AntiaritmiaFrans D. SuyatnaModified by Sulistia 1010Departemen Farmakologi & Terapeutik FKUI

OBJECTIVEABLE TO 1. describe antiarrythmic mechanisms of 4 classes of antiarrhytmias 2. mention 3 examples of each class and its indications 3. describe important pharmacokinetics of antiarhytmias 4. describe serious adverse effect and drug interaction of antiarhytmias

Mechanisms of cardiac arrhythmias1. Disturbances in impulse formation - Failure of impulse formation * vagal discharge more negative max. diastolic potential, reducing phase 4 slope * receptor-blocking drugs reducing phase 4 slope

Mechanisms of cardiac arrhythmias- Acceleration of impulse formation (enhanced automatically) * Hypokalemia, adrenoreceptor stimulation, fiber stretch, acidosis, partial depolarization by currents of injury increasing phase 4 slope

Mechanisms of cardiac arrhythmias2. Disturbances in impulse conduction - Failure of impulse propagation (A V) heart block - Reentry * presence of an anatomically defined circuit * unidirectional block * slow conduction in one part of the circuit

Afterdepolarizations & triggered automatically1. Delayed afterdepolarizations (DAD), (in rapid HR) Ca++i occurs in myoc. ischemia, adrenergic stress, digitalis intoxication

2. Early afterdepolarization (EAD), (in slow HR), K+o , certain antiarrhythmic drugseg. torsades de pointes long QT syndrome

Mechanism of action of antiarhytmias1. Alter automatic rhythm max. diastolic potential adenosine, Ach- phase - 4 slope -blockers- threshold potential class 1 (blocking of Na+, Ca2+ channels- AP duration blocking of K+ channels

Mechanism of action2. inhibition of development of afterdepolarization - interfere inward current (Na+ , Ca2+ channels) eg. verapamil for digitalis-induced DAD quinidine for digitalis-induced DAD (blocks Na+ channels threshold ) isoproterenol shortens AP duration in EAD Mg++ inhibits triggered beats from EAD blocker for prevention of torsades de pointes in cong. prolonged QT interval

Anatomically determined reentry Ca++ blocking agents, blockers, digitalis prolong AV nodal refractoriness & slow AV nodal conduction block propagation of AP

Functionally determined reentryNa+ channel blocking agents shift voltage dependent of recovery from block prolong refractoriness Also blocking delayed rectifier currents, Ca++ channels prolong refractoriness

Antiarrhythmic drugsClassificationI. Na+ channel blocker (local anesthetic of action) I.a. Quinidine, procainamide, disopyramide lengthen AP duration I.b. Lidocaine, mexiletine, flecainide, phenytoin, shorten AP duration I.c. propafenone, Flecainide no effect on or slightly lengthen AP durationII. Sympathoplegic, beta-blocker: propranolol, acebutolol,metoprolol, esmolol

Antiarrhythmic drugsIII. Prolong effective refractory period by prolonging AP duration Blocking K+ channels or enhancing inward current through Na+ or Ca++ channels example: amiodarone (multiple action), sotalolIV. Calcium channel blocking drugs: verapamil, diltiazem

Class I. a: Quinidine(1)1. Mechanism of action - Blocks Na+ current (open state blocker) threshold of excitability , automaticity - Blocks multiple K+ currents prolongs APD! At slow HR EAD produced, esp. when [K]o ~ low - Prolongs refractoriness due to Na+ channel blocking and prolongation of APD - 2. Indication : atrial fibrill./flutter, prevention of VT or VF ; premature ventricular contraction

Quinidine (2)3. Adverse effects - Non cardiac : diarrhea (30-50%, be aware of hypokalemia torsades de pointes ) - Others (non dose dependent, immunologic): thrombocytopenia, hepatitis, bone marrow depression, LE cinchonism (dose dependent) - Cardiac: QT prolongation, torsade de pointes (2-8%) ventricular tachycardia, may excacerbate heart failure

Quinidine (3)ADR(Continued)Additional effect : -adrenergic receptor blockade vagal inhibition hypotension & tachycardia

