LOCAL ANAESTHETICS

Local anaesthetics (LA) are used to produce loss of sensation by

reversibly inhibiting excitation and conduction in peripheral
nerves.
Local anaesthetics have a common structure of:
• a lipophilic aromatic ring
• a hydrophillic amine
• a ''link'' molecule which is either an ester or amide bond.
It is the variations with in these chemical components that
determine the clinical properties of different LAs. LAs are usually
classified by either chemical structure (principally the 'link'
molecule) into either esters or amides .
Most LAs are weak bases and presented in acidic solutions
(usually their hydrochloric salt) and the LA molecule are
therefore ionised, water-soluble and stable in solutions
The figure below shows the structure of local anaesthetics
Mechanism of Action
• LAs disrupts conduction of impulses along the nerve axons by
inhibiting the action of sodium channels required for cellular
depolarization. In addition, LAs interact with other ionopores
and Gprotein-regulated channels suggesting a more complex
mechanism.
• Unionized LA molecules traverse the lipid bilayer and enter the
nerve cells. Aproportion of the drug then returns to its ionized
state (depends on pKa and intracellular pH) and may bind to
activated sodium channels preventing cellular depolization.
(see the next figure).
• LAs display phasic block i.e when a nerve undergoes
depolarization the sodium channels are activated and open
allowing direct entry of ionized drug molecules into the cell.
This leads to faster onset of action of LAs in stimulated nerves
A figure showing mechanism of action of local anaesthetics
Isomerism and LA
 Stereoisomers are molecules with the same chemical formula
and bond structures but different 3-D, spatial arrangements.
Optical stereoisomers occur when 4 different chemical groups are
bound to a carbon or quaternary nitrogen atom know as a chiral
centre.
 Two isomers are produced are produced which are mirror images
of each other and can not be superimposed on each other.
 A mixture containing equal amounts of both isomers is called a
'racemic mixture'. Bupivacaine and prilocaine are racemic
mixtures. Each optimal isomer is known as an enantiomer and
share the same physio-chemical properties, but differs in its
interaction with target receptor sites.
 This unique property of stereoisomers has led to the development
of single enantiomer preparations with an improved toxicity profile.
 Levobupivacaine and ropivacaine are the enantiomer LAs in
widespread clinical use. Levobupivacaine (the S-anantiomer of
bupivacaine) has supperior cardiotoxicity profile compare to
racemic mixture due to its faster dissociation of the LA from
cardiac sodium chanenls.
Ripivacaine (also S-anantiomer) when compared to racemic
bupivacaine displays reduced cardiac and CNS toxicity and when
cardio-toxicity does occur it may be easier to treat due to reduced
affinity for cardiac sodium channels.
• Potency is closely correlated to lipid solubility. However other
factors like vasodilator properties and tissue distribution
determine the amount of LA that is available at the nerve
• The duration of action is closely associated with the extent of
protein binding. Local anaesthetics with limited protein binding
have a shorter duration action, and conversely those with more
extensive protein binding ability have a longer duration of action.
• The onset of action is closely related to the pKa. LA are weak
bases and exist mainly in the ionised form at a normal pH.
Those with a high pKa have a greater fraction present in the
ionised form, which is unable to penetrate the phospholipid
membrane, resulting in a slow onset of action . Conversely a
low pKa reflects a higher fraction present in unionized form and
therefore a faster onset of action as more is available to cross
the phospholipid membrane.
• The intrinsic vasodilator activity varies between drugs and
influences potency and duration of action. In general, LAs cause
vasodilation in low concentrations(prilocaine> lidocaine>
bupivacaine> ropivacaine) and constriction at higher
concentrations. Cocaine has solely vasoconstrictor effect by
inhibiting the neuronal uptake of catecholamines and inhibiting
monoa mine oxidase (MOAs)
Lidocaine/ Lignocaine
• It is an amide local anaesthetic that is also used to control
ventricular tarchacardia VT.
• It is formulated as hydrochloride and presented as a colourless
solution (0.5 - 2%) with or without adrenaline (1 in 80-200,000); a
2% gel ; 5% ointment; a spray delivering 10mg per dose and 4%
solution for topical use on mucous membranes.
• dose 4mg/kg without adrenalin and 6-7mg/kg with adrenaline
Kinetics
It is 70% protein bound alpha1-acid glycoprotein. It is extensively
metabolised in the live by dealylation to monoethylglycine-xylidide
and acetyldehyde.
The former is further is hydrolysed while the later is hydroxylated
to 4-hydroxy-2,6xylidine forming the main metabolite whice is
excreted in urine. Some of the metabolite have anti-arrhythmic
properties whereas others pontentiate lidocaine - induced seizures.
Clearance is reduced in presence of hepatic or cardiac failures
Bupivacaine
• It is prepared in 0.25% and 0.5% solutions with( adrenaline
1:200,000) or without adrenaline. A 0.5% preparation with
glucose 80mg/ml is available for subarachnoind block.
DOSE
Local infiltration, epidural top ups and peripheral nerve blocks 1-2
mg/kg
Subarachnoid block 0.3mg/kg do not exceed 20mg
Kinetics
The onset is intermediate or slower than lidocaine, it is highly
protein bound amide LA metabolised in the liver by deslkylation to
pipecolic acid and pipecolylxylidine.
Levobupivacaine
It is S-entantiomer of bupivacaine, which is the racemic mixture of S-
and R- enantiomer.
Preparation It comes as a 2.5, 5, and 7.5mg/ml sloution. its's used in
the same way as bupivacaine. Maximum single dose of 150mg is
recomended and 400mg maximum dose in 24 hours.
Properties of some local anaesthetics
Drug Onset Duration pKa %unionized Relative
at pH 7.4 lipid
solubility
Procaine slow short 8.9 3 1

