Lecture 3 - Clinical Uses Of Local Anaesthetics

Question 1

Why do puffer fish not get affected by their own tetrodotoxin?

Answer 1

Differences in amino acid residues of puffer fish Na+ channels - tetrodotoxin cannot bind

Question 2

Why cannot charged LA+ molecules diffuse through the membrane?

Answer 2

The phospholipid bilayer is impermeable to charged molecules

Question 3

Why are LAs easily protonated?

Answer 3

Due to their pka / pH value - they are weak bases

Question 4

Who first discovered cocaine?

Answer 4

Freud - from the coca leaf, used to treat stomach upsets, side effect was that people’s lips went numb

Question 5

Who first discovered the anaesthetic properties of cocaine?

Answer 5

Carl Koehler

• drew on the fact that people’s lips went numb after using coca leaf, used it in eye operations

Question 6

Where does topical administration of LAs occur?

Answer 6

The epidermis (outer) layer of the skin

Question 7

Where does the Intrathecal injection occur?

Answer 7

Between vertebrae (missing the bone)
Penetrates through fatty tissue and the arachnoid & dura mater membranes into the cerebral spinal fluid (CSF)

Question 8

Where is the best location for an Intrathecal injection?

Answer 8

In L3, L4 and L5, as the spinal cord thins in the lumbar region so there is less risk of hitting the spinal cord, which could cause paralysis

Question 9

Describe the anaesthesia provided by Intrathecal injections

Answer 9

More gross-scale, widespread anaesthesia

Question 10

Where does the epidural injection occur?

Answer 10

L3
Between the vertebrae
Doesn’t penetrate the arachnoid & dura mater membranes, stops before it reaches the fatty tissue, in order to only anaesthetise the spinal nerves flowing out of the spinal cord at this particular level

Question 11

Where does subcutaneous administration of LAs occur?

Answer 11

Close to the nerve trunk (not into the actual nerve fibre)
Used for anaesthetising a larger area

Question 12

Where does intradermal administration of LAs occur, and what is an example of when it is used?

Answer 12

Into the dermal layer of the skin, around the nerve ending
E.g. used when stitching up wounds

Question 13

What is topical administration of LAs used for?

Answer 13

Cornea - eye drops
Oropharynx - lozenges etc.
*not often as it can cause irritation, but also used for skin

Question 14

What is the time scale for a short, intermediate and long duration of LA action?

Answer 14

Short = <30 mins
Intermediate = 2-3 hours
Long = 3+ hours

Question 15

What is the target for LAs?

Answer 15

Blocking (open & closed) Na+ channels

Question 16

What is the site of action of LAs?

Answer 16

Na+ channels
LAs have to penetrate INSIDE the cell to access the binding site

Question 17

What is the pH of LAs?

Answer 17

7.4

Question 18

What does the hydrophobic pathway (of LA action) block?

Answer 18

CLOSED Na+ channel - inactivation gate open, activation gate closed

Question 19

How does the hydrophobic pathway of LA action work?

Answer 19

Blocks CLOSED Na+ channel

1. LA molecule diffuses into the membrane and through the open holes in the structure of the ion channel (gaps between amino acids)
2. LA gets protonated inside the ion channel (LA + H+ = LA+) and blocks it

Question 20

What does the hydrophilic pathway of LA action do?

Answer 20

Blocks OPEN Na+ channels - inactivation & activation gates both open

Question 21

How does the hydrophilic pathway of LA action work?

Answer 21

Blocks OPEN Na+ channel

1. LA molecule diffuses across membrane
2. LA + H+ = LA+, charged ion blocks the open channel by binding inside the channel

Question 22

What is the ending for LAs?

Answer 22

-Caine

Question 23

What is the difference between the breakdown of esters and amides?

Answer 23

Esters are broken down faster (by esterases)
Amides last longer as they have to go through the liver to be metabolised - they are not as prone to hydrolysis

Question 24

What is tetrodotoxin and how does it work?

Answer 24

Comes from puffer fish

Blocks Na+ channels from the outside surface of the cell (therefore doesn’t need to penetrate inside the cell)
Stops the generation of APs - therefore stops muscle contraction - causing paralysis so prey cannot move away

Very potent, works at nM concentrations

Question 25

Where does spinal anaesthesia occur?

Answer 25

Injection into the subarachnoid space

Question 26

What is peripheral nerve block?

Answer 26

Injection close to major sensory nerve trunks

Question 27

What is peripheral nerve block used for?

Answer 27

To anaesthetise a limb
Or used for patients who shouldn’t / can’t go under general anaesthesia (e.g. the elderly)

Question 28

Where does infiltration occur?

Answer 28

Injection AROUND nerve endings
*not into nerve endings as it would damage the nerve

Question 29

What is an example of a use of infiltration?

Answer 29

Dentistry
(Time delay before feeling the effect of LA)

Question 30

What does epidural anaesthesia do, and what is it used for?

Answer 30

Anaesthetises specific nerve roots in the lumbar region of the vertebral column

Used in childbirth

Question 31

What are the 4 methods of administration of LAs?

Answer 31

1. Topical
2. Infiltration
3. Peripheral nerve block
4. Central nerve block

Question 32

What are the 3 peripheral routes of LA administration ?

Answer 32

1. Topical
2. Intradermal
3. Subcutaneous

Question 33

What are the 3 components of the structure of LAs?

Answer 33

1. Aromatic group
2. Ester / amide
3. Basic side chain - secondary / tertiary amine

Question 34

What are the 2 types of central nerve block?

Answer 34

1. Spinal anaesthesia
2. Epidural anaesthesia

Question 35

What are the 2 pathways of action of LAs?

Answer 35

1. Hydrophobic pathway
2. Hydrophilic pathway

Question 36

What are the 2 central routes of LA administration?

Answer 36

1. Epidural injection
2. Spinal (Intrathecal) injection

Question 37

What are 4 currently used LAs?

Answer 37

1. Lignocaine (lidocaine)
2. Prilocaine
3. Amethocaine (Tetracaine) - only for oral use
4. Bupivacaine

Question 38

Due to LA’s pka value of ~ 8-9, they are mostly charged at pH 7.4. How do they penetrate the cell membrane to arrive at their internal site of action?

Answer 38

Due to Le Chatelier’s principle… although most LA will be in its charged form (LA+), some (~10%) still exists in its uncharged form (LA) which can diffuse through the membrane to the inside surface of Na+ channels.

Inside the cell, the LA molecule becomes protonated (LA + H+ = LA+). LA+ blocks the Na+ channel.

Question 39

How can we prolong the duration of action of LAs?

Answer 39

Reduce local blood flow
Use adrenaline - causes VASOCONSTRICTION of blood vessels