ANTI-ARRHYTHMIC

DRUGS

Dr. Rika Yuliwulandari, Ph.D

17 dec 2015

ANTI ARRHYTHMIC DRUGS

Electrophysiology
Terminology of arrhythmia
Classification of arrythmic agents

ELECTROPHYSIOLOGY OF NORMAL
CARDIAC RHYTHM

To understand how antiarrhythmic

drugs work, need to understand
electrophysiology of normal
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 PurkinyaVentrikel

K++

Na, Ca

ECG (EKG) showing wave

segments

Contraction
of atria

Contraction of
ventricles

Repolarization of
ventricles

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

Two mechanisms: one or both

Disorders of impulse conduction

Disorders 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
Causes of arrhythmias
Cardiac ischemia (AMI)
Excessive discharge or sensitivity to autonomic transmitters
Exposure to toxic substances: Digitalis, anesthetic drug
Unknown etiology

Epidemiologi 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
/ conduction
excitability of
velocity
cardiac cells

Suppress
abnormal
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
- Paroxysmal Tachycardia
- Multifocal Atrial
Tachycardia
- Atrial Fibrillation
- Atrial Flutter

- Wolff-Parkinson-White
(pre-excitation syndrome)

- Ventricular Tachycardia
- Ventricular Fibrillation
- Premature Ventricular
Contraction

CLASSIFICATION OF ANTIARRHYTHMIC
Class I
(Na channel
blocker

Class II
Beta blocker

Class III
K channel
blocker

Class IV
Ca channel
blocker

Other

Dysopyramide (IA)

Esmolol

Amiodaron

Diltiazem

Adenosin

Phlecainid (IC)

Metoprolol

Bretillium

Verapamil

Digoxin

Lidocain (IB)

Pindolol

Sotalol

Mexilletin (IB)

Propanolol

Pracainamid (IA)
Propafenon (IC)
Quinidin (IA)
Tocainid (IB)

Atropin

Electrolyte
supplement

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
t = 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:
>2g/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

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
- t = 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

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
- t = 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
t = 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 -blocking activity ---- slows conduction
in all cardiac tissues
t = 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 1 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 1 & 2
Selective 1 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

CLASS III-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 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 & blocking property and block Ca++ influx
Perivascular dilatation - blocking property and Ca++ channel-inhibiting effects

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
t = 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

t 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 ANTIARRHYTHMIC

Class

Drug Classification

Basic Mechanism

IA

IB

Na channel blocker
MODERATE
- Quinidine 1st antiarrhythmic used, treat both atrial and ventricular
arrhythmias, increases refractory period
- Procainamide - increases refractory period but side effects
- Disopyramide extended duration of action, used only for treating
ventricular arrthymias

WEAK
- Lidocane (also acts as local anesthetic) blocks Na+ channels mostly in
ventricular cells, also good for digitalis-associated arrhythmias
- Mexiletine - oral lidocaine derivative, similar activity
- Phenytoin anticonvulsant that also works as antiarrhythmic similar to
lidocane
STRONG
Flecainide (initially developed as a local anesthetic)
Slows conduction in all parts of heart,
Also inhibits abnormal automaticity

IC
Propafenone
Also slows conduction
Weak blocker
Also some Ca2+ channel blockade

Reduce phase 0 slope

and peak of action
potential.
Moderate reduction in
phase 0 slope
Prolong repolarization
Increase APD
Increase ERP.
Small reduction in
phase 0 slope
Shortened
depolarization
Reduce APD
Decrease ERP.

Strong reduction in
phase 0 slope
No effect on APD or
ERP.

APD, action potential duration; ERP, effective refractory period; SA, sinoatrial node; AV, atrioventricular node.

BASIC MECHANISM OF ANTIARRHYTHMIC

Class

II

III

Drug Classification
Beta blocker
Propranolol
Causes both myocardial adrenergic blockade and membrane-stabilizing
effects
Slows SA node and ectopic pacemaking
Can block arrhythmias induced by exercise
Other adrenergic blockers have similar therapeutic effect :
Metoprolol, Nadolol, Atenolol, Acebutolol
Pindolol, Satolol, Timolol, Esmolol
Potassium channel blocker
Amiodarone prolongs action potential by delaying K+ efflux
Ibutilide slows Na inward movement and delaying K + influx.
Bretylium first developed to treat hypertension but found to also suppress
ventricular fibrillation associated with myocardial infarction
Dofetilide - prolongs action potential by delaying K+ efflux with no other
effects

Basic Mechanism

Block sympathetic
activity ( adrenergic
rec)
Stabilize cell
membrane
Increase P-R interval
Developed because
some patients
negatively sensitive to
Na channel blockers
(they died!)
Delay repolarization
(phase 3)
Increase APD and ERP

BASIC MECHANISM OF ANTIARRHYTHMIC

Class

IV

Drug Classification
Calcium-channel blockade
Verapamil
- blocks Na+ channels and Ca2+;
- Slows SA node in tachycardia
Diltiazem
Bepridil

Others

Adenosine
Electrolyte supplement:
- Magnesium
- Potassium
Atropin

Basic Mechanism

Block L-type calcium-channels

Most effective at SA and AV nodes
Reduce rate and conduction.
Slow rate of AV-conduction in
patients with atrial fibrillation

Inhibits AV conduction & increases

AV refractory period

Na+/K+ ATPase, Na+, K+, Ca++

channels
Normalize K+ gradients
Muscarinic receptor agonist

INDICATION
Condition

Drug

Sinus tachycardia

Class II, IV

Atrial fibrillation/flutter

Class IA, IC, II, III, IV

digitalis

Paroxysmal supraventricular
tachycardia

Class IA, IC, II, III, IV

adenosine

AV block
Ventricular tachycardia

atropine
Class I, II, III

Premature ventricular complexes

Class II, IV
magnesium sulfate

Digitalis toxicity

Class IB
magnesium sulfate