ANTI-ARRHYTHMIC DRUGS Dr. Marjan Nassiri-Asl 4/27/2017

Normal rhythm Atrial arrhythmia 4/27/2017

Ventricular Arrhythmia 4/27/2017

ELECTRO-PHYSIOLOGY OF NORMAL CARDIAC RHYTHM ANTI – ARRHYTHMIC DRUGS SA node ELECTRO-PHYSIOLOGY OF NORMAL CARDIAC RHYTHM ATRIA AV node His-Purkinje System VENTRICLES 4/27/2017

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 ions: Sodium, Potassium, Calcium The movement of these ions produces currents that form the basis of the cardiac action potential 4/27/2017

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 4/27/2017

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 4/27/2017

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 4/27/2017

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 g 2-4/ day 4/27/2017

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 4/27/2017

ANTI – ARRHYTHMIC DRUGS CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: QUINIDINE Toxicity: Antimuscarinic actions → inh. vagal effects Quinidine syncope (lightheadedness, fainting) Arrhythmia or asystole Depress contractility & ↓ BP Widening QRS duration Diarrhea, nausea, vomiting Cinchonism (HA, dizziness, tinnitus) Rare: rashes, fever, hepatitis, thrombocytopenia,etc S, 4/27/2017

نکات مهم ANTI – ARRHYTHMIC DRUGS CLASS IA: QUINIDINE نکات مهم استفاده از محلول های تزریقی بی رنگ (نور سبب کریستالیزه شدن و قهوه ای رنگ شدن محلول می گردد) شروع درمان با دوز کم کنترل بیمار از نظر نشانه های حساسیت به دارو (اختلالات تنفسی) به هنگام تجویز دارو مرتبا فشار خون اندازه گیری شود مانیتورینگ قلبی بیمار: طولانی شدن فاصلهPR ، محو موج P و .....دلایل قطع دارو هستند S, 4/27/2017

ANTI – ARHYTHMIC DRUGS CLASS IA: PROCAINAMIDE 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) 4/27/2017

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 = 3-4 h 4/27/2017

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 4/27/2017

ANTI – ARHYTHMIC DRUGS Toxicity: - new arrhythmias - LE-like syndrome CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: PROCAINAMIDE Toxicity: - new arrhythmias - LE-like syndrome - pleuritis, pericarditis, parenchymal pulmonary disease - nausea, rash, fever, hepatitis, agranulocytosis 4/27/2017

نکات مهم ANTI – ARHYTHMIC DRUGS عدم استفاده از محلول تغییر رنگ یافته CLASS IA: PROCAINAMIDE نکات مهم عدم استفاده از محلول تغییر رنگ یافته انفوزیون آهسته وریدی در حالت انفوزیون بیمار دراز کشیده و مرتبا فشار خون اندازه گیری شود پایداری محلول تزریقی پروکائین آمید در دکستروز 5% به مدت 24 ساعت در دمای اتاق و یک هفته در یخچال 4/27/2017

بدلیل جذب ناکافی دارو باید با معده خالی مصرف شود ANTI – ARHYTHMIC DRUGS CLASS IA: PROCAINAMIDE نکات مهم بدلیل جذب ناکافی دارو باید با معده خالی مصرف شود در بیمار تحت درمان خوراکی کنترل بیمار از نظر علائم لوپوس اریتماتوز 4/27/2017

افزایش عوارض جانبی دارو ANTI – ARHYTHMIC DRUGS CLASS IA: PROCAINAMIDE تداخل پروکائین آمید افزایش عوارض جانبی دارو لیدوکائین کاهش دفع کلیوی دارو و افزایش اثر آن بیکربنات سدیم افزایش خطر آریتمی کشنده فلوروکینولون ها افزایش غلظت دارو تری متوپریم، سایمتدین سبب افزایش اثر آنتی کولینرژیکی آنها میگردد داروهای آنتی کولینرژیکی 4/27/2017

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 h 4/27/2017

ANTI – ARHYTHMIC DRUGS Dosage: 150 mg TID up to 1 g/day CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: DISOPYRAMIDE Dosage: 150 mg TID up to 1 g/day Therapeutic Use: Ventricular arrhythmias Toxicity: - Negative inotropic action - Urinary retention, dry mouth, blurred vision, constipation, worsening glaucoma 4/27/2017

