S3: Local Anaesthetics Flashcards
What is the function of Local Anaesthetics (LAs)?
LAs produce a loss of pain sensation without affecting consciousness - this is different to general anaesthetics where you lose consciousness. They act locally so you are avoiding the systemic effects of the drug. They work by preventing perception of pain by the CNS and do this by blocking vgNa+ channels thus stopping conduction of APs.
History of LAs
- The first LA used was cocaine by south americans to increase stamina (via sympathetic action) but then it was found to produce a numb sensation in mouth and tongue.
- Cocaine was then isolate and used to produce LA when given subcutaneously for dentistry and surgery.
- In early 1900s, the synthetic substitute procaine was developed.
- Today procaine has been replaced with lignocaine.
Compare chemical structure of procaine and lignocaine
The point of interest is the bond linking the basic group to the aromatic group.
- In procaine there is the ester bond which is susceptible to hydrolysis.
- In lignocaine there is the amide bond.
In our bodies we have esterases that will break down procaine quickly producing a short half life of procaine so we will have to use higher concentrations or give more regularly. Lignocaine has an amide bond that is much stronger and doesn’t get broken down so has a longer half life.
So the bonds the LA has dictate how quickly it will be broken down and therefore its half-life and the amount of LA we have to give and how regularly.
What is the important chemical property of LAs?
- Local anaesthetics are weak bases (pKa 7-9).
- Physiology pH is about 7.2 (below pKa) at this pH there are more protons flying around so the base accepts protons and so more of the LA is in its ionised form.
- If the base finds itself in a more strongly alkaline enviroment (pH>pKa) then it will not bind protons so more LA will be in its unionised form therefore it is more membrane permeable.
Describe the effect of pH on LAs and the role of ion trapping
- If the LA finds itself in a more alkaline enviroment it will behave as a weak acid and donates protons so it becomes neutral, hence making it easier to cross membranes and get into cells.
- Once inside the cell, the pH is more tightly controlled around 7.2. This is more acidic than LA so it will behave as a weak base and accept protons from the enviroment making it ionised (LAH+ form). This form is more effective at blocking the vgNa+ channels. It is also trapped inside the axon because it is ionised and cannot cross the ‘fatty’ myelin sheath and axonal membrane. This is called ion trapping so LA are more effective at blocking Na+ channels when ionised as the channel is accessed from the inside of the cell.
- This is one of the ways we can alter the effectiveness of LAs, by administering them in alkaline solution in order to promote getting the LA into the cell in the first place.
Once in, the LA will get ionised and trapped and start blocking the channels.
Describe generation and conduction of resting membrane potential in terms of pain
- Resting membrane potential (-90 mV - more like -75mV) where 3Na+/2K+ ATPase fires out three Na+ and two K+ into axon. The membrane is selectively permeable to K+ so some leaks out bringing RMP higher. There is a small amount of Na+ diffusing into cell.
- During stimulation the membrane depolarises to about -50mV. During pain, receptors are stimulated that produce a change in potential in the cell and if this is above the threshold potential (-50mV) the vgNa+ channels will open causing rapid influx of Na+ down its electrochemical gradient into the axon. This causes an upstroke of action potential called depolarisation.
- The depolarisation of the cell will cause opening of vgK+ channels and K+ will efflux out of the cell down its electrochemical gradient and this will cause the repolarisation (i.e. cell becomes negative again) this is the downstroke of the AP.
- There is a bit of an overshoot and the potential goes below resting which is hyperpolarisation, then the 3Na+/2K+ helps get the membrane back to resting.
- At the nodes of ranvier this leads to saltatory conduction.
- The APs reach the spinal cord and brain and we register this as pain.
Mechanism of action of LAs
LAs block the inward flow of Na+ by blocking the vgNa+ channels (e.g. during step 2) so no upstroke is produced. This therefore blocks the generation and conduction of APs which means no information is sent to the CNS and there is no perception of pain despite the trigger still being there (e.g. being pinched).
Why are LAs given locally?
