Antiarrhythmias Agents: By: Tirta Darmawan Susanto, Dr.,Mkes

Antiarrhythmias Agents
By :
Tirta Darmawan Susanto, dr.,MKes
Introduction
• Cardiac arrhythmias are common  25% of
patients treated with digitalis, 50% of
anesthetized patients, over 80% of patients with
acute myocardial infarction
• Need to be treated because if too rapid, too slow
or asynchronous can reduce cardiac output and
also can precipitate more serious disturbances.
• But all anti arrhythmias drugs can prepicipitate
arrhythmia risks and benefits
Electrophysiology of Normal Cardiac
Rhythm
Rhythm
• SA node (60 – 100bpm)  atria  AV node
(slow, 0,15 seconds)  His  Purkinje 
Ventricle less than 0,1 seconds synchronous
(endocardial apex  epicardial base).
• Arrhythmias  cardiac depolarizations
deviate from above description  abnormal
site of origin, abnormal rate, irregular,
abnormal conduction
Rhythm
• Transmembrane potential of cardiac cells  Na+,
K+, Ca 2+, Cl-, (water soluble ions) spesific pore
forming protein  aqueous channels for
diffusion
• Movement of ions  currents  cardiac action
potentials
• Conductance of fast sodium channel suddenly
increases in response to a depolarizing stimulus
• Stable transmembrane ion gradientsNa+ K+
ATP-ase
Rhythm
• Phase 0:
Activation of fast Na+ channel-- initial depolarization; slope &
magnitude of a 0 will be dependent on the resting membrane
potential
Phase 1:
Partial repolarization; K+ efflux
Phase 2:
Ca2+ entry with continued K+ efflux = "plateau phase". Initial Ca2+
influx through slow L- type Ca2+ channels initiates further Ca2+
release from and sarcoplasmic reticulum stores: Free Ca2+ binds to
contractile proteins (e.g. troponin C) promoting/enhancing muscle
contraction
catecholamines (sympathomimetic amines e.g. epinephrine,
norepinephrine (Levophed)) increase slow-inward Ca2+ currents-- a
mechanism by which sympathomimetic agents enhance inotropism
Rhythm
• Phase 3
This phase is dominated by K+ efflux, i.e. repolarization. The
membrane potential moves towards the original resting
level. Phase 3 corresponds to the effective/absolute
refractory period.
Restoration of ionic gradients to "pre-action potential"
levels requires the action of the Na+/K+ membrane ATPase-
dependent transporter
Phase 4
This phase is between action potentials. In some cell types,
phase 4 depolarization (diastolic depolarization) can occur
{especially, for example in "pacemaker" cells}.
Mechanisms of Arrhythmias
• Key factor in the pathophysiology of arrhythmias and
the actions of antiarrhythmic drugs  relation
between resting potential and the action potentials
that can be evoked in it.
• Precipitate or exacerbate arrhythmias  ischemia,
hypoxia, acidosis or alkalosis, electrolyte abnormalities,
excessive catecholamine exposure, autonomic
influences, drug toxicity (e.g, digitalis, antiarrhythmic
drugs,overstretching of cardiac fibers, scarred or
diseased tissue.
Two main pathophysiology of arrhythmia :
1. Disturbance of Impulse Formation
2. Disturbance of Impulse Conduction
Interval between depolarizations of pacemaker cell 
duration of the action potential + duration of diastolic
interval  shortening of either duration  increase
pace maker rate.
The most important  diastolic interval  phase 4
depolarization (pacemaker potential)reduced by
vagal and beta blocker , increased by hypokalemia,
stimulation of beta receptor, positive chronotropic
drugs, fiber stretch, acidosis, currents of injury.
Afterdepolarizations  early (EAD) and delayed (D
AD)
EAD  transient depolarization interrupt phase 3
 at slow heart rate  arrhythmias of long QT
 genetic
DAD  transient depolarization interrupt phase 4
 at fast heart rate  when Ca Intracell
increased, digitalis excess, cathecolamin,
myocardial ischemia
2.1. Block
Severely depressed conduction  simple block
 AV, BB
Parasympathetic control of AV conduction 
partial AV block  relieved by atropine.
2.2. Reentry (Circus movement)
Impulse reenters and excites areas of the hearts
more than once.
