25. Antiarrhythmic Drugs Flashcards
Describe the classification of antiarrhythmic drugs.
Fig. 25.1 Cardiac myocyte action potential
Diagram Fig. 25.1 Cardiac myocyte action potential Phase 0 Fast depolarisation −Na+ in
Phase 1
Early repolarisation
− K+ out, Cl− in
Phase 2
Voltage gated L-type Ca2+ channels open
Phase 3
Rapid repolarisation
− K+ out
Phase 4
Resting membrane potential
Fig. 25.1 Cardiac myocyte action potential
Phase 4
Resting membrane potential
Phase 0
Fast depolarisation
−Na+ in
Phase 1
Early repolarisation
− K+ out, Cl− in
Phase 2
Voltage gated L-type Ca2+ channels open
Phase 3
Rapid repolarisation
− K+ out
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Table 25.1 Vaughn-Williams classification of antiarrhythmics
IA
Class Mechanism Drug
Ia
Blocks fast Na+ channels in cardiac myocytes.
Quinidine, procainamide, disopyramide
↑ Refractory period
IB
Ib
Blocks fast Na+ channels in cardiac myocytes.
Lignocaine, phenytoin, mexiletine
↓ Refractory period
Ic
Ic
Blocks fast Na+ channels in cardiac myocytes.
Flecainide, propafenone
No effect on refractory period
II
II β-adrenoreceptor blockade
Atenolol, propranolol, esmolol
III
III
K+ channel blockade
Amiodarone, sotalol,
bretylium
IV
IV
Ca2+ channel blockade
Verapamil, diltiazem
How do class I drugs exert their effects?
Refer to the cardiac myocyte AP graph (Figure 25.1):
The sodium channel blockers
exert their effects by blocking fast Na+ channels,
therefore reducing the
influx of Na+ into cardiac myocytes
and
increasing the time it takes
the cell to reach threshold potential.
By doing this they decrease the slope
of Phase 0 of the AP
and
decrease cardiac conduction velocity.
For this reason,
they are effective at
abolishing reentrant
arrhythmias.
These fast Na+ channels are
not found in nodal tissue,
where
Phase 0 depolarisation results
from the influx of Ca2+ ions.
Class I drugs are
further sub-classified according to their effects on the refractory period (RP) of the myocyte.
Class I drugs may prolong or decrease
the time taken for repolarisation,
and therefore the RP,
by their action on the
K+ channels responsible
for Phase 3 of the AP
How do class II drugs exert their effects?
Refer to the sinoatrial node AP graph (Figure 25.2):
β-blockers are antagonists
at β adrenoceptors
and so
decrease sympathetic
tone on the heart,
which reduces the slope of Phase 4 of the AP.
β-adrenoceptors are found in nodal, conducting and myocardial tissues and are coupled,
via G proteins, to Ca2+ channels
that open when the
receptor is activated.
In the cardiac tissues there are relatively more
β1 than β2 adrenoceptors, and the
newer generations of β-blockers are much more
cardioselective,
(β1 > β2).
Blocking β adrenoceptors causes a decrease in Ca2+ flux into cells and so reduces the slope of Phase 0 of the AP.
A decrease in
Ca2+ influx causes:
> Decrease in heart rate (chronotropy)
> Decrease in contractility (inotropy)
as less Ca2+ is available
to the sarcomeres
in the myocytes
β-blockers also inhibit the action of myosin light chain kinase
and so they
decrease the heart’s relaxation rate (lusitropy).
How do class III drugs exert their effects?
Refer to the sinoatrial node AP graph (Figure 25.2):
Class III antiarrhythmics
block K+ channels,
decreasing K+ flux out of
the cells,
which delays repolarisation both in
nodal tissue
and
in the cardiac myocytes.
This decreases the slope of Phase 3 of the AP,
which leads to an increase
in the cells’ refractory period and hence reduces its
arrhythmogenicity.
How do class IV drugs exert their effects?
Refer to the sinoatrial nodal AP graph (Figure 25.2):
Class IV antiarrhythmics
block L-type Ca2+ channels, while leaving
T-, N- and P-type channels unaffected.
L-type channels are widespread throughout
the cardiovascular system.
T-type are
structurally similar to L and are present in the cardiac cells that have
T-tubule systems, e.g. SA node and some vascular tissues.
N-type are found in nerve cells and P in the Purkinje
fibres.
L-type Ca2+ channels are responsible for the
plateau phase of the
cardiac action potential.
Class IV drugs decrease
the slope of Phase 0 of the
nodal AP,
decreasing heart rate.
These channels are
also found in cardiac
myocytes and blood vessels and
decreasing Ca2+ flux reduces
cardiac conduction velocity and contractility
What are the main differences
between verapamil and
nifedipine?
Verapamil is a racemic mixture
whose L isomer
has a high affinity for the
L-type Ca2+
channels at the
SA and AV nodes.
This results in slowing of conduction through the pacemaker cells, a decrease in heart rate and an increase in the RP.
Verapamil’s effect on cardiac contractility and vascular tone is less marked
though it does cause some coronary artery vasodilation.
Nifedipine has little effect on the SA or AV nodes
but causes a marked
decrease in arterial tone.
For this reason it is used for arterial spasm in coronary angiography, Raynaud’s phenomenon, hypertension and angina.
svts
vts
SVTs VTs
Ia Ia
Ic Ib
III (but not bretylium) Ic
IV III
QUINIDINE
type
moa
uses
QUINIDINE
Class 1a antiarrhythmic
MOA
• Class 1a antiarrhythmic
• Blocks fast Na+ channels
- Prolongs phase 0 of action potential
- Increases refractory period
- ↓ Vagal tone
USES • Termination of SVTs including AF/Flutter • Termination of ventricular arrhythmias
