5. Local Anaesthetics Flashcards
Amides include
lidocaine, prilocaine, bupivacaine and ropivacaine Mepivicaine
More common in practice
esters
amethocaine procaine Cocaine Chloroprocaine Tetracaine, and Articaine.
Lipid solubility influences
Lipid solubility influences the time it takes the local anaesthetic to penetrate the neuronal membrane and is one of the most important determinants of potency, particularly in vitro
dissociation constant, pKa
affects the speed of onset of action and it determines the proportion of drug in the un-ionised (that is, lipid soluble) form.
When the pH equals the pKa of the drug, the ionised and un-ionised forms are present in equal proportions (that is, 50:50).
At phys pH
Buipvicaine / ropicane - unionised %
pKa
Lido + prilo unionised %
pkA
At physiological pH (pH 7.4)
17% unionised form for bupivacaine (pKa 8.1)
/ropivacaine
33% in unionised form for lidocaine (70% prot bound) and prilocaine (pKa 7.7)
Procaine pka 8.9
Bupivicaine Type Dose Mix + affects Pka
Affect on heart
Amide
Dose 2mg/kg Racemic S- less cardiotox block voltage Na affect ph 0 of potential S- also affect RyR2 - Ca rel from SR pka 8.1 long duration lido
Produce dilatation @ clin dose
Subclin intradermal - vascon biphasic peripheral CV
Expressed as- %
what is 1%
Local anaesthetic agents and glucose-containing solutions are expressed as a percentage.
A 1% solution is 1 g per 100 ml solution or 1000 mg per 100 ml solution.
10 ml of a 1% solution contains 100 mg of solute.
Ambulatory surgery
The ideal local anaesthetic for a spinal anaesthetic for day case surgery are chloroprocaine (duration of surgery up to 40 minutes) and prilocaine (duration of surgery up to 90 minutes). Accurate estimation of duration of surgery is key to the choice of drug.
TNS w/ lidocaine & mepivicane - unsuit
failure rate w/ bupivicaine / may need fentanyl or top up
Lidocaine
Type
Chirality
Group?
Broken down by what
pKa
uv:m vs bupivicaine
Lidocaine is an achiral amide local anaesthetic and contains a lipophilic aromatic group, an intermediate amide (-NH.CO-) chain and a hydrophilic group.
Amide local anaesthetics are broken down by amidases in the liver, whereas ester local anaesthetics are rapidly hydrolysed by plasma cholinesterase.
The pKa of lidocaine is 7.8-7.9
In general, highly protein-bound drugs have a low umbilical vein to maternal blood ratio (uv:m). The uv:m ratio for bupivacaine is approximately 0.2; and for lidocaine and prilocaine it is 0.5. Therefore, lidocaine transfers across the placenta more than bupivacaine.
ivra
ntravenous regional anaesthesia is prilocaine. It has the largest therapeutic index of all the amide local anaesthetics. Prilocaine has become the agent of choice for Bier’s block, since 1983 when the product licence of bupivacaine was withdrawn for this purpose owing to fatal or serious complications.
Lidocaine is a suitable alternative but the volume and dose is likely to be inadequate for this procedure.
Lipid solubility
Protein binding -
pka
A) to act they need to penetrate the lipid cell membrane to enter the cell. The higher the lipid solubility the more penetration there is through the cell membrane.
Protein binding reflects on the ability of the drug to be bound to membrane proteins so the greater the binding the longer the duration of action.
All local anaesthetics are weak bases and it is the unionised form that diffuses more readily across the nerve membrane than its protonated form. So, a drug with a higher pKa will have more ionised drug than a LA with a lower pKa at a given pH, and so a slower onset of action.
LAST likelihood depends
The likelihood of local anaesthetic toxicity is dependent on a number of factors. These include:
Site of injection, i.e. vascularity and presence of fat
Drug dose and concentration
Use of vasoconstrictors, and
Changes in protein binding in relation to intracellular pH.
