Lecture 3 - Clinical Uses Of Local Anaesthetics Flashcards
Why do puffer fish not get affected by their own tetrodotoxin?
Differences in amino acid residues of puffer fish Na+ channels - tetrodotoxin cannot bind
Why cannot charged LA+ molecules diffuse through the membrane?
The phospholipid bilayer is impermeable to charged molecules
Why are LAs easily protonated?
Due to their pka / pH value - they are weak bases
Who first discovered cocaine?
Freud - from the coca leaf, used to treat stomach upsets, side effect was that people’s lips went numb
Who first discovered the anaesthetic properties of cocaine?
Carl Koehler
- drew on the fact that people’s lips went numb after using coca leaf, used it in eye operations
Where does topical administration of LAs occur?
The epidermis (outer) layer of the skin
Where does the Intrathecal injection occur?
Between vertebrae (missing the bone)
Penetrates through fatty tissue and the arachnoid & dura mater membranes into the cerebral spinal fluid (CSF)
Where is the best location for an Intrathecal injection?
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
Describe the anaesthesia provided by Intrathecal injections
More gross-scale, widespread anaesthesia
Where does the epidural injection occur?
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
Where does subcutaneous administration of LAs occur?
Close to the nerve trunk (not into the actual nerve fibre)
Used for anaesthetising a larger area
Where does intradermal administration of LAs occur, and what is an example of when it is used?
Into the dermal layer of the skin, around the nerve ending
E.g. used when stitching up wounds
What is topical administration of LAs used for?
Cornea - eye drops
Oropharynx - lozenges etc.
*not often as it can cause irritation, but also used for skin
What is the time scale for a short, intermediate and long duration of LA action?
Short = <30 mins
Intermediate = 2-3 hours
Long = 3+ hours
What is the target for LAs?
Blocking (open & closed) Na+ channels
What is the site of action of LAs?
Na+ channels
LAs have to penetrate INSIDE the cell to access the binding site
What is the pH of LAs?
7.4
What does the hydrophobic pathway (of LA action) block?
CLOSED Na+ channel - inactivation gate open, activation gate closed
How does the hydrophobic pathway of LA action work?
Blocks CLOSED Na+ channel
- LA molecule diffuses into the membrane and through the open holes in the structure of the ion channel (gaps between amino acids)
- LA gets protonated inside the ion channel (LA + H+ = LA+) and blocks it
What does the hydrophilic pathway of LA action do?
Blocks OPEN Na+ channels - inactivation & activation gates both open
How does the hydrophilic pathway of LA action work?
Blocks OPEN Na+ channel
- LA molecule diffuses across membrane
- LA + H+ = LA+, charged ion blocks the open channel by binding inside the channel
What is the ending for LAs?
-Caine
What is the difference between the breakdown of esters and amides?
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
What is tetrodotoxin and how does it work?
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
Where does spinal anaesthesia occur?
Injection into the subarachnoid space
What is peripheral nerve block?
Injection close to major sensory nerve trunks
What is peripheral nerve block used for?
To anaesthetise a limb
Or used for patients who shouldn’t / can’t go under general anaesthesia (e.g. the elderly)
Where does infiltration occur?
Injection AROUND nerve endings
*not into nerve endings as it would damage the nerve
What is an example of a use of infiltration?
Dentistry
(Time delay before feeling the effect of LA)
What does epidural anaesthesia do, and what is it used for?
Anaesthetises specific nerve roots in the lumbar region of the vertebral column
Used in childbirth
What are the 4 methods of administration of LAs?
- Topical
- Infiltration
- Peripheral nerve block
- Central nerve block
What are the 3 peripheral routes of LA administration ?
- Topical
- Intradermal
- Subcutaneous
What are the 3 components of the structure of LAs?
- Aromatic group
- Ester / amide
- Basic side chain - secondary / tertiary amine
What are the 2 types of central nerve block?
- Spinal anaesthesia
- Epidural anaesthesia
What are the 2 pathways of action of LAs?
- Hydrophobic pathway
- Hydrophilic pathway
What are the 2 central routes of LA administration?
- Epidural injection
- Spinal (Intrathecal) injection
What are 4 currently used LAs?
- Lignocaine (lidocaine)
- Prilocaine
- Amethocaine (Tetracaine) - only for oral use
- Bupivacaine
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?
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.
How can we prolong the duration of action of LAs?
Reduce local blood flow
Use adrenaline - causes VASOCONSTRICTION of blood vessels
