Antiarrythmic Drugs

Antiarrhythmic Drugs

Myocardial cells maintain transmembraneion gradients by movement of the Na+, Ca2+ and K+ through membrane channels. The resting potential of a cardiac cell is– 85 mV compared to the extracellular environment.Depolarization is initiated by a rapid influxof Na+ (phase 0). BASIC ELECTROPHYSIOLOGY

Depolarization

Rapid repolarization
Final repolarization
Plateau
Resting potential
Spontaneous depolarization


In the AV node depolarization is due to the slower influx of calcium ions. This results in slower conduction of the impulse through the AV node than in other parts of the heart.

During the period between phase 0 and the end of phase 2, the cell is refractory to the further depolarization (absolute refractory period) since the sodium channels are inactivated. During phase 3, a sufficiently large stimulus can open enough sodium channels to over- come the potassium efflux. This is the relative refractory period.



The cardiac action potential

Arrhythmia

Heart condition where disturbances in Pacemaker impulse formation Contraction impulse conduction Combination of the two Results in rate and/or timing of contraction of heart muscle that is insufficient to maintain normal cardiac output (CO) To understand how antiarrhythmic drugs work, need to understand electrophysiology of normal contraction of heart

Normal heartbeat and atrial arrhythmia

Normal rhythm
Atrial arrhythmia
AV septum

Ventricular Arrhythmia

Ventricular arrhythmias are common in most people and are usually not a problem but…VA’s are most common cause of sudden deathMajority of sudden death occurs in people with neither a previously known heart disease nor history of VA’sMedications which decrease incidence of VA’s do not decrease (and may increase) the risk of sudden death treatment may be worse then the disease!

Electrophysiology - resting potential

A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative with respect to outside the cellCaused by unequal distribution of ions inside vs. outside cellNa+ higher outside than inside cellCa+ much higher “ “ “ “K+ higher inside cell than outsideMaintenance by ion selective channels, active pumps and exchangers

ECG (EKG) showing wave segments

Contraction of atria
Contraction of ventricles
Repolarization of ventricles

Cardiac Action Potential

Divided into five phases (0,1,2,3,4)Phase 4 - resting phase (resting membrane potential)Phase cardiac cells remain in until stimulatedAssociated with diastole portion of heart cycle Addition of current into cardiac muscle (stimulation) causes Phase 0 – opening of fast Na channels and rapid depolarization Drives Na+ into cell (inward current), changing membrane potentialTransient outward current due to movement of Cl- and K+ Phase 1 – initial rapid repolarizationClosure of the fast Na+ channelsPhase 0 and 1 together correspond to the R and S waves of the ECG

Cardiac Na+ channels

Cardiac Action Potential (con’t) Phase 2 - plateau phasesustained by the balance between the inward movement of Ca+ and outward movement of K + Has a long duration compared to other nerve and muscle tissueNormally blocks any premature stimulator signals (other muscle tissue can accept additional stimulation and increase contractility in a summation effect)Corresponds to ST segment of the ECG.Phase 3 – repolarization K+ channels remain open, Allows K+ to build up outside the cell, causing the cell to repolarizeK + channels finally close when membrane potential reaches certain levelCorresponds to T wave on the ECG

Differences between nonpacemaker and pacemaker cell action potentials

PCs - Slow, continuous depolarization during rest Continuously moves potential towards threshold for a new action potential (called a phase 4 depolarization)

Mechanisms of Cardiac Arrhythmias

Result from disorders of impulse formation, conduction, or both Causes of arrhythmias Cardiac ischemia Excessive discharge or sensitivity to autonomic transmitters Exposure to toxic substances Unknown etiology

Disorders of impulse formation

No signal from the pacemaker siteDevelopment of an ectopic pacemakerMay arise from conduction cells (most are capable of spontaneous activity)Usually under control of SA node  if it slows down too much conduction cells could become dominantOften a result of other injury (ischemia, hypoxia)Development of oscillatory afterdepolariztionsCan initiate spontaneous activity in nonpacemaker tissueMay be result of drugs (digitalis, norepinephrine) used to treat other cardiopathologies

Afterdepolarizations

Disorders of impulse conduction
May result in Bradycardia (if have AV block) Tachycardia (if reentrant circuit occurs)
Reentrant circuit

Antiarrhythmic drugs

Biggest problem – antiarrhythmics can cause arrhythmia!Example: Treatment of a non-life threatening tachycardia may cause fatal ventricular arrhythmiaMust be vigilant in determining dosing, blood levels, and in follow-up when prescribing antiarrhythmics

