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ANTI-ARRHYTHMIC DRUGS
Dr. Marjan Nassiri-Asl 4/27/2017
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Normal rhythm Atrial arrhythmia 4/27/2017
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Ventricular Arrhythmia
4/27/2017
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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: mg orally tid Adv. effects: dizziness, nausea 4/27/2017
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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
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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
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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
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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
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Atenolol Less effective than metoprolol in preventing the complications of hypertension. 4/27/2017
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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
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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
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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
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Pharmacokinetics Steady-state blood concentrations are reached within 30 min with doses of µg/kg per min The time to ss may be reduced to 5 min by giving an appropriate loading dose. 4/27/2017
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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: mg daily, divided in 3-4 doses Use: SVT, atrial fib Toxicity: AV block, sinus arrest constipation, lassitude, nervousness, peripheral edema 4/27/2017
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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
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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
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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
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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
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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
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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
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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
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