Antiarrhythmics
Tomáš Goněc 19.11.2012
Arrhythmia
 alteration in the normal sequence of heart
electrical impulse activation
 abnormality in the rate, site of origin or
conduction pathway of impulse
Arrhythmias
Physiological contraction
Arrhythmia therapy
 Invazive: intracardial cardiostimulators,
defibrilators
 Medication: antiarrhythmics
Antiarrhythmics: classification
Class I A.
N
CH3O
OH
H
NH
Quinidine
Quinidine synthesis
Class I A.
NH2
N
H
O
N
N
H
O
N
O
Procainamide Acekainid
Procainamide synthesis
Class I A.
N
N
OH
H
H
OH
CH3
CH3
OCOCH2Cl
lorajmin
N
N
OH
H
H
OH
CH3
CH3
CH2CH2CH3
CH2CHCH2NCH2CH3
CH2CH3
OH
ajmalin
+
prajmalium detajmium
Class I A.
N
NH2
O
N
N
NH2
O
N
OH
N
N
Disopyramide Pentisomide Pirmenol
Disopyramide synthesis
Pirmenole synthesis
Class I B.
NH
O
N
NH
O
N
NH
O
NH2
O
NH2
Lidocain Trimecain Tocainide
Mexilethine
Tocainide synthesis
Mexilethine synthesis
Class I B.
N
H
NH
O
O
Phenytoin
Class I C.
O O
OH
N
H
CH2CH2CH3
CH3
CH3
CH3
propaphenon
dipraphenon
Propaphenone synthesis
Class I C.
N
H
O
N
H
OF3C
OF3C
N
H
O
N
H
O
Flecainide Encainide
Flecainide synthesis
Encainide synthesis
Class I C.
S
NN
H
O
O
O N
O
Morizicine
Moricizine synthesis
Class II.
 β-adrenergic receptor antagonists, used as
antihypertensives; see lecture Antiadrenergics
 as antiarrhythmics used mainly: atenolol,
acebutolol, bisoprolol, metipranolol,
metoprolol, pindolol, oxprenolol, karteolol,
penbutolol, talindolol, esmolol (ultra-short
action), nadoxolol, propranolol
Class II.
O N
H
R1
OH OH
N
H
R1
R2
R2
SAR: (-propoxy-) spacer -O- can be replaced by isosteric
-COO-; -NHCOO- or =C=N- group
R1: isopropyl-, isobutyl- or arylalkylR2:
various substituents
o-substitution or another ring = non-selective
p-substitution = cardioselectivity
Aryloxypropanolamines Arylethanolamines
example of synthesis
Class III.
K+ channel inhibitors
OH
N
H
CH3
CH3
N
H
S
CH3
O
O
OH
N
H
S
CH3
O
O
N
N
H
N
H
S
CH3
O
O
N
H
S
CH3
O
O
sotalol
ibutilide
dofetilide
Sotalol synthesis
Dofetilide synthesis
Class III.
O
O
I
I
O
N
Br
N
+
S
OO
O
Amiodarone Bretylium tosylate
Amiodarone synthesis
Bretylium tosylate synthesis
Class IV.
 Ca2+ channel blockers
N
CN
O
O
O
O
Verapamil
Class IV.
S
N
CH2CH2N(CH3)2
O
H
H
OMe
OCOCH3
diltiazem
NR3 CH3
R4
R5
R2OOC COOR1
H
2
4
6
2
1
DIHYDROPYRIDINES
Class IV.
Drugs within classification
 digoxin – see cardiotonics
 adenosine
 both prolongs duration of action potential