ANTI-ARRHYTHMIC

DRUGS

Dr. Rika Yuliwulandari, Ph.D

24 dec 2012
 ANTI – ARRHYTHMIC DRUGS

• Electrophysiology
• Terminology of arrhythmia
• Classification of arrythmic agents
• Explanation of each
ELECTROPHYSIOLOGY OF NORMAL
CARDIAC RHYTHM
• To understand how antiarrhythmic
drugs work, need to understand
electrophysiology of normal K++ Na, Ca
contraction of heart
– Caused by unequal distribution of
ions inside vs. outside cell
• Na+ higher outside than inside cell
• Ca+ much higher outside than inside
• K+ higher inside cell than outside

• Maintenance by ion selective

channels, active pumps and
exchangers
• SA node-Atria-AV node-His Purkinya-
Ventrikel
 Contraction of
ECG (EKG) showing wave ventricles
segments

Repolarization of
Contraction
ventricles
of atria
FACTORS PRECIPITATING CARDIAC
ARRHYTHMIAS:

1. Ischemia
 pH & electrolyte abnormalities
 80% – 90% asstd with MI
2. Excessive myocardial fiber stretch/ scarred/ diseased
cardiac tissue
3. Excessive discharge or sensitivity to autonomic
transmitters
4. Excessive exposure to foreign chemicals & toxic
substances
 20% - 50% ----- General Anesthesia
 10% - 20% ----- Digitalis toxicity
5. Two mechanisms: one or both
• Disturbance of impulse conduction
• Disturbance of impulse formation
DISORDERS OF IMPULSE CONDUCTION

• Impulses from the SA node

pass down bifurcate
pathway to activate the
entire ventricular surface
• In case of unidirectional
block (myocardial injury,
prolonged refractory
period), impulse travels in
retrograde direction and
cause reexcitation and
irregular beat
DISORDERS OF IMPULSE FORMATION

• No signal from the pacemaker site

• Development of an ectopic pacemaker
• Development of oscillatory afterdepolariztions
– Result of drugs (digitalis, norepinephrine) used to treat other
cardiopathologies
• May result in
– Bradycardia (if have AV block)
– Tachycardia (if reentrant circuit occurs)
ARRHYTHMIA

• Arrhythmia is any deviation from a normal heart beat

– Faster
– Slower
– Irregular
– ectopic
• Result from disorders of impulse formation, conduction, or both
• Causes of arrhythmias
– Cardiac ischemia (AMI)
– Excessive discharge or sensitivity to autonomic transmitters
– Exposure to toxic substances: Digitalis, anesthetic drug
– Unknown etiology
Cardiac Arrhythmias:
- 25% treated with digitalis
- 50% anesthetized patients
- 80% patients with AMI
 reduced cardiac output
 drugs or nonpharmacologic:
- Drugs: 4 classes and others
- Nonpharmacologic:
pacemaker, cardioversion,
catheter ablation, surgery
 Purpose of Antiarrhythmic Agent
Restore normal rhythm
Restore normal conduction
*Prevent more serious and lethal arrhytmias

Alter Suppress
↓/↑ conduction
excitability of abnormal
velocity
cardiac cells automaticity
ANTI-ARRHYTHMIC DRUGS

• Most antiarrhythmic drugs have major

mechanism of action blocking of 1 or more
cardiac ion current(s)
• Biggest problem – antiarrhythmics can cause
arrhythmia!
– Must be careful when determine dose, blood
levels, and in follow-up when prescribing
antiarrhythmics drugs
ARRHYTHMIA

• Supraventricular: • Ventricular:

- Atrial Tachycardia - Wolff-Parkinson-White

- Paroxysmal Tachycardia (pre-excitation syndrome)
- Multifocal Atrial - Ventricular Tachycardia
Tachycardia - Ventricular Fibrillation
- Atrial Fibrillation - Premature Ventricular
- Atrial Flutter Contraction
CLASSIFICATION OF ANTI-
ARRHYTHMIC

