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ANTI-ARRHYTHMIC DRUGS

Learn about the classification, pharmacokinetics, therapeutic uses, and toxicities of Class IA Sodium Channel Blockers like Quinidine and Procainamide. Understand their mechanisms, dosages, and monitoring necessities.

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ANTI-ARRHYTHMIC DRUGS

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  1. ANTI-ARRHYTHMICDRUGS Dr. Marjan Nassiri-Asl

  2. Normal rhythm Atrial arrhythmia

  3. Ventricular Arrhythmia

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

  5. 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

  6. ANTI – ARRHYTHMIC DRUGS PHASES OF ACTION POTENTIAL Phase 0 >Rapid depolarization >Opening fast Na+ channels→ Na+ rushes in →depolarization 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 4 >Resting Membrane Potential >High K+ efflux >Ca++ influx

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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 Pو .....دلایل قطع دارو هستند

  13. 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)

  14. ANTI – ARHYTHMIC DRUGS 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

  15. ANTI – ARHYTHMIC DRUGS 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

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

  17. ANTI – ARHYTHMIC DRUGS 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

  18. 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

  19. ANTI – ARHYTHMIC DRUGS CLASS IA: PROCAINAMIDE تداخل پروکائین آمید

  20. 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

  21. ANTI – ARHYTHMIC DRUGS 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

  22. ANTI – ARHYTHMIC DRUGS 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

  23. ANTI – ARHYTHMIC DRUGS 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

  24. ANTI – ARHYTHMIC DRUGS 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

  25. ANTI – ARHYTHMIC DRUGS 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

  26. ANTI – ARHYTHMIC DRUGS 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

  27. ANTI – ARHYTHMIC DRUGS 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)

  28. ANTI – ARHYTHMIC DRUGS 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

  29. ANTI – ARHYTHMIC DRUGS 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

  30. ANTI – ARHYTHMIC DRUGS 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

  31. ANTI – ARHYTHMIC DRUGS 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

  32. ANTI – ARHYTHMIC DRUGS 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)

  33. ANTI – ARHYTHMIC DRUGS 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

  34. 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

  35. Atenolol • Less effective than metoprolol in preventing the complications of hypertension.

  36. 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)

  37. 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

  38. 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

  39. 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.

  40. 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.

  41. 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

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

  43. 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

  44. 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

  45. ANTI – ARHYTHMIC DRUGS 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 - αblocking property and Ca++ channel-inhibiting effects

  46. ANTI – ARHYTHMIC DRUGS 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

  47. ANTI – ARHYTHMIC DRUGS 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

  48. 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

  49. ANTI – ARHYTHMIC DRUGS CLASS III: AMIODARONE نکات مهم • در هنگام انفوزیون وریدی تجهیزات کافی برای کنترل وضع قلب باید در دسترس باشد

  50. ANTI – ARHYTHMIC DRUGS CLASS III: AMIODARONE تداخل آمیودارون

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