Antiarrhythmics (1)

8/3/2019 Antiarrhythmics (1)

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4/22/12

Anti-arrhythmics

J.ONACRUZ,MD,MHPED,FPOGS


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CARDIAC ACTION

POTENTIALS


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Action Potential in SANodal Cells


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4/22/12 ACTION POTENTIAL OF VENTRICULAR

MYOCYTES


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4/22/12 OUTSIDE CELL INSIDE CELL

Na+ Na+Na+

Na+ Na+

Na+ Na+Na+

Na+ Na+ Na+

Cell Membrane

Phase O: FASTUPSTROKE


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Phase I: PartialRepolarization

Cell Membrane

OUTSIDE CELL INSIDE CELL

Na+

K+

K+ K+ K+


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Phase 2: Plateau

CellMembrane


Ca++Ca++

Ca++

K+ K+K+K+


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Phase 3: Repolarization

Ca++

K+

K+ K+ K+

CellMembrane



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Phase 4: ForwardCurrent

Increasing depolarization results fromgradual increase in permeability tosodium

Resting membrane potential isrestablished


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Determination of FiringRate


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Factors DeterminingFiring Rate

1.Rate of spontaneous depolarization inphase 4

2.Threshold potential3.Resting membrane potential


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What are arrhythmias?


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Dysfunctions of-

Impulse formation and/or

Impulse conduction


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Disturbance in impulseformation

Altered automaticity (increased activity ofpacemakers)

Triggered Activity (EADs. DADs)


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Altered automaticity

Physiologic

Pathologic

latent pacemakers takeover

escape, ectopic beats

direct tissue injury


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Triggered Activity

Afterdepolarizations: occur when a normalaction potential triggers an EXTRAdepolarization


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Afterdepolarizations


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Disturbances of ImpulseConduction

Simple block

Reentry or circus movement

Accessory Tracts


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Basic Pharmacology


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MECHANISM of Action

1. Sodium channel blockade

2. Blockade of sympathetic autonomic

effects in the heart3. Prolongation of effective refractory

period

4. Calcium channel blockade


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State-dependent ionchannel block

Ion channels can change into variousconformational states

Changes in membrane permeability to aparticular ion is mediated byconformational changes in the channelsthrough which that ion passes


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State-dependent ionchannel block

Antiarrhythmic agents often havedifferent affinities for differentconformational states of the ionchannel


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Antiarrhythmics prefer-

Ectopic pacemakers

Depolarized tissues, ischemic tissues

Activated channels (phase 0) orinactivated channels (phase 2)- use orstate dependent drug action

i i ll i h


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Drug Action in cells withabnormal automaticity

Reduction of phase 4 slope by blockingsodium or calcium

Increase threshholdBlockade of positive chronotropic action

of norepinephrine in the heart (beta

blockers)


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Drug action in reentry

Slows conduction by:

1. steady state reduction of available

unblocked channels2. prolongation of recovery time of

channels that are able to reach rested and

available state (increased refractory period)


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Specific Antiarrhythmics


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Sodium Channel Blockers

Generally decrease reentry and preventarrhythmia by:

1.decreasing conduction velocity2.increasing the refractory period


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Sodium Channel Blockers

Although all three subclasses have similareffects on action potential in the SA node,there are important differences in theireffects on ventricular action potential


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Class IA

Moderate sodium channel blockade(Moderate reduction in slope of phase 0)

Prolongs repolarization in both SA nodeand ventricles

Prolongs action potential duration

Increases Effective Refractory Periodduration


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Class IB

Weak sodium channel blockade (Smallreduction in phase 0 slope)

Shortens action potential duration in sometissues of the heart

Decreases effective refractory period


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Class IC

Strong sodium blockade

Pronounced reduction in slope of phase 0

No effect on APD or ERP


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Na Channel Blockers

Sodium Blockade

IC>IA>IB

ERP

IA-increase, IB-shortens, IC-no effect

Action Potential Duration (K+repolarization current)

IA > IB IC-no effect


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Classs IA: procainamide

Slows phase 4 depolarization therebydecreasing abnormal automaticity

Increases threshold for excitation inatrium and ventricles- direct depressantactions


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procainamide

EXTRACARDIAC EFFECTS

ganglion blocking properties reduces

peripheral vascular resistance*

hypotension (esp.IV)


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Procainamide toxicity

CARDIAC

excessive slowing of conduction

precipitation of new arrhythmias suchas torsades de pointes*

syncope


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Procainamide toxicity

EXTRACARDIAC

lupus-like syndrome

nausea and diarrhea

rash

fever

hepatitis

agranulocytosis


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Procainamide : Pkinetics

IV,IM, PO(good absorption)

NAPA metabolite- Class III activity*

Liver metabolism and renal excretionHalf life is 3-4 h (frequent dosaging)

