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.
what are the effects of lipid solubilty?
the greater, the more potent
also increases duration, speed of onset
what are the effects of pH and local anaesthetic?
acidity increases ionised form
reduces amount for diffusion - hence less effective in an abscess
therefore less potent
however reduces the protein binding in blood and can increase toxicity
when using LA in paediatrics, what considerations should be made?
Adsorption - higher cardiac output, so increased absorption
distribution - less plasma protiens, increase free portion, risk of toxicity
metabolism - immature liver enzymes, slower to clear
when using LA in elderly, what considerations should be made?
pharmacodynamics - more sensitive to LA due to changes to nerve morphology
pharmacokinetics
* absorption - lower CO, less well vascularised.
* distribution - less because of above, same PB effect
* metabolism - slower
what is LAST?
local anaesthetic systemic toxicity syndrome.
Caused by high levels of LA systemically resulting in neurological and cardiac instability
this is a anaesthetic emergency and should be recognised and treated promptly.
The definitive management is intralipid 20%
what are the symptoms of LAST?
neurological
* at first excitatory - due to inhibition of inhibitory neurons - lip tingling, tinnitus, slurred speach, agitation, tongue numbness, seizures, twiching
* then inhibitory as all neurons inhibited - coma and apnoea
cardiac
* tachycardiac , HTN
* then myocardial depression - bradycardia, hypoT
* then arrhythmias - wide QRS, long QT, VF
* arrest
how is LAST managed?
recognise
stop administration
call for help
15L 100% O2
ABC
if arrest - start CPR
intralipid 20%
1.5ml/kg bolus
15ml/kg/hr infusion
after 5 mins repeat bolus and can increase infusion to 30ml/kg/hr
max dose** 12ml/kg ** (not mg)
supportive for seizures, arrhythmias, hypotension
what are the risk factors for LAST?
blcok factors
* large volumes
* vascular site e.g. intercostal , caudal
* prolonged duration - bupivacaine more likely
* amides > esters because they are longer lasting and more effected by liver metabolism being poor
patient factors
* acidosis - promotes ionised form and less PB
* hypercarbia - cerebral vasodilation, more delivered to brain
* extremes of ages , pregnancy.
* decreased plasma proteins
* liver, renal and cardiac disease
practioner factors
* wrong dose right site
* wrong site right dose
* poor technique - IV access
how does intralipid work?
acts as an emulsifier binds LA within plasma preventing free form causing toxicity
propofol could technically be used but would cause too much hypotension at doses needed.
pKA values of lidocaine, prilocaine, ropivacaine, bupivacaine, cocaine
lidocaine = 7.9
prilocaine = 7.7
bupivacaine = 8.1
ropivacaine = 8.1
cocaine = 8.6
PB of lidocaine, prilocaine, ropivacaine, bupivacaine, cocaine
lidocaine = 70%
prilocaine = 50%
bupivacaine and ropivacaine and levo = 95%
cocaine = 95%
lipid solubility / potency of lidocaine, prilocaine, ropivacaine, bupivacaine, cocaine
bupivacaine, ropivacaine - high
lidocaine and prilocaine - low
dose lidocaine, prilocaine, ropivacaine, bupivacaine, cocaine
lidocaine = 3mg/kg (7mg/kg with adrenaline)
prilocaine = 6mg/kg (9mg/kg)
bupivacaine = 2mg/kg
levo = 2.5mg/kg
ropivacaine = 3.5mg/kg
cocaine = 3mg/kg
compare 2 local anaesthetics
draw a table
amide / ester
pKA
PB
onset
duration
potency / lipid solubilty
max dose
metabolism
what drugs may be co-adminstered with LA ?
adrenaline
* vasoconstriciton, improves local action, prolongs duration, reduces toxicity, increases max dose that can be given.
* shouldnt be used for blocks involving end arteries e.g. finger/ penile
opioids + clonidine
* partially in axial blocks - spinal, cuasal, epidural
* potentiates block by adding analgesc effect
glucose:
* increases density of LA e.g. heavy bupivacaine
* helps to manipulate position of block
sodium bicarb
* alkalinises the environment - promotes unionised form, improves potency / speed of onset. mostly used in epidural block, not really peripherally
which LA can precipitate methamoglobinaemia ? how is this managed?
prilocaine
metabolism of prilocaine produces O-toludine which can precipitate the formation of Fe3+ which are unable to bind O2. this is the basis of methamoglobinaemia.
can be treated with methyl blue (although large doses of methyl blue can promote methamoglobin)
what are the sats reading with methamoglobin and methyl blue?
methamoglobin - 85% - due to absorbance of this type of Hb, may not be true reflection of actual sats
methyl blue - 65% - looks worse at first, again not true reflection of absorption just because methylblue mimics absorption of deoxygenated hb
what is transient neurological syndrome?
