Antiarrhythmic Drugs

The heart: electrical activity

Sinus node

Sinus node action potential

Atrioventricular node

His bundle
QRS complex
Purkinje fibers
Regulation of heart rate
The pacemaker current If

f for funny
Na+-K+ inward current activated by hyperpolarization
Typically present in primary and subsidiary cardiac
pacemaker cells
Directly modulated by intracellular cyclic nucleotides
Recently cloned (HCN1-4)
 Sinus node cell

AR AC Gi
M2
Gs

Ca channel
L-type
f-channel

Ca channel
K channel
T-type
If current and action potential
0 mV

-40 mV

-70 mV

If
If determines the diastolic depolarization slope,
the frequency of action potentials, and thus heart rate
 Sinus node automatism:
the If channel

open
closed closed

Sinus node 0 mV
membrane
potential
-40 mV

-70 mV
If

DiFrancesco and Camm, Drugs 64: 1757-1765, 2004

 f-channel
Closed state Open state

K+

Na+
 HCN 1 1 2 3 4 5 P 6 CNBD

HCN 2 1 2 3 4 5 P 6 CNBD

HCN 3 1 2 3 4 5 P 6 CNBD

HCN 4 1 2 3 4 5 P 6 CNBD

Na
Na
Na Na
Na

Na
Na Na
Na

Extracellulare

Intracellulare
K
K
K
K
K
K
K
K
K K
 HCN channels responsible for
If current generation

Inhibition of
If current Exclusive heart rate
HCN4 channels
reduction
Sinus node cells
HCN
isoforms

HCN1 channels
HCN2 channels BRAIN
HCN3 channels

HCN: hyperpolarization-activated, cyclic nucleotide-gated cation currents

DiFrancesco and Camm, Drugs 64: 1757-1765, 2004

 funny
-AR ACh-MR channel

Gs AC Gi

cAMP
 f-current modulation and the autonomic

0 control of sinus-node rhythm

-2
Acetylcholine
Basal

1s
0 1
0
2
b/
mi
n 7
8
b
/
mi
n 6
3
b
/
mi
n
Noradrenaline
m
V

-50 -
+

1s
threshold
ARRHYTHMOGENIC
MECHANISMS
ARRHYTHMOGENIC
MECHANISMS
 Vaughan Williams antiarrhythmic drug classification

Class I Sodium channel blockers

A Modest sodium channel effect
Prolong action potential duration

B Less potent effect on sodium channel

No change or shortening of action potential duration

C Potent sodium channel effect

Mild prolongation or no effect on action potential duration

Class II -Adrenergic blockers

Class III Prolong action potential duration

Class IV Calcium antagonists

Class I antiarrhythmic Drugs
 Regulation of cardiac rhythm
Noradrenaline
Noradrenaline
+ Beta-Blocker

Modified from Kaupp and Seifert, Annu Rev Phys, 2001

 Comparison among antiarrhythmics
based on molecular properties

High
Medium
Low
100 ms

Agonist/antagonist 1s
Agonist
10 s
Pharmacodynamic profile of Amiodarone

Drug Channels Receptors Pumps

Na C K If Na/K
a ATPase
Fa M S
st ed l IK,r IKs IK,Ac IK, ITO
o
w h Na

Amio(acute) I

Amio (chronic)

Dofetilide

d -Sotalolo

d,l - Sotalolo

Azimilide
Ivabradine and its effects on If