Antiarrythmic Drugs

Armen Muchtar

Antiarrythmic Drugs

Cardiac Electrophysiology
Mechanisms of Cardiac Arrythmias
Mechanisms of Antiarrythmic Drug Action
Classifying Antiarrythmic Drugs
Pharmacology of Antiarrythmic Drugs

Cardiac Electrophysiology
5 phases of action potential:
1. phase 0: immediate depolarization
2. phase 1: initial rapid repolarization
3. phase 2: slow repolarization (plateau)
4. phase 3: diastolic repolarization
5. phase 4: spontaneous slow
depolarization

0 mV

100 ms

-85 mV
Na +

Ca 2+
Na+

Na+

Na+ Ca2+

outside
Membrane
Inside
K+

Ca2+

K+ CChannel currents

Pump

Exchanger

K1+
Diastolic
Channel
currents

Parameters of
Cardiac Electrophysiology
1.
2.
3.
4.
5.
6.
7.
8.

Resting potential
Threshold potential
Conduction velocity
Refractoriness (Absolute vs. Relative)
Automaticity
Excitability
Action potential duration (APD)
Membrane responsiveness

Mechanisms of Cardiac Arrythmias

1. Enhanced automaticity:
May occur at SA, AV, and His-Purkinje; caused by
beta-adrenergic stimulation, hypokalemia, stretching
that increase phase-4 slope.
ACH reduces pace maker rates by decreasing
phase-4 slope and by hyperpolarization.
Ischemia may produce automaticity

Mechanisms Cardiac Arrythmias

2. After depolarization and triggered
automaticity: a normal CAP may be followed or
interrupted by an abnormal depolarization
a. delayed after depolarization (DAD): at phase-4,
under condition of intracellular Ca+ overload in
ischemia, adrenergic stress, digitalis intoxication,
or cardiac failure.
b. early after depolarization (EAD): at phase-3;
occurs when HR is low, extracellular K+ is low,
drugs that prolong APD; when cardiac
repolarization is prolonged, polymorphic VT with a
long QT interval (torsades de pointes) may occur

DAD

EAD

Mechanisms of Cardiac Arriythmias

3. Reentry
a. anatomically defined re-entry: occurs when
impulses propagate by more than one way between
two points and those pathways have heterogenous
EP properties (WPW syndrome that may cause AF,
AV nodal re-entrant tachycardia, and PSVT)).
b. functionally defined re-entry: absence of distinct,
anatomically defined pathway; may be caused by
ischemia or post infarction scarring; manifested as
atrial or ventricular fibrillation

Mechanisms of
Antiarrythmic Drug Action
1. Slowing automatic rhythm by:
increase maximum diastolic potential
(adenosine, ACH), decrease phase-4
slope (beta-blockers), decrease
threshold potential (Na+/Ca++
blockers), or increase APD (K
blockers)

+20

Membrane potential (mV)

0
-20
-40
-45
-60

-80
-80
-100

-65

-100
500 ms

Mechanisms of
Antiarrythmic Drug Action
2. DAD & EAD can be blocked by inhibiting
the development of after depolarization
and by interfering inward current with Na+
or Ca++ blocker.
DAD can be inhibited by verapamil which
blocks the development of DAD or by
quinidine which elevates TP required to
produce abnormal AP.
EAD can be inhibited by shortening APD or
accelerating HR with isoproterenol, or by
giving Mg++ which blocks EAD
development

Mechanisms of
Antiarrythmic Drug Action
3. Tiadakan Re-entry dengan cara:
3.1. Sindroma W-P-W
perpanjang MR AV
perlambat konduksi AV

Ca blockers

3.2. Functional Re-entry:

perpanjang masa refrakter
perpanjang APD
perbaiki konduksi dengan lidokain

Na blockers

Klasifikasi Obat Antiaritmia

Kelas

Obat

I.

Na+ channel blocking agents

A. Quinidine, procainamide, disopyramid
B. Lidocain, mexiletine, phenytoin, tocainide
C. Encainide, flecainide, propafenone

Cara kerja

Depresi fase 0 (++),

Repolarisasi
Depresi fase 0 (+),
Repolarisasi
Depresi fase 0 (+++),
Repolarisasi

II.

blockers

Automatisitas ,
Repolarisasi AV

III.

Amiodarone, bretylium, sotalol, ibutilide,

dofetilide

Repolarisasi

IV.

