Antiarrhythmic DrugsAntiarrhythmic DrugsOrOr

Doing Drugs for Your HeartbeatDoing Drugs for Your Heartbeat

BackgroundBackground

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

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

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

ArrhythmiaArrhythmia

Heart condition where disturbances in Heart condition where disturbances in Pacemaker impulse formationPacemaker impulse formation Contraction impulse conductionContraction impulse conduction Combination of the twoCombination of the two

Results in rate and/or timing of contraction of Results in rate and/or timing of contraction of heart muscle that is insufficient to maintain heart muscle that is insufficient to maintain normal cardiac output (CO)normal cardiac output (CO)

To understand how antiarrhythmic drugs work, To understand how antiarrhythmic drugs work, need to understand electrophysiology of need to understand electrophysiology of normal contraction of heartnormal contraction of heart

Normal heartbeat and atrial arrhythmiaNormal heartbeat and atrial arrhythmia

Normal rhythm Atrial arrhythmia

AV septum

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

VA’s are most common cause of VA’s are most common cause of sudden deathsudden death

Majority of sudden death occurs in Majority of sudden death occurs in people with neither a previously people with neither a previously known heart disease nor history of known heart disease nor history of VA’sVA’s

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

Electrophysiology - resting potentialElectrophysiology - resting potential

A transmembrane electrical gradient (potential) is A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative with maintained, with the interior of the cell negative with respect to outside the cellrespect to outside the cell

Caused by unequal distribution of ions inside vs. outside Caused by unequal distribution of ions inside vs. outside cellcell

NaNa++ higher outside than inside cell higher outside than inside cell CaCa++ much higher “ “ “ “ much higher “ “ “ “ KK++ higher inside cell than outside higher inside cell than outside

Maintenance by ion selective channels, active pumps Maintenance by ion selective channels, active pumps and exchangersand exchangers

ECG (EKG) showing wave segments

Contraction of atria

Contraction of ventricles

Repolarization of ventricles

Cardiac Action PotentialCardiac Action PotentialDivided into five phases (0,1,2,3,4)Divided into five phases (0,1,2,3,4)

Phase 4Phase 4 - resting phase (resting membrane potential) - resting phase (resting membrane potential)Phase cardiac cells remain in until stimulatedPhase cardiac cells remain in until stimulatedAssociated with diastole portion of heart cycle Associated with diastole portion of heart cycle

Addition of current into cardiac muscle (stimulation) Addition of current into cardiac muscle (stimulation) causes causes

Phase 0Phase 0 – opening of fast Na channels and rapid depolarization – opening of fast Na channels and rapid depolarization Drives NaDrives Na++ into cell (inward current), changing membrane potential into cell (inward current), changing membrane potentialTransient outward current due to movement of ClTransient outward current due to movement of Cl-- and K and K++

Phase 1Phase 1 – initial rapid repolarization – initial rapid repolarizationClosure of the fast NaClosure of the fast Na++ channels channelsPhase 0 and 1 together correspond to the R and S waves of the Phase 0 and 1 together correspond to the R and S waves of the ECGECG

Cardiac Na+ channelsCardiac Na+ channels

Cardiac Action Potential (con’t)Cardiac Action Potential (con’t)

Phase 2Phase 2 - plateau phase - plateau phase sustained by the balance between the inward movement of Casustained by the balance between the inward movement of Ca+ + and and

outward movement of K outward movement of K ++ Has a long duration compared to other nerve and muscle tissueHas a long duration compared to other nerve and muscle tissue Normally blocks any premature stimulator signals (other muscle tissue Normally blocks any premature stimulator signals (other muscle tissue

can accept additional stimulation and increase contractility in a can accept additional stimulation and increase contractility in a summation effect)summation effect)

Corresponds to ST segment of the ECG.Corresponds to ST segment of the ECG.

Phase 3Phase 3 – repolarization – repolarization KK+ + channels remain open, channels remain open, Allows KAllows K++ to build up outside the cell, causing the cell to repolarize to build up outside the cell, causing the cell to repolarize K K + + channels finally close when membrane potential reaches certain channels finally close when membrane potential reaches certain

levellevel Corresponds to T wave on the ECG Corresponds to T wave on the ECG

Differences between nonpacemaker and Differences between nonpacemaker and pacemaker cell action potentialspacemaker cell action potentials

PCs - Slow, continuous depolarization during restPCs - Slow, continuous depolarization during rest

Continuously moves potential towards threshold for a Continuously moves potential towards threshold for a new action potential (called a phase 4 depolarization)new action potential (called a phase 4 depolarization)