TNS
presents 24 hours within LA following full recovery from spinal anaesthesia
consists of diasthesia in buttock, leg, lower back pain
most recover within a week
no EMG or radiological abnormality
should exclude abscess or haematoma.
mostly causes by lidocaine and least by bupivacaine
what is the risk of LA in pregnancy?
can cross placenta as unionised form
fetal blood is more acidic so becomes ionised and trapped
especially if fetus is distressed
worse with amides as slower metabolism.
compare the speed of onset of lidocaine and bupivacaine
speed of onset mostly goverened by pKA
pKA lidocaine 7.9
pKA bup = 8.1
at physiologcial pH 7.4, because they are both bases, lidocaine more unionised
therefore steeper gradient to drive into neurons
therefore quicker onset
DESPITE bupivacaine being more lipid soluble and potent
why does adrenaline not increase the safe dose of bupivacaine?
duration of action of bupivacaine is too long, effects of adrenaline have worn off before and then bupivacaine toxicity can develop.
plus bupivacaine has its own vasoconstrictor potential which adrenaline does not significantly increase
(lidocaine is vasodilatory and shorter duration)
how can the volume/ conc of a LA be manipulated for affect?
can dilute the LA - decreases onset and duration and amount of motor block however may be needed to span larger area without giving toxic dose
increase concentration - longer duration and quicker onset.
what topical LA agents do you know?
Eutectic mixture of LA (EMLA) - mixture of prilocaine 2.5% and lidocaine 2.5%
Ametop gel - 4% tetracaine
what is meant by a eutectic mixture ?
2 compounds are mixed to produce a substance that behaves with a single set of physical characteristics
in case of EMLA cream
the mixture has a lower melting point and thus oil at room temp, whereas the individual ones are crystaline solids at room temp.
so now can be used topically
how are topical LA used?
mostly for cannulation in children
applied 30 mins before as a cream
compare ametop and EMLA
Ametop
- lasts longer
- vasodilation so helps with canulation
- liscensed for children under 1 whereas EMLA isnt
EMLA
- shorter in duration
- vasoconstricition
- slighter quicker to work.
- prilocaine - theoretical risk of methamoglobinaemia
why may lidocaine be used as an infusion intraoperatively?
analgesic adjunct
decreases pain score, need for opoids etc
which local anaesthetic is most often used topically e.g. opthalmic?
tetracaine
tell me about lidocaine
amide LA and also class 1b anti-arrhythmic
commonly used for SC infiltration before minor proceedure but also in ALS second line to amiodarone (VT treatment)
found as a 1% and 2% solution for injection.
can also be found as a spray in varying concentrations and topical patch and 2% gel.
max safe dose is 3mg/kg or 7 with adrenaline
it works via use dependant blockage of VG Na channels to stop AP propagation, this inhibits transmission of pain and also have anti-arrhtyhmic actions in the heart (reduces phase 0, reduces AP and refractory period). It also has vasodilatory action
has a number of side effects linked to toxicity
overall it has rapid onset and short duration.
pharmacokinetics
it is a weak base with pKA 7.9
rapid 1st pass, poor BO, usually injection. absorption depends on location
70% PB
hepatic metabolism - meg X active metabolite
renal excretion
tell me about bupivacaine
Amide LA agent
commonly used in regional anaesthesia for its longer duration of action
comes as 0.25 - 0.5% preparations for injection.
consists of racemic mixture of R and S bupivacaine
can be combined with 8% glucose for heavy marcaine solution.
dose = 2mg/kg
pharamacodynamics
reversible use dependant VG Na blockage
hence prevents pain transmission and also results in motor and sympathetic blockade
slower onset, and longer duration
most cardiotoxic - the S entatiomer - levobupivacaine is less so.
pharmacokinetics
poor BO, systemic depends on site
95% PB - long duration
hepatic metabolic
renal excretion
tell me about cocaine?
ester LA
mostly used as a topical LA for its analgesic and vasoconstrictor properies e..g ENT surgery or fibroptic intubation.
also well known for recreational use.
comes as a spray or topical paste
safe dose 3mg/kg max
reversible use dependant VG Na blockade - prevents transmission of pain fibres.
also works as a NA/ Dopamine reuptake inhibitor
cardiovascular - HTN, tachycardia, long QT, vasoconstriction - ACS
neuro - euphoria, anxiety, addiction
other - hyperthermia
kinetics
weak base, pka 8.6
a - rapid absorption through mucosal membrane
d - 95% PB
m - ester metabolism + liver
e - renal
how is cocaine toxicity managed?
ABC
be aware of rhabdomyolysis - check CK
be aware of ACS and long QT - check ECG + troponins
supportive - benzos, cooling.
for HTN - use alpha 1 blockers - avoid B blockers as alpha blockade from NA will be not tolerated with lower CO. can result in decompensaiton
tell me about levobupivacaine
this is the S enatiomer of bupivacaine
bupivacaine is well known for being more cardiotoxic than other LA. it consists of a racemic mixture where the cardiotoxic effects are mostly from the R enatiomer.
hence levobupivacaine is less toxic