 Wolff – Parkinson – White syndrome
 AF, VF  daughter impulses  one or some
extrabeats or sustained takikardia
Three conditions for reentry to occur :
a. Obstacle (anatomic or physiologic)
b. Unidirectional block at some point but continue
in the opposite direction
c. Conduction time must be long enough that
retrograde impulse does not enter refractory
tissue
Basic Pharmacology of The
Antiarrhythmic Agents
Aim of therapy reduce ectopic pacemaker activity and
modify conduction or refractoriness in reentry to
disable circus movement.
To achieve that aim :
1. Sodium channel blockade
2. Blockade sympathetic autonomic
3. Prolongation of effective refractory period
4. Calcium channel blockade.
 Decrease automaticity of ectopic pacemakers, reduce
conduction and excitability, increase refractory
period.
1. Use dependent or state dependent channels
blocker
2. Steady state reduction in unblocked channel
 reduces excitatory currents to a level
below that required for propagation
3. Prolongation of recovery time of the
channels  increase effective refractory
period.
 As dosage is increased  depress conduction
in normal tissues  drug induced arrhythmia
 Antiarrhythmic  proarrhythmic if fast heart
rate, acidosis, hyperkalemia, ischemia.
Specific Antiarrhythmic Agents
Classification of antiarrhythmic drug 4 classes:
1. Class 1  Sodium channel blockade
2. Class 2  Sympatholytic  reduce  adrenergic
3. Class 3  Prolongation of Action Potential Duration
 block rapid component of the delayed rectifier
potassium current
4. Class 4  blockade of the cardiac calcium current 
slows conduction in regions where the action
potential upstroke is Calcium dependent  SA, AV
nodes
Some drugs may have multiple classes of action, e.g.
Amiodarone has all four classes of action.
1. Class 1  Sodium channel blockade  local
anesthetic reduce sodium current – oldest
group and still widely used.
Subclasses effect on of Action Potential Duration
(APD)
Subclasses 1A  prolong APD, dissociate from
channel with intermediate kinetics
Subclasses 1B  shorten the APD, dissociate from
channel with rapid kinetics
Subclasses 1C  minimal effects on the APD and
dissociate from the channel with slow kinetics
1.1. Subclasses 1A
1.1.1. Procainamide
Cardiac Effects
Slows upstroke of the action potential, slows conduction, prolong
QRS.
Also prolong APD (class 3).
Less effective than quinidine in suppresing abnormal ectopic
pacemaker activity, more effective in blocking sodium channels in
depolarized cell, direct depressant action on SA and AV nodes.
Extracardiac Effects
 Ganglion blocking properties  reduces peripheral vascular
resistance  hypotension (less prominent than quinidine)
1.1. Subclasses 1A
1.1.1. Procainamide
Toxicity
 Cardiotoxic effect  excessive action potential prolongation,
QT – interval prolongation, induction torsades de pointes
and syncope  new arrhythmias
 Syndrome resembling Lupus erythematosus  arthralgia
and arthritis  reversible
 Pleuritis , pericarditis, pulmonary disease, renal lupus,
serologic abnormalities, nausea, diarrhea, rash, fever,
hepatitis, agranulositosis.
1.1. Subclasses 1A
1.1.1. Procainamide
Pharmacokinetics and Dosage
 Can be administered i.v or i.m, well absorbed p.o.
 Metabolite  N-acetylprocainamide (NAPA) class 3
activity accumulation can be torsades de pointes
 Eliminated by hepatic metabolism to NAPA  renal
elimination, half life 3 – 4 hours.
 i.v. loading dose  12mg / kg  0,3 mg /kg/minutes.
