use dependent & voltage dependent

“In the name of Allah the most beneficent and merciful”.

“ASSALAM-O-ALAIKUM”

Presented to: Sir Amir Rashid

Presented by: Syed Usman Farooq Gilani

Bpd01093202

Semester: 5th C

DEPARTMENT OF PHARMACY

The University Of Lahore

USE DEPENDENT & VOLTAGE DEPENDENT

Sodium Channels

GENERATION OF ACTION POTENTIAL

LOCAL ANESTHETICS

MECHANISM OF LOCAL ANESTHETICS

USE DEPENDENT

VOLTAGE DEPENDENT

Sodium Channels

Excitable tissues possess special voltage-gated sodium channels. These voltage-gated sodium channels can exist in three functional states.

1) Closed channel(resting)

2) Open channel (activated)

3) Blocked channel (inactivated)

Sodium Channels

Sodium channels consist of two gates;

h-gates

m-gates

Sodium Channels

At the RMP, most h-gates are open and the m-gates are closed (closed channel).

Sodium Channels

Depolarization causes the m-gates to open (open channels).

Sodium Channels

but intense depolarization of the action potential then causes the h-gates to close the channel (inactivation).

GENERATION OF ACTION POTENTIAL

Phase (0) Rapid depolarization; generation of action potential

Phase (1) Partial re-polarization; slight re-polarization

Phase (2) The plateau; potassium efflux, balanced by calcium influx

Phase (3) Re-polarization; if potassium efflux is not balanced by sodium influx

Phase (4) Resting membrane potential (RMP)

LOCAL ANESTHETICS

Local anesthetics bind reversibly to a specific receptor site within the pore of the sodium channels in nerves and block ion (i.e. sodium) movement through this pore.

When applied locally, local anesthetics can act on any part of the nervous system and on every type of nerve fiber, reversibly blocking the action potentials responsible for nerve conduction.

MECHANISM OF LOCAL ANESTHETICS Local anesthetics penetrate into the interior of the axon

in the form of the lipid-soluble free base.

MECHANISM OF LOCAL ANESTHETICS There, protonated molecules are formed, which then

enter and plug the sodium channels after binding to a ‘receptor’.

MECHANISM OF LOCAL ANESTHETICS Local anesthetics blocks the sodium channel, largely by

preventing the opening of h-gates (i.e. by increasing the inactivation).

MECHANISM OF LOCAL ANESTHETICS Eventually, so many channels are inactivated that their

number falls below the minimum necessary for depolarization to reach threshold and, because action potential cannot be generated, nerve block occurs.

MECHANISM OF LOCAL ANESTHETICS Local anesthetics block sodium channels by physically

plugging the trans-membrane pore. Their activity is strongly dependent upon pH(i.e. highest at basic pH and lowest at acidic pH).

MECHANISM OF LOCAL ANESTHETICS At basic pH most of the molecules are unionized, so can

easily penetrate in membrane to reach the inner and of sodium channel where the local anesthetic binding site resides.

USE DEPENDENT

Local anesthetics are ‘use dependent’ (i.e. the degree of block is proportional to the rate of nerve stimulation).

This indicates that more drug molecules (in their protonated form) enter the sodium channels when they are open and cause more inactivation.

USE DEPENDENT

Use dependent means more of the channels are open; the greater will be the block becomes.

Because molecules can easily cross the channel, in open state.

Local anesthetics have affinity for blocking channels in open and block state.

VOLTAGE DEPENDENT

The site of anesthetic action is at the inner surface of the cell membrane.

At tissue pH the drug is in the form of lipophilic, uncharged, secondary or tertiary amines and thus diffuses across cell membrane where it is ionized to a charged cation (+ve).

VOLTAGE DEPENDENT

The cation form is the active form that blocks the action potential.

Due to the ionic nature of anesthetic drugs, it poorly penetrates out of the cell and hence, prolongs the duration of action potential.