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Editd anti arrhythmic

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Editd anti arrhythmic Editd anti arrhythmic Presentation Transcript

  • ANTI-ARRHYTHMIC DRUGS Ma. Janetth B. Serrano, M.D.,DPBA
    • Cardiac Arrhythmias:
      • 25% treated with digitalis
      • 50% anesthetized patients
      • 80% patients with AMI
    • reduced cardiac output
    • drugs or nonpharmacologic :
    • - pacemaker, cardioversion, catheter ablation, surgery
    ANTI – ARRHYTHMIC DRUGS
  • ELECTRO-PHYSIOLOGY OF NORMAL CARDIAC RHYTHM
    • SA node
    AV node ATRIA His-Purkinje System VENTRICLES 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
    ANTI – ARRHYTHMIC DRUGS
  • PHASES OF ACTION POTENTIAL
    • Phase 0
    • >Rapid depolarization
    • >Opening fast Na+
    • channels -> Na+ rushes in ->depolarization
    Phase 1 >Limited depolarization >Inactivation of fast Na+ channels -> Na+ ion conc equalizes >↑ K+ efflux & Cl- influx Phase 2 >Plateau Stage >Cell less permeable to Na+ >Ca++ influx through slow Ca++ channels >K+ begins to leave cell Phase 3 >Rapid repolarization >Na+ gates closed >K+ efflux >Inactivation of slow Ca++ channels Phase 4 >Resting Membrane Potential >High K+ efflux >Ca++ influx 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
    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 – ARRHYTHMIC DRUGS
    • 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
    ARRHYTHMIAS: 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
    ANTI – ARRHYTHMIC DRUGS
    • Increase AV nodal conduction
    • Increase PR interval
    • Prolong AV refractoriness
    • Reduce adrenergic activity
    • Propranolol, Esmolol, Metoprolol, Sotalol
    CLASS II: BETA-BLOCKING AGENTS ANTI – ARRHYTHMIC DRUGS
    • Prolong effective refractory period by prolonging Action Potential
      • Amiodarone - Ibutilide
      • Bretylium - Dofetilide
      • Sotalol
    CLASS III: POTASSIUM CHANNEL BLOCKERS 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
    • DIGITALIS -> Indirectly alters autonomic outflow
    • MAGNESIUM -> Na+/K+ ATPase, Na+, K+, Ca++ channels
    • POTASSIUM -> normalize K+ gradients
    ANTI – ARRHYTHMIC DRUGS
    • 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 Blocking Drugs CLASS IA: QUINIDINE ANTI – ARRHYTHMIC DRUGS
  • CLASS I: SODIUM CHANNEL BLOCKERS
    • 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
    CLASS IA: QUINIDINE ANTI – ARRHYTHMIC DRUGS
  • CLASS I: SODIUM CHANNEL BLOCKERS
    • Therapeutic Uses:
      • Atrial flutter & fibrillation
      • Ventricular tachycardia
      • IV treatment of malaria
    • Drug Interaction:
      • Increases digoxin plasma levels
    CLASS IA: QUINIDINE ANTI – ARRHYTHMIC DRUGS
  • CLASS I: SODIUM CHANNEL BLOCKERS
    • 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
    CLASS IA: QUINIDINE ANTI – ARRHYTHMIC DRUGS
    • 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)
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: PROCAINAMIDE ANTI – ARRHYTHMIC DRUGS
    • PHARMACOKINETICS:
    • Oral, IV, IM
    • N-acetylprocainamide (NAPA) -> major metabolite
    • Metabolism: hepatic
    • Elimination: renal
    • t½ = 3 to 4 hrs.
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: PROCAINAMIDE ANTI – ARRHYTHMIC DRUGS
    • Dosage:
    • Loading IV – 12 mg/kg at 0.3 mg/kg/min or less rapidly
    • Maintenance – 2 to 5 mg/min
    • Therapeutic Use:
    • 2 nd DOC in most CCU for the treatment of sustained ventricular arrhythmias asstd. with MI
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: PROCAINAMIDE ANTI – ARRHYTHMIC DRUGS
    • Toxicity:
    • - ppt. new arrhythmias
    • - LE-like syndrome
    • - pleuritis, pericarditis, parenchymal pulmonary disease
    • - ↑ ANA
    • - nausea, DHA, rash, fever, hepatitis, agranulocytosis
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: PROCAINAMIDE ANTI – ARRHYTHMIC DRUGS
    • More marked cardiac antimuscarinic effects than quinidine -> slows AV conduction
    • Pharmacokinetics:
    • - oral administration
    • - extensive protein binding
    • - t½ = 6 to 8 hrs
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: DISOPYRAMIDE ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: DISOPYRAMIDE ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: AMIODARONE ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: AMIODARONE ANTI – ARRHYTHMIC DRUGS
    • Pharmacokinetics:
    • > t ½ = 13 to 103 days
    • > effective plasma conc: 1-2 μ g/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
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: AMIODARONE ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IA: AMIODARONE ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: LIDOCAINE ANTI – ARRHYTHMIC DRUGS
    • Pharmacokinetics:
    • - Extensive first-pass hepatic metabolism
      • - t ½ = 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.