Class I Class II Class III Class IV Other

(Na channel Beta blocker K channel Ca channel
blocker blocker blocker
Dysopyramide (IA) Esmolol Amiodaron Diltiazem Adenosin
Phlecainid (IC) Metoprolol Bretillium Verapamil Digoxin
Lidocain (IB) Pindolol Sotalol Atropin
Mexilletin (IB) Propanolol Electrolyte
supplement
Pracainamid (IA)
Propafenon (IC)
Quinidin (IA)
Tocainid (IB)
CLASS I: NA CHANNEL BLOCKER
CLASS IA: QUINIDINE
• Prototype of Class 1A drugs
• Binds to Na channel and prevent the activation of the channel ----- ↑
refractor period, ↓ conduction rate,  pacemaker rate,  conduction &
excitability
• Affect on ischemic heart > normal heart
– Class IA binds to depolarized membrane
– Class IA binds to low pH membrane
• Pharmacokinetics:
– Oral → rapid GI absorption , t max: 60-90’
– Quinidine gluconas: slower absorption, t max: 3-4 hrs
– 80% plasma protein binding
– 20% excreted unchanged in the urine → enhanced by acidity
– t½ = 6 hours
– Parenteral → hypotension, pain in inj site, ↑ creatine kinase
• Dosage: 0.2 to 0.6 gm 2-4X a day
 Toxicity:
– Antimuscarinic actions → inh. vagal effects
– Quinidine syncope (lightheadedness, fainting)
– Arrhythmia or asystole
– Depress contractility & ↓ BP
– Widening QRS duration
– Diarrhea, nausea, vomiting
– Cinchonism (dizziness, tinnitus)
– Rare: rashes, fever, hepatitis, thrombocytopenia,etc
 Drug Interaction:
– Increases digoxin plasma levels
 Therapeutic Uses:
– Atrial flutter & fibrillation
– Ventricular tachycardia
• Side effect :
– Slight cinconism: tinnitues, deafness, blurry, GI tr symptom
– Heavier Se: headache, diplopia, fotofobia, flushing,
delirium, psichosis
– General SE:
• >2μg/ml  widening of QRS complex and Q-T interval (can be
used for tx monitoring) ---- if QRS >50%, ↓ dose
• High dose: Blockage SA, AV, Ventricular arrhytmia, asistole
• Takikardia ventrikel polimorfik (torsades de pointes)  fatal
• If QT widen at low dose of Quinid ---- tend to get torsades de
pointes arrhytmia ----- find other drug
 Antiaritmia Kelas Ia:
Prokainamid
• Prokainamid  prototip kelas Ia, menekan aktivitas
Na+ & jg aktivitas kanal K+
• Diberikan IV  terapi aritmia supraventrikular &
ventrikular akut ; Oral  penggunaan jk panjang
• Prokainamid diasetilasi di hati mjd N-asetil
Prokainamid (NAPA) (memp sifat obat klas 3), eksresi
mll ginjal
• ES KV: kadar >>  perubahan EKG mirip kuinidin,
interval QT memanjang & torsades de pointes 
jarang, kecuali kadar NAPA >>>
• ESO prokainamid: 60-70% pasien akan membentuk
antibodi antinuklear dlm 2 th  20-30% SLE 
reversibel
 Antiarrhythmia class IA,
Procainamide
• Derivative of local anesthetic: Procaine
• Moa = Quinidine
• Pharmacokinetics:
– Oral: absorbtion good, for long term tx
– Iv: rarely used, cause hypotention
– Metabolism: acetylated in liver --- N-acetyl procainamide
(NAPA) (class III action) ----eliminated via kidney
• Se: high dose ---- EKG changes like Quinidine
(widen Q-T interval)
• Long term effect: 25-30% of px develop
antibodi antinuklear within 2 years  SLE
reversible
• Toxicity:
- Cause new arrhythmias
- LE-like syndrome
- Pleuritis, pericarditis, parenchymal
pulmonary disease
- ↑ ANA
- nausea, DHA, rash, fever, hepatitis,
agranulocytosis
CLASS IA: DISOPYRAMIDE

• Stronger antimuscarinic effects than quinidine →

slows AV conduction
• Pharmacokinetics: oral administration
- extensive protein binding
- t½ = 6 to 8 hrs
 Dosage: 150 mg TID up to 1 g/day
 Therapeutic Use: Ventricular arrhythmias
 Toxicity:
- Negative inotropic action (Heart fail without prior
myocardial dysfunction)
- Urinary retention, dry mouth, blurred vision,
constipation, worsening glaucoma
CLASS IA: AMIODARONE