4. Pharmacokinetics - Well absorbed, 80% bound to plasma proteins - Extensive hepatic oxidative metabolism, 20% excreted unchanged by kidney - 3-OH quinidine ~ quinidine as Na+ channel blocker

Quinidine (4)5. Drug InteractionsPotent inhibitor of CYP 2D6 (reduced analgetic effect of codein, increased plasma propafenone & adrenergic blockade) - Reduces clearance of digoxin & digitoxin - Cimetidine & verapamil increases plasma quinidine (modest)

Procainamide (1)1. Mechanism of action - ~ quinidine, but vagolytic activity (-) & -adrenergic blocking activity (-) - N-acetyl procainamide (metabolite) lacks Na+ channel blocking activity 2. Indication: - acute therapy (i.v.) in supra-ventricular and ventricular arrhythmias

Procainamide (2)3. Adverse effects - Hypotension, marked slowing of conduction (i.v.) - Nausea (oral), bone marrow aplasia, lupus syndrome (parent drug) - Torsade de pointes

4. Pharmacokinetics - t : 3-4 h, renal & hepatic - lupus develops often in slow acetylators

DisopyramideMechanism of action ~ quinidine -adrenergic blocking activity (-), vagolytic action (+)Indication :atrial flutter, fibrillation, prevention of recurrence of VT or VFSide effects: glaucoma, constipation, dry mouth, urinary retention, torsade de pointes*Oral administration (well absorbed)

* List of non-antiarrhytmic drug list of drug implicated in the occurance of Torsades the pointes can be found at www.torsade.org

Lidocaine(1)

1. Mechanism of action- Local anesthetic (i.v.)- Blocks open & inactivated Na+ channels in ventricle- Reduces slope of phase 4 & threshold for excitability, AP duration is unaffected - repair intraventricular conduction

Lidocaine(2)2. Indication: drug of choice for VT & VF after cardioversion incidence of VF in acute myocardial infarction but routine prophylactic use in myocardial infarction is no longer practiced, because of lidocaine-exacerbated heart block or congestive heart failure Not effective for : atrial arrhythmias

Lidocaine (3)3. Adverse effect- Seizures (rapid & large iv dose)- Tremor, dysarthria, altered level of consciousness, nystagmus (early sign)4. Pharmacokinetics- t : 2 htherapeutics plasma level : 2-4 g/ml- Decrease doses (loading & maintenance) when volume of distribution and total body water are decreased (congestive heart failure)

Propafenone(1)1C1. Mechanism of action- Na+ channel blocker (1c) with slow T recoveryAlso blocks K+ channels ~ quinidine S (+) propafenone has adrenergic receptor blocker activity 2. Indication: supraventricular tachycardia , modestly effective in ventricular arrhythmias

Propafenone(2)2. Adverse effects - Arrhythmias exacerbation, metallic taste, constipation

3. Pharmacokinetics- t : 5 h- metabolized by CYP2D6

Class IIBeta adrenergic blocking drugsBeta adrenergic blocking & membrane stabilizing effects Suppresive effect on ventricular arrhythmias is lower than class I- Prevent recurrent infarction & sudden death in myocardial infarctionCauses EAD, torsade de pointes

Class IIIAmiodaroneSotalolbretylium

Amiodarone (Analog of thyroid hormone)1. Multiple mechanisms of action (exhibiting class I,II,III, IV action) Blocks inactivated Na+ channels, Ca++ currents, transient outward, delayed rectifier & inward rectifier K+ currents -- non competitive adrenergic blocking effect - Potent inhibitor of abnormal automaticity, prolongs AP 2. Indication: severe, recurrent VT or VF resistant to other drugs, atrial fibrillation, PSVT

Amiodarone (2)3. PharmacokineticsPoorly absorbed per oral (bioavail. ~ 30%), highly lipophilic distributed in lipid >> plasmaSlowly accumulated in tissue (needs high-dose oral loading for several weeks)Metabolized by CYP3A4 to desethyl-amiodarone (effect ~ parent drug)Inhibitor of CYP3A4, CYP2C9 and P-glycoproteinReduce dosage of warfarin, flecanide, procainamide, quinidine, digoxin when used together