Mechanisms of Cardiac ArrhythmiasMechanisms of Cardiac Arrhythmias

Result from disorders of impulse Result from disorders of impulse formation, conduction, or both formation, conduction, or both

Causes of arrhythmiasCauses of arrhythmias Cardiac ischemiaCardiac ischemia Excessive discharge or sensitivity to Excessive discharge or sensitivity to

autonomic transmittersautonomic transmitters Exposure to toxic substancesExposure to toxic substances Unknown etiologyUnknown etiology

Disorders of impulse formationDisorders of impulse formation

No signal from the pacemaker siteNo signal from the pacemaker site

Development of an ectopic pacemakerDevelopment of an ectopic pacemaker May arise from conduction cells (most are capable of May arise from conduction cells (most are capable of

spontaneous activity)spontaneous activity) Usually under control of SA node Usually under control of SA node if it slows down too much if it slows down too much

conduction cells could become dominantconduction cells could become dominant Often a result of other injury (ischemia, hypoxia)Often a result of other injury (ischemia, hypoxia)

Development of oscillatory afterdepolariztionsDevelopment of oscillatory afterdepolariztions Can initiate spontaneous activity in nonpacemaker tissueCan initiate spontaneous activity in nonpacemaker tissue May be result of drugs (digitalis, norepinephrine) used to treat May be result of drugs (digitalis, norepinephrine) used to treat

other cardiopathologiesother cardiopathologies

Afterdepolarizations Afterdepolarizations

Disorders of impulse conductionDisorders of impulse conductionMay result inMay result in Bradycardia (if have AV block)Bradycardia (if have AV block) Tachycardia (if reentrant circuit occurs)Tachycardia (if reentrant circuit occurs)

Reentrant circuit

Antiarrhythmic drugsAntiarrhythmic drugs

Biggest problem – antiarrhythmics can Biggest problem – antiarrhythmics can cause arrhythmia!cause arrhythmia!

Example: Treatment of a non-life threatening Example: Treatment of a non-life threatening tachycardia may cause fatal ventricular tachycardia may cause fatal ventricular arrhythmiaarrhythmia

Must be vigilant in determining dosing, blood Must be vigilant in determining dosing, blood levels, and in follow-up when prescribing levels, and in follow-up when prescribing antiarrhythmicsantiarrhythmics

Therapeutic overviewTherapeutic overview

NaNa++ channel blockade channel blockade

ββ-adrenergic receptor blockade-adrenergic receptor blockade

Prolong repolarizationProlong repolarization

CaCa2+2+ channel blockade channel blockade

AdenosineAdenosine

Digitalis glycosidesDigitalis glycosides

Classification of antiarrhythmicsClassification of antiarrhythmics(based on mechanisms of action)(based on mechanisms of action)

Class I – blocker’s of fast NaClass I – blocker’s of fast Na++ channels channels Subclass IA Subclass IA

Cause moderate Phase 0 depressionCause moderate Phase 0 depressionProlong repolarizationProlong repolarizationIncreased duration of action potentialIncreased duration of action potentialIncludes Includes

QuinidineQuinidine – 1 – 1stst antiarrhythmic used, treat both atrial and antiarrhythmic used, treat both atrial and ventricular arrhythmias, increases refractory periodventricular arrhythmias, increases refractory period

ProcainamideProcainamide - increases refractory period but side - increases refractory period but side effectseffects

DisopyramideDisopyramide – extended duration of action, used only – extended duration of action, used only for treating ventricular arrthymiasfor treating ventricular arrthymias

Classification of antiarrhythmicsClassification of antiarrhythmics(based on mechanisms of action)(based on mechanisms of action)

Subclass IBSubclass IBWeak Phase 0 depressionWeak Phase 0 depression

Shortened depolarizationShortened depolarization

Decreased action potential durationDecreased action potential duration

IncludesIncludes LidocaneLidocane (also acts as local anesthetic) – blocks Na+ (also acts as local anesthetic) – blocks Na+

channels mostly in ventricular cells, also good for channels mostly in ventricular cells, also good for digitalis-associated arrhythmiasdigitalis-associated arrhythmias

MexiletineMexiletine - oral lidocaine derivative, similar activity - oral lidocaine derivative, similar activity PhenytoinPhenytoin – anticonvulsant that also works as – anticonvulsant that also works as

antiarrhythmic similar to lidocaneantiarrhythmic similar to lidocane

Classification of antiarrhythmicsClassification of antiarrhythmics(based on mechanisms of action)(based on mechanisms of action)

Subclass ICSubclass ICStrong Phase 0 depressionStrong Phase 0 depressionNo effect of depolarizationNo effect of depolarizationNo effect on action potential durationNo effect on action potential duration

