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.