• Only for serious ventricular arrhythmias

• Broad spectrum of action on the heart
• Very effective Na+ channel blocker but low affinity for activated
channels
• Lengthens AP by blocking also K+ channels
• Weak Ca++ channel blocker
• Noncompetitive inhibitor of β adrenoceptors
• Powerful inhibitor of abnormal automaticity
• Slows sinus rate & AV conduction
• Markedly prolongs the QT interval
• Prolongs QRS duration
• ↑ atrial, AV nodal & ventricular refractory periods
• Antianginal effects – due to noncompetetive α & β blocking property
and block Ca++ influx
• Perivascular dilatation - α blocking property and Ca++ channel-
inhibiting effects
• Pharmacokinetics:
- t½ = 13 to 103 days
- effective plasma conc: 1-2 μg/ml
• Dosage: - Loading – 0.8 to 1.2 g daily
- Maintenance – 200 to 400 mg daily
• Drug Interaction: reduce clearance of warfarin,
theophylline, quinidine, procainamide, flecainide
• Therapeutic Use: Supraventricular & Ventricular arrhythmias
• Toxicity: fatal pulmonary fibrosis, yellowish-brown
microcrystals corneal deposits, photodermatitis, grayish blue
discoloration, paresthesias, tremor, ataxia & headaches,
hypo/hyperthyroidism, Symptomatic bradycardia or heart
block, heart failure, Constipation, hepatocellular necrosis,
inflam’n, fibrosis, hypotension
 Antiaritmia Kelas Ib (1)

• Lidokain, Fenitoin, Tokainid, Meksiletin

• Lidokain  prototipe Kelas Ib
• Depresi ringan fase 0, konduksi lambat,
repolarisasi singkat
• Lidokain dpt menekan automatisasi serabut
purkinje yg terdepolarisasi & teregang
• Lidokain & fenitoin  efektif meniadakan
triggered activity pd delayed afterdepolarization
karena digitalis  drug of choice utk aritmia krn
digitalis
 Antiaritmia Kelas Ib (2)

• Lidokain
– Metabolisme di hati ekstensif  harus diberikan IV
– Indikasi: hanya utk pengobatan aritmia ventrikel yg
disebabkan oleh IMA, bedah jantung terbuka, digitalis
– ES: SSPdisosiasi, parestesia, mengantuk, agitasi. Dosis
tinggi: gangguan pendengaran, disorentasi, kejang, henti
napas
• Fenitoin
– IV intermiten  dpt sebabkan flebitis. T ½ panjang 
Oral: dimulai dgn dosis tinggi  diturunkan hingga dosis
pemeliharaan
– Indikasi: aritmia atrium & ventrikel krn digitalis, aritmia
krn bedah jantung terbuka & infark miokard
– ES: SSP  nystagmus, mengantuk, vertigo, ataksia, mual-
muntah
 Antiaritmia Kelas Ic (1)

• Fleikainid, Enkainid, Profenon

• Afinitas tinggi terhadap kanal Na+ di sarkolema,
memperlambat konduksi, menekan arus masuk Na+
ke dalam sel
• Indikasi: aritmia ventrikel yg mengancam jiwa 
aritmia maligna, gagal jantung kongestif,
bifasicular block, gangguan fungsi sinus
• ES: efek proaritmia 8-15% pasien dg aritmia
ventrikel maligna. Dosis tinggi: gangguan
penglihatan
Antiarrhythmia agent Class IB

• Lidocaine, Phenitoin, Tocainide, Mexiletine

• Lidocaine: Prototype of Class IB
• Work on Na+ channels
• Potent abnormal cardiac activity suppressor
• Only iv
• Pharmacokinetics:
- Extensive first-pass hepatic metabolism
- t½ = 1 to 2 hrs
• Dosages: loading- 150 to 200 mg, maintenance- 2-4
mg
• Drug Interaction: propranolol, cimetidine – clearance
• Therapeutic Use: DOC for suppression of recurrences
of ventricular tachycardia & fibrillation after AMI.
• Toxicity:
– Worsen impaired conduction
– Exacerbates ventricular arrhythmias
– Hypotension in HF
– Neurologic: paresthesias, tremor, nausea,
lightheadedness, hearing disturbances, slurred
speech, convulsions
CLASS IB: TOCAINIDE & MEXILETENE