IncludesIncludes FlecainideFlecainide (initially developed as a local anesthetic) (initially developed as a local anesthetic)

Slows conduction in all parts of heart, Slows conduction in all parts of heart, Also inhibits abnormal automaticityAlso inhibits abnormal automaticity

PropafenonePropafenoneAlso slows conductionAlso slows conductionWeak Weak ββ – blocker – blockerAlso some CaAlso some Ca2+2+ channel blockade channel blockade

Classification of antiarrhythmicsClassification of antiarrhythmics(based on mechanisms of action)(based on mechanisms of action)

Class II – Class II – ββ–adrenergic blockers–adrenergic blockers Based on two major actionsBased on two major actions

1) blockade of myocardial 1) blockade of myocardial ββ–adrenergic receptors–adrenergic receptors2) Direct membrane-stabilizing effects related to Na2) Direct membrane-stabilizing effects related to Na+ + channel blockadechannel blockade

IncludesIncludesPropranololPropranolol

causes both myocardial causes both myocardial ββ–adrenergic blockade and membrane-–adrenergic blockade and membrane-stabilizing effectsstabilizing effects

Slows SA node and ectopic pacemakingSlows SA node and ectopic pacemaking Can block arrhythmias induced by exercise or apprehensionCan block arrhythmias induced by exercise or apprehension Other Other ββ–adrenergic blockers have similar therapeutic effect –adrenergic blockers have similar therapeutic effect

MetoprololMetoprololNadololNadololAtenololAtenololAcebutololAcebutololPindololPindololStalolStalolTimololTimololEsmololEsmolol

Classification of antiarrhythmicsClassification of antiarrhythmics(based on mechanisms of action)(based on mechanisms of action)

Class III – KClass III – K+ + channel blockers channel blockers Developed because some patients negatively Developed because some patients negatively

sensitive to Na channel blockers (they died!)sensitive to Na channel blockers (they died!) Cause delay in repolarization and prolonged Cause delay in repolarization and prolonged

refractory periodrefractory period IncludesIncludes

Amiodarone Amiodarone – prolongs action potential by delaying K– prolongs action potential by delaying K++ efflux efflux but many other effects characteristic of other classesbut many other effects characteristic of other classesIbutilideIbutilide – slows inward movement of Na – slows inward movement of Na++ in addition to in addition to delaying K delaying K ++ influx. influx.BretyliumBretylium – first developed to treat hypertension but found to – first developed to treat hypertension but found to also suppress ventricular fibrillation associated with also suppress ventricular fibrillation associated with myocardial infarctionmyocardial infarctionDofetilide - prolongs action potential by delaying KDofetilide - prolongs action potential by delaying K++ efflux efflux with no other effects with no other effects

Classification of antiarrhythmicsClassification of antiarrhythmics(based on mechanisms of action)(based on mechanisms of action)

Class IV – CaClass IV – Ca2+ 2+ channel blockerschannel blockers slow rate of AV-conduction in patients with slow rate of AV-conduction in patients with

atrial fibrillationatrial fibrillation

IncludesIncludesVerapamil – blocks NaVerapamil – blocks Na+ + channels in addition to channels in addition to CaCa2+; 2+; also slows SA node in tachycardiaalso slows SA node in tachycardia

DiltiazemDiltiazem

PacemakersPacemakers

Surgical implantation of electrical leads attached to a Surgical implantation of electrical leads attached to a pulse generatorpulse generatorOver 175,000 implanted per yearOver 175,000 implanted per year

1)1) Leads are inserted via subclavicle vein and advanced to the Leads are inserted via subclavicle vein and advanced to the chambers on the vena cava (right) side of the heartchambers on the vena cava (right) side of the heart

2)2) Two leads used, one for right atrium, other for right ventricleTwo leads used, one for right atrium, other for right ventricle3)3) Pulse generator containing microcircuitry and battery are Pulse generator containing microcircuitry and battery are

attached to leads and placed into a “pocket” under the skin attached to leads and placed into a “pocket” under the skin near the claviclenear the clavicle

4)4) Pulse generator sends signal down leads in programmed Pulse generator sends signal down leads in programmed sequence to contract atria, then ventriclessequence to contract atria, then ventricles

Pulse generator can sense electrical activity generated Pulse generator can sense electrical activity generated by the heart and only deliver electrical impulses when by the heart and only deliver electrical impulses when needed. needed. Pacemakers can only speed up a heart experiencing Pacemakers can only speed up a heart experiencing bradycardia, they cannot alter a condition of bradycardia, they cannot alter a condition of tachycardiatachycardia

Implantation of PacemakerImplantation of Pacemaker