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: LIDOCAINE ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: LIDOCAINE ANTI – ARRHYTHMIC DRUGS
    • Congeners of lidocaine
    • Oral route - resistant to first-pass hepatic metabolism
    • Tptic use: ventricular arrhythmias
    • Elimination t ½ = 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
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: TOCAINIDE & MEXILETENE ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IB: PHENYTOIN ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IC: FLECAINIDE ANTI – ARRHYTHMIC DRUGS
    • (+) 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
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IC: PROPAFENONE ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS I: SODIUM CHANNEL BLOCKERS CLASS IC: MORICIZINE ANTI – ARRHYTHMIC DRUGS
    • ↑ 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 Ca 2+ overload & inhibit after depolarization automaticity
    • Prevent recurrent infarction & sudden death in patients recovering from AMI
    CLASS II: BETA ADRENOCEPTOR BLOCKERS ANTI – ARRHYTHMIC DRUGS
    • “ 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
    CLASS II: BETA ADRENOCEPTOR BLOCKERS ANTI – ARRHYTHMIC DRUGS
    • 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)
    CLASS II: BETA ADRENOCEPTOR BLOCKERS Specific agents: ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS III: POTASSIUM CHANNEL BLOCKERS ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS III: POTASSIUM CHANNEL BLOCKERS BRETYLIUM ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS III: POTASSIUM CHANNEL BLOCKERS BRETYLIUM ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS III: POTASSIUM CHANNEL BLOCKERS SOTALOL ANTI – ARRHYTHMIC DRUGS
    • Slows repolarization
    • Prolong cardiac action potentials
    • MOA: > enhance inward Na+ current
    • > by blocking I kr-
    • > both
    • routes: Oral, IV (1 mg over 10min)
    • Clin. Uses: atrial flutter, atrial fibrillation
    • Toxicity: Torsades de pointes
    CLASS III: POTASSIUM CHANNEL BLOCKERS IBUTILIDE ANTI – ARRHYTHMIC DRUGS
    • A potential I kr- blocker
    • Dosage: 250-500 ug bid
    • Clin. Uses: Atrial flutter & fibrillation
    • Renal excretion
    • Toxicity: Torsade de pointes
    CLASS III: POTASSIUM CHANNEL BLOCKERS DOFETILIDE ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS IV: CALCIUM CHANNEL BLOCKERS VERAPAMIL ANTI – ARRHYTHMIC DRUGS
    • Oral administration -> 20% bioavailability
    • t ½ = 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
    CLASS IV: CALCIUM CHANNEL BLOCKERS VERAPAMIL ANTI – ARRHYTHMIC DRUGS
    • 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
    CLASS IV: CALCIUM CHANNEL BLOCKERS DILTIAZEM & BEPRIDIL ANTI – ARRHYTHMIC DRUGS
    • Indirectly alters autonomic outflow by increasing parasympathetic tone & decreasing sympathetic tone
    • Results in decreased conduction time & increased refractory period in the AV node
    MISCELLANEOUS ANTIARRHYTHMIC AGENTS: DIGITALIS ANTI – ARRHYTHMIC DRUGS
    • A nucleoside that occurs naturally in the body
    • t ½ ≈ 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
    MISCELLANEOUS ANTIARRHYTHMIC AGENTS: ADENOSINE ANTI – ARRHYTHMIC DRUGS
    • 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
    MISCELLANEOUS ANTIARRHYTHMIC AGENTS: ADENOSINE ANTI – ARRHYTHMIC DRUGS
    • Effective in patients with recurrent episodes of torsades de pointes (MgSO 4 1 to 2 g IV) & in digitalis-induced arrhythmia
    • MOA: unknown -> influence Na+/K+ ATPase, Na+ channels, certain K+ and Ca++ channels
    MISCELLANEOUS ANTIARRHYTHMIC AGENTS: MAGNESIUM ANTI – ARRHYTHMIC DRUGS
    • 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
    ANTI – ARRHYTHMIC DRUGS MISCELLANEOUS ANTIARRHYTHMIC AGENTS: POTASSIUM