Local anaesthesia Flashcards
Outline neuronal actin potential
-70mV:
Rapid depolaisation (ie due to pain):
Resting Na+ channels open (VSSC)
Na+ enters cells
Na+ channels close after a couple of ms (inactivation)
K+ channels open, K+ leaves cell
Na+ channels restored to resting state but K+ channels still open therefore cell refractory (greater stimulus would still be required, because some of the depolarisation would be loss due to the open K+ channels)
Na+ and K+ channels restored to resting state therefore cell will respond normally to further depolarizing stimulus
Define local anaesthetics
LAs = Drugs which reversibly block neuronal conduction when applied locally
Differentiate AP and motor end plate potentials
With neuronal, it’s all or nothing
With the motor end plate you can get graded potentials at the nAChR
Improve
Differentiate 2 different LAs
CONSTANT:
1. Aromtic region (benzene)
- Basic amine side-chains
DIFFERENCE:
Linked by bridging ester or amide group
Give example of LAs with ester and an amide bridging group
ESTER: Cocaine
(remember that ester smokes cocaine)
AMIDE: Lidocaine
(lignocaine)
Which LA doesn’t have an amine sidechain
What is the effect on function
Benzocaine
It just has alkly side chain
Weak LA properties, and is lipid soluble (used as a surface anaesthetic). It is useful in throat lozenges.
Why is the 2 structures of LA important
Because it affects their PD and their DOA
Why are LAs denoted by B
They are all weak bases
What is connective tisse sheath
Contains lots of axons
Which form of the LA can gain access to the connective tissue sheath and get into the neurons
Unionised form (there is equilibrium betwen cation and unionised form in the blood, and only the UNionised form is lipid soluble enough to get through the connective tissue sheath AND across the axon membrane of the nociceptive neurone )
What must LAs do to get into the sensory neuron
They must gain access to the inside of the sensory neuron. To do this, they must be in their unionised form.
They cannot work from the outside, they have to get into the axon to work
Outline the hydrophilic pathway
The unionised form of the LA gains access to the neuron by diffusing through the plasma membrane fo the axon.
Then inside, the equilibrium between unionised and ionised form of LA re-establises. And now it is the IONISED form of the LA inside the neuron that can have the action, but stereochemically blocking the VGSC and preventing depolarisation of the sensory neurone
The cationic form of LA blocks the VGSC
Why is there use dependency of LAs
They work better when the sensory neuron is being used more
(the more rapidly they are firing, the more effect they will have)…
this is because, the more active the sensory neuron, the longer the Na+ channels are open, and the higher the chance that the ionised LA (inside the neuron) gains access to and blocks the Na+ channels, from the inside.
This means that the LAs have a degree of selectivity, because of the USE DEPENDENCY, and the fact that the neurons that are transmitting the pain will be firing more, means that these will be more affected by the LA.
Not that the selectivity is not total though, as motor fibres can be blocked by LA and this can cause muscle weakness and relaxation
Compare the hydrophilic and hydrophobic pathway for VGSS
Hydrophilic is the MAJOR pathway.
However, for lipid-soluble LAs (i.e. the ones without the amine side chain, benzocaine), the hydrophobic one is important.
As the unionised form crosses the axonal membrane, some can drop into the ion channel and convert into the cation ionised form to block the ion channel.
This means that, by the hydrophobic route, the LAs can drop into a closed channel AS WELL AS an open channel.
How do LAs affect the resting potential
They don’t
They only affect the generation of the action potential in the nociceptive neurons
How do LAs affect the channel gating
The sodium channels can exist in resting, open and inactivated state.
LAs can bind to VGSC, and some bind preferably to the inactivated state, and hold the channel in the inactivated state. This prolongs the absolute refractory period
Contributes to mechanism of action.
What are LA selective to
Small diameter fibres
Non-myelinated fibres
This good because:
A-Delta and C fibres are both small diameter
C fibres also are unmyelinated
These are the pain fibres which are more selective for the LA
(and neurons which are firing more often because of the use dependent block)
What is the pKa of LA
LAs are weak bases (pKa 8-9)
So they will be largely ionised in physiological pH and not loads will gain access to the neurons
What is the impact of infected tissue for LAs
Infected tissue
There is acidic metabolited produced, so more of the LA will be in its ionised form and less will gain acces
Where is the surface anaesthesia used
Mucosal surface (mouth, bronchial tree)
