prof. andrás varró department of pharmacology and...

Antiarrhythmic drugs

Prof. András Varró

Department of Pharmacology and Pharmacotherapy

University of Szeged

1. Basic cardiac electrophysiologyaction potential – ion channels – impulse conduction - effective refractory period

2. Mechanism of arrhythmia

3. Proarrhythmic mechanism of antiarrhythmic drugs

4. Frequency dependent effect of antiarrhythmic drugs

5. Classification of antiarrhythmic drugs

6. Induvidual properties of the antiarrhythmic drugs used in the therapy

7. Brief summary of the therapeutic application of the antiarrhythmic drugs

ANTIARRHYTHMIC DRUGS

Na-channel / Na-current from extracellullar space

Ca- channel / Ca- current to intracellular space

DEPOLARIZATION

K- channel / K- current from intracellular space

to extracellullar space

REPOLARIZATION

Action potential

RE

PO

LA

RIZ

ATIO

N

DE

PO

LA

RI Z

AT

ION

40

0

-40

-80 ERP

ERP

Na-channel

Ca-channel

stimulus

mV

SA/AV node

ERP = Effective Refractory PeriodThe shortest time needed for reactivation of the heart muscle

Depends on ?

1. Repolarization of the myocytes (K-channels)2. The actual size of the depolarizing currents (Na- and Ca - channels)

REFRACTORINESS

Ventricle/atria

1. The speed of depolarization (Vmax)- depends on fast sodium current

2. Action potential amplitude- depends on fast sodium current

3. Threshold of activation- depends on fast sodium current

4. The cells internal resistance / the resistancebetween the cells (ri) - depends on the gap junctions

Velocity at which each domino falls

Height of the domino

The energy needed to push the domino

What is the medium resistance(water, air, vacuum)

IMPULSE CONDUCTION

Direction of the impulse propagation

Sodium channels (atria, ventricle) or calcium channels (sinus and AV- node)

Disorder of the automaticity

Abnormal automaticity I.EAD = Early AfterDepolarization

OK: Extrem repolarization lengtheninga, hypokalaemiab, extrem bradycardiac, genetic malfunctiond, K-channel blockers

(ex. terfenadine, erythromycin, sotalol)

Treatment

a, serum potassium (K+) elevationb, magnesium (Mg2+)c, drugs that facilitate repolarization

(ex. mexiletin, verapamil)

early afterdepolarization

1 sec

0 mV

50

mV

Disorder of the automaticity

Treatment

decrease of the intracellular calcium level

a) ββββ-receptor blockers (propanolol)

b) Ca-channel antagonists (verapamil)c) Na-channel blockers (phenytoine,

lidocaine)

Abnormal automaticity II.DAD = Delayed AfterDepolarization

OK: CALCIUM OVERLOADa, ischaemiab, digitalis intoxication

delayed afterdepolarization

0.5 sec

0 mV

50

mV

The re-entry arrhythmias

Antiarrhythmic mechanisms

Proarrhythmic mechanisms

A B

C D

E F

1 2

1 2

1 2

1 2

1 2

1 2

m

h

++Na Na

outside

Resting state

inside -

mh

++Na Na

outside

Active state

inside -

m

+

+

Na

Na

outside

Inactive state

inside +

h

MODULATED RECEPTOR HYPOTHESIS

The binding of a drug depends on the function state od Na+ or Ca2+ channels

Na

+-C

HA

NN

EL

AC

TIO

N P

OT

EN

TIA

L

0 mV

-85 mV

bin

din

g

un

bin

din

g

bin

din

g

un

bin

din

g

bin

din

g

un

bin

din

g

AC

TIV

E

ch

an

nel

INA

CT

IVE

ch

an

ne

l

RE

ST

ING

ch

ann

el

Channel stateresting

diastole

inactive

systole

active

I/B

I/AI/C

lidocaine

quinidine

flecainidedru

gfr

ee

ch

an

nels

(%)

mem

bra

ne

po

ten

tial

resting

diastole

inactive

systole

active

resting

diastole

active

THE Na+ and Ca2+ CHANNEL BLOCKES INHIBIT THE CHANNELSIN A FREQUENCY DEPENDENT MANNER (”USE DEPENDENCY”)

The fastest is the heart rate the strongest is the channel inhibition

fast

unbindin

g

slow unbinding

So

diu

mch

an

nel

inh

ibit

ion

(%)