ANTI – ARHYTHMIC DRUGS IV route only Arrhythmias asstd with MI CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: LIDOCAINE IV 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 4/27/2017

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 of Lidocaine Therapeutic Use: DOC for suppression of recurrences of ventricular tachycardia & fibrillation in the first few days after AMI 4/27/2017

ANTI – ARHYTHMIC DRUGS Toxicity: CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: LIDOCAINE Toxicity: SA nodal standstill or worsen impaired conduction Exacerbates ventricular arrhythmias Hypotension in HF Neurologic: paresthesias, tremor, nausea, lightheadedness, hearing disturbances, slurred speech, convulsions 4/27/2017

ANTI – ARHYTHMIC DRUGS Attention!! CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: LIDOCAINE Attention!! شکل تزریقی آن باید فاقد ماده نگهدارنده و اپی نفرین باشد عدم افزودن آن به خون و مشتقات آن 4/27/2017

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 Topic 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 4/27/2017

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 (Enz inducer) 4/27/2017

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 4/27/2017

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 Topic use: supraventricular arrhythmias Adv. effects: metallic taste, constipation, arrhythmia exacerbation 4/27/2017

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 Do not prolong AP duration Dosage: 200 - 300 mg orally tid Adv. effects: dizziness, nausea 4/27/2017

ANTI – ARHYTHMIC DRUGS Propranolol, Esmolol, Sotalol CLASS II: BETA ADRENOCEPTOR BLOCKERS Propranolol, Esmolol, Sotalol ↑ 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 4/27/2017

ANTI – ARHYTHMIC DRUGS Specific agents: Propranolol – (+) MSA CLASS II: BETA ADRENOCEPTOR BLOCKERS Specific agents: Propranolol – (+) MSA Esmolol - short acting hence used primarily for intra-operative & other acute arrhythmias Sotalol – has K+ channel blocking actions (class III) 4/27/2017

ANTI – ARHYTHMIC DRUGS “membrane stabilizing activity” CLASS II: BETA ADRENOCEPTOR BLOCKERS “membrane stabilizing activity” 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 4/27/2017

Metoprolol Cardioselective, are the most widely used blockers in the treatment of hypertension Sustained-release metoprolol is effective in reducing mortality from HF and is particularly useful in patients with hypertension and HF 4/27/2017

Atenolol Less effective than metoprolol in preventing the complications of hypertension. 4/27/2017

Labetalol Has a 3:1 ratio of β:α antagonism after oral dosing BP is lowered by reduction of systemic vascular resistance (via α blockade) without significant alteration in HR or C.O.P Is useful in treating the hypertension of pheochromocytoma and hypertensive emergencies (combined β- and α-blocking activity) 4/27/2017

Carvedilol Nonselective β and α-adrenoceptor blocker Metabolized in the liver The average half-life is 7–10 h Reduces mortality in patients with HF and is therefore particularly useful in patients with both HF and hypertension 4/27/2017

اسمولول β1-selective blocker that is rapidly metabolized via hydrolysis by RBC esterases It has a short half-life (9–10 min) Is administered by constant IV infusion Is used for management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia 4/27/2017

Pharmacokinetics Steady-state blood concentrations are reached within 30 min with doses of 50-300 µg/kg per min The time to ss may be reduced to 5 min by giving an appropriate loading dose. 4/27/2017

Pharmacokinetics Blood concentrations decline in a biphasic manner with a distribution half-life of about 2 min Esmolol has low lipid solubility and is about 55% bound to plasma proteins It is excreted in urine, primarily as the de-esterified metabolite. 4/27/2017

Pindolol, Acebutolol, & Penbutolol Partial agonists, ie, β blockers with some intrinsic sympathomimetic activity (ISA) They lower blood pressure by decreasing vascular resistance and appear to depress C.O.P or HR less than other β blockers Significantly greater agonist than antagonist effects at β2 receptors Beneficial for patients with bradyarrhythmias or peripheral vascular disease 4/27/2017

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 Dofetilide Sotalol 4/27/2017

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 Amiodarone → prolong AP duration Bretylium & Sotalol → prolong AP duration & refractory period Ibutilide & Dofetilide → “pure” class III agents 4/27/2017

