Antiarrhythmic drugs work to regulate irregular heartbeats by affecting the electrical signaling and contraction of heart muscle. They are classified based on their mechanisms of action, such as blocking sodium, potassium, calcium, or beta-adrenergic channels. First generation drugs like quinidine block sodium channels, while later drugs prolong repolarization by blocking potassium channels or calcium influx. Precise dosing is important as antiarrhythmics can paradoxically cause dangerous arrhythmias. Pacemakers provide an alternative treatment by electrically stimulating the heart to maintain normal rhythm.

1. Antiarrhythmic DrugsAntiarrhythmic Drugs
OrOr
Doing Drugs for Your HeartbeatDoing Drugs for Your Heartbeat

2. BackgroundBackground
Recall: to function efficiently, heart needs to contractRecall: 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 forRelaxation must occur between contractions (not true for
other types of muscle [exhibit tetanyother types of muscle [exhibit tetany  contract and holdcontract 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 membranecoordinated sequence of changes in membrane
potentials and electrical discharges in various heartpotentials and electrical discharges in various heart
tissuestissues

3. ArrhythmiaArrhythmia
Heart condition where disturbances inHeart 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 ofResults in rate and/or timing of contraction of
heart muscle that is insufficient to maintainheart 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 ofneed to understand electrophysiology of
normal contraction of heartnormal contraction of heart

4. Normal heartbeat and atrial arrhythmiaNormal heartbeat and atrial arrhythmia
Normal rhythm Atrial arrhythmia
AV septum

5. Ventricular ArrhythmiaVentricular Arrhythmia
Ventricular arrhythmias areVentricular arrhythmias are
common in most people and arecommon in most people and are
usually not a problem but…usually not a problem but…
VA’s are most common cause ofVA’s are most common cause of
sudden deathsudden death
Majority of sudden death occurs inMajority of sudden death occurs in
people with neither a previouslypeople with neither a previously
known heart disease nor history ofknown heart disease nor history of
VA’sVA’s
Medications which decreaseMedications which decrease
incidence of VA’s do not decreaseincidence of VA’s do not decrease
(and may increase) the risk of(and may increase) the risk of
sudden deathsudden death treatment may betreatment may be
worse then the disease!worse then the disease!

6. Electrophysiology - resting potentialElectrophysiology - resting potential
A transmembrane electrical gradient (potential) isA transmembrane electrical gradient (potential) is
maintained, with the interior of the cell negative withmaintained, 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. outsideCaused by unequal distribution of ions inside vs. outside
cellcell

NaNa++
higher outside than inside cellhigher outside than inside cell

CaCa++
much higher “ “ “ “much higher “ “ “ “

KK++
higher inside cell than outsidehigher inside cell than outside
Maintenance by ion selective channels, active pumpsMaintenance by ion selective channels, active pumps
and exchangersand exchangers

7. ECG (EKG) showing wave
segments
Contraction of
atria
Contraction of
ventricles
Repolarization of
ventricles

8. Cardiac Action PotentialCardiac Action Potential
Divided 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 stimulated
Associated with diastole portion of heart cycleAssociated with diastole portion of heart cycle
Addition of current into cardiac muscle (stimulation)Addition of current into cardiac muscle (stimulation)
causescauses

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 potentialinto cell (inward current), changing membrane potential
Transient outward current due to movement of ClTransient outward current due to movement of Cl--
and Kand K++

Phase 1Phase 1 – initial rapid repolarization– initial rapid repolarization
Closure of the fast NaClosure of the fast Na++
channelschannels
Phase 0 and 1 together correspond to the R and S waves of thePhase 0 and 1 together correspond to the R and S waves of the
ECGECG

9. Cardiac Na+ channelsCardiac Na+ channels

10. 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++
andand
outward movement of Koutward 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 tissueNormally blocks any premature stimulator signals (other muscle tissue
can accept additional stimulation and increase contractility in acan 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 repolarizeto build up outside the cell, causing the cell to repolarize

KK ++
channels finally close when membrane potential reaches certain levelchannels finally close when membrane potential reaches certain level

Corresponds to T wave on the ECGCorresponds to T wave on the ECG

11. Differences between nonpacemaker andDifferences 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 aContinuously moves potential towards threshold for a
new action potential (called a phase 4 depolarization)new action potential (called a phase 4 depolarization)

12. Mechanisms of Cardiac ArrhythmiasMechanisms of Cardiac Arrhythmias
Result from disorders of impulseResult from disorders of impulse
formation, conduction, or bothformation, conduction, or both
Causes of arrhythmiasCauses of arrhythmias

Cardiac ischemiaCardiac ischemia

Excessive discharge or sensitivity toExcessive discharge or sensitivity to
autonomic transmittersautonomic transmitters

Exposure to toxic substancesExposure to toxic substances

Unknown etiologyUnknown etiology

13. 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 ofMay arise from conduction cells (most are capable of
spontaneous activity)spontaneous activity)

Usually under control of SA nodeUsually under control of SA node  if it slows down too muchif 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 treatMay be result of drugs (digitalis, norepinephrine) used to treat
other cardiopathologiesother cardiopathologies

14. AfterdepolarizationsAfterdepolarizations

15. Disorders of impulse conductionDisorders of impulse conduction
May 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

16. Antiarrhythmic drugsAntiarrhythmic drugs
Biggest problem – antiarrhythmics canBiggest problem – antiarrhythmics can
cause arrhythmia!cause arrhythmia!