Therapeutic overview

Na+ channel blockadeβ-adrenergic receptor blockadeProlong repolarizationCa2+ channel blockadeAdenosineDigitalis glycosides

Classification of antiarrhythmics(based on mechanisms of action)

Class I – blocker’s of fast Na+ channels Subclass IA Cause moderate Phase 0 depressionProlong repolarizationIncreased duration of action potentialIncludes Quinidine – 1st antiarrhythmic used, treat both atrial and ventricular arrhythmias, increases refractory periodProcainamide - increases refractory period but side effectsDisopyramide – extended duration of action, used only for treating ventricular arrthymias

Class IA - Na+ Channel BlockersProcainamide/Quinidine/Disopyramide

Mode of actionDepress conduction and prolong refractorinessAtrial, His-Purkinje, ventricular tissuePeripheral alpha blockVagolyticNegative inotropeECG changesIncrease PR, QRS (Diso: PR  > QRS  )Toxicity: QTc increases by 30% or QT > 0.5 secCa++ channel blockade / potent anticholinergic (Diso)

Class IA - Na+ Channel Blockers Procainamide

UsesSVT (reentry) or VTAfib/flutter (on digoxin)Drug interactions-Decrease metabolism of AmiodaroneDoseIV: load 15 mg/kg over 1 hour, then 30-80 g/kg/min (level 5-10 ng/ml)PO: 30-70 mg/kg/daySide effects: Lupus- in slow acetylatorsANA + : 50-90% Symptoms: 20-30 %

Arrhythmia Therapy

Procainamide has been a long-used intravenous infusion for a wide range of dysrhythmias: Narrow complex tachycardia: Atrial tachycardia, resistant re-entrant tachycardia Wide-complex tachycardia: Ventricular tachycardia Downside: Side effects, negative inotrope, pro-arrhythmic


Classification of antiarrhythmics(based on mechanisms of action)
Subclass IBWeak Phase 0 depressionShortened depolarizationDecreased action potential durationIncludesLidocane (also acts as local anesthetic) – blocks Na+ channels mostly in ventricular cells, also good for digitalis-associated arrhythmiasMexiletine - oral lidocaine derivative, similar activityPhenytoin – anticonvulsant that also works as antiarrhythmic similar to lidocane

Class IBLidocaine/Mexiletine/Phenytoin

Mode of actionLittle effect on normal tissuesDecreases Purkinje ERP/ automaticityIncreases Ventricular fibrillation thresholdDepresses conduction, esp. at high rates (Mexiletine)Suppresses dig-induced delayed afterdepolarizations (Phenytoin)ECG changesSlight  QTc (Lidocaine/Phenytoin)

Class IBLidocaine

Use: VT (acute) Acts rapidly; no depression of contractility/AV conduction Kinetics t1/2 : 5-10 min (1st phase); 80-110 min (2nd phase) Drug interactions Decreased metabolism w/ CHF/hepatic failure, propranolol, cimetidine Increased metabolism w/ isuprel, phenobarbital, phenytoin

Class IBLidocaine

Dose1 mg/kg, then 20-50 g/kg/min (level: 2-5 g/ml)Side effectsCNS toxicity w/ levels > 5 g/ml

Class IBMexiletine

Use: VT (post-op CHD) Kinetics: t1/2 = 8 - 12 hrs Drug interactions- rare Dose 3-5 mg/kg/dose (adult 200-300mg/dose) po q 8 hrs Side effects Nausea (40%) CNS - dizziness/tremor (25%)

Class IBPhenytoin

UsesVT (post-op CHD), digoxin-induced arrhythmiasDrug interactionsCoumadin-  PT; Verapamil-  effect (displaces from protein)DosePO: 4 mg/kg q 6 hrs x 1 day, then 5-6 mg/kg/day ч q 12hrIV: bolus 15 mg/kg over 1 hr; level 15-20 g/mlSide effectsHypotension, gingival hyperplasia, rash

Arrhythmia-focused Therapy

Class IB antiarrhythmics are very effective and very safe.Little or no effect on “normal” tissuesFirst line for ischemic, automatic arrhythmia's (Ventricular tachycardia)Not a lot of effect on normal conduction tissue – not a good medicine for reentry and atrial tachycardias.