 Maintenance dosage 2 – 5 mg / minutes (2 – 5 g / day)
 Cardiac toxicity or GI toxicity  plasma conct > 8mcg/mL,
NAPA > 20mcg /mL
1.1. Subclasses 1A
1.1.1. Procainamide
Therapeutic Use
 Atrial and ventricular arrhythmias
 Second or third choice after amiodarone or
lidocaine for sustained ventricular arrythmias
associated with AMI
1.1. Subclasses 1A
1.1.2. Quinidine
Cardiac Effects
 Slows upstroke of the action potential, slows conduction,
prolongs QRS duration, by blockade sodium channels and
some potassium channels  toxic cardiac effect (excessive
QT – interval prolongation and induction of torsades de
pointes, slowed conduction throughout the heart
Extra cardiac Effects
 GI (diarrhea, nausea, vomiting on 1/3 – ½ patients)
 Headache, dizziness, tinnitus (cinchonism)
 Idiosyncratic or immunologic (thrombocytopenia,
angioneurotic edema, fever)
1.1. Subclasses 1A
1.1.2. Quinidine
Pharmacokinetics and Therapeutic Use
 Absorbed from GI tract, and eliminated by hepatic
metabolism
 Rarely used because of the adverse effects
1.1. Subclasses 1A
1.1.3. Disopyramide
Cardiac Effects
 Antimuscarinic effect  accompany drug that slows AV
conduction when treating AF
Toxicity
 All quinidine side effects, may precipitate heart failure (If
there is depression of left ventricular function)
 Atropine like activity urinary retention, dry mouth, blurred
vision, constipation, worsening glaucoma
1.1. Subclasses 1A
1.1.3. Disopyramide
Pharmacokinetics and Dosage
 p.o 3 x 150mg up to 1 gr / day.
 Reduced dosage in renal impairment
 Loading doses not recommended
Therapeutic Uses
 SV arrhythmias, ventricular arrythmias
1.1. Subclasses 1B
1.1.1. Lidocaine
Cardiac Effects
 Blocks activated and inactivated sodium channels with rapid
kinetics  effects on cells with long action potentials such as
Purkinje and ventricle greater than atrial
 No effects on conduction
Toxicity
 Least cardiotoxic, Proarrhythmic effects uncommon
 Depressing myocardial contractility
 Neurologic : paresthesias, tremor, nausea, lightheadedness,
hearing disturbances, slurred speech, convulsion
 Save plasma levels <9mcg / mL
1.1. Subclasses 1B
1.1.1. Lidocaine
Pharmacokinetics and Dosage.
 First pass hepatic metabolism  must be given parenterally.
 T ½ : 1 – 2 hours
 Loading dose 150 – 200 mg  15 minutes, maintenance 2 -
4mg / minutes
 Therapeutic plasma level : 2 – 6 mcg / mL
 In heart failure  volume distribution and total body
clearance decreased  doses should be decreased
 Liver disease  clearance decreased, volume distribution
increased  t ½ increase 3x maintenance dose decreased,
loading dose should not decreased.
1.1. Subclasses 1B
1.1.1. Lidocaine
Pharmacokinetics and Dosage.
 Drugs that decrease liver blood flow (propanolol, cimetidine)
 reduce clearance
 Infusion > 24hours  clearance fall
 Renal disease  no effect
Therapeutic Use
 D.O.C termination VT and prevention VF after cardioversion.
 Prophylactic use  increase asystole.
1.1. Subclasses 1B
1.1.2. Mexiletine
 Similar effect with lidocaine
 Can be given orally
 T ½ 8 – 20 hours  given 2 – 3 times a day
 Usual daily dosage  600 – 1200mg/d
 A.E  neurologic  tremor, blurred vision, lethargy (also
nausea)
 Relieving chronic pain  450 – 750 mg / day orally.
1.1. Subclasses 1C
1.1.1. Flecainide
 Potent blocker of sodium and potassium channels with slow
unblocking kinetics.
 Does not prolong action potential or QT interval
 Treat normal heart with SV arrhythmia
 No antimuscarinic effect
 Effective suppressing premature ventricular contraction
 Severe arrhythmia to patient with preexisting ventricular
tachyarrhythmia and previous M.I.
 T ½ 20hour
 Elimination  hepatic metabolism and kidney
 Dose 2x 100 – 200mg
1.1. Subclasses 1C
1.1.2. Propafenone
 Posses weak beta blocking activity
 Similar with quinidine but does not prolong the action
potential.
 Metabolized in liver
 T ½ 5 – 7 hours
 450 – 900 mg 3divided dosages
 For supraventricular arrhythmias
 A.E  mettalic taste, constipation, arrhythmias
2. Class 2  Beta adrenoceptor blocking drugs
2.1. Propanolol
Cardiac Effects
Beta receptor blocking  selective cardiac
beta1 receptor and direct effect to membrane
 not fully known
Efficacy lower than sodium channel blocker,
good evidence prevent recurrent infarction
and sudden death in patient recovering from
AMI .
