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 depolarization2. phase 1: initial rapid repolarization 3. phase 2: slow repolarization (plateau)4. phase 3: diastolic repolarization 5. phase 4: spontaneous slow depolarization

Membrane

outside

Inside

-85 mV

0 mV

100 ms

K+ C-

Ca 2+

Na +

Na+ Na+

K+ K1+Ca2+

Ca2+Na+

Channel currents Pump Exchanger

Diastolic Channel currents

Parameters of Cardiac Electrophysiology

1. Resting potential

2. Threshold potential

3. Conduction velocity

4. Refractoriness (Absolute vs. Relative)

5. Automaticity

6. Excitability

7. Action potential duration (APD)

8. 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

EAD

DADA

B

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)

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+20

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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

3.2. Functional Re-entry:– perpanjang masa refrakter– perpanjang APD– perbaiki konduksi dengan lidokain

Ca blockers

Na blockers

Klasifikasi Obat AntiaritmiaKelas Obat Cara kerja

I. Na+ channel blocking agents

A.

B.

C.

Quinidine, procainamide, disopyramid

Lidocain, mexiletine, phenytoin, tocainide

Encainide, flecainide, propafenone

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 - adrenergic 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 PGP-mediated digoxin transport

Procainamide

• Pharmacodynamics ~ quinidine; but is better tolerated when given IV, and lacks of vagolytic and alpha-adrenergic 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 µg; 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 desethyl-

amiodarone• Very slow elimination• Weeks to develop effects• Therapeutics conc.: 0,5 – 2,0 µg/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 ½

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 ½ 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