Local Anaesthetic Flashcards
Describe the chemical structure of local anaesthetics
what do they act as in physiological pH vs Alkaline conditions?
Local anaesthetics are weak bases (pKa of 7-9)
At physiological pH (7.2), LA’s act as proton acceptors (more LA in ionised form)
BUT in alkaline conditions (pH>pKa), LA’s act as proton donors (more is in non-ionised form!)
Note: ionised form doesn’t cross membranes well
Recap the resting membrane potential and membrane depolarisation
Resting Membrane is ~ -90 mV
High K+ inside cell due to Na+/K+ ATPase
Membrane selectively permeable to K+ ions
In stimulation membrane depolarises to ~ -50mV, open Na+ channels-> a.potential
Open K+ channels and repolarisation
Describe the function and action of local anaesthetics + why are they given locally?
compare structure of procaine vs lignocaine
LAs block Na+ channels, which block generation + conduction of APs - no info sent to CNS = no pain perception
LAs block any vgNa irrespective of the tissue - therefore drugs are given locally to reduce systemic effects!
Procaine has ester bonds susceptible to hydrolysis so has shorter t1/2 than lignocaine, which has an amide bond
How do LAs block Na channels?
Recap that Na channels have a closed, open and inactive state before going back to closed again. LAs:
Slightly block Na channels in their closed and open state
Substantially block Na channels in inactivated state! This means that the channel can’t go back to the closed state + hence can’t be reactivated
Note that blocking of open and inactivated vgNa occurs when the LA is charged/ionised
Describe how some LAs rely on use dependence block
Some LAs only block Na+ channels in an inactivated state
=use-dependent drugs, only work when neurones fire at high activity (pain)
Less side effects, low activity neurones not affected
Why is pH important in local anaesthetics? How does pH contribute to LA function?
LA action is increased in alkaline pH BUT ionised LAs = more effective at blocking Na channels!
This is as Alkaline pH makes more drug into non-ionised form (LA), which crosses myelin sheath + axon membrane. Then, once inside the cell (pH 7.2), more drug is ionised into LAH+ form, which blocks Na+ channel
All nerve fibres use Na+ channels to generate and conduct APs
Why are pain fibres blocked before other sensory or motor nerves?
LAs block small diameter + un-myelinated axons before large + myelinated ones
Nociceptive impulses are conducted in A delta fibres (small/thin diameter myelinated) + C fibres (thin unmyelinated)
Pain sensation is lost 1st, but as you increase conc/time LAs block all axonal conduction, causing local paralysis
Give some potential unwanted effects of LAs on the CNS
If LAs enter brain, it leads initially to stimulation-> then to tremor, agitation, convulsions - then to subsequent CNS depression + resp problems!
2 unwanted effects of LAs on the CVS + what this can lead to?
Decreased CO: LAs block cardiac Na+ channels–> decreased Ca2+ influx –> so less contractility of heart
Increased vasodilatation: LAs inhibit symp nerve activity innervating blood vessels –> decreasing vascular tone
Both above actions decrease BP –> decrease BF to vital organs
compare the surface vs local routes of administration for LAs
Surface anaesthesia: applied to mucosal surface e.g., bronchial (bronchoscopy), nose, cornea – LAs do not cross skin well
Local nerve block: LA injected close to sensory nerve, e.g., dentistry
compare spinal anaesthesia vs Epidural routes of administration for LA’s?
Spinal anaesthesia: LA injected into subarachnoid space between 2nd and 5th lumbar vertebrae - enters straight into CSF.
Used in surgery when inappropriate to use general anaesthetic - e.g frail/elderly patient
Epidural: LA injected into epidural space outside the meninges, where it diffuses to and blocks nerve roots. e.g., childbirth
Describe how LAs can be administered with adrenaline + 4 benefits of this?
LAs can be administered with adrenaline-> vasoconstriction (a1 on vsmcs w/in blood vessel walls). 4 benefits:
-Keeps LA localised to area of injection
-Inhibits LA absorption from extracellular spaces into blood –> reducing chance of systemic toxicity!
-Prevents bleeding
-Prolongs LA action