Ca++ antagonists

Automatisitas SA
Repolarisasi AV

V.

Lain-lain (MgSO4, adenosine)

State-dependent Na channel block

Afinitas tinggi thd kanal yg activated &
inactivated
Afinitas rendah thd kanal yg resting state
Bila HR, disosiasi , kanal terhambat
Afinitas tinggi pada kanal inactivated APD
panjang
Bila iskemia, disosiasi lambat
Kecepatan pemulihan: cepat (lidokain); sedang
(kinidine); lambat (flecainide)

Electrophysiology of Na+ Blockers

Excitability
Conduction velocity at fast response
tissues, QRS , PR
APD , refractoriness
TP , automaticity
Inhibit DAD & EAD
Bidirectional inhibition or re-entry

Electrophysiology of K Blockers
+

APD , QT , refractoriness
Automaticity
Heterogeneity of refractoriness
No pure K+ blockers, except for dofetilide
Amiodarone, quinidine, sotalol is a K +
blocker
Trigger EAD Torsades des pointes

Electrophysiology of Ca++ Blockers

Block at sinus & AV nodes

Conduction velocity , refractoriness
Bidirectional block of re-entry
Reduction of VR in AF & AF
Bepridil increase APD Torsades des
pointes

Electrophysiology of Blockers

AV Conduction velocity , PR interval

AV nodal refractoriness
Bidirectional block of re-entry
Automaticity
Intracellular Ca++ , hypokalemia
Na+ blocking of propranolol
K+ blocking activity of sotalol

Quinidine Pharmacodynamics
Blocks activated Na+ channels, T recovery 3
Prolongs QRS & QT
Na++, K+ and Ca++ blockings
Excitability
Automaticity
Prolongs APD at slow rate
Elicits EAD at slow rate
- adrenergik blockade
Vagal inhibition

Quinidine Side Effects

Diarrhea Hypokalemia Torsades D.P.

Thrombocytopenia
Cinchonism
QT prolongation Torsades de Pointes

Quinidine Pharmacokinetics

80% bound to plasma protein

Extensive hepatic oxidative met.
3 hydroxyquinidine ~ quinidine
Individual variability of dosage
Inhibitor of CYP 2 D6, potentially interacts
with codein, propafenone
Interaction with digoxin by inhibiting PGPmediated digoxin transport

Procainamide
Pharmacodynamics ~ quinidine; but is better tolerated
when given IV, and lacks of vagolytic and alphaadrenergic blocking activity, can induce torsades de
pointes.
Long-term oral treatment is poorly tolerated because of
marrow aplasia & LE syndrome
N-acetyl transferase NAPA as active metabolite
Rapid >< slow acetylator

Disopyramide
Pharmacodynamics ~ quinidine, can induce
torsades de pointes
Prominent anticholinergic, but no alpha
adrenergic blocking activity
Depress contractility
Hepatic metabolism
Reduced dose in renal failure

Lidocaine Pharmacodynamics

Block activated & inactivated Na+ channels

T recovery << 1
Greater effects in depolarized tissues
Not useful in atrial arrythmia
Hyperpolarize depolarized Purkinje fibres
Increase conduction velocity in re-entry
Decreases automaticity
Depresses excitability
APD is not affected or shortened

Lidocaine Side Effects

Heart block/CHF in MI
Seizures
Nystagmus is an early sign of toxicity

Lidocaine Pharmacokinetics
Extensive 1st hepatic metabolism, it cannot be given
orally
Loading dose & maintenance dose
Therapeutic conc.: 1,5 4 g; loading dose of 3-4
mg/kgBW, followed by 50 mg every 8 minutes for three
doses.

Mexiletine & Tocainide

Analogs of lidocaine
Oral therapy is effective
Induce tremor & nausea
BM aplasia & pulmonary fibrosis by
tocainide
Combine with quinidine in VA

Moricizine

Phenotiazine analog
Blocks activated & inactivated channels
T recovery ~ flecainide
Prolongs QRS of 15%
Shortens AP & QT interval
Extensive 1st hepatic metabolism
Short t 1/2 , long effect due to active
metabolites

Phenytoin

Blocks inactivated Na+ channels

T recovery is short
Little QRS prolongation
Extensive, saturable 1st hepatic met.
Highly bound to plasma proteins
CNS side effects

Flecainide

Blocks activated/open Na+ channels

Very long T recovery (> 10)
Block K+ channels and Ca++ channels
APD
Prolong PR, QRS and QT
Exacerbate CHF
Lethal arrythmias
Mediated by CYP 2D6

Propafenone
Blocks activated & inactivated Na+ channels
Also blocks K+ channels
Slow conduction in fast response
Prolongs PR & QRS
blocking effects
Mediated by CYP 2D6
Extensive 1st hepatic met.

