local anaesthetics Flashcards
what is the cell body of the sensory neurone called?
dorsal root ganglion
function, diameter and myelination of a delta fibre?
pain and temperature sensor
2-5 um
heavy myelination
function, diameter and myelination of C fibre?
pain sensor
0.3-1.2um
unmyelinated
how do DRG neurons differ from ‘general’ neuron structure
Their cell bodies are located in the dorsal root ganglia
have single axon that splits (bifurcates) with one branch going to the periphery and the other to the spinal cord
feature of peripheral axon terminal of nociceptor
The peripheral axon terminal is a bare nerve ending that possesses receptors for noxious stimuli
what stimuli do nociceptors detect
high or low temperatures
mediators such as H+
ATP that are released by damaged tissue
mechanical stimuli
polymodal nociceptors
contain receptors for several types of stimulus
local anaesthetic mechanisms
Local anaesthetics act by blocking sodium channels
therefore
blocking action potentials
blocking nociception
what is the simplest voltage gated ion channel
potassium channels
four identical subunits
voltage gated potassium channels
Subunits are transmembrane cross the membrane six times fully
Dipping domain between 5th and 6th domains forms the lining of the channel
-voltage sensor
local anaesthetic structures
Most local anaesthetics are variations on the structure of cocaine
They have and aromatic group, an amine group and either an ester of amide group linking the two
where are amide linked local anaesthetics broken down
the liver
what are ester linked anaesthetics broken down by?
plasma esterases
what local anaesthetics last longest
Amide linked drugs tend to have a longer duration of action than ester linked
example of amide link local anaesthetic
lidocaine
examples of ester linked local anaesthetic
procaine
what means that local anaesthetics can become protonated?
the amide group
what does protonation do
give a positive charge
what does the amount of protonated form present depend on?
the concentration of protons, therefore is pH dependent
feature of unprotonated form? what does this mean?
lipid soluble so is able to cross cell membranes (uncharged form cannot)
the uncharged form exists on both sides of the membrane
relationship between charged and uncharged LA
in equilibrium
when to LAs block sodium channels less well
the lower the pH
that the lower the pH, the less well local anaesthetics block sodium channels.
2 ways this can be explained
1) it is the uncharged form of the local anaesthetic that binds to the sodium channel
2) it is the charged form, but acting from the INSIDE of the cell i.e. the drug has to first cross the cell membrane.
what did experiments using QX314 show?
QX314 is a tertiary amine (has four groups on its nitrogen) and so has a permanent positive charge.
As expected, it does not block sodium channels when applied to the outside of cells.
when injected into the cell through a fine glass needle, it is able to block sodium channels.
QX314 does not have local anaesthetic properties despite being structurally related to lidocaine.
therefore
it is the charged form, but acting from the INSIDE of the cell i.e. the drug has to first cross the cell membrane.
LA extracellularly
inactive
why is the uncharged form of LA important
is necessary to allow the local anaesthetics to pass through the membrane.
Once inside the cell, local anaesthetics become protonated again and it is the charged form that blocks the channel
when do local anaesthetics block sodium channel better?
when pH is higher
when sodium channels are open or inactive
use dependence
channels that are more active (and thus either open or becoming inactivated) are blocked more strongly than resting channels.
hydrophilic pathway
Extracellular LA
LA dissolves in membrane
LA enters cytoplasm
LA becomes protonated
Channel opens
LA blocks open channel
Channel inactivates
(LA can also block inactivated state)
hydrophobic pathway
LA starts outside the cell
LA dissolves in the membrane (bilayer)
LA enters channel and is protonated
- unlike the hydrophilic pathway, the channel activation gate doesn’t need to open for the LA to access the binding site – therefore this mechanism is use independent
where can LAs be used to block the nociceptive pathway
at any point along the spinal nerve and in the spinal cord
topical anesthesia
In topical anaesthesia, local anaesthetics are formulated as a cream, as drops or as a spray and are applied directly to the surface of the body.
-0skin or mucosal tissues such as the nose, throat or eye.
blocking the transmission of signals close to, or at, the peripheral nerve terminal.
what is EMLA
topical anaesthesia
Eutectic Mixture of Local Anaesthetics
what is topical anaesthesia used for?
used for pain relief from minor conditions such as sore throats, mouth ulcers and haemorrhoids
used in minor procedures or to reduce pain caused by the insertion of a hypodermic needle
infiltration anaesthesia
local anaesthetic is injected into the tissue around the area that needs to be numbed and usually
only affects the more distal parts of the nerve (terminal branches).
what is important to avoid in infiltration anaesthesia
injecting directly into bloodstream as local anaesthetics can have serious systemic effects
how to prolong action of vasoconstriction anaesthesia
add a vasoconstrictor such as adrenaline to the injected local anaesthetic in order to prolong the duration of anaesthesia
when is infiltration anaesthesia used?
minor procedures such as suturing a wound and is used extensively in dentistry
what is nerve block anaesthesia?
anaesthetic is injected around a spinal nerve trunk
Everything distal (away from the body) to this point will then be numbed.
what is it important avoid in nerve block anaesthesia?
injecting LA directly into the blood stream
why is adrenaline often used adjunct to nerve block anaesthesia?
in order to extend the duration of anaesthesia.
reduces blood flow to region it is injected into as it is a vasoconstrictor
LA stays near site of injection longer)
what is often needed for nerve block anaesthesia?
often, the needle has to be guided into place with the aid of imaging techniques such as ultrasound.
comparison of nerve block to other LA methods
can give better pain relief than infiltration or topical anaesthesia and so allows more complicated surgical procedures, for example knee replacement surgery, to take place.
what is intravenous regional anaesthesia?
a pressure cuff is used to cut off the blood supply to a limb.