0

100

0

-80Acti

on

po

ten

tial(m

V)

A A A AI I I IRRR

1 2 3 4

Drug ττττ (s)

-lidokaine-mexiletine-phenytoine-amiodarone

0,130,180,140,28

fast unbinding(I/B)

slow unbinding(I/A és I/C)

-quinidine-prokainamide-dysopyramide-flekainide-enkaidine-propafenone-prajmaline

5,64,5

37,415,520,35,4

75,7

RESTING → (R)INA

CT

IVE

→(I

)

AC

TIV

E →

(A)

K+-channel blockers

REVERSE FREQUENCY DEPENDENCE

The slower is the frequency, the greatest is the lengthening effectof the drug on the repolarization

Disadvantageous: 1. tachycardia little - ERP lengthening effect

2. Bradycardia - extreme lengthening ���� proarrhythmic, EAD

ERP

ERP

ERP

sinus rhythm (SR) sinus rhythm

1

47

ERP

ERP

ERP

65

extrasystole extrasystole

32

vulnerable period

*

* extrasystole (ES)

ES

SR

Ventricular muscle

50 mV

Control

*

30 µM SOTALOL

*

Purkinje fibre

Purkinje fibre

Ventricular muscle

ME 2

ME 1

C

The demonstration of the arrhythmogenic effect of the earlyafterdepolarization (EAD) in canine heart preparations

*stimulation

QUINIDINE - Wenkebach, 1914 Frey, 1918 DIRECT cardiac cellular electrophysiological effect:

INa, IK and ICa, inhibition

ECG effect: PQ, QRS and QT lengthening

INDIRECT cardiac effect: anti-cholinergic → facilitationof A-V impulse conduction → paradox tachycardia

SIDE EFFECTS: - hypotension →→→→ due to alfa receptor block- myasthenia gravis → anticholinerg- negative inotropic → INa and/or ICa inhibition- PROARRHYTHMIA →IK (torsade pointes) and

INa inhibition impulse conduction related- tinnitus- diarrhea- trombocytopaenia- allergic reatition

CLASS IA effect

INDICATION: atrial fibrillation or supraventricular tachycardiasp.o.

CONTRAINDICATION: - heart failure hypotension- sick sinus synd. - SA – blokk- long QT syndrome, wide QRS- glaucoma

DRUG INTERACTION: QUINIDINE + DIGITALIS

Procaine → local anaestheticum ester-amid less CNS effect

MECHANISM: Like quinidine – no anti-cholinergic effect

INDICATION: Less popular

ventricular arrhythmias

iv / oral application

activ metabilite N-acetylprocainamide (NAPA) pure class III effect

SIDE EFFECT: Proarrhythmia

special: Lupus erythamasus syndrome (allergic skin reaction, arthralgia, arthrosis)

PROCAINAMIDE - Mautz, 1936

Mechanism like Quinidine but:MORE anticholinergic and negative inotropic effect

SIDE EFFECT: - proarrhythmia- urine retention- negative inotropy

INDICATION: atrial fibrillation, supraventricular arrhythmiap.o. i.v.

CONTRAINDICATIONS: myasthenia gravisglaucomaheart failurehypotension

DISOPYRAMIDE

Mechanism like Quinidine but: not-anticholinergic

INDICATION: Brugada syndrome → diagnosissupraventricular arrhythmias

SIDE EFFECTS: proarrhythmiahaedachecholestasisvisual disturbancesopstipation

PRAJMALINE

MECHANISM: inhibition of INa with fast unbinding kineticsbinding prefers inactivated Na+ channels → depolarized

ischaemic tissuepostrepolarization refractoriness ERP / APD ↑no known effect on other ion channels

INDICATION: only i.v. in ventricular arrhytmias (coronary care unit)less popular, short half life t1/2 = 1.5 - 2 h

SIDE EFECT: CNS → tremor, cramps, coma

LIDOCAINE

CLASS IB effect

MECHANISM: like lidocaine but orally active”oral lidocaine”

SIDE EFFECT: toxic and therapeutic serum conc is closeCNS tremor, cramps, comabradycardia, negative inotropicdizziness, confusion

INDICATION: ventricular arrhythmiadiabetic neuropathy ?

