ANTI-ARRHYTHMIC DRUGS Ma. Janetth B. Serrano, M.D.,DPBA

ANTI – ARRHYTHMIC DRUGS Cardiac Arrhythmias: 25% treated with digitalis 50% anesthetized patients 80% patients with AMI reduced cardiac output drugs or nonpharmacologic: - pacemaker, cardioversion, catheter ablation, surgery

ELECTRO-PHYSIOLOGY OF NORMAL CARDIAC RHYTHM ANTI – ARRHYTHMIC DRUGS SA node ELECTRO-PHYSIOLOGY OF NORMAL CARDIAC RHYTHM ATRIA AV node His-Purkinje System VENTRICLES

IONIC BASIS OF MEMBRANE ELECTRICAL ACTIVITY ANTI – ARRHYTHMIC DRUGS IONIC BASIS OF MEMBRANE ELECTRICAL ACTIVITY Transmembrane potential of cardiac cells is determined by the concentrations of the ff. ions: Sodium, Potassium, Calcium The movement of these ions produces currents that form the basis of the cardiac action potential

PHASES OF ACTION POTENTIAL ANTI – ARRHYTHMIC DRUGS PHASES OF ACTION POTENTIAL Phase 2 >Plateau Stage >Cell less permeable to Na+ >Ca++ influx through slow Ca++ channels >K+ begins to leave cell Phase 1 >Limited depolarization >Inactivation of fast Na+ channels→ Na+ ion conc equalizes >↑ K+ efflux & Cl- influx Phase 3 >Rapid repolarization >Na+ gates closed >K+ efflux >Inactivation of slow Ca++ channels Phase 0 >Rapid depolarization >Opening fast Na+ channels→ Na+ rushes in →depolarization Phase 4 >Resting Membrane Potential >High K+ efflux >Ca++ influx

MECHANISMS OF ARRHYTHMIA ANTI – ARRHYTHMIC DRUGS MECHANISMS OF ARRHYTHMIA ARRHYTHMIA – absence of rhythm DYSRRHYTHMIA – abnormal rhythm ARRHYTHMIAS result from: Disturbance in Impulse Formation 2. Disturbance in Impulse Conduction Block results from severely depressed conduction Re-entry or circus movement / daughter impulse

FACTORS PRECIPITATING CARDIAC ARRHYTHMIAS: ANTI – ARRHYTHMIC DRUGS FACTORS PRECIPITATING CARDIAC ARRHYTHMIAS: 1. Ischemia pH & electrolyte abnormalities 80% – 90% asstd with MI 2. Excessive myocardial fiber stretch/ scarred/ diseased cardiac tissue 3. Excessive discharge or sensitivity to autonomic transmitters 4. Excessive exposure to foreign chemicals & toxic substances 20% - 50% asstd with General Anesthesia 10% - 20% asstd with Digitalis toxicity

ANTI – ARHYTHMIC DRUGS Ventricular: Supraventricular: ARRHYTHMIAS: Wolff-Parkinson-White (preexcitation syndrome) Ventricular Tachycardia Ventricular Fibrillation Premature Ventricular Contraction Supraventricular: - Atrial Tachycardia - Paroxysmal Tachycardia Multifocal Atrial Tachycardia - Atrial Fibrillation - Atrial Flutter

CLASS I: Sodium Channel Blocking Drugs ANTI – ARRHYTHMIC DRUGS CLASS I: Sodium Channel Blocking Drugs IA - lengthen AP duration - Intermediate interaction with Na+ channels - Quinidine, Procainamide, Disopyramide IB - shorten AP duration - rapid interaction with Na+ channels - Lidocaine, Mexiletene, Tocainide, Phenytoin IC - no effect or minimal  AP duration - slow interaction with Na+ channels - Flecainide, Propafenone, Moricizine

CLASS II: BETA-BLOCKING AGENTS ANTI – ARRHYTHMIC DRUGS CLASS II: BETA-BLOCKING AGENTS Increase AV nodal conduction Increase PR interval Prolong AV refractoriness Reduce adrenergic activity Propranolol, Esmolol, Metoprolol, Sotalol

CLASS III: POTASSIUM CHANNEL BLOCKERS ANTI – ARRHYTHMIC DRUGS ANTI – ARRHYTHMIC DRUGS CLASS III: POTASSIUM CHANNEL BLOCKERS Prolong effective refractory period by prolonging Action Potential Amiodarone - Ibutilide Bretylium - Dofetilide Sotalol