The most vascular areas into which local anaesthesia is more prone to systemic absorption (in order) are:
Intercostal and paracervical block Caudal block Lumbar and thoracic epidural block Brachial plexus block Sciatic/femoral nerve block Subcutaneous infiltration.
Levobupivicaine
Enantiopure
D isomer of bupivacaine had a higher potential for toxicity
Blockade of the sodium channels is stereoselective
D isomer - potenter - includes cardiac
pKa of levobupivacaine is 8.1
Protein binding of levobupivacaine >97% (vs 95 for bupiv)
3% is free - toxic effects
In nephrotic + other hypoprotinaemic patients - higher potential tox - less prot for bind)
LAST
Why light head
Side effect - bupiv v levo
VF easy to rx
Light-headedness is usually due to the direct effect of local anaesthetic toxicity on the central nervous system.
Fentanyl is not a local anaesthetic and therefore cannot cause local anaesthetic toxicity.
L-bupivacaine and ropivacaine have better side effect profiles than bupivacaine and are considered safer in the event of toxicity. Intermittent boluses of 0.1% bupivacaine are not usually associated with cardiac side effects in healthy patients.
Ventricular fibrillation due to bupivacaine is resistant to treatment (refractory) and resuscitative efforts are usually prolonged.
Adjuvant drugs for LA
work by
Adjuvant drugs interact with neurotransmitters at the dorsal horn systems and block nociceptive transmission in the spinal cord.
The most widely used include:
Alpha 2 adrenergic drugs (clonidine) Anticholinesterases (neostigmine) NMDA receptor antagonists (ketamine) N-specific calcium-channel antagonists (ziconotide) Opioids Adrenaline.
EMLA
mix of what & what percent
Phsyical prop
Speed onset
Forms what by what
Where can it be used
is the Eutectic Mixture of Local Anaesthetics. Eutectic mixture is formed by two compounds mixing to produce a substance of a single set of physical characteristics. EMLA contains 2.5% lidocaine and 2.5% prilocaine in oil:water emulsion. The melting point is lowered to produce an oil at room temperature.
Unlike amethocaine (22-25 minutes), it has a slower speed of onset of 60 minutes.
EMLA may cause the formation of methaemoglobin due to the o-toluidine produced when prilocaine is metabolised. Therefore, it should be avoided in patients with methaemoglobinaemia.
It should not be used on mucous membrane due to excessive systemic absorption.
Which LA are chrial
Anaesthetic activity of LA
- vs Bupivicaine
S - or R +
activity
Potency
Vasoconstriction
Toxicity
Chirocaine is…
Prilocaine and bupivacaine are chiral compounds.
(prilo safe dose 6mg kg)
Most ester local anaesthetics, as well as lidocaine are achiral.
Individual enantiomers have approximately equal local anaesthetic activity, although R (+) bupivacine may be more potent than the S (-) enantiomer.
The S (-) enantiomers produce enhanced vasoconstriction and have prolonged local anaesthetic activity; they may also be less cardiotoxic.
The S (-) enantiomers (nor R) may have reduced potential for toxicity when compared with the racemic mixture of the drug.
Chirocaine is the S (-) enantiomer of bupivacaine and is commercially available for clinical use.
Local anaes are weak -
Produce what
How do they act
Esters metabolised by -
effect pregnancy
effect lvier disease
Amides metabolised by
Depends on
Infected tissues?
Local anaesthetics are poorly water soluble weak bases
Produce a reversible block of conduction along nerves.
They enter the nerve in lipid soluble form and once in the nerve the ionised form binds to and blocks the sodium channels from within. Thus sodium entry during depolarisation is prevented, which results in failure to reach the threshold potential and failure of propagation of the action potential (membrane stabilising effect).
Esters are metabolised by plasma and liver cholinersterases and the level of these enzymes is low in pregnancy and liver disease.
Amides are metabolised by liver microsomal enzymes, which are dependent on liver function and blood flow (not independent).
The pH in infected tissues is lower than normal, so the effects of local anaesthetics is reduced (not increased).