ANTI – ARHYTHMIC DRUGS CLASS III: POTASSIUM CHANNEL BLOCKERS CLASS III: 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 Non-competetive inhibitor of β receptors Powerful inhibitor of abnormal automaticity 4/27/2017

ANTI – ARHYTHMIC DRUGS Slows sinus rate & AV conduction CLASS III: POTASSIUM CHANNEL BLOCKERS CLASS III: 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 4/27/2017

ANTI – ARHYTHMIC DRUGS Pharmacokinetics: t½ = 20 to 100 days CLASS III: POTASSIUM CHANNEL BLOCKERS CLASS III: AMIODARONE Pharmacokinetics: t½ = 20 to 100 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 4/27/2017

ANTI – ARHYTHMIC DRUGS Toxicity: - fatal pulmonary fibrosis CLASS III: POTASSIUM CHANNEL BLOCKERS CLASS III: 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 - heart failure - Constipation, hepatocellular necrosis, inflam’n, fibrosis, hypotension 4/27/2017

نکات مهم ANTI – ARHYTHMIC DRUGS CLASS III: AMIODARONE نکات مهم بدلیل جذب ناکافی دارو باید با معده خالی مصرف شود محافظت پوست بیمار از نور در طول درمان و حداقل 4 ماه پس از قطع آن انجام آزمایشات مرتب برای ارزیابی کار تیروئید برای تزریق داخل وریدی آمیودارون در محلول تزریقی دکستروز 5% رقیق شده و انفوزیون گردد انفوزیون مکرر وریدی می تواند سبب درد و التهاب موضعی گردد 4/27/2017

نکات مهم ANTI – ARHYTHMIC DRUGS CLASS III: AMIODARONE نکات مهم در هنگام انفوزیون وریدی تجهیزات کافی برای کنترل وضع قلب باید در دسترس باشد 4/27/2017

تشدید اثر داروها داروهای ضد انعقاد ANTI – ARHYTHMIC DRUGS CLASS III: AMIODARONE تداخل آمیودارون تشدید اثر داروها داروهای ضد انعقاد افزایش خطر کاهش فشار خون و برایکاردی بتا بلوکرها افزایش خطر بلوک دهلیزی-بطنی و هیپوتانسیون CCBs احتمال افزایش سطح دیگوکسین دیگوکسین افزایش سطح پلاسمایی آمیودارون سایمتدین 4/27/2017

ANTI – ARHYTHMIC DRUGS SOTALOL CLASS III: POTASSIUM CHANNEL BLOCKERS SOTALOL Nonselective B-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 B-blockade symptoms 4/27/2017

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 4/27/2017

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 → Effective in Hypertention & vasospastic disorders 4/27/2017

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 Use: SVT, atrial fib Toxicity: AV block, sinus arrest constipation, lassitude, nervousness, peripheral edema 4/27/2017

ANTI – ARHYTHMIC DRUGS CLASS IV: CALCIUM CHANNEL BLOCKERS DILTIAZEM & BEPRIDIL Similar efficacy to verapamil in supraventricular arrhythmias & rate control in atrial fibrillation 4/27/2017

ANTI – ARRHYTHMIC DRUGS Miscellaneous: ADENOSINE → inhibits AV conduction & increases AV refractory period MAGNESIUM → Na+/K+ ATPase, Na+, K+, Ca++ channels POTASSIUM → normalize K+ gradients 4/27/2017

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 4/27/2017

ANTI – ARHYTHMIC DRUGS ADENOSINE MISCELLANEOUS ANTIARRHYTHMIC AGENTS: ADENOSINE A nucleoside that occurs naturally in the body t½ ≈ 10 seconds 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 4/27/2017

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 [enhancer] Toxicity: flushing, chest burning, atrial fibrillation, headache, hypotension, nausea, paresthesia 4/27/2017

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 Mechanism unknown → influence Na+/K+ ATPase, Na+ channels, certain K+ and Ca++ channels 4/27/2017

ANTI – ARHYTHMIC DRUGS POTASSIUM MISCELLANEOUS ANTIARRHYTHMIC AGENTS: POTASSIUM Therapy directed toward normalizing K+ gradients & pools in the body Hypokalemia: ↑ risk of early & delayed afterdepolarization ↑ ectopic pacemaker activity esp if (+) digitalis Hyperkalemia: Depression of ectopic pacemakers Slowing of conduction 4/27/2017