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ANTI-ARRHYTHMIC DRUGS

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 :

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ANTI-ARRHYTHMIC DRUGS

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  1. ANTI-ARRHYTHMICDRUGS Ma. Janetth B. Serrano, M.D.,DPBA

  2. 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

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

  4. 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

  5. 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

  6. 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

  7. 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

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

  9. 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

  10. 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

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

  12. 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

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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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)

  19. 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 to 4 hrs.

  20. 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

  21. ANTI – ARHYTHMIC DRUGS 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

  22. 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

  23. ANTI – ARHYTHMIC DRUGS 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

  24. 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

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

  26. ANTI – ARHYTHMIC DRUGS 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

  27. ANTI – ARHYTHMIC DRUGS 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

  28. ANTI – ARHYTHMIC DRUGS 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

  29. 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 • Therapeutic Use: DOC for suppression of recurrences of ventricular tachycardia & fibrillation in the first few days after AMI.

  30. ANTI – ARHYTHMIC DRUGS 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

  31. ANTI – ARHYTHMIC DRUGS 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

  32. 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

  33. 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

  34. 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 • Tptic use: supraventricular arrhythmias • Adv. effects: metallic taste, constipation, arrhythmia exacerbation

  35. ANTI – ARHYTHMIC DRUGS 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

  36. ANTI – ARHYTHMIC DRUGS 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

  37. ANTI – ARHYTHMIC DRUGS 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

  38. ANTI – ARHYTHMIC DRUGS 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)

  39. 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

  40. ANTI – ARHYTHMIC DRUGS 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

  41. ANTI – ARHYTHMIC DRUGS CLASS III: POTASSIUM CHANNEL BLOCKERS • 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 BRETYLIUM

  42. ANTI – ARHYTHMIC DRUGS 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

  43. ANTI – ARHYTHMIC DRUGS CLASS III: POTASSIUM CHANNEL BLOCKERS • 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 IBUTILIDE

  44. ANTI – ARHYTHMIC DRUGS 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

  45. ANTI – ARHYTHMIC DRUGS 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

  46. ANTI – ARHYTHMIC DRUGS 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

  47. ANTI – ARHYTHMIC DRUGS CLASS IV: CALCIUM CHANNEL BLOCKERS • 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 DILTIAZEM & BEPRIDIL

  48. 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

  49. ANTI – ARHYTHMIC DRUGS 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

  50. ANTI – ARHYTHMIC DRUGS 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

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