Local anaesthetic is then injected intravenously and after a wait of 20 minutes the cuffs can be deflated and surgery can begin.
why is there a 20 min wait time after intravenous regional anaesthesia injection?
to allow anaesthesia to develop and to reduce the concentration of local anaesthetic in the blood vessels (thereby avoiding systemic toxicity).
when is intravenous regional anaesthesia used?
a safe and simple technique and is often used for short procedures on the limbs (especially the lower arms).
spinal anaesthesia
local anaesthetic is injected into the subarachnoid space just above the spinal cord.
This results in pain sensation being lost from all regions supplied by nerves that emerge from the spinal cord below the level of the injection.
use of spinal anaesthesia
Spinal anaesthesia often used for surgery on the lower body but can only be used in the bottom part of the spinal column as this is where the subarachnoid space is large enough to avoid damage to the spinal cord when placing the needle.
This makes it less versatile than epidural anaesthesia
comparison of anaesthesia to other LAs
less versatile than epidural anaesthesia.
It also tends to produce more motor block than an epidural and so is no good for vaginal childbirth.
advantages of spinal anaesthesia over epidural
spinal anaesthesia has a faster onset and less anaesthetic is needed than with an epidural.
epidural anaesthesia
the local anaesthetic is injected into the epidural space, just below the vertebral column.
Usually this is performed via a catheter, which can be left in place to facilitate further doses being administered.
comparison of epidural and spinal anaesthesia
The epidural space is a larger volume than the subarachnoid space (see above), so more anaesthetic is needed and the onset of anaesthesia is slower.
However, the placement of an epidural needle is easier than a spinal needle and can be performed anywhere along the spinal column.
use of epidurals
Low dose epidurals are often used for analgesia alone e.g. during childbirth or for the treatment of chronic pain.
They do not tend to affect motor function as much as spinal anaesthesia, which is an advantage in childbirth.
At higher doses, epidurals can also be used for surgical anaesthesia and are common in procedures where it is desired to keep the patient awake during surgery e.g. a Caesarean section or where the health of the patient makes a general anaesthetic too risky e.g. hip replacements in older people.
selective manner of local anaesthetics (differential blockadde)
Sympathetic nervous system function is lost first, followed by pain sensation with touch and motor functions only being lost at higher doses
three factors affecting the sensitivity of a nerve fibre to block by local anaesthetic
degree of myelination
fibre diameter
position within the nerve
how does degree of myelination affect sensitivity of a nerve fibre to block by local anaesthetic
spinal nerve fibres can differ in their degree of myelination.
A fibres have the most myelin, and C fibres are unmyelinated.
Myelinated neurones transmit action potentials viasaltatory conductionand have their sodium channels concentrated at the nodes of Ranvier.
Saltatory conduction is very energy efficient, but it only takes blockage of a few nodes to completely prevent action potential transmission
thus the higher the degree of myelination, the more sensitive to local anaesthetic.
how does fibre diameter affect sensitivity of a nerve fibre to block by local anaesthetic
Thin fibres are more sensitive to local anaesthetics than thicker ones.
This is simply a function of the surface area to volume ratio of the fibre.
how does position within the nerve affect sensitivity of a nerve fibre to block by local anaesthetic
Fibres that are close to the surface of the nerve will be affected more strongly than those towards the centre.
This is a function of the need for the anaesthetic to diffuse from outside the nerve into its core.
Effect of local anaesthetics on the brain
at very low doses neuronal activity is depressed but as the concentration is raised,the activity of inhibitory neurones is suppressed more than excitatory ones, so convulsions can result.
At higher doses there is a profound depression of CNS activity leading to coma and ultimately death.
effect of local anaesthetics on the heart and cardiovascular system
local anaesthetics slow the heart rate and reduce blood pressure.
They can cause serious disturbances in cardiac rhythm (arrhythmias).
can be used therapeutically to reduce the heart rate in emergency situations e.g. administered IV in ventricular fibrillation.
Another effect on the vasculature is that local anaesthetics, with the notable exception of cocaine,arevasodilators. This means that blood flow will increase when they are injected, washing the drug into the systemic circulation and diminishing its analgesic effects. To avoid this problem, local anaesthetics can be co-injected with adrenaline (a vasoconstrictor). This limits systemic effects and prolongs the duration of action but this technique must not be used in tissues with limited blood supply.
allergic reactions to LA
True allergic reactions to local anaesthetics are rare.
However, ester linked drugs can be metabolised to para-aminobenzoic acid, which can produce allergy.
Allergies also can occur to preservatives used in formulating the drug for injection.