Example: Treatment of a non-life threateningExample: Treatment of a non-life threatening
tachycardia may cause fatal ventriculartachycardia may cause fatal ventricular
arrhythmiaarrhythmia

Must be vigilant in determining dosing, bloodMust be vigilant in determining dosing, blood
levels, and in follow-up when prescribinglevels, and in follow-up when prescribing
antiarrhythmicsantiarrhythmics

17. Therapeutic overviewTherapeutic overview
NaNa++
channel blockadechannel blockade
ββ-adrenergic receptor blockade-adrenergic receptor blockade
Prolong repolarizationProlong repolarization
CaCa2+2+
channel blockadechannel blockade
AdenosineAdenosine
Digitalis glycosidesDigitalis glycosides

18. 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++
channelschannels

Subclass IASubclass IA
Cause moderate Phase 0 depressionCause moderate Phase 0 depression
Prolong repolarizationProlong repolarization
Increased duration of action potentialIncreased duration of action potential
IncludesIncludes

QuinidineQuinidine – 1– 1stst
antiarrhythmic used, treat both atrial andantiarrhythmic 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

19. Classification of antiarrhythmicsClassification of antiarrhythmics
(based on mechanisms of action)(based on mechanisms of action)

Subclass IBSubclass IB
Weak 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 forchannels 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

20. Classification of antiarrhythmicsClassification of antiarrhythmics
(based on mechanisms of action)(based on mechanisms of action)

Subclass ICSubclass IC
Strong Phase 0 depressionStrong Phase 0 depression
No effect of depolarizationNo effect of depolarization
No 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

PropafenonePropafenone
Also slows conductionAlso slows conduction
WeakWeak ββ – blocker– blocker
Also some CaAlso some Ca2+2+
channel blockadechannel blockade

21. 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 myocardial1) blockade of myocardial ββ–adrenergic receptors–adrenergic receptors
2) Direct membrane-stabilizing effects related to Na2) Direct membrane-stabilizing effects related to Na++
channel blockadechannel blockade

IncludesIncludes
PropranololPropranolol

causes both myocardialcauses 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

OtherOther ββ–adrenergic blockers have similar therapeutic effect–adrenergic blockers have similar therapeutic effect
MetoprololMetoprolol
NadololNadolol
AtenololAtenolol
AcebutololAcebutolol
PindololPindolol
StalolStalol
TimololTimolol
EsmololEsmolol

22. Classification of antiarrhythmicsClassification of antiarrhythmics
(based on mechanisms of action)(based on mechanisms of action)
Class III – KClass III – K++
channel blockerschannel blockers

Developed because some patients negativelyDeveloped because some patients negatively
sensitive to Na channel blockers (they died!)sensitive to Na channel blockers (they died!)

Cause delay in repolarization and prolongedCause delay in repolarization and prolonged
refractory periodrefractory period

IncludesIncludes
AmiodaroneAmiodarone – prolongs action potential by delaying K– prolongs action potential by delaying K++
effluxefflux
but many other effects characteristic of other classesbut many other effects characteristic of other classes
IbutilideIbutilide – slows inward movement of Na– slows inward movement of Na++
in addition toin addition to
delaying Kdelaying 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 withalso suppress ventricular fibrillation associated with
myocardial infarctionmyocardial infarction
Dofetilide - prolongs action potential by delaying KDofetilide - prolongs action potential by delaying K++
efflux withefflux with
no other effectsno other effects

23. 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 withslow rate of AV-conduction in patients with
atrial fibrillationatrial fibrillation

IncludesIncludes
Verapamil – blocks NaVerapamil – blocks Na++
channels in addition to Cachannels in addition to Ca2+;2+;
also slows SA node in tachycardiaalso slows SA node in tachycardia
DiltiazemDiltiazem

24. PacemakersPacemakers
Surgical implantation of electrical leads attached to aSurgical implantation of electrical leads attached to a
pulse generatorpulse generator
Over 175,000 implanted per yearOver 175,000 implanted per year
1)1) Leads are inserted via subclavicle vein and advanced to theLeads 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 ventricle
3)3) Pulse generator containing microcircuitry and battery arePulse generator containing microcircuitry and battery are
attached to leads and placed into a “pocket” under the skinattached to leads and placed into a “pocket” under the skin
near the claviclenear the clavicle
4)4) Pulse generator sends signal down leads in programmedPulse generator sends signal down leads in programmed
sequence to contract atria, then ventriclessequence to contract atria, then ventricles
Pulse generator can sense electrical activity generatedPulse generator can sense electrical activity generated
by the heart and only deliver electrical impulses whenby the heart and only deliver electrical impulses when
needed.needed.
Pacemakers can only speed up a heart experiencingPacemakers can only speed up a heart experiencing
bradycardia, they cannot alter a condition ofbradycardia, they cannot alter a condition of
tachycardiatachycardia

25. Implantation of PacemakerImplantation of Pacemaker