• Similar to lidocaine
• Oral route - resistant to first-pass hepatic metabolism
• Usage: ventricular arrhythmias
• t½ = 8 to 20 hrs
• Dosage: Mexiletene – 600 to 1200 mg/day
Tocainide – 800 to 2400 mg/day
• Side effect: tremors, blurred vision, lethargy, nausea, rash,
fever, agranulocytosis
Other CLASS IB: PHENYTOIN
• Anti-convulsant with anti-arrhythmic properties
• Suppresses ectopic pacemaker activity
• Useful in digitalis-induced arrhythmia
• Extensive, saturable first-pass hepatic metabolism
• Highly protein bound
• Toxicity: ataxia, nystagmus, mental confusion, serious
dermatological & BM reactions, hypotension, gingival
hyperplasia
• D/I: Quinidine, Mexiletene, Digitoxin, Estrogen, Theophyllin,
Vitamin D
CLASS IC: FLECAINIDE

• Fleicainide, Encainide, Prophenon

• Potent blocker of Na+ & K+ channels
• No antimuscarinic effects
• Used in patients with supraventricular arrhythmias
• Hepatic metabolism & renal elimination
• Dosage: 100 to 200 mg bid
• Indication: ventricular arrhythmia ---- malignant
arrhythmia, CHF, biphasic block
• Se: proarrhythmia in 8-15% px with malignant
ventricular arrhythmia, blurred vision in high dose
CLASS IC: PROPAFENONE

• Action = flecainide
• (+) weak β-blocking activity ---- slows
conduction in all cardiac tissues
• t½ = 5 to 7 hrs.
• Dosage: 450 – 900 mg TID
• Usage: supraventricular arrhythmias, broad
spectrum antiarrhythmic agents
• SE: metallic taste, constipation, arrhythmia
exacerbation
CLASS IC: MORICIZINE

• Antiarrhythmic phenothiazine derivative

• Used in ventricular arrhythmias
• Potent Na+ channel blocker
• Dosage: 200 to 300 mg orally tid
• SE: dizziness, nausea
CLASS II: BETA ADRENOCEPTOR
BLOCKERS
• Moa:
– Block receptor ß1  Block catecholamine endogen
– Increase K+ inward, block Na+ channel & decrease membrane response
• Most effective in px with increased sympathetic activity (stress pre anesthetic/surgery,
MI, CHF, Hyperthyroidism)
• Effect: ↑ AV nodal conduction time (↑ PR interval), Prolong AV nodal refractorines
• Usage: reentrant arrhythmias, controlling ventricular response in AF & A.fib.,
Depresses phase 4 → slows recovery of cells, slows conduction & decrease
automaticity, Reduces HR, decrease IC Ca2+ overload & inhibit after depolarization
automaticity, Prevent recurrent infarction & sudden death in patients recovering from
AMI
• “membrane stabilizing effect”
 Exert Na+ channel blocking effect at high doses
 Acebutolol, metoprolol, propranolol, labetalol, pindolol
• “intrinsic sympathetic activity”
 Less antiarrhythmic effect
 Acebutolol, celiprolol, carteolol, labetalol, pindolol
• Therapeutic indications: Supraventricular & ventricular arrhythmias, hypertension
 Specific beta blocker agents:

• Propranolol: block ß1 & ß2

• Selective ß1 blocker
– Acebutolol : as effective as quinidine in suppressing ventricular ectopic
beats
– Esmolol: short acting hence used primarily for intra-operative & ther
acute arrhythmias
– Sotalol :
• Block K+ channel as well as beta blocker
• T1/2 long (20 hrs), 1 dd
• has K+ channel blocking actions (class III)
• Nonselective beta-blocker that also slows repolarization & prolongs AP
duration
• Used in supraventricular & ventricular arrhythmias in pediatric age group
• Renal excretion
• Dosage: 80 – 320 mg bid
• Toxicity: torsades de pointes , beta-blockade symptoms
CLASS III: POTASSIUM CHANNEL
BLOCKERS
• Bretillium, dophetillid, amiodarone
• Sotalol  beta blocker, + class III effect
• Moa: blocking K+ channel
• Drugs that prolong effective refractory period by
prolonging action potential
• Prolong AP by blocking K+ channels in cardiac muscle
(↑ inward current through Na+ & Ca++ channels)
• Quinidine & Amiodarone → prolong AP duration
• Bretylium & Sotalol → prolong AP duration & refractory
period
• Ibutilide & Dofetilide → “pure” class III agents
• Reverse use-dependence
• Indication: Ventricular arrhythmia & atrial arrhythmia
BRETYLIUM

• Antihypertensive, increase refractory periode,

interferes with neuronal release of
catecholamines, Lengthens ventricular AP
duration & effective refractory period, (+)
inotropic action
• Intravenous administration
• Dosage: 5 mg/kg
• Usage: ventricular fibrillation, when lidocaine &
cardioversion have failed (In emergency
setting/resuscitation)
• SE: postural hypotension, ventricular arrhythmia,
nausea & vomiting
CLASS III: POTASSIUM CHANNEL
BLOCKERS

IBUTILIDE

• Slows repolarization
• Prolong cardiac action potentials
• Mech of action: ↑ inward Na+ current, blocking Ikr-
channel or both
• routes: Oral, IV (1 mg over 10min)
• Clin. Uses: atrial flutter, atrial fibrillation
• Toxicity: Torsades de pointes
DOFETILIDE

• A potential Ikr- blocker

• Dosage: 250-500 ug bid
• Clin. Uses: Atrial flutter & fibrillation
• Renal excretion
• Toxicity: Torsade de pointes
CLASS IV: CALCIUM CHANNEL
BLOCKERS
VERAPAMIL

• Blocks both activated & inactivated calcium channels

• Prolongs AV nodal conduction & effective refractory period
• Suppress both early & delayed afterdepolarizations
• May antagonize slow responses in severely depolarized tissues
• Peripheral vasodilatation
• Oral administration → 20% bioavailability
• t½ = 7 hrs
• Liver metabolism
• Dosage:
IV: 5-10 mg every 4-6 hrs or infusion of 0.4 ug/kg/min
Oral: 120-640 mg daily, divided in 3-4 doses
• Uses: SVT, AF, atrial fib, ventricular arrhythmias
• Toxicity: AV block, can cause sinus arrest, constipation, nervousness,
peripheral edema
DILTIAZEM & BEPRIDIL

• Similar efficacy to verapamil in

supraventricular arrhythmias & rate control
in atrial fibrillation
• Bepridil
- AP & QT prolonging action→ ventricular
arrhythmias but may cause torsade de pointes
- Rarely used → primarily to control refractory
angina
OTHER ANTI-ARRHYTHMIC AGENTS:
DIGITALIS

• Indirectly alters autonomic outflow by increasing parasympathetic

tone & decreasing sympathetic tone
• Results in decreased conduction time & increased refractory period
in the AV node

ADENOSINE
• A nucleoside that occurs naturally in the body
• t½ ≈ 10 seconds
• MOA: enhances K+ conductance & inhibits cAMP-induced Ca++ influx
→ results in marked hyperpolarization & suppression of Ca++-
dependent AP
• IV bolus: directly inhibits AV nodal conduction & ↑ AV nodal
refractory period
ADENOSINE
• DOC for prompt conversion of paroxysmal SVT to sinus
rhythm due to its high efficacy & very short duration of
action
• Dosage: 6-12 mg IV bolus
• D/I:
– theophylline, caffeine – adenosine receptor
blockers
– Dipyridamole – adenosine uptake inhibitor
• Toxicity: flushing, SOB or chest burning, atrial
fibrillation, headache, hypotension, nausea,
paresthesia
MAGNESIUM
• Effective in patients with recurrent episodes of torsades de pointes
(MgSO4 1 to 2 g IV) & in digitalis-induced arrhythmia
• MOA: unknown → influence Na+/K+ ATPase, Na+ channels, certain
K+ and Ca++ channels