CONTRAINDICATION: impaired A-V conductionpregnancy, lactation

PHENYTOINE → in digitalis arrhythmiaTOCAINIDE → bone marrow toxicity

MEXILETINE

FLECAINIDEENCAINIDE

CLASS IC effect

MECHANISM: stong Na+ channel inhibition with slow unbinding kinetics fromthe Na+ channel

widen QRS at normal heart rate

SIDE EFFECT: proarrhythmia (conduction type) → reentrynegative inotropy

INDICATION: atrial fibrillation, supraventricular arrhythmias

CAST (Cardisc Arrhythmia Supression Trial)

PROPAFENONE Like flecainide but also weakbeta receptor inhibition

CASH (Cardiac Arrhythmia Study Hamburg)

lipophylic drugs - metoprolol (selective beta 1 inh)- propanolol (Na+ channel inh)- oxprenolol (ISA)- pindolol (ISA + Na+ channel inh)- esmolol (acute i.v. t ½ = 9h)

Nonlipophylic drugs: - atenolol- sotalol (racem) (K+- channel inhibition

repolarization lengthening)

INDICATION: supraventricular and ventricular tachycardias (adrenerg backround)atrial fibrillation, flatterdigitalis intoxication

CONTRAINDICATION: - bradycardia- AV block- asthma bronchiale

CLASS II effect

BETA ADRENOCEPTOR INHIBITION

CLASS III effect

AMIODARONE → Chronic oral

MECHANISM: repolarization lengthening, K+ channel inhibition / dowregulationQT lengtheningNa+ channel inhibition with fast unbinding kinetics(lidocaine like effect)Ca2+ channel inhibitionBeta receptor inhibition

Acute effect → Na+ channel – beta rec – Ca+ channel inhibition

SIDE EFFECT: Serious and frequent ! Extracardiacthyroid dysfunctionphotodermatitishepatocellular necrosisPULMONARY FIBROSIS ~ 5% X-ray controlcornea deposits”gray man” syndromeCNS – GI disturbanceslow proarrhythmic risk

AMIODARONE → Chronic oral

INDICATION: ventricular arrhythmias – heart failure arrhythmiasatrial fibrillation

APPLICATION:loading dose 400-600 mgmaintainig dose 200 mg

PHARMACOKINETIC: long half life 60-80 days!

MECHANISM: K+ channel inhibition, repolarization lengtheningbeta receptor inhibition

dSOTALOL SWORD (Survival With Oral D-sotalol)INDICATION: atrial fibrillation

ventricular tachycardiast 1/2 = 15 óra

SOTALOL (racem)

BRETYLIUM

MECHANISM: K+ channel inhibition, repolarization lengtheningadrenerg neuron inhibitionchemical defibrillation

INDICATION: only iv use

DOFETILIDE: pure K+ channel block (DIAMOND study)

IBUTILIDE: indication: atrial fibrillation

CLASS IV effect

VERAPAMIL

MECHANISM: Ca2+ channel inhibitionA-V conduction slowing or blockhypotension, negative inotrop, antianginal

INDICATION: paroxismal supraventricular tachycardiaflatter and atrial fibrillation → save ventricle

CONTRAINDICATION: heart failurebradycardiaimpaired A-V conductionnew AMI

INTERACTION: do not combine with quinidine, beta blockers, dysopyramide

NIFEDIPINE

DILTIAZEM

ADENOSINE

OTHER MECHANISMS

MECHANISM: indirect Ca2+ channel inhibition → purinergreceptor → Gi system cAMP↓ = Class IV effectopen adenosine dependent K+ channel → hyperpolarization →→ A-V conduction slowing, SA inhibition

IMPORTANT: t 1/2 = 10 seconds !!! 6-12 mg iv

INDICATION: supraventricular A-V reentry tachycardiasno side effect

DIGITALISMECHANISM: indirect vagus effect → M receptor → Gi

M receptor dependent K+ channels open → hyperpolarization,shortened atrial ERP flatter converted to atrial fibrillationdecrease A-V conduction, increase A-V refractoriness

INDICATION: supraventricular tachycardia

MECHANISM: Ca2+ antagonismNa+ / K+ pump inhibition

INDICATION: Torsade de pointes tachycardia

MECHANISM: If channel inhibition

INDICATION: antianginalheart failuresupraventricular sinus tachyarrhythmia

MgSO4

IVABRADINE