Prilocaine
type of anaesthetic
Amide
- liver
- can undergo renal and pulmonary biotransformation.
Amide hydrolysis
- O-toluidine
development of methaemoglobinaemia.
N-propylamine.
All LA membrane stabilisers
-Block sodium channels in excitable tissue.
44-50% protein bound
- alpha-1-acid glycoprotein
Prilocaine spray can produce topical anaesthesia when used as a spray but gets rapidly absorbed.
It is more effective when combined with lidocaine (as a eutectic mixture) or phenylephrine.
Local anaesthetics are
Drugs compounds that produce temporary blockade of neuronal transmission when apply to a nerve fibre
Both consist liphilic aromatic ring, link hydrophil amine
Difference between esters and amides
draw the basic structure
Structural & functional differences
Structural
Link between aromatic ring & amine,
ester have -O-CO-
Amides have -Nh-CO-
Draw - page 203
Functional difference - stability sooln
Ester - unstable
Amide remain stable 2 year
PL prop
ester minimally protein bound
Amid more extense bound
Metabolism diffce
Ester rapidly hydrolysed plsama cholinesterase - > inactive
Amide meatbolised - slower in liver - amidases
Acummulate in dysfnx
Ester - higher incidence allergy - paraminobenozate
How do LA work
Entering Neurone * block inward Na current @ vol gate Na channekl
Prevent depol - & AP propagation
Block Na chenle from inside - higher affin for Na open / inact vs resting
Weak base
Ion at neutral ph cause pka >7.4
Amt unionised epend on pKa
uni of port lip soulbe free to diffuse thru PL memnbrae
Axoplasm - proteinated & pattract to open na chaennl
Ion form -bind internal aspec * block
Uni - dossble in PL mewmbrane - cause swell - inactibvating
PKA significane
Pka - Half drug ion & half union
pKa & pH surround - dictate % Ion vs uni-
Hendreson haselbach - calculate ratios of two states
Acid pH - Pka + log (ion)/(uni)
Base = pKa +log (uni)/(I)
@pH
Hendo hasselbac acid
Acid pH - Pka + log (ion)/(uni)
Hendo hasselbach - Base
Base = pKa +log (uni)/(I)
Why is pKa signifcant
Will know how Ionised or unionised drug will be and if exert action
At pH & acid/bases
Greater proport weak base will exist in ioniosed form
pH above pKa - grewater proportion will be unionised
Pka Lido + bupiv
Lido 7.9
Bupic 8.1
Cocaine 8.6
Explains why lido has faster onset action
Local anaes - weak bases intro to phsy pH 7.4
-> below pka - partially union
Proportion of uni drug is more the lower the pKa
Lido - higer proprt uni drug @ phys pH vs bupiv / cocaine
Inflence speed onset
As it is uni drug diffused - drugs w/ lower pka have quicker onset
Relevance of pKa
`Thio is acid - pka 7.6
Patient acidotic - proprtion unionised drug increased - reduce amount thio induction
Ion trapping
Acidotic foetus = LA becomes more unI when crosses over and trapped
Lipid solublity
More lipid solbuility = more potent
in vivo - other factos tissue distrb & bvasodiln
Protein binding
A/w duration action
Highly - bound - longer action
Also infenced vasodilatation, and potency
Vasodil - reduce potency & duration
Generall LA - cause vasodiln - low conc
Vasocon - high conc
Cocaine exception - cascon at all conc
Compare bupiv + lido
Draw them - 205
Amid
Bupiv > lido potent
Lip sol
bupiv 1000
Lido 150
Tox dose 2mg w/ or wiout adren
Lido 3mg/kg
7 with adren
TOx plas 5ug ml
Duration bupiv - longer acting - protein bound
Bupiv 95%
Lido 70%
Elim half
Ldio 100m
Bupiv 160
Onset action lido quick
pKa 7.9 25% uni at phys ph
Bupiv pKa 8.1 - 15 %