Dose reduction in renal failure and heartfailure


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Procainamide:Uses

Atrial and ventricular arrhythmias

Sustained ventricular arrhythmias with

acute MI (second choice)


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Class IA Quinidine

CARDIAC EFFECTS

similar to procainamide

more cardiac antimuscarinic effectsthan procainamide

Cardiac toxicities- excessive QT

interval prolongation, torsades de pointes,excessive slowed conduction


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quinidine


diarrhea, nausea, vomiting

cinchonism (headache, dizziness,tinnitus)

thrombocytopenia

hepatitis

angioneurotic edema

fever


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Quinidine: Pkinetics

Rapid absorption after oral intake

Binds to albumin and alpha glycoprotein

Hepatic metabolismHalf life 6-8 hrs

Slow release formulations


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Class IA: Disopyramide

CARDIAC EFFECTS

similar to procainamide and quinidine

greater cardiac antimuscarinic effect thanquinidine*


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Disopyramide

CARDIAC TOXICITIES

similar to quinidine

precipitation of heart failure*


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disopyramide

EXTRACARDIAC TOXICITIES

ATROPINE-LIKE EFFECTS-

urinary retention

dry mouth

blurred vision

constipation

glaucoma worsening

Disopyramide:


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Disopyramide:Pkinetics, Use

Oral

Reduced dose in renal failure

Ventricular arrhythmias


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Class IB: Lidocaine

Low incidence of toxicity

Highly effective for arrhythmias in acute

MIIV use only


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lidocaine

CARDIAC EFFECTS

greater effects on purkinje and ventricular

cells than atrial

Selective depression of conduction in

depolarized and not in resting cells


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Lidocaine: Toxicity

CARDIAC

least cardiotoxic among class I

uncommon proarrhythmic effects

hypotension in large doses (heart failurecases)*


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Lidocaine: toxicity

EXTRACARDIAC

Neurologic*

paresthesia, tremor, nausealightheadedness, hearing disturbances

slurred speech, seizures


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Lidocaine: Pkinetics

Extensive first pass hepatic metabolism*

Parenteral (infusion)

Half-life 1-2h (can be as short as 20 mins)Higher concentration may be needed in

some cases of MI or other acute illness**


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Lidocaine: Pkinetics

Doses are decreased in those with heartfailure, liver disease

Drug interaction:*propranolol

cimetidine

(Renal disease has no effect)


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Lidocaine: Use

DOC- tx for ventricular tachycardia andprevention of ventricular fibrillation aftercardioversion in acute MI


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Class IB: Mexiletine

Oral active congener of lidocaine

Adverse effects are dose-related and

frequently occur at therapeutic doses(neurologic)*

Elimination half-life is 8-20 h*


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Mexiletene: Use

Ventricular arrhythmias

Chronic pain conditions


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Class IC: Flecainide

Potent sodium and potassium blocker*

Does not prolong APD or QT interval

Well absorbed orallyHalf-life- 20h

Hepatic metabolism, renal elimination

No antimuscarinic effects


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Flecainide

TOXICITY:

severe arrhythmia exacerbation*

USE:

Supraventricular arrhythmias,PVCs


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Class IC: Propafenone

With weak beta blocking action

Structural similarity: propranolol

Spectrum of action: QuinidineLiver metabolism


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propafenone

TOXICITY:

metallic taste

constipationarrhythmia exacerbation

USE:

supraventricular arrhythmias

l i i i


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Class IC: Moricizine

Potent sodium channel blocker

No APD prolongation

Many metabolites*

i i i


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Moricizine

TOXICITY:

Dizziness

NauseaArrhythmia exacerbation

USE:

ventricular arrhythmias

Cl II B Bl k


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Class II: Beta Blockers

Cardiac Effects: anti-arrhythmic

beta receptor blockade

direct membrane effects

Well tolerated but less effective thansodium channel blockers*

B bl k


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Beta blockers

Propranolol

Esmolol

Sotalol*

Class 3: Potassium


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Class 3: PotassiumChannel Blockers

Drugs that prolong effective refractoryperiod via prolongation of action potential

Blocks K+ channel or enhance inwardcurrents of sodium

reverse-use dependence*

Cl 3 A i d


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Class 3: Amiodarone

CARDIAC EFFECTS:

marked prolongation of the APD and QT

interval by blocking Ik

blocking effect occurs in all ranges of

heart rates*-the exception

broad range of actions- Class I-IV actions

A i d


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Amiodarone

CARDIAC EFFECTS

slows heart rate and AV node conduction

highly efficacious, low risk of torsadeseven if QT is prolonged

A i d


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Amiodarone


Peripheral vasodilatation*

USES

ventricular arrhythmias, tachycardia

supraventricular arrhythmias (atrial fib)

A i d


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Amiodarone

Accumulates in many tissues (heart, lung,

liver, skin, tears)

