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ANTIARRHYTHMIC DRUGS 1 INTRODUCTION • The heart contains specialized cells that exhibit automaticity; that is, they can generate rhythmic action potentials in the absence of external stimuli • This phenomenon of automaticity is carried out by the “pacemaker” cell that spreads the depolarization from the SA node → AV node → Bundle of His → Purkinje cells • Dysfunction of impulse generation or conduction at any level in the heart can cause an abnormality in cardiac rhythm called Arrhythmia 2 Types OF Arrhythmia • Altered Rate • Premature beats • Altered Conduction • http://www.cvpharmacology.com/clinical%20topi cs/arrhythmias-2 • http://www.skillstat.com/tools/ecg-simulator 3 Reentry For reentry to occur, certain conditions must be met that are related to the following: 1) the presence of a unidirectional block within a conducting pathway 2) critical timing 3) the length of the effective refractory period of the normal tissue 4 CONSEQUENCES OF ARRHYTHMIA • Cause the heart to beat too slowly • To beat too rapidly (vent tachycardia, atrial flutter • To respond to impulses originating from sites other than the SA node • To respond to impulses traveling along accessory pathways that lead to deviant depolarization 5 Action Potential in cardiac &HisPurkinje system Plateau Phase (Opening of Ca-Na Channels and Decrease K permeability) + 20 mV Depolarization Phase (Opening of Fast Na Channels) - 80 mV Repolarization Phase (Opening of K Channels) 0.2 to 0.3 sec Resting Membrane Potential 6 PHASES OF AP in Fast fibers • Phase 0 - depolarization - opening of Na channels( fast sodium current) • Blocked by class I drugs • phase 1 – Inactivation of Na channels, • phase 2 – Plateau phase -- slow but prolonged opening of Ca channels balanced by late outward K⁺ current. • Phase 3 – Final repolarization – closure of Ca channels and rapid K efflux. • Blocked by class III drugs • Phase 4 ---- return of membrane to resting potential by the activity of Na⁺/K⁺-ATPase 7 Three ion channel mechanisms contribute to the pacemaker potential – The first is a progressive reduction in potassium permeability. Second is presence of funny channels. Third is presence of T-type calcium channels (T transient). ANS Regulation of Heart Rate • SA & AV nodes are innervated by both PANS & SANS fibers activating M2 & b1 receptors respectively. • Phase 4 slope increased by increase cAMP (b1 activation) & slowed by decrease cAMP (M2 activation). 9 CLASSES OF DRUGS • CLASS I ANTIARRHYTHMIC DRUGS • CLASS II ANTIARRHYTHMIC DRUGS • CLASS III ANTIARRHYTHMIC DRUGS • CLASS IV ANTIARRHYTHMIC DRUGS 10 Class I – (Na CHANNEL BLOCKERS) 11 Effects on depolarization Effects on repolarization Effects on automaticity Indirect vagal effects 12 Na+ Channel Blockers - Class IA • Decrease Vmax(phase 0) via block of fast Na channels in the open or activated state • Increase APD & Effective Refractory Period (ERP) 13 QUINIDINE • Increase HR & AV conduction due to its muscarinic blockade • Vasodilation due to blockade of alpha receptor → hypotension • orally effective 14 THERAPEUTIC USES • WIDE RANGE • A-Fib, Ventricular tachyarrhythmias • MAINTAIN NORMAL RHYTHM AFTER CARDIOVERSION 15 16 Adverse effects • nausea & vomiting, • cinchonism (GI, tinnitus, ocular dysfunction, CNS excitation), • syncope due to prolongation of QT interval (torsades), AV & SA block • At toxic doses: ventricular tachycardia. • Interactions: hyperkalemia increases its cardiotoxicity; enhances digoxin toxicity; Decrease effects of AChE inhibitors in myasthenia. 