Amiodarone (3) Pharmacokineticst : 40-60 daysElimination : 4. Adverse effectsHypotension, nauseaPulmonary fibrosis, corneal microdeposits, hepatic dysfunction, hypo-hyperthyroidism, neuromuscular symptoms, photosensitivityProlong QT interval and marked bradycardia, but torsade de pointes is rare

Class IVCalcium channel blocking agents - (verapamil, diltiazem, bepridil)

Verapamil Blocks activated and inactivated Ca++ channels Marked effect on tissues that fire frequently, depolarized, SA & AV nodesUse of: reentrant supraventricular tachycardia (verapamil & adenosine are more preferred to propranolol, digoxin, edrophonium, vasoconstrictor agents & cardioversion)

Class IVReduce ventricular rate in atrial fibrillation and flutter Misuse of verapamil in patients with VT mistakenly diagnosed as SVT hypotension and cardiac arrest

Miscellaneous1. Adenosine- Naturally occurring nucleoside- Effects are mediated by interaction with G protein-coupled adenosine receptors- Enhances K+ conductance - Inhibits cAMP-induced Ca++ influxAP shortening, hyperpolarization, slowing automaticity

Indication - acute termination of reentrant SVT - VT of DAD mediated - Produces controlled hypotension during surgical procedure in the diagnosis of CAD

- t : < 10 secsAdministration : rapid bolus IVEffects is potentiated in patients receiving dipyridamole (adenosine-uptake inhibitor) and patients with cardiac transplants (due to denervation hypersensitivity)Xanthine drinks block adenosine receptors- Adverse effects : short-lived, transient asystole (< 5sec), chest fullness & dyspnea, sometimes atrial fibrillation

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Electrophysiology of the heart

Cardiac action potential (AP)Ion movement across cell membrane- electrical gradient- concentration gradientNormal AP at rest:- 90 mV- Na/K- ATPase- fixed anion charges in the cellsNa+o Na+I ; but Na channels are closed (in resting membrane)K+o K+I ; inward rectifier channels open

Cardiac action potential (AP)4. Nersnt equationEx = - 61 log ( [x]i / [x]o)

for K+ , ([K]o = 4 mM , [K]i = 140 mM) EK = - 94 mM ~ resting APHyperkalemia : EK rises to more positive K+ enters cellEK changes ~ [K]o changes , [K]o major determinant of resting potential

Addendum of antiarrhytmic drug

Tocainide and mexiletineAnalogs of lidocaine for oral chronic administrationTocainide is rarely used, it can cause fatal bone marrow aplasia and pulmonary fibrosisMetabolism :tocainide renal excretionmexiletine hepatic metabolismUse of: ventricular arrhythmias

Flecainide(1)1. Mechanism of action- Blocks Na+ current(1c) & delayed rectifer K+ current- Very long T recovery from Na+ channel block - Use of: supraventricular arrhythmias (incl. atrial fibrillation)2. Adverse effects - Exacerbate congestive heart failure, lethal arrhythmias (increase ventricular rate in atrial flutter, frequency of reentrant ventricular tachycardia, mortality in myocardial infarction) - Subjected, dose-related blurred vision

Flecainide(2)3. Pharmacokinetics-Well absorbed - Metabolized by CYP2D6

2. Magnesium - Used in digitalis induces arrhythmias in hypomagnesemic patients - Mechanism of action : ? through Na/K ATPase, Na+-channel, Ca++ channels- Has been used in preventing torsade de pointes, chronic therapy, antiarrhythmic effects

Moricizineclass ICPhenothiazine analogChronic therapy for ventricular arrhythmiasUndergoes extensive hepatic metabolism

Bretylium(Class III)Bretylium1. Mechanism of action- Prolongs AP in Purkinje cells Interferes with reuptake of NE by sympathetic nerves- Use of: VF (when lidocaine & cardioversion have failed)2. Adverse effect- Transient hypertension and increased arrhythmias (e.g. digitalis intoxication) - Hypotension (can be inhibited when coadministered with protryptiline)3. Pharmacokinetics- Excreted in unchanged form by kidneys

PhenytoinAn antiepileptic drug, classified as Ic antiarrhytmic drug

Used for acute and chronic ventricular arrhythmias and in digitalis intoxication when other drug failsExhibit saturation metabolism phenomene

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