CLASS IV: CALCIUM CHANNEL BLOCKERS ANTI – ARRHYTHMIC DRUGS ANTI – ARRHYTHMIC DRUGS CLASS IV: CALCIUM CHANNEL BLOCKERS Blocks cardiac calcium currents → slow conduction → increase refractory period *esp. in Ca++ dependent tissues (i.e. AV node) Verapamil, Diltiazem, Bepridil

ANTI – ARRHYTHMIC DRUGS Miscellaneous: ADENOSINE → inhibits AV conduction & increases AV refractory period MAGNESIUM → Na+/K+ ATPase, Na+, K+, Ca++ channels POTASSIUM → normalize K+ gradients

ANTI – ARRHYTHMIC DRUGS ANTI – ARRHYTHMIC DRUGS CLASS I: Sodium Channel Blocking Drugs CLASS IA: QUINIDINE Depress pacemaker rate Depress conduction & excitability Slows repolarization & lengthens AP duration → due to K+ channel blockade with reduction of repolarizing outward current → reduce maximum reentry frequency → slows tachycardia (+) alpha adrenergic blocking properties → vasodilatation & reflex ↑ SA node rate

CLASS I: SODIUM CHANNEL BLOCKERS ANTI – ARRHYTHMIC DRUGS CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: QUINIDINE Pharmacokinetics: Oral → rapid GI absorption 80% plasma protein binding 20% excreted unchanged in the urine → enhanced by acidity t½ = 6 hours Parenteral → hypotension Dosage: 0.2 to 0.6 gm 2-4X a day

ANTI – ARRHYTHMIC DRUGS CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: QUINIDINE Therapeutic Uses: Atrial flutter & fibrillation Ventricular tachycardia IV treatment of malaria Drug Interaction: Increases digoxin plasma levels

ANTI – ARRHYTHMIC DRUGS CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: QUINIDINE Toxicity: Antimuscarinic actions → inh. vagal effects Quinidine syncope (lightheadedness, fainting) Ppt. arrhythmia or asystole Depress contractility & ↓ BP Widening QRS duration Diarrhea, nausea, vomiting Cinchonism (HA, dizziness, tinnitus) Rare: rashes, fever, hepatitis, thrombocytopenia,etc S,

ANTI – ARHYTHMIC DRUGS CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: PROCAINAMIDE Less effective in suppressing abnormal ectopic pacemaker activity More effective Na+ channel blockers in depolarized cells Less prominent antimuscarinic action (+) ganglionic blocking properties → ↓PVR → hypotension (severe if rapid IV or with severe LV dysfunction)

ANTI – ARHYTHMIC DRUGS Oral, IV, IM CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: PROCAINAMIDE PHARMACOKINETICS: Oral, IV, IM N-acetylprocainamide (NAPA) → major metabolite Metabolism: hepatic Elimination: renal t½ = 3 to 4 hrs.

ANTI – ARHYTHMIC DRUGS Dosage: CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: PROCAINAMIDE Dosage: Loading IV – 12 mg/kg at 0.3 mg/kg/min or less rapidly Maintenance – 2 to 5 mg/min Therapeutic Use: 2nd DOC in most CCU for the treatment of sustained ventricular arrhythmias asstd. with MI

ANTI – ARHYTHMIC DRUGS Toxicity: - ppt. new arrhythmias CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: PROCAINAMIDE Toxicity: - ppt. new arrhythmias - LE-like syndrome - pleuritis, pericarditis, parenchymal pulmonary disease - ↑ ANA - nausea, DHA, rash, fever, hepatitis, agranulocytosis

ANTI – ARHYTHMIC DRUGS CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: DISOPYRAMIDE More marked cardiac antimuscarinic effects than quinidine → slows AV conduction Pharmacokinetics: - oral administration - extensive protein binding - t½ = 6 to 8 hrs

ANTI – ARHYTHMIC DRUGS Dosage: 150 mg TID up to 1 gm/day CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: DISOPYRAMIDE Dosage: 150 mg TID up to 1 gm/day Therapeutic Use: Ventricular arrhythmias Toxicity: - negative inotropic action (HF without prior myocardial dysfunction) - Urinary retention, dry mouth, blurred vision, constipation, worsening glaucoma

