prof. andrás varró department of pharmacology and...
TRANSCRIPT
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