Principles of Local Anaesthesia Flashcards
what are the steps of action potential generation?
- Depolarising stimulus
– Na+ channels open, Na+ enters cell. - Inactivation
– Na+ channels close, K+ channels open, K+ leaves cell. - Cell refractory state (TARGET to prolong)
– Na+ channels restored to resting state but K+ channels still open so cell is refractory. - Resting state
– Na+ and K+ channels restored to resting state.
all or nothing events
(EPPs are graded however)
what are local anaesthetics?
they induce reversible neuronal conduction block when applied locally
what are the 3 components of LAs?
o Aromatic region (ring) – very lipid-soluble/hydrophobic. o Amine side-chain – hydrophilic. o Ester or Amide bond
how do the two types of LA differ in structure?
ester or amide linkage
example of LA with ester linkage
cocaine
example of LA with amide linkage
lidocaine
what LA is an exception in terms of structure?
benzocoaine
has no basic amine group therefore weaker potency
what are two main pathways of action of LAs?
1) hydrophilic (channel open)
2) hydrophobic
describe the hydrophilic pathway of LA action
- The drug remains in equilibrium between ionised and unionised forms (as all LAs are weak bases).
- Unionised form passes into axonal membrane
– can pass across membranes but CANNOT have any action once inside (need to be ionised) - when equilibrium is reached in the axon, Ionised form can bind to Na+ channel from the inside
– is needed to have an ACTION but can’t pass across membranes. - This pathway is use-dependent as the channels need to be open for the cation drug to access the VGSCs.
describe the hydrophobic pathway LA action
Lipid-soluble drugs can access the hydrophobic pathway and drop into the sodium channel at axonal membrane level even when the channel is closed (they are NOT use-dependent).
how do the hydrophilic and hydrophobic pathways differ?
the hydrophilic pathway is use dependent and needs the sodium channel to be open
the hydrophobic pathway is not use dependent and does not need an open sodium channel
what does use-dependency mean for the effect of the LA?
the more rapidly a neurone fires (i.e. spends a lot of time in the open state) , the better it can be blocked
important for the hydrophilic pathway using an open channel
what kind of neurones are targeted by LAs?
why do they target VGSCs?
sensory neurones with small diameter fibres or non-myelinated fibres (tend to be pain neurones)
preferably to sodium channels in the inactivated stage to increase the refractory period
what are the effects of LAs?
- Prevent generation and conduction of APs.
- Do not influence resting membrane potentials.
- May influence:
a. Channel gating – e.g. hold an inactivated state in a channel.
b. Surface tension – lower surface tension.
what fibres do LAs selectively block?
the slower conduction fibres a. Small diameter fibres – e.g. nociceptive pain fibres. b. Non-myelinated fibres – pain fibres are often small (Adelta-fibres) and unmyelinated (C-Fibres).