ANTI – ARHYTHMIC DRUGS CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: AMIODARONE Approved only in serious ventricular arrhythmias Broad spectrum of action on the Very effective Na+ channel blocker but low affinity for activated channels Markedly lengthens AP by blocking also K+ channels Weak Ca++ channel blocker Noncompetetive inhibitor of beta adrenoceptors Powerful inhibitor of abnormal automaticity

ANTI – ARHYTHMIC DRUGS Slows sinus rate & AV conduction CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: AMIODARONE Slows sinus rate & AV conduction Markedly prolongs the QT interval Prolongs QRS duration ↑ atrial, AV nodal & ventricular refractory periods Antianginal effects – due to noncompetetive α & β blocking property and block Ca++ influx in vascular sm.m. Perivascular dilatation - α blocking property and Ca++ channel-inhibiting effects

ANTI – ARHYTHMIC DRUGS Pharmacokinetics: > t½ = 13 to 103 days CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: AMIODARONE Pharmacokinetics: > t½ = 13 to 103 days > effective plasma conc: 1-2 μg/ml Dosage: - Loading – 0.8 to 1.2 g daily - Maintenance – 200 to 400 mg daily Drug Interaction: reduce clearance of warfarin, theophylline, quinidine, procainamide, flecainide Therapeutic Use: Supraventricular & Ventricular arrhythmias

ANTI – ARHYTHMIC DRUGS Toxicity: - fatal pulmonary fibrosis CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: AMIODARONE Toxicity: - fatal pulmonary fibrosis - yellowish-brown microcrystals corneal deposits - photodermatitis - grayish blue discoloration - paresthesias, tremor, ataxia & headaches - hypo - / hyperthyroidism - Symptomatic bradycardia or heart block - Ppt. heart failure - Constipation, hepatocellular necrosis, inflam’n, fibrosis, hypotension

ANTI – ARHYTHMIC DRUGS Intravenous route only CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: LIDOCAINE Intravenous route only Arrhythmias asstd with MI Potent abnormal cardiac activity suppressor Rapidly act exclusively on Na+ channels Shorten AP, prolonged diastole → extends time available for recovery Suppresses electrical activity of DEPOLARIZED, ARRHYTHMOGENIC tissues only

ANTI – ARHYTHMIC DRUGS Pharmacokinetics: CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: LIDOCAINE Pharmacokinetics: - Extensive first-pass hepatic metabolism - t½ = 1 to 2 hrs Dosages: loading- 150 to 200 mg maintenance- 2-4 mg Drug Interaction: propranolol, cimetidine – reduce clearance Therapeutic Use: DOC for suppression of recurrences of ventricular tachycardia & fibrillation in the first few days after AMI.

ANTI – ARHYTHMIC DRUGS Toxicity: CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: LIDOCAINE Toxicity: Ppt. SA nodal standstill or worsen impaired conduction Exacerbates ventricular arrhythmias Hypotension in HF Neurologic: paresthesias, tremor, nausea, lightheadedness, hearing disturbances, slurred speech, convulsions

ANTI – ARHYTHMIC DRUGS Congeners of lidocaine CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: TOCAINIDE & MEXILETENE Congeners of lidocaine Oral route - resistant to first-pass hepatic metabolism Tptic use: ventricular arrhythmias Elimination t½ = 8 to 20 hrs Dosage: Mexiletene – 600 to 1200 mg/day Tocainide – 800 to 2400 mg/day S/E: tremors, blurred vision, lethargy, nausea, rash, fever, agranulocytosis

ANTI – ARHYTHMIC DRUGS Anti-convulsant with anti-arrhythmic properties CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: PHENYTOIN Anti-convulsant with anti-arrhythmic properties Suppresses ectopic pacemaker activity Useful in digitalis-induced arrhythmia Extensive, saturable first-pass hepatic metabolism Highly protein bound Toxicity: ataxia, nystagmus, mental confusion, serious dermatological & BM reactions, hypotension, gingival hyperplasia D/I: Quinidine, Mexiletene, Digitoxin, Estrogen, Theophyllin, Vitamin D

ANTI – ARHYTHMIC DRUGS Potent blocker of Na+ & K+ channels CLASS I: SODIUM CHANNEL BLOCKERS CLASS IC: FLECAINIDE Potent blocker of Na+ & K+ channels No antimuscarinic effects Used in patients with supraventricular arrhythmias Effective in PVC’s Hepatic metabolism & renal elimination Dosage: 100 to 200 mg bid