2. Class 2  Beta adrenoceptor blocking drugs
2.2. Esmolol
Cardiac Effects
Short acting Beta receptor blocking 
intraoperative and other acute arrhythmia
2.3. Sotalol  nonselective beta blocking drug
that prolong action potential (class 3)
3. Class 3  Prolong effective refractory period
by prolonging the action potential
Blocking potassium channels or by enhancing
inward current.
Undesirable property “reverse use-
dependence”  action potential prolongation
least marked at fast rates (desirable) most
marked at slow rates  risk torsades de
pointes
QT prolongation  TDP
3. Class 3
3.1. Amiodarone
 Oral and intravenous to treat ventricular arrhythmias and
supraventricular arrhythmias.
Cardiac Effects  high efficacy, low TDP, significance QT prolong
 Prolong action potential  prolong QT interval  blockade
on IKr and Ks
 Prolongation uniformly in wide range of HR  doesn’t have
reverse use-dependent action.
 Also block inactivated sodium channel, adrenergic and
calcium channel slowing HR and AV conduction
3. Class 3
3.1. Amiodarone
Extracardiac Effects
 Peripheral vasodilatation
Toxicity
 Symptomatic bradycardia, heart block (esp. in AV node
disease)
 Dose related pulmonary toxicity  even in low dose 200mg/d
fatal pulmonary fibrosis in 1%
 Hepatitis  monitor LFT
 Photodermatitis, gray-blue skin discoloration in sun exposed
area.
3. Class 3
3.1. Amiodarone
Toxicity
 Halo
 Optic neuritis  blindness
 Block conversion T4 to T3, source of inorganic iodine  hypo
or hyperthyroidism  monitor thyroid function
Pharmacokinetics
Bioavailability 35 – 65 %
 Hepatic metabolism  desethylamiodarone (bioactive)
 T ½ complex, 50 % rapid 3 – 10 days, the slower several
weeks, after discontinuation effects 1 – 3 months.
3. Class 3
3.1. Amiodarone
Pharmacokinetics
 total loading dose 10 gr  0,8 – 1,2 gr daily, maintenance
dose 200 – 400 mg daily
 Levels increased by drugs that inhibit CYP3A4 H2 blocker
 Levels decreased by drugs that induce CYP3A4  rifampin
 Inhibits Cytochrome P450 enzymes  high levels of statin,
digoxin, warfarin  dose of warfarin reduced 1/3 to ½
Therapeutic Use
 Low dose 100 – 200 mg /d maintaining SR in AF, prevent
reccurent VT, increase pacing and defib threshold.
3. Class 3
3.2. Dronedarone
 Iodine atoms removed methanesulfonyl group added 
eliminate effect on thyroxine metabolism and modify half life.
 Also have beta adrenergic blocking actions
 T ½ 24 hours, 2 x 400mg
 Absorption increse 2 x – 3 x taken with food.
 Elimination primary non renal., inhibit tubular secretion 
increase creatinin 10 – 20%
 Inhibitor CY3A4  should not co-administered with azole and
antifungal agents
3. Class 3
3.3. Vernakalant
Multi ion channel blocker for treatment atrial fibrillation, no
effect on heart rate
Adverse effect  dysgeusia, sneezing, paresthesia, cough,
hypotension
 Undergoing clinical trial
3. Class 3
3.4. Sotalol
 Has class 2 and class 3 action
 Beta blocking action is not cardioselective.
 Orally bioavailability almost 100%
 Not metabolized in liver, not bound to plasma proteins
 Excretion in kidney in unchanged form, t ½ 12 hours
 TDP 6% at highest recommended dose
 For treatment life threatening ventricular arrhythmia and
maintenance SR in AF. Safe in paediatric
 Decrease threshold for cardiac defibrillation
3. Class 3
3.5. Dofetilide
Show less action potential prolongation at
rapid rates  especially for AF
100% bioavailable
Verapamil increase peak concentration by
increasing intestinal blood flow.
80% eliminated unchanged by kidney.
Baseline QTc > 450 ms and hypokalemia is
relative CI.
