Mechanisms of action and use of blockers of sodium channels

Mechanisms of action and use of blockers of sodium channels

1. Molecular Physiology

2. BABAJIDE SALEM 1214 Mechanisms of action and use in medicine of blockers of Na channels.

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  ( Na V ) 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  ( Na v )  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. 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; 

9. 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.

10. 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

11. Enhanced sodium channel inactivation

12. 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 .  

13. 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.

14. 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

15. THANK YOU! Reference: The internet