Classification of antiarrhythmics(based on mechanisms of action)
Subclass ICStrong Phase 0 depressionNo effect of depolarizationNo effect on action potential durationIncludesFlecainide (initially developed as a local anesthetic)Slows conduction in all parts of heart, Also inhibits abnormal automaticityPropafenoneAlso slows conductionWeak β – blockerAlso some Ca2+ channel blockade

Class ICFlecainide/Propafenone/Ethmozine

Mode of actionDepresses abnormal automaticity (Flec/Ethmozine)Slows conduction in AV node, AP, ventricle (Flec/Prop)Shortens repolarization (Ethmozine)Negative inotrope (Propafenone)Prolongs atrial/ventricular refractoriness (Propafenone)ECG changes PR, QRS QTc (Propafenone)

Class ICFlecainide

Uses: PJRT, AET, CAT, SVT, VT, Afib Kinetics t1/2 = 13 hrs (shorter if between 1-15 mos old) Drug interactions Increases digoxin levels (slight) Amiodarone: increases flecainide levels

Class ICFlecainide

Dose70-225 mg/m2/day ч q 8-12 hrLevel: 0.2-1.0 g/mlSide effectsNegative inotrope- use in normal hearts only (NO POST-OPs)PROARRHYTHMIA - 5-12% (CAST)

Arrhythmia –focused Therapy IC’s have a lot of side effects that make them appropriate for use only by experienced providers.

Classification of antiarrhythmics(based on mechanisms of action)

Class II – β–adrenergic blockersBased on two major actions1) blockade of myocardial β–adrenergic receptors2) Direct membrane-stabilizing effects related to Na+ channel blockadeIncludesPropranolol causes both myocardial β–adrenergic blockade and membrane-stabilizing effectsSlows SA node and ectopic pacemakingCan block arrhythmias induced by exercise or apprehensionOther β–adrenergic blockers have similar therapeutic effect MetoprololNadololAtenololAcebutololPindololStalolTimololEsmolol

Classification of antiarrhythmics(based on mechanisms of action)

Class III – K+ channel blockers Developed because some patients negatively sensitive to Na channel blockers (they died!)Cause delay in repolarization and prolonged refractory periodIncludesAmiodarone – prolongs action potential by delaying K+ efflux but many other effects characteristic of other classesIbutilide – slows inward movement of Na+ in addition to delaying K + influx.Bretylium – first developed to treat hypertension but found to also suppress ventricular fibrillation associated with myocardial infarctionDofetilide - prolongs action potential by delaying K+ efflux with no other effects


Can be very powerful antiarrhythmics but limited indications for first-line use – beyond the spectrum of primary care providersAmiodarone: may become a first-line medicine for a broad spectrum of arrhythmias, currently still high-risk

Classification of antiarrhythmics(based on mechanisms of action)

Class IV – Ca2+ channel blockers slow rate of AV-conduction in patients with atrial fibrillationIncludesVerapamil – blocks Na+ channels in addition to Ca2+; also slows SA node in tachycardiaDiltiazem

Purinergic AgonistsAdenosine

Mode of action Vagotonic Anti-adrenergic Depresses slow inward Ca++ current Increases K+ conductance (hyperpolarizes) ECG/EP changes Slows AV node conduction

Purinergic AgonistsAdenosine

UsesSVT- termination of reentryAflutter- AV block for diagnosisKineticst1/2 = < 10 secsMetabolized by RBCs and vascular endothelial cellsDose IV: 100-300 g/kg IV bolus

Purinergic AgonistsAdenosine

Drug interactions Methylxanthines (caffeine/theophylline) Side effects AFib/ sinus arrest/ sinus bradycardia Bronchospasm Flushing/headache Nausea Great medicine: quick onset, quick degradation.

Digoxin

Mode of action Na-K ATPase inhibition Positive inotrope Vagotonic ECG changes Increases PR interval Depresses ST segment Decreases QT interval

Digoxin

Use: SVT (not WPW)Kineticst1/2 = preemie (61hrs), neonate (35hrs), infant (18hrs), child (37hrs), adult (35-48hrs )InteractionsCoumadin-  PT Digoxin levelQuinidine, amiodarone, verapamil renal function/renal tubular excretion (Spironolactone)Worse with  K+,  Ca++


Digoxin Toxicity
Nausea/vomiting, lethargy, visual changes Metabolic Hyper K+, Ca++ Hypo K+, Mg++ Hypoxemia Hypothyroidism Proarrhythmia AV block- decreased conduction SVT- increased automaticity VT- delayed afterdepolarizations

Digoxin ToxicityTreatment

GI decontaminationIpecac/lavage/charcoal w/ catharticArrhythmiasSA node /AV node depression- Atropine; if dig > 6, may need pacingSVT- Phenytoin or  -blockerVT- Lidocaine (1 mg/kg) or Phenytoin DC Cardioversion may cause refractory VT/VF!!

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