Amethocain slow long 8.5 7 200

e

Lidocaine fast medium 7.9 28 150

Prilocaine fast medium 7.7 33 50

Mepivacaine slow medium 7.6 40 50

Ropivacaine medium long 8.1 15 400

Bupivacaine medium long 8.1 15 1000

Local Anaesthetic Toxicity (LAST)
Local anaesthetic toxicity occurance is estimated at 1 in 1000 in
general and 1 in 10000 blocks.
Causes
• Drug overdose (exceeding the maximum dose)
• Inadvertent intravascular injections; needle tip in a blood
vessel, epidural vein canulation and connection of LA infusions
to an IV cannula.
• Rapid absorption of a bolus dose.
• Cumulative effect of infussions or repeated doses.
• Susceptible patients (metabolic mitochondrial diffects, pre-
existing cardiac conduction blocks) may be at high risk of
toxicity.
Pathophysiology
The CNS and CVS are principally affected by systemic toxicity.
The pattern of of toxicity is broadly similar for all LAs but
variations exist in the relative severity and timing of CNS and CVS
symptoms.

Bupivacaine toxicity presents with earlier and more severe CVS

sequelle than lidocaine.
It is not necessary or likely that patients will exhibit all the signs
and symptoms described below in a progressive manner.
Therefore, Local anaesthetic toxicity should considered with
presentation of any of the signs and aymptoms listed.

The clinical scenario may also influence the observed pattern of

symptoms;
• Doses of benzodiazepines (given as anxiolytics before regional
blockade) sedation, or general anaesthesia may raise the
seizure threshold.
• Tonic clonic seizures may not be noticed with the use of
muscle relaxants.
Similary th signs and symptoms can easily be attributed to each
other causes (whic can make the accurate estimates of the
incidence of LAST difficult):
• The combination of surgery and anaesthesia offers many
routes to cardiovascular colapse.
• In obstetric patients, seizures is often first attributted to
eclampsia
• CVS collapse from anaphylaxis.
• Hypotension (and CVS collapse) from a neuraxial blocks
Signs and Symptoms of LAST
CNS signs and symptoms
 Perioral tingling.
 Tinitus.
 Light headedness.
 Slurred speech.
 Muscle twitches.
 Loss of consciousness.
 Convulsions/seizures.
 Coma.
 Respiratory arrest.
CVS signs and symptoms
 Myocardial depression - bradycardia, hypotension
 Conduction deffects.
 Dysrhythmias.
 Cardiac arrest.
Mechanism
• Clinically LAs were thought to act by binding and inhibiting
voltage-gated sodium channels, dampening action potentials
along the nerve.
• Most used LAs are amphipathic (have hydrophobic and
hydrophilic moiesties) so they are apt to bind both hydrophillic
proteins (dissolved in cytosol) and hydrophobic proteins
(dissolved in lipid bilayer of the cell or organelle wall).
• More specifically, LAs have been shown to bind voltage -gated
potassium and calcium channels as well as sodium channels
and also inhibit intracellular signal transduction after Gprotein
activation.
• These different actions can be correlated with the detail of the
cardiovascular collapse during intoxication. Inhibition of voltage
-gated calcium channels slows the cardiac automaticity
(bradycardia) and conduction (conduction blocks)
• Inhibition of voltage -gated sodium and potassium channels
slows the action potential propagation and repolarisation,
promoting re-entrant tachycardia before asytole supervens.
Treatment.
lipid emulsion
It should be given only when the patient is in circulatory arest.
However it is sensible to give it before a full circulatory collapse.
Dose: bolus of 1.5ml/kg of 20% lipid emulsion followd by an
infusion of 15ml/kg/hr
Mechanism of action.
It remains unclear. It may act as alipid sink binding free LA
molecules and thus resducing the plasma concentration below
toxic levels.
The use of lipid emulsion to succefully treat overdoses of other
lipophillic drugs supports this mechanism of action.
Prevention
Excessive doses
• Thoughtless adherence to ostensibly safe dosages breeds
compliancy, instead doses should be tailored to the patient and
perherps moderated where absorption will be faster. Epinephrine
added to racemic bupivacaine slows absoeption and reduces
peak plasma concentration after a peripheral nerve block.
• Injection of a single short over a minute or so reduces the peak
plasma concentration to which the heart is exposed too.
Inadvertent iv injection.
• Intermitent aspiration during the injection of a single shot dose
is obviously essential but it is fallible.
• The use of US-guided regional anaesthesia should reduce the
risk of Iv injections; but it has still been reported.
• Addition of a marker low concentration (1:400,000 adrenaline)
to a LA can reveal inadvertent IV injection before the entire
inted dose is delivered.