ANTI – ARHYTHMIC DRUGS (+) weak β-blocking activity CLASS I: SODIUM CHANNEL BLOCKERS CLASS IC: PROPAFENONE (+) weak β-blocking activity Potency ≈ flecainide Average elim. t½ = 5 to 7 hrs. Dosage: 450 – 900 mg TID Tptic use: supraventricular arrhythmias Adv. effects: metallic taste, constipation, arrhythmia exacerbation

ANTI – ARHYTHMIC DRUGS Antiarrhythmic phenothiazine derivative CLASS I: SODIUM CHANNEL BLOCKERS CLASS IC: MORICIZINE Antiarrhythmic phenothiazine derivative Used in ventricular arrhythmias Potent Na+ channel blocker Donot prolong AP duration Dosage: 200 to 300 mg orally tid Adv. effects: dizziness, nausea

ANTI – ARHYTHMIC DRUGS ↑ AV nodal conduction time (↑ PR interval) CLASS II: BETA ADRENOCEPTOR BLOCKERS ↑ AV nodal conduction time (↑ PR interval) Prolong AV nodal refractoriness Useful in terminating reentrant arrhythmias that involve the AV node & in controlling ventricular response in AF & A.fib. Depresses phase 4 → slows recovery of cells, slows conduction & decrease automaticity Reduces HR, decrease IC Ca2+ overload & inhibit after depolarization automaticity Prevent recurrent infarction & sudden death in patients recovering from AMI

ANTI – ARHYTHMIC DRUGS “membrane stabilizing effect” CLASS II: BETA ADRENOCEPTOR BLOCKERS “membrane stabilizing effect” Exert Na+ channel blocking effect at high doses Acebutolol, metoprolol, propranolol, labetalol, pindolol “intrinsic sympathetic activity” Less antiarrhythmic effect Acebutolol, celiprolol, carteolol, labetalol, pindolol Therapeutic indications: Supraventricular & ventricular arrhythmias hypertension

ANTI – ARHYTHMIC DRUGS Specific agents: Propranolol – (+) MSA CLASS II: BETA ADRENOCEPTOR BLOCKERS Specific agents: Propranolol – (+) MSA Acebutolol – as effective as quinidine in suppressing ventricular ectopic beats Esmolol - short acting hence used primarily for intra-operative & other acute arrhythmias Sotalol – has K+ channel blocking actions (class III)

ANTI – ARHYTHMIC DRUGS CLASS III: POTASSIUM CHANNEL BLOCKERS Drugs that prolong effective refractory period by prolonging action potential Prolong AP by blocking K+ channels in cardiac muscle (↑ inward current through Na+ & Ca++ channels) Quinidine & Amiodarone → prolong AP duration Bretylium & Sotalol → prolong AP duration & refractory period Ibutilide & Dofetilide → “pure” class III agents Reverse use-dependence

ANTI – ARHYTHMIC DRUGS BRETYLIUM Antihypertensive CLASS III: POTASSIUM CHANNEL BLOCKERS BRETYLIUM Antihypertensive Interferes with neuronal release of catecholamines With direct antiarrhythmic properties Lengthens ventricular AP duration & effective refractory period Markedly ↑ strength of electrical stimulation needed to induce V.fib. & delays onset of fibrillation after acute coronary ligation (+) inotropic action

ANTI – ARHYTHMIC DRUGS BRETYLIUM Intravenous administration CLASS III: POTASSIUM CHANNEL BLOCKERS BRETYLIUM Intravenous administration Dosage: 5 mg/kg Tptic Use: ventricular fibrillation In emergency setting, during attempted resuscitation from ventricular fibrillation when lidocaine & cardioversion have failed S/E: postural hypotension*** ppt. ventricular arrhythmia nausea & vomiting

ANTI – ARHYTHMIC DRUGS SOTALOL CLASS III: POTASSIUM CHANNEL BLOCKERS SOTALOL Nonselective beta-blocker that also slows repolarization & prolongs AP duration Effective antiarrhythmic agent Used in supraventricular & ventricular arrhythmias in pediatric age group Renal excretion Dosage: 80 – 320 mg bid Toxicity: torsades de pointes beta-blockade symptoms

