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

2.  Presented to:
 Sir Amir Rashid
 Presented by:
 Syed Usman Farooq Gilani
 Bpd01093202
 Semester:
 5th C
DEPARTMENT OF PHARMACY
The University Of Lahore

3. USE DEPENDENT &
VOLTAGE DEPENDENT
 Sodium Channels
GENERATION OF ACTION POTENTIAL
LOCAL ANESTHETICS
MECHANISM OF LOCAL ANESTHETICS
USE DEPENDENT
VOLTAGE DEPENDENT

4. 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)

5. Sodium Channels
 Sodium channels consist of two gates;
 h-gates
 m-gates

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

7. Sodium Channels
 Depolarization causes the m-gates to open (open
channels).

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

9. 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)

10. 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.

11. MECHANISM OF LOCAL
ANESTHETICS
 Local anesthetics penetrate into the interior of the
axon in the form of the lipid-soluble free base.

12. MECHANISM OF LOCAL
ANESTHETICS
 There, protonated molecules are formed, which then
enter and plug the sodium channels after binding to a
‘receptor’.

13. MECHANISM OF LOCAL
ANESTHETICS
 Local anesthetics blocks the sodium channel, largely by
preventing the opening of h-gates (i.e. by increasing
the inactivation).

14. 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.

15. 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).

16. 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.

17. 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.

18. 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.

19. 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).

20. 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.