Local anaesthetics (L13) Flashcards
what are anaesthetics?
drugs which are used to prevent pain for a limited period of time for surgical or other procedures
what are analgesics?
used to control pain
whats the difference between local and general anaesthetics?
local prevent localised pain or nociception and also prevent tactile sensation
general also induce loss of consciousness
what do local anaesthetics do?
block electrical signalling in neurones by blocking vg Na+ channels
can’t have propagation of AP
no signalling = no pain
what are vg ion channels composed of?
3 subunits:
• alpha
• beta 1
• beta 2
alpha subunit of vg ion channels
a single polypeptide
contains extracellular domains, 4 transmembrane domains each comprising 6 alpha-helical regions
contained voltage sensors in the hydrophobic domains that change orientation when voltage varies
• opening and closing of the pore
beta subunits of vg ion channels
they flank the alpha subunit
beta 2 is linked covalently to alpha
beta 1 is not linked
the 2 units anchor the alpha subunit into the lipid membrane
how do local anaesthetics interact with vg ion channels
thought to interact with eh alpha subunit and physically ‘plug’ the transmembrane pore
Na+ cannot rush into neurone
bindin gisten is located in the inner end of the channel - drug needs to gain access intracellularly
• unionised forms gain access through nerve sheath and axon membrane
• ionised form bind in the channel
general structure of local anaesthetics
aromatic group
ester or amide group
amine group
why is the structure of local anaesthetics important?
basic side chain ensures molecules are poised at physiological pH
aromatic domain ensures lipid solubility
duration of action is limited by the hydrolysis of the ester/amide bond and by the lipid solubility of the agent
whats the difference in having an ester or having an amide group?
esters
• metabolised in plasma by esterases
• shorter half-life
amides
• metabolised in liver by CYP 3A4, 1A2
• longer half-life
anaesthetic action
anaesthetic (weak base), is injected as HCl salt in an acid solution
following injection, pH increases and drug dissociated and free base is released
lipid soluble free base enters axon where pH is lower and re-ionisation takes place
re-ionised portion enters Na+ channels and blocks them, preventing depolarisation
how can we manipulate local anaesthetics?
restrict site of action and prolong durations of action
• co-anminister adrenaline
accelerate speed of onset of anaesthetic
• using slightly alkaline solution assists absorption of anaesthetic into nerve tissue
do all nerves show similar susceptibility to local anaesthetics?
different types of axons show different sensitively
all axons depend on vg ion channels - all affected
block conduction is smaller dimeter fibres better than larger ones
what is use dependent block?
when the depth of block increases with an increase in action potential frequency