ANTI – ARHYTHMIC DRUGS IBUTILIDE Slows repolarization CLASS III: POTASSIUM CHANNEL BLOCKERS IBUTILIDE Slows repolarization Prolong cardiac action potentials MOA: > enhance inward Na+ current > by blocking Ikr- > both routes: Oral, IV (1 mg over 10min) Clin. Uses: atrial flutter, atrial fibrillation Toxicity: Torsades de pointes

ANTI – ARHYTHMIC DRUGS A potential Ikr- blocker Dosage: 250-500 ug bid CLASS III: POTASSIUM CHANNEL BLOCKERS DOFETILIDE A potential Ikr- blocker Dosage: 250-500 ug bid Clin. Uses: Atrial flutter & fibrillation Renal excretion Toxicity: Torsade de pointes

ANTI – ARHYTHMIC DRUGS VERAPAMIL CLASS IV: CALCIUM CHANNEL BLOCKERS VERAPAMIL Blocks both activated & inactivated calcium channels Prolongs AV nodal conduction & effective refractory period Suppress both early & delayed afterdepolarizations May antagonize slow responses in severely depolarized tissues Peripheral vasodilatation → HPN & vasospastic disorders

ANTI – ARHYTHMIC DRUGS VERAPAMIL CLASS IV: CALCIUM CHANNEL BLOCKERS VERAPAMIL Oral administration → 20% bioavailability t½ = 7 hrs Liver metabolism Dosage: IV: 5-10 mg every 4-6 hrs or infusion of 0.4 ug/kg/min Oral: 120-640 mg daily, divided in 3-4 doses Tptic use: SVT, AF, atrial fib, ventricular arrhythmias Toxicity: AV block, can ppt. sinus arrest constipation, lassitude, nervousness, peripheral edema

ANTI – ARHYTHMIC DRUGS CLASS IV: CALCIUM CHANNEL BLOCKERS DILTIAZEM & BEPRIDIL Similar efficacy to verapamil in supraventricular arrhythmias & rate control in atrial fibrillation Bepridil AP & QT prolonging action→ ventricular arrhythmias but may ppt. torsade de pointes Rarely used → primarily to control refractory angina

ANTI – ARHYTHMIC DRUGS MISCELLANEOUS ANTIARRHYTHMIC AGENTS: DIGITALIS Indirectly alters autonomic outflow by increasing parasympathetic tone & decreasing sympathetic tone Results in decreased conduction time & increased refractory period in the AV node

ANTI – ARHYTHMIC DRUGS ADENOSINE MISCELLANEOUS ANTIARRHYTHMIC AGENTS: ADENOSINE A nucleoside that occurs naturally in the body t½ ≈ 10 seconds MOA: enhances K+ conductance & inhibits cAMP-induced Ca++ influx → results in marked hyperpolarization & suppression of Ca++-dependent AP IV bolus: directly inhibits AV nodal conduction & ↑ AV nodal refractory period

ANTI – ARHYTHMIC DRUGS ADENOSINE MISCELLANEOUS ANTIARRHYTHMIC AGENTS: ADENOSINE DOC for prompt conversion of paroxysmal SVT to sinus rhythm due to its high efficacy & very short duration of action Dosage: 6-12 mg IV bolus D/I: theophylline, caffeine – adenosine receptor blockers Dipyridamole – adenosine uptake inhibitor Toxicity: flushing, SOB or chest burning, atrial fibrillation, headache, hypotension, nausea, paresthesia

ANTI – ARHYTHMIC DRUGS MISCELLANEOUS ANTIARRHYTHMIC AGENTS: MAGNESIUM Effective in patients with recurrent episodes of torsades de pointes (MgSO4 1 to 2 g IV) & in digitalis-induced arrhythmia MOA: unknown → influence Na+/K+ ATPase, Na+ channels, certain K+ and Ca++ channels

ANTI – ARHYTHMIC DRUGS POTASSIUM MISCELLANEOUS ANTIARRHYTHMIC AGENTS: POTASSIUM Therapy directed toward normalizing K+ gradients & pools in the body Effects of increasing serum K+: 1. resting potential depolarizing action 2. membrane potential stabilizing action Hypokalemia: ↑ risk of early & delayed afterdepolarization ↑ ectopic pacemaker activity esp if (+) digitalis Hyperkalemia: Depression of ectopic pacemakers Slowing of conduction