analgesia and anaesthesia Flashcards
local anaesthetics: explain the cellular mechanisms of action of local anaesthetics, their pharmacokinetic profiles and adverse effects
define local anaesthetic
drug which reversibly blocks neuronal conduction when applied locally
describe process of generation of neuronal action potential (“all or nothing” response in 10-15ms)
depolarisation (from -70mV) -> resting voltage-sensitive Na+ channels open -> Na+ enters cell -> Na+ channels close (inactivation), K+ channels open (start at depolarisation but take longer) -> K+ leaves cell -> Na+ channels restored to resting state, but K+ channels still open, so cell refractory (can create new depolarisation if greater stimulus) -> Na+ and K+ channels restored to resting state, so cell will respond normally to further depolarising stimuli
5 examples of local anaesthetics
procaine, cocaine, lidocaine, bupivacaine, benzocaine (doesn’t have amine side-chain so surface anaesthetic as weak but more lipid soluble)
what is structure of local anaesthetic important for
mechanism of action, pharmacokinetics
3 main areas of structure of local anaesthetics
aromatic region, ester or amide bond, basic amine side-chain
example of local anaesthetic with ester bond
cocaine
example of local anaesthetic with amide bond
lidocaine
mechanism of action of local anaesthetics with Na+ channels of sensory neurone: hydrophilic pathway (main)
applied close to trunk -> ionised and unionised form reach equilibrium -> unionised form crosses connective tissue sheath -> crosses neurone -> ionised and unionised form reach equilibrium -> ionised (cation) form binds inside voltage-sensitive Na+ channel (channel must be open, so if firing more rapidly, local anaesthetic has greater effect - use dependency so gives degree of selectivity) -> prevent Na+ influx
describe local anaesthetic effect in motor vs sensory neurones
block of motor neurone not as effective as sensory neurone (due to myelination)
mechanism of action of local anaesthetics with Na+ channels of sensory neurone: hydrophobic pathway
increased lipid solubility: diffuse in membrane -> ionised and unionised form reach equilibrium -> ionised (cation) form binds inside voltage-gated Na+ channels (channels don’t need to be open) -> prevent Na+ influx
4 effects of local anaesthetics
prevent generation and conduction of action potentials, don’t influence resting membrane potential, may influence channel gating (e.g. binding preferentially to inactivated voltage-gated Na+ channels, increasing refractory period), selectively block small diameter (ad and C-fibres) and non-myelinated fibres (as well as firing rate)
what are local anaesthetics (acid or base), and effect on mechanism of action
weak bases (pKa 8-9), so mechanism of action is pH dependent
why is it more difficult to anaethetise infected tissue
tends to be more acidic, so more is ionised so less can enter neurone
6 routes of local anaesthetic administration
surface, infiltration, i.v. regional, nerve block, spinal, epidural
describe surface local anaesthetic administration (where, how and dose)
mucosal surface (mouth, bronchial tree) by spray (or powder), requiring high concentration