POTASSIUM

• Therapy directed toward normalizing K+ gradients & pools in the body

• Effects of increasing serum K+:
1. resting potential depolarizing action
2. membrane potential stabilizing action
• Hypokalemia:
- ↑ risk of early & delayed afterdepolarization
- ↑ ectopic pacemaker activity esp if (+) digitalis
• Hyperkalemia:
- Depression of ectopic pacemakers
- Slowing of conduction
BASIC MECHANISM OF ANTI-
ARRHYTHMIC
Class Drug Classification Basic Mechanism
• Reduce phase 0 slope
I Na channel blocker and peak of action
potential.
MODERATE • Moderate reduction in
- Quinidine – 1st antiarrhythmic used, treat both atrial and ventricular phase 0 slope
arrhythmias, increases refractory period
IA • Prolong repolarization
- Procainamide - increases refractory period but side effects
- Disopyramide – extended duration of action, used only for treating • Increase APD
ventricular arrthymias • Increase ERP.
WEAK • Small reduction in
- Lidocane (also acts as local anesthetic) – blocks Na+ channels mostly in phase 0 slope
ventricular cells, also good for digitalis-associated arrhythmias • Shortened
IB
- Mexiletine - oral lidocaine derivative, similar activity depolarization
- Phenytoin – anticonvulsant that also works as antiarrhythmic similar to • Reduce APD
lidocane • Decrease ERP.
STRONG
Flecainide (initially developed as a local anesthetic)
Slows conduction in all parts of heart, • Strong reduction in
Also inhibits abnormal automaticity phase 0 slope
IC
Propafenone • No effect on APD or
Also slows conduction ERP.
Weak β – blocker
Also some Ca2+ channel blockade
APD, action potential duration; ERP, effective refractory period; SA, sinoatrial node; AV, atrioventricular node.
BASIC MECHANISM OF ANTI-
ARRHYTHMIC

Class Drug Classification Basic Mechanism

Beta blocker
Propranolol • Block sympathetic
• Causes both myocardial β–adrenergic blockade and membrane-stabilizing
effects activity ( adrenergic
II • Slows SA node and ectopic pacemaking rec)
• Can block arrhythmias induced by exercise • Stabilize cell
• Other β–adrenergic blockers have similar therapeutic effect : membrane
• Metoprolol, Nadolol, Atenolol, Acebutolol
Pindolol, Satolol, Timolol, Esmolol • Increase P-R interval

• Developed because
Potassium channel blocker some patients
• Amiodarone – prolongs action potential by delaying K+ efflux
• Ibutilide – slows Na inward movement and delaying K + influx. negatively sensitive to
• Bretylium – first developed to treat hypertension but found to also suppress Na channel blockers
III ventricular fibrillation associated with myocardial infarction (they died!)
• Dofetilide - prolongs action potential by delaying K+ efflux with no other • Delay repolarization
effects
(phase 3)
• Increase APD and ERP
BASIC MECHANISM OF ANTI-
ARRHYTHMIC

Class Drug Classification Basic Mechanism

Calcium-channel blockade
• Verapamil • Block L-type calcium-channels
- blocks Na+ channels and Ca2+; • Most effective at SA and AV nodes
IV - Slows SA node in tachycardia • Reduce rate and conduction.
• Diltiazem • Slow rate of AV-conduction in
• Bepridil patients with atrial fibrillation

• Inhibits AV conduction & increases

• Adenosine AV refractory period
• Electrolyte supplement:
- Magnesium • Na+/K+ ATPase, Na+, K+, Ca++
Others
- Potassium channels
• Atropin • Normalize K+ gradients
• Muscarinic receptor agonist
INDICATION

Condition Drug

Sinus tachycardia Class II, IV

Class IA, IC, II, III, IV

Atrial fibrillation/flutter
digitalis
Paroxysmal supraventricular Class IA, IC, II, III, IV
tachycardia adenosine
AV block atropine
Ventricular tachycardia Class I, II, III
Class II, IV
Premature ventricular complexes
magnesium sulfate
Class IB
Digitalis toxicity
magnesium sulfate