Local anaesthetics will block any vgNa+ channel irrespective of the tissue, which is why we give these drugs locally, where we are triggering the pain, to reduce systemic effects.
This is because we don’t want APs being blocked throughout our whole body.
How do LAs block Na+ channels?
LA block vgNa+ by several mechanisms:
- Some of the LA that in unionised will block vgNa+ in their closed state.
- Some of the LA that is ionised (LAH+) will block the vgNa+ in their open state.
- However, LA generally target the blocking of channels in their inactivated state and its LAH+ that does this. This is substantial and gives the drug the ability to be use dependent.
This essentially keeps the channel inactivated (absolute refractory) and therefore extends the refractory period where APs cannot be fired.
This means no signals can be sent to the CNS.
Why is LA being a use dependence block clinically important?
It is significant the way LAs block in a use-dependent way and this links with the fact it blocks channels in their inactivated state and only work when there is high activity.
We don’t want to block all nerves in that area we want to block the nerves that are firing at high frequency, because if we have painful stimulus to the skin (e.g. pinch) then the nociceptor fibres will be the ones firing a lot higher than the other type of fibres in the hand (e.g. ones that move the hand). So we selectively block to not cause paralysis.
How do LAs selectively block high frequency firing nerves?
Some LAs only block Na+ channels in their inactivated state. When there is a nerve with low activity, you have few AP firing and therefore few channels go into the inactivated state. If you have high firing, there is lots of cycling of channels going from closed to open to inactive over and over therefore you can trap a lot of vgNa+ in this condition. Hence higher frequency firing nerves will be preferentially blocked because more of their vgNa+ channels are in the inactivated state which the LA likes to block!
There will be some blocking in the low activity, but no where near as much as the high frequency.
Why are pain fibres blocked before sensory or motor nerves by LA (they all use vgNa+ for AP)?
- Firstly LAs block smaller diameter axons before large ones and usually block un-myelinated before myelinated fibres. This is due to ease.
- Nociceptive impulses are conducted in A-delta fibres (which are small diameter myelinated axons) and C fibres (unmyelinated axons) so LA preferentially block nociceptive fibres.
Therefore the LAs find it easier to get into these fibres first and hence pain sensation is lost first. However over time LA will get into the larger sensory or motor fibres, this will cause local paralysis (e.g. dentist pain relief first, then when you leave you’re dribbling a lot because facial muscles are paralysed).
Unwanted effects of LA in CNS
If LAs enter the circulation, they can enter the CNS and brain which initially leads to stimulation (such as tremor, agitation and may produce convulsions) due to blocking of the effects of inhibitory neurones. However, if you get a large amount in your brain it can cause CNS depression resulting in respiratory problems and sedation.
Unwanted effects of LA in CVS
- If LA get into the blood stream it will have an effect because cardiac action potentials is also due to vgNa+. If these get blocked it will not lead to proper AP and there will not be a Ca2+ influx and therefore a decreased force of contraction in the heart.
- It will also produce vasodilation as sympathetic nerves innervate the vessels releasing NA action on a1 receptors producing vascular tone, which is very important for BP. If the LA block these nerves coming into blood vessel wall it means that they can’t set tone and the vessels will be more dilated.
Both of these actions will cause a drop in blood pressure (heart due to decreased SV and hence CO and dilated blood vessels meaning less TPR) this can potentially affect blood flow to vital organs.
Routes of administration of LA
- Surface anaesthesia - LA can be applied to mucosal surfaces e.g. brochial surface. Note LAs do not cross the skin well.
- Nerve block where LA is injected close to sensory nerve.
- Spinal anaesthesia - LA is injected into the subarachnoid space between 2nd-5th lumbar vertebrae where spinal cord has ended. LA therefore enters the CSF which prevents AP from being generated as they come from peripheral. This is used in surgery where it is inappropriate to use general anaesthesia.
- Epidural where LA is injected into the epideral space outside the meninges where it diffuses to and blocks the nerve roots coming out of the spinal cord. This is used in childbirth.