3. Class 3
3.6. Ibutilide
 Rapidly cleared by hepatic metabolism  excreted by kidney
 T ½ 6 hours
 Acute conversion from AF to normal sinus rhytm
 More effective for atrial flutter than atrial fibrillation  need
20minutes
 AE  QT prolong and TDP
4. Class 4  Calcium channel blocking drugs
Prototype  verapamil
Verapamil and diltiazem have antiarrhythmias effects,
dihydropyridines  may precipitate arrhythmias
4.1. Verapamil
Blocks activated and inactivated L-type calcium
channels. Effect more marked in SA and AV nodes 
slows SA node but hypotension effect cause slight
increase
Suppress early and delayed afterdepolarization
4.1. Verapamil
Peripheral vasodilatation
In patient with ventricular tachycardia 
hypotension and ventricular fibrillation
Negative inotropic  limited in diseased
heart
AV block  atropin
Constipation, lassitude, peripheral edema,
nervousness
4.1. Verapamil
T ½ 7 hours
Bioavailability 20%
Metabolized in liver extensively
 Can terminate SVT w.o. HF or SA AV diseases
although adenosine is d.o.c
Initial bolus 5 mg in 2 – 3 minutes  5 – 10 mg every
4 – 6 hours or 0,4 mcg / kg / minute
Oral doses higher because high FPM  120 – 640 mg
divided 3 – 4 doses.
4.1. Verapamil
Major indication SVT
 reduce ventricular rate in Atrial Fibrilation or
Flutter.
rarely convert AF to sinus rhytm
4.2. Diltiazem
 Same effect with verapamil but hypotension
and bradyarrhythmias relative infrequent.
Miscellaneous Antiarrhythmic Agents
Antiarrhythmias unfit to class 1 – 4.
1. Adenosine
Natural nucleoside in the body.
Half life < 10 seconds
 M . O . A. activation inward rectifier K+ current and
inhibition calcium current  marked
hyperpolarization and suppression calcium
dependent action potential.
 Inhibit AV node, increase AV node refractory period,
lesser effect on SA node.
1. Adenosine
d.o.c for paroxysmal SVT  high efficacy 90 –95 %
and very short acting
 Bolus 6mg than 12 mg i.v.
 Less effective in the presence of adenosine receptor
blocker such as theophyllin, caffeine.
 Potentiated by adenosine uptake inhibitor
(dypiridamol)
 Flushing in 20%, shortness of breath, chest burning
in 10 %, high grade AV block, AF, headaches,
hypotension, nausea, paresthesia.
2. Magnesium
 Originally used in digitalis induced
arrhythmias who hypomagnesemia.
 Also antiarrhythmic in normal magnesium
especially in TDP.
 Mechanism of effect not known but influence
many channels
 1gr at sulfate i.v 20 minutes can be repeated
once.
3. Pottasium
 Resting potential depolarizing
 Membrane potential stabilizing by increased
pottasium permeability
 Hypokalemia  afterdepolarization, ectopic
pacemaker activity
 Hyperkalemia deppress ectopic pacemaker
(suppress SA node) and suppress conduction
 Hyper and hypokalemia  arrhythmogenic 
target therapy normalize potassium gradient and
pool
Miscellaneous Antiarrhythmic
Agents
4. Digitalis
Cardiac glycosides  digoxin
Inhibit Na+K+ ATP-ase
 p.o. absorbed 65% - 80%
2/3 excreted unchanged by kidney
T ½ 36 – 40 hours
Agents
4. Digitalis
Cardiac effects
1. Mechanical  increase contraction by
increase free calcium concentration by
increase intracellular sodium and reduction
calcium expulsion.
Agents
4. Digitalis
Cardiac effects
2. Electrical  SA node decrease rate, atrial decrease
refractory period (arrhythmia), AV node decrease
conduction velocity, increase refractory period
(decrease refractory period,arrhythmia), purkinje
ventricle  slight decrease refractory period
(extrasystole, tachycardia, fibrillation), ECG increase
PR interval decrease QT interval (tachycardia,
fibrillation, arrest)
Agents
4. Digitalis
Other organ effects
anorexia, nausea, vomiting, diarrhea.
vagal, CTZ stimulation, disorientation, hallucination,
visual disturbance (color)
 gynaecomastia
Agents
5. Atropine
Reversible blockade on muscarinic receptors
 highly selective for muscarinic receptors and
much lower effect on nicotinic.
SA node very sensitive to muscarinic blockade
 tachycardia, blockade of vagal
Lower doses  initial bradycardia before
blockade vagal.
AV node  reduce PR interval
THANK YOU

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