3. Introduction
Sodium channels are integral membrane proteins that form
a Na+ permeable pore through the plasma membrane and allow ion
flux.
There are two very different types of sodium channels:
• voltage-gated sodium channels (NaV) and
• epithelial sodium channels (ENaC).
4. The epithelial sodium channel (short: ENaC,
also: amiloride-sensitive sodium channel) is
a membrane-bound ion channel that is
selectively permeable to
the ions of sodium (Na+) and that is
assembled as a heterotrimer composed of
three homologous subunits α or δ, β, and
γ, These subunits are encoded by four
genes: SCNN1A, SCNN1B, SCNN1G,
and SCNN1D. It is involved primarily in the
reabsorption of sodium ions at the collecting
ducts of the kidney's nephrons.
They are responsible for sodium reabsorption
by the epithelia lining the distal part of the
kidney tubule and fulfil similar functional
roles in some other tissues such as the
airways and the distal colon.
5. Voltage-gated sodium (Nav) channels are integral membrane proteins
that change conformation in response to depolarization of the
membrane potential, open a transmembrane pore, and
conduct sodium ions inward to initiate and propagate action
potentials.
All the voltage-gated Sodium channels open when the membrane
potential reaches around -55 mV and there's a large influx of Sodium,
causing a sharp rise in voltage.
6. Action potentials are caused by an exchange
of ions across the neuron membrane. A
stimulus first causes sodium channels to open.
Because there are many more sodium ions on
the outside, and the inside of the neuron is
negative relative to the outside, sodium ions
rush into the neuron. Sodium has a positive
charge, so the neuron becomes more positive
and becomes depolarized. It takes longer for
potassium channels to open. When they do
open, potassium rushes out of the cell,
reversing the depolarization. Also at about this
time, sodium channels start to close. This
causes the action potential to go back toward
-70 mV (a repolarization).
7. Sodium channel blockers
A class of drugs that act by inhibition of sodium influx through cell
membranes. Blockade of sodium channels slows the rate and amplitude of
initial rapid depolarization, reduces cell excitability, and reduces conduction
velocity. An anti-anginal drug used for the treatment of chronic angina.
Each sodium channel exists in three states:
1. Resting – Channel allows passage of sodium into the cell.
2. Open – Channel allows increased flux of sodium into the cell.
3. Refractory (inactivation) – Channel does not allow passage of sodium
into the cell.
8.
9. Mechanism of Action
During the action potential these channels exist in the active state and
then undergo fast inactivation. This inactivation prevents the channel
from opening and ends the action potential and occurs within
milliseconds. Many AEDs that target sodium channels prevent the
return of the sodium channels to the active state by stabilizing them in
the inactive state;
10.
11. Drugs that target the fast inactivation selectively reduce the firing of all
active cells. In addition to fast inactivation these voltage-gated sodium
channels may also undergo slow inactivation that occurs over seconds
to minutes.
Slow inactivation is believed to result from a structural rearrangement
of the sodium channel and does not result in a complete blockade of
voltage-gated sodium channels. Rather, these drugs only affect neurons
that are depolarized or active for long periods of time.
These are typically the neurons at the epileptic focus. There appears to be
synergy combining slow and fast sodium channel blocking agents
together.
12. Some antiepileptic drugs stabilize inactive configuration
of sodium (Na+ ) channel, preventing high-frequency
neuronal firing thus reducing the number of
action potentials elicited.
• Fast channel sodium channel blockers = phenytoin,
carbamazepine, oxcarbazepine, lamotrigine, felbamate,
topiramate, valproic acid, zonisamide,
rufinamide, eslicarbazepine
• Slow channel sodium channel blockers = lacosamide
14. THE USE OF SODIUM
CHANNEL BLOCKERS IN
MEDICINE
Antiarrhythmics, also known as
cardiac dysrhythmia medications,
are a group of pharmaceuticals
that are used to suppress abnormal
rhythms of the heart (cardiac
arrhythmias), such as atrial
fibrillation, atrial flutter,
ventricular tachycardia, and
ventricular fibrillation.
15. Class 1 Antiarrhythmics: they
block sodium channels resulting in
a slower action potential.
Subtypes
1A: Disopyramid, Quinidine,
Procainamide
These drugs increase the Action
potential duration.
SIDE EFFECTS:
Quinidine Increases QT interval
Procainamide can cause drug
induced lupus which we often
associate with the classic butterfly
rash or malar rash.
16. 1B: Mexiletine, tocainide, Lidocaine
1B drugs decrease action potential duration. They also weakly inhibit
phase 0.
They are the best choice for Post-Mi Arrhythmia
1C: Moricizine, Flecainide, Propafenone
1C drugs does not affect action potential duration.
They strongly inhibit phase 0. significantly prolong the refractory period in
the AV node.
These drugs are given to healthy patients.
Contraindication: Heart disease.
Note: any of these drugs can be used to break ventricular tachycardia