17 PROCAINAMIDE • CLASS 1A • DERIVATIVE OF LOCAL ANAESTHETIC PROCAINE • ADVANTAGES • LESS ANTIMUSCARINIC EFFECTS 18 Pharmacokinetics • Well absorbed via oral route • Short half-life • Metabolized via N-acetyltransferase to Nacetyl procainamide (NAPA), an active metabolite • NAPA is eliminated via the kidney 19 SIDE EFFECTS • SLE LIKE SYNDROME, Hematotoxic • CNS effect: DEPRESSION, HALLUCINATIONS, & PSYCHOSIS. • CVS: TORSADES • Toxic dose: ASYSTOLE, ventricular arrhythmia 20 21 DISOPYRAMIDE • CLASS I A • NEGATIVE IONOTROPIC • ANTI MUSCARINIC EFFECT – GREATER • SIDE EFFECTS • ANTICHOLINERGIC EFFECTS • NOT FIRST LINE DRUG. USED AS AN ALTERNATIVE TO OTHER CLASS 1A DRUGS • CI: in patients with heart failure 22 Na+ Channel Blockers - Class IB • Decrease Vmax – • block fast Na+ channels in the inactivated state - preference for tissues partly depolarized (ischemic or hypoxic tissues) • Decrease APD( blockade of slow Na⁺ window current in the plateau) • (SHORTENS PHASE 3 REPOLARISATION) 23 • ROUTE – I.V. • EXTENSIVE FIRST PASS METABOLISM preclude oral use. • USES : arrhythmias during an MI, & DOC (Drug Of Choice) for arrhythmias following attempted cardioversion. • MC : VENTRICULAR ARRHYTHMIAS • Digoxin toxicity 24 Lidocaine • Adverse effects: CNS toxicity culminating in seizures. • Least cardiotoxic of conventional antiarrhythmics. 25 OTHER CLASS 1 B • MEXILETINE • TREATMENT OF VEN. ARRHY. MOSTLY WITH PAST H/O OF MI. • Side effects: • Epigastric burning: • nausea (common) • Neurologic side effects: – diplopia, vertigo, slurred speech, tremor 26 CLASS 1B • TOCAINIDE - VTA • SIDE EFFECTS • fatal bone marrow aplasia • pulmonary fibrosis. • RARELY USED 27 Na+ Channel Blockers - Class IC • Decrease Vmax - block fast Na+ channels in all states • No effect on APD 28 CLASS 1 C - FLECAINIDE • • • • • Na channel blocker at all states SLOWS PHASE O NEGATIVE IONOTROPIC EFFECT CI : HEART FAILURE-CAN INDUCE V TAC (proarrhythmic) SIDE EFFECTS : DIZZINESS, BLURRED VISION • USES : reserved for management of life-threatening arrhythmias or refractory VA 29 CLASS II ( BETA BLOCKERS) • Decrease SA & AV nodal activity • Decrease slope of phase 4 (diastolic currents) of AP in pacemakers • prevent b1 adrenoceptors activation which would normally increase cAMP 30 • Propranolol (non-selective) & • cardioselective drugs – acebutolol, metoprolol esmolol 31 • Rx uses: • prophylaxis post-MI & in SVTs & Atrial arrhythmias; • esmolol (IV) is used in acute SVTs. 32 Class III (K+ Channel Blockers) • Increase APD & ERP especially in Purkinje & ventricular tissues • Decrease IK (delayed rectifier current) slowing phase 3 of AP. 33 34 CLASS III ( K CHANNEL BLOCKERS) • AMIODARONE • Dofetilide • SOTALOL • PROLONGS PHASE 3 REPOLARIZATION • BLOCKS K OUTLFOW, ↑ APD & ERP • All class III drugs prolong QT-interval except Amiodarone 35 SOTALOL • β₁ blocker but acts as a K⁺ channel blocker • • • • USES: Treatment of life threatening arrhythmia SUPPRESS ECTOPIC BEATS DECREASES rate of sudden death following an acute MI & IN PTS with SUSTAINTED VENT. TACHYCARDIA. 36 AMIODARONE • Both antianginal & antiarrhythmic activity. • Shows actions of class I, II, III, IV . • Does not prolong the QT-interval • Use: • in treatment of severe refractory Supraventricular and VTA. • SE: GI intolerance , photosensitivity, ataxia, blue skin discoloration, tremor, dizziness, liver toxicity, pul. Fibrosis hepatotoxicity, hypo/hyperthyroidism. 37 CLASS IV (Ca Channel blockers) • Verapamil • Diltiazem • Decrease the influx of Ca²⁺ – decrease the rate of phase 0 depolarization and phase 4 spontaneous depolarization • Decrease conduction velocity 38 USES • Used in treatment of atria than ventricular arrhythmia • SVTs of nodal arrhythmias • They also have effect on the vascular smooth muscle and the heart. • So can be used in treatment of hypertension also. • CI: in pts with depressed heart function 39 SE: • GI distress: CONSTIPATION • dizziness • flushing • Hypotension • AV block • Interaction: Verapamil displaces digoxin from binding sites 40 Other drugs: ADENOSINE 1. Activates adenosine receptor 2. Gi-coupled decreasing cAMP • Decrease SA and AV nodal activity • USES: • Used mainly for the abolishing paroxysmal Supraventricular tachycardia( IV route ) • AV nodal arrhythmia 41 • Possible side effects - flushing, sedation & dyspnea , bronchospasm • Antagonized by theophylline. 42 • DIGOXIN • Prolongs ERP • Diminishes conduction velocity in purkinje fibers. • Can be used in atrial fib and flutter. • Toxic dose: results in ventricular tachycardia 43