III; Potassium channel blocking agents Amiodarone, Sotalol, Dofetilide, Ibutilide, Bretylium Prolong repolarization, widening the QRS and prolonging the QT interval Decrease automaticity and conduction and prolong refractoriness. Amiodarone – Major effect acutely is depression of AV node – Acute Rx/prophylaxis – Atrial and ventricular arrhythmias – Oral or IV (central line) – Loading and maintenance doses – T1/2 54 days – Large volume of distribution – Accumulates –December Saturday, Hepatic30, 2023metabolism-biliary and intestinal excretion N.E. EL-reyani 22  Class III; Potassium channel bloc k ing agents dofetilide; – AF and flutter sotalol; – VT, AF bretylium; – VF, VT ibutilide; – conversion of AF or flutter Saturday, December 30, 2023 N.E. EL-reyani 23  Amiodarone – adverse effects Photosensitive rashes Grey/blue discolouration of skin Thyroid abnormalities 2% Pulmonary fibrosis Corneal deposits CNS/GI disturbance Pro-arrhythmic effects (torsade de pointe) Heart block Nightmares 25% Abnormal LFT 20% Interacts with digoxin, warfarin (reduces clearance) Saturday, December 30, 2023 N.E. EL-reyani 24  Class IV ; Calcium channel blockers Verapamil, Diltiazem Class IV (calcium channel blocker) Prolongs conduction and refractoriness in AV node, slows rate of conduction of SA node Acute Rx /prophylaxis Used IV/oral SUPRAVENTRICULAR NOT VENTRIC ULAR ARRHYTHMIAS (cardiovascular collapse) Do not use IV verapamil with ß- blocker (heart block) T1/2 6-8 hours Saturday, December 30, 2023 N.E. EL-reyani 25  Verapamil- adverse effects Heart failure Constipation Bradycardia Nausea Saturday, December 30, 2023 N.E. EL-reyani 26  Class V ; miscellaneous Used mainly for supraventricular tachycardia i.e. Adenosine, Digoxin Adenosine – Not in Vaughan Williams class – Purine nucleotide (activates adenosine receptors) – Slows AV nodal conduction – Acute Rx – Termination of SVT/ diagnosis of VT – Given IV only (rapid bolus) – T1/2 < 2seconds Saturday, December 30, 2023 N.E. EL-reyani 27  Adenosine- adverse effects Feeling of impending doom! Flushing, dyspnoea, chest pain, transient arrhythmias Contraindicated in asthma, heart block Saturday, December 30, 2023 N.E. EL-reyani 28  Digoxin Not in Vaughan Williams class Cardiac glycoside (digitalis, foxglove) Act on Na/K-ATPase of cell membrane (inhibits Na+/K+ pump, increases intracellular Na+ and calcium)/ increases vagal activity Increase cardiac contraction and slows AV conduction by increasing AV node refractory period Saturday, December 30, 2023 N.E. EL-reyani 29  Digoxin Atrial fibrillation or flutter (controls ventricular rate) Acute Rx/prophylaxis Oral/IV Loading and maintenance doses T1/2 36 hours Excreted by kidneys Narrow therapeutic index Therapeutic drug monitoring Reduce dose in elderly/renal impairment Saturday, December 30, 2023 N.E. EL-reyani 30  Digoxin – adverse effects Arrhythmias, heart block, anorexia, nausea, diarrhoea, xanthopsia, gynaecomastia, confusion, agitation AE potentiated by hypokalaemia and hypomagnesaemia Overdose –Digibind (digoxin binding antibody fragments), phenytoin for ventricular arrhythmias, pacing, atropine Saturday, December 30, 2023 N.E. EL-reyani 31  Pacemakers Surgical implantation of electrical leads attached to a pulse generator Over 175,000 implanted per year 1) Leads are inserted via subclavicle vein and advanced to the chambers on the vena cava (right) side of the heart 2) Two leads used, one for right atrium, other for right ventricle 3) Pulse generator containing microcircuitry 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 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 Implantation of Pacemaker