More lido union - block na chanel
Ropiv
Propyl group
Present pure S entation
Reduce potency vs bupiv
Lower lip sol vs bupic
slower onset vs lido
Lower lip sol - slower penetration larger motor fibre
- less motor
Shoul prduve slower onset short duratio
less dneser
less cardiotoxdose 3mg/kg
Cardiac effects
Bupiv & lido Block na chanell 0 slower increase Delay arrival - threhold potatnet - spont depol Prolong refactor PR & QRS prolong
Buiv - persist depression x10 longer dfiffuser vs lido
Arrhythmya VF Ca & K may also block
Rpiv less tox than bupiv
Infected tissues
Acidic envrinment
Low pH
- reduce uni framge to diffuse accross lipid emmbrae -
Inflamm vasodlain - faster removal
Conc of LA used in Spinal & epidural
Vary
general spinal 0.5% bupic
Bense block
Epidural
- dense motor block not re - lower conc 0.1 bupiv
High conc - inadeq
eg top .25%
epidural top .5% bupiv
or 15 ligno - top
Heavy marcaine
Bupivicane soln glub 80mg/ml
Gluc - subarach bock - predict block
Increase density - gravy manipulate level block
Max / tox dose
Guide max amt LA admin
However vary site, agent, vascon
Max Ligno
3/mg w,out - adrenalie
If accidntrelay inject in vessell - severe side
Ligno 3mg/lg
Ligno w/ adren 7
Bupic 2 w/wout
Ropib
3mg w/ wout
Prilo 6 wout
9 w adren
LAST fettuares
Depen plasma levels
Neuro occur first Lip tingling Paraesthesia Ligh head/ dizzy blur vision / tinnitus Shivering twhich grand mal convulsion
Cardiac dysthryhma -> VF
Factors predispose to LAST
Vasularity
More - high absorption - high risk toxicity
Blocks - intercostal paracervical, caudal epidural
Adipose - reduce absorpotion
Drug use & dose
More dilute - less risk
Concur use vascon
Acidosis & hypox increase - as reduced protein bind
Manage LAST
Standard initial abc
Antiarrythtmic drugs
Amio - unless VF - dccv
Bupiv - prolong
Grand mal - diaz. pheny, thio
Intralipid - early severe cases
EMLA
Eutectic mix La
Two compound mix - behave diff
2.5% lido 2.5% prilo
whit oil water emulsion
5 or 30gram
appply skin under dressing for 60m
anaesthic skin prior to can in paeds
Avoid methb
or drugs that can iduce - siulphona / pheny
O toluditon prilo metab - not apply meucous membnra -absortip
Patient take class 1 antiarrhym - toxic / additive affects
Amides bound to what?
All amides are basic - extens bound a1 acid glycoprotein
Lidocaine what type antiarrt
1b
vent arryht
bupivicaine cross membrane
95% deliver - protein bound
unable x lipid membarne
5% remain - 17% unI
able x palcenta - .85% dose
Ropivicaine
enantiomer?
R - less potent and more toxic
Local - mixed what what
alkaline agent - increased unI fraction
how coke metab
hepatically -> inactive
rare for ester
Baricity
alchol
glucose
acohol - hypobaric
neutro discont
hypo <0,9990
glucose as low .8% = hyperbaric
hyper = >1.001
dropping temp buipv acts hyperbaric in csf
dibucaine
amide
ester criss placenta
rapidly metabolised = dont cross placenta signif
Lidocaine toxicity
CNs tox
may occur conc >4ug/ml circumoral tingling dizzy paresthseia
10ug - conulvsion / loc
max dose 3mg plain
7mg epi
aryhtmia = 20ugml + arrest resp
25ug ml vent arrest
increased in liver failure
A 2% SOLUTION CONTAINS
20MG/ML
therefor a 70kg man should recieve upper lim of 10.5ml 2%
icnre
Intrathecal local
Vasoconstrictor
Same spread
duration action altered
Alkinisation -
affect duration block
no effect speed
Isobaric not affected positon
Min affect hpyerbaric
- increases reliability
Spread stop 20-25mins
baricity indep
d/t bulk movement csf