TOXICITY: CARDIAC

symptomatic bradycardia and heart block*

A i d


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Amiodarone

TOXICITY:EXTRACARDIAC

dose-related pulmonary fibrosisabnormal liver function tests and hepatitis

photodermatitis, gray blue discoloration of

exposed skin

asymptomatic corneal microdeposits

i d


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amiodarone

KINETICS

bioavailability 35-65%

hepatic metab: desethylamiodarone*elimination half-life

50% rapid component (3-10days)

50% slow (weeks)

*effects are maintained up to 3 months

i d


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amiodarone

KINETICS

drug interaction

increase with cimetidinedecrease with rifampicin

increases levels of warfarin and digoxin

Cl 3 B t li


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Class 3: Bretylium

Direct antiarrhythmic effect and inhibitor ofneuronal catecholamine release

CARDIAC EFFECTS

lengthens ventricular* APD and ERP esp.

in ischemic tissues- reverses shorteningof APD due to ischemia


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bretylium


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bretylium

KINETICS

available for IV use

USES (rare)

emergency- resuscitation from ventricular

fibrillation after failure of lidocaine andcardioversion (amiodarone preferred)

Class 3: Sotalol


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Class 3: Sotalol

Class 3 (APD prolongation) and Class 2(beta blocker) actions

Racemic mixture:

*Beta blocking effect is in the l-isomer

APD prolongation in d- and l-isomers

Sotalol


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Sotalol

KINETICS

100% bioavailability

excreted unchanged in the kidneyshalf-life of 12 h

few direct drug interactions

sotalol


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sotalol

CARDIAC TOXICITIES

torsades des pointes*

further depression of LV function**

USES

life threatening ventricular arrhythmias

maintaining sinus rhythm in atrial fib

supraventricular and ventricular

Class 3: Dofetilide


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Class 3: Dofetilide

Dose dependent blockade rapidcomponent of delayed rectifier potassiumcurrent Ikr* (esp. in hypokalemia)

Ability to block is independent onstimulation frequency due to slow rate ofrecovery from the blockade*


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dofetilide


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dofetilide

Contraindication:

baseline QT interval of > 450ms,intraventricular delay, bradycardia of


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Class 3: Ibutilide

Blockade of rapid component of delayedrectifier potassium current and activationof slow inward sodium current

Ibutilide


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Ibutilide

KINETICS

rapid by hepatic metabolism

renal excretionhalf-life 6 h

USES

acute conversion of atrial fibrillation andflutter

ibutilide


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ibutilide

CARDIAC TOXICITY

extreme prolongation of QT interval

torsades des pointes

Class 4: Calcium Channel


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Blocker

Initially introduced for management ofangina pectoris

Class 4: Verapamil


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Class 4: Verapamil

CARDIAC EFFECTS

blocks activated and inactivated L-typecalcium channels especially in rapidly firingtissues, less completely polarized at rest,those whose activation depends more oncalcium channels*

SA and AV NODES

verapamil


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verapamil

CARDIAC EFFECTS

suppression of EAD and DAD


Peripheral vasodilatation

verapamil


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verapamil

TOXICITY: CARDIAC*

hypotension and ventricular fibrillationwhen given for a misdiagnosed SVT**

negative inotropic effect

AV block

sinus arrest

verapamil


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verapamil

TOXICITY: EXTRACARDIAC

constipation

lassitudenervousness

peripheral edema

verapamil


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verapamil

KINETICS

half life 7 h

extensive liver metabolism20% bioavailability

verapamil


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verapamil

USES

SVT (also adenosine)

reduction of ventricular rate in atrial fib orflutter

Ventricular arrhythmias (occasional)

Class 4: Diltiazem


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Class 4: Diltiazem

Similar to verapamil

Miscellaneous:


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ADENOSINE

Naturally occuring nucleoside

Half life 10 mins

Activates inward K+ rectifier current andinhibits Ca current: marked

hyperpolarization and suppression ofcalcium dependent action potentials

adenosine


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adenosine

Bolus inhibits AV node conduction andincreases AV node refractory period*

DOC- prompt conversion of paroxysmal

SVT to sinus rhythm

Interactions

caffeine, theophylline

dipyridamole

adenosine


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adenosine

TOXICITY:

flushing in 20%

shortness of breath, chest burning in 10%brief AV block

atrial fibrillation

headache, hypotension, nausea, paresthesias

Miscellaneous:


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Magnesium

Effects on Na+/K+ ATPase, sodiumchannels, calcium channels

USES:

Digitalis-induced arrhythmias in

hypomagnesemic patientsTorsades des pointes

Miscellaneous:


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Potassium

Hypokalemia and hyperkalemia are botharrhythmogenic

Therapeutic goal: normalization ofpotassium gradients and pools in thebody

Antiarrhythmics (1)

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