LOCAL ANAESTHETICS Flashcards
what is meant by a 1% concentration?
1g solute per 100mls of solution
for example 10mg/ml
How can local anaesthetics be classified?
There are 2 main groups of LA
- esters - cocaine, procaine
- amides - lidocaine, bupivacaine, prilocaine, ropivacaine
these are classified by their structure. both contain an aromatic ring and an amine group. The link between these may either be an ester link of an amide link
draw the general structure of a LA ..
lipophilic aromatic group
hydrophilic amine - usually tertiary amine
joined by ester/amide link.
what are the chemical characteristics of LA
weak bases
pKA usually 7.9 to 8.1
therefore at physiological pH, slightly more ionised but good proportion is unionised,
highlight the key differences between the 2 groups of LA
structure
- ester link vs amide link
pharmacodynamics
* amides have a quicker onset
* amides have longer duration
* amides penetrate tissues better
* amides are less linked to allergy, esters produce PABA (allergenic)
* clinically amides are more commonly used compared to esters
pharamcokinetics
* esters are metabolised by ester hydrolysis - plasma cholinesterases (cocaine some liver metabolism too)
* amides have hepatic metabolism
how do local anaesthetics work?
reversibly Block VG Na channels to prevent propagation of action potential.
they bind and block this from inside the neuron and when the channels are in their active state.
- their lipid soluble unionised form can cross neuronal membrane
- inside the neuron, pH is lower, become ionised and trapped
- in ionised form, can bind and block open VG NA channels
- prevents further depolarisations/ AP propagation
which fibres do LA agents preferentially block?
affect smaller fibres preferentially
affect myelinated fibres preferentially
affect active neurons that are firing - use dependant block
therefore most sensitive are small myelinated = B fibres = preganglionic ANS - hence sympathetic block
then Ad = sharp pain and temp
then Ag = muscle tone
then Aa = motor and proprioception
finally C fibres - hence pressure and touch can still be felt.
describe in more detail the VG NA channel and how LA effect these
VG Na channels exist in 3 states and have 2 gates.
gates M and H
inner H gate and outer M gate
at rest H is open and M is closed
depolarisation opens M and then ions can flow
after some time H shuts - inactive - absolute refractory
as membrane repolarises, H open and M closes back to rest
LA bind when both are open
(inner H = H for home. doors inside the home are open and outside are closed)
what is meant by use dependant block?
LA bind to open channels
therefore block neurons in use
hence fibres with high frequency firing - pain and sensation are blocked preferentially (over motor)
are there any other theories for LA mechanism?
lipid expansion theory = LA dissolve in lipid bilayer and disrupt functioning of ion channels.
other than neuronal inhibition. what are the other effects of LA…
Cardio
* antiarrhythmic - lidocaine in VT/ VF
* pro-arrhythmic at higher doses - can lead to long QT, VT and torsades
* reduce contractility - less depolarisation, less Ca release.
* cardiac toxicity - can inhibit uptake of Ca and hence hypercontractile state. bupivacaine is worse for this.
* sympathetic block - bradycardia, hypotension
Neuro
* effects on other ion channels can result in excitation
* transient neurological syndrome - abnormal sensations e.g. pins and needles following LA
immune and inflammatory
* allergy and anaphylaxis - mostly from PABA from esters. or preservatives in amides
vascular
* some are vasodilatory - lidocaine
* other vasoconstriction - cocaine
metabolism
- prilocaine can cause methamoglobinaemia due to O toludine metabolite.
what factors affect the potency of a LA?
mostly lipid solubility - will more readily diffuse across lipid bilayer to have an effect. i.e. the larger the carbohydrate side cahins the more lipid soluble.
other factors - vasoconstrictor potential. some that have this ability, keep the agent local and thus there is less systemic absorption and hence more available for effect, so less is needed i.e. more potent.
what factors affect the duration of LA
mostly protein binding
- acts as a reservoir to prolong action.
- the LA cant be cleared/ metabolised when protein bound. only the free portion can be.
- hence prilocaine, least PB 50% has shortest duration, whereas bupivaciane has more and acts longer.
also
blood supply to the area - the less vascular, the longer duration.
vasocontriction - also prolongs
lipid solubility - also prolongs, as less gets into water soluble blood.
dose - the bigger the dose, the longer.
metabolism - the slower the metabolism, e..g amides longer acting than esters
what affects speed of onset of LA?
pKA is the main factor here - the lower the pKA, the more unionised, hence larger gradient for diffusion into the neuron.
other factors
* conc gradient = the more given, the steeper the gradient, hence the less potent, the more can be given
* lipid solubility
* warming to body temp can increase rate of diffusion
* sodium bicarb - increases pH and hence unionised proportion
* how much it remains local - vasoconstriction and vascularity of the area
in general which main properties effect potency, duration and speed of onset of LA?
potency - lipid solubilty
duration - protein binding
speed of onset - pKA
what is the effect of adrenaline on LA
adrenaline causes vasoconstriciton
often can be given with LA to prolong duration, reduce systemic toxicity.
however adrenaline solutions are more acidic so promotes the ionised form.
describe the pharamacokinetics of LA
Adsorption
- oral - rapid 1st pass metabolism, not used
- mostly S/C, intrathecal, epidural or surrounding nerve plexus
- acts locally so the closer to the site of action, the quicker the onset. e.g. epidural space will take longer than spinal
- for action needs to absorb into neuron - depends on pKA and lipid solubility
- systemic absorption is important as it is linked to toxicity and shortening of duration - this depends on location, cardiac output and use of vasoconstrictors.
distribution
* amides more protein bound than esters
* depends on local blood supply to area - less distibution if less blood supply
* also depends on cardiac output
* also depends on lipid vs water solubility - more lipid soluble, less water soluble in blood.
metabolism
* esters - plasma cholinesterases - short half life - produces PABA
* cocaine - esterases + liver
* amides - hepatic metabolism
excretion - renal.
in terms of systemic absorption which routes have most systemic absorption to least?
this depends on vascularity of the location
IV - most
around lungs tracheal>intercostal>intrapleural
around spine paravertebral > caudal > epidural
specific
brachial plexus > sciatic nerve
then
subcut, spinal, intact skin
what are the effects of protein binding for LA?
acts as a reservoir
higher the protein binding…
* less free for metabolism
* less free for toxicity
* increased duration of action
what conditions affect protein binding of LA?
more acidic the blood, the less protein binding , more risk of toxicity
what safety measures are employed when using LA?
max safe dose is used for all
adrenaline - keep LA local
monitoring and trained staff in case of toxicity
USS guidance
aspirate before injection
awake patient - can ask them to report symptoms of LAST.
compare 2 local anaesthetics
draw a table
amide / ester
pKA
PB
onset
duration
potency / lipid solubilty
max dose
metabolism
