Antiarrhythmic DrugsOrDoing Drugs for Your Heartbeat

BackgroundRecall: to function efficiently, heart needs to contract sequentially (atria, then ventricles) and in synchronicity

Relaxation must occur between contractions (not true for other types of muscle [exhibit tetany contract and hold contraction for certain length of time])

Coordination of heartbeat is a result of a complex, coordinated sequence of changes in membrane potentials and electrical discharges in various heart tissues

ArrhythmiaHeart condition where disturbances in Pacemaker impulse formationContraction impulse conductionCombination 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 arrhythmiaNormal rhythmAtrial arrhythmiaAV septum

Ventricular ArrhythmiaVentricular arrhythmias are common in most people and are usually not a problem but

VAs are most common cause of sudden death

Majority of sudden death occurs in people with neither a previously known heart disease nor history of VAs

Medications which decrease incidence of VAs do not decrease (and may increase) the risk of sudden death treatment may be worse then the disease!

Electrophysiology - resting potentialA transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative with respect to outside the cell

Caused by unequal distribution of ions inside vs. outside cellNa+ higher outside than inside cellCa+ much higher K+ higher inside cell than outside

Maintenance by ion selective channels, active pumps and exchangers

ECG (EKG) showing wave segmentsContraction of atriaContraction of ventriclesRepolarization of ventricles

Cardiac Action PotentialDivided 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 (cont)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 potentialsPCs - Slow, continuous depolarization during restContinuously moves potential towards threshold for a new action potential (called a phase 4 depolarization)

Mechanisms of Cardiac ArrhythmiasResult from disorders of impulse formation, conduction, or both

Causes of arrhythmiasCardiac ischemiaExcessive discharge or sensitivity to autonomic transmittersExposure to toxic substancesUnknown etiology

Disorders of impulse formationNo signal from the pacemaker site

Development 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 conductionMay result inBradycardia (if have AV block)Tachycardia (if reentrant circuit occurs)

Reentrant circuit

Antiarrhythmic drugsBiggest 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 overviewNa+ channel blockade-adrenergic receptor blockadeProlong repolarizationCa2+ channel blockade

AdenosineDigitalis glycosides

Classification of antiarrhythmics(based on mechanisms of action)Class I blockers 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

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

Classification of antiarrhythmics(based on mechanisms of action)Subclass ICStrong Phase 0 depressionNo effect of depolarizationNo effect on action potential duration

IncludesFlecainide (initially developed as a local anesthetic)Slows conduction in all parts of heart, Also inhibits abnormal automaticity

PropafenoneAlso slows conductionWeak blockerAlso some Ca2+ channel blockade

Classification of antiarrhythmics(based on mechanisms of action)Class II adrenergic blockersBased on two major actions1) blockade of myocardial adrenergic receptors2) Direct membrane-stabilizing effects related to Na+ channel blockade

IncludesPropranolol causes both myocardial adrenergic blockade and membrane-stabilizing effectsSlows SA node and ectopic pacemakingCan block arrhythmias induced by exercise or apprehensionOther 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

Classification of antiarrhythmics(based on mechanisms of action)Class IV Ca2+ channel blockers slow rate of AV-conduction in patients with atrial fibrillation

IncludesVerapamil blocks Na+ channels in addition to Ca2+; also slows SA node in tachycardiaDiltiazem

PacemakersSurgical implantation of electrical leads attached to a pulse generatorOver 175,000 implanted per yearLeads are inserted via subclavicle vein and advanced to the chambers on the vena cava (right) side of the heartTwo leads used, one for right atrium, other for right ventriclePulse generator containing microcircuitry and battery are attached to leads and placed into a pocket under the skin near the claviclePulse generator sends signal down leads in programmed sequence to contract atria, then ventriclesPulse generator can sense electrical activity generated by the heart and only deliver electrical impulses when needed. Pacemakers can only speed up a heart experiencing bradycardia, they cannot alter a condition of tachycardia

Implantation of Pacemaker