Bretylium

Inhibits reuptake of NE
Prolongs APD
Reduces heterogenity of repolarization
Blocks K+ channels
No effect on Na+ channels
No direct effect on automaticity
NE releaser
SE: hypertension, arrythmias, hypotension
Excreted unchanged
Poor oral absorption
Less torsades des pointes

Amiodarone

Analog of thyroid hormone

Blocks inactivated Na+ channels
Also blocks K+ & Ca++ channels
Non competitive adrenergic blocking
Potent inhibitor of abnormal automaticity
Decreases conduction velocity
Prolongs PR, QRS, QT
Prolongs refractoriness

Amiodarone Side Effects

Hypotension
Tissue accumulation: pulmonary fibriosis,
carneal microdeposit,
hypo/hyperthyroidism, hepatic dysfunction
Less torsades de pointes

Amiodarone Pharmacokinetics
Highly lipophilics
30% bioavailable
Hepatic metabolism desethylamiodarone
Very slow elimination
Weeks to develop effects
Therapeutics conc.: 0,5 2,0 g/ml
Loading dose & maintenance dose

Sotalol

Non-selective blocker
Blocks K+ channels, prolong APD, prolong QT
Decreases automaticity
Slows AV nodal conduction
Prolongs AV refractoriness
No effect on conduction in fast response tissue
Causes EAD torsades de pointes

Ppopranolol, Esmolol, Metroprolol

Beta-adrenergic blocking agents

Decrease AV conduction, prolong AV refractoriness, decrese
automaticity
Exert Na+ channel-blocking
No K+ channel-blocking
Esmolol is cardioselective & short T

Magnesium Sulfate

Probably block Na+, K+, Ca++ channels

Prevents torsades de pointes
Treats digitalis intoxication
Treats arrythmias in AMI

Verapamil & Diltiazem

Block activated and inactivated Ca++ channels

Prolong refractoriness in SA & AV nodus
Slow conduction SA & AV nodus
Depress myocardial contractility

Adenosine
Natural nucleoside
Activate ACH-sensitive K+ channels:
shortening APD, cause hyperpolarization,
slow normal automaticity
Inhibit EF effect of sympathetic stimulation
Reduces Ca++ current
Increases AV nodus refractoriness

Adenosine Side Effects & Pharmakocinetics

Transient sympathetic stimulation

Transient asystolic
Dyspnea
T of seconds, uptake by carrier
Requires a rapid bolus dose
Potentiated by dipyridamole
Antagonized by theophylin & caffeine

Dofetilide

Pure K+ blocker
Effective in atrial fibrillation
Torsades de pointes, 1% - 3%
Monitor QT prolongation
Excreted unchanged

Ibutilide
K+ blocker
Activates an inward Na+
Effectiveness in atrial flutter > atrial
fibrillation
Torsades des pointes, 1% - 6%
Undergoes extensive 1st pass met.

Acute therapy of arrythmias

a. Paroxysmal supraventricular tachycardia
Adenosine
Verapamil
b. Atrial flutter & atrial fibrillation
Diltiazem, Esmolol, Ibutilide, Procainamid
c. Ventricular tachycardia & ventricular fibrillation
Amiodarone, Bretylium, Lidocain,
Procainamide,
Propranolol
d. Torsades de Pointes: magnesium sulfat

Long Term Therapy of Arrythmias

a. Paroxysmal supraventricular tachycardia:
Flecainide, Propranolol, Propafenon, Verapamil, atau
Digoxin
b. Atrial flutter or fibrillation
Amiodarone, Digoxin, Disopyramide, Diltiazem,
Flecainide, Procainamide, Propafenone, Quinidine,
Sotalol, atau Verapamil. Tambahkan warfarin untuk
cegah trombosis di atrium/emboli serebrovaskuler.
c. Ventricular tachycardia or fibrillation:
Amiodarone, Mexiletine, Moricizine, Procainamide,
Propranolol, Quinidine, Sotalol, atau Tocainide