The Pharmacology of Local
Anaesthetic Agents
Classification
Local anaesthetic agents can be
defined as drugs which are used
clinically to produce reversible loss
of sensation in a circumscribed
area of the body.
Structure
Most of the clinically useful local
anaesthetic agents consist of an
aromatic ring linked by a carbonyl
containing moiety through a
carbon chain to a substituted
amino group.
Classification
ester
cocaine, procaine, amethocaine
and chloroprocaine
amides
lignocaine, prilocaine, mepivacaine
and bupivacaine.
Esters
relatively unstable in solution and
are rapidly hydrolysed in the body
by plasma cholinesterase (and
other esterases).
main breakdown products is para-
amino benzoate (PABA) which is
associated with allergic phenomena
and hypersensitivity reactions.
amides
relatively stable in solution, are
slowly metabolised by hepatic
amidases
hypersensitivity rare.
In current clinical practice esters
have largely been superseded by
the amides.
Mode of Action
LA cause reversible interruption of
the conduction of impulses in
peripheral nerves.
These effects are due to blockade
of sodium channels, thereby
impairing sodium ion flux, across
the membrane.
Mode of Action
Most local anaesthetic agents are
tertiary amine bases (B) that are
administered as water soluble
hydrochlorides (B.HCl).
After injection, the tertiary amine
base is liberated by the relatively
alkaline pH of tissue fluids:
B.HCl + HCO <--> B + H CO + Cl-
3 2 3
In tissue fluid the LA present in both an
ionised (BH+) and non-ionised form (B);
Rel. proportions depend on the pH of
the solution and the pKa of the
individual drug.
The non-ionised base (B) then diffuses
through the nerve to axoplasm where it
partially ionises again:
B + H+ <--> BH+
Mode of Action
In the ionised form BH+, the LA
enters the Na+ channel (from the
interior of the nerve fibre)
results in channel blockade.
Preparations of Local
Anaesthetics
Most LAs bases almost insoluble in
water. Solubility greatly increased
hydrochloride salts
Dilute preparations of local anaesthetics
are usually acid (pH range 4.0-5.5),
contain a reducing agent (e.g. sodium
metabisulphite) to enhance the stability
of added vasoconstrictors.
also contain a preservative and a
fungicide.
preparations
dilute preparations are presented as
percentage solutions of local anaesthetic.
lignocaine 0.5, 1.0, 1.5 and 2% solutions for
injection ( with or without adrenaline).
A solution 1% contains 1g of substance in each
100mls.
mg/ml easily calculated by multiplying the
percentage strength by 10.
1% solution of lignocaine contains 10mg/ml of
solution .
0.25% solution of bupivacaine has 2.5mg/ml.
Preparation-
Vasocontrictors
Adrenaline most commonly used
vasoconstrictor,
added to LAs in concentrations
ranging from 1 in 80,000 to 1 in
300,000, although most are
usually prepared to contain a 1 in
200,000 (5 microgram /ml)
concentration of adrenaline.
Practical Point
Adrenaline 1:1000 contains 1 gram of
adrenaline per 1000mls solution i.e.
1mg/ml.
To prepare a 1 in 200,000 solution the
1:1000 must be diluted 200 times. This
is achieved by taking 0.1ml (= 0.1mg)
and adding 19.9 mls of local anaesthetic
solution.
Vasocontrictors
Adrenaline containing solutions-
never end-arteries
i.e. penis, ring block of fingers or
other areas with a terminal
vascular supply
Clinical Uses of Local
Anaesthetics
LA req and activity vary
considerably.
Selection requires knowledge of the
clinical needs and pharmacological
properties of the various LAs
Topical Anaesthesia
Infiltration Anaesthesia
Conduction Anaesthesia
Extradural Anaesthesia
Spinal Anaesthesia
Intravenous Local Anaesthesia
topical anaesthesia
LA - skin, the eye, the ear, the
nose and the mouth & other
mucous membranes
have a rapid onset of action (5-
10mins) and a moderate duration
of action (30-60 mins).
cocaine, amethocaine, lignocaine
and prilocaine are the most useful
topical anaesthesia- EMLA
EMLA cream is a eutectic mixture
of local anaesthetics
provide surface anaesthesia of the
skin (particularly in paediatric
practice).
mixture of the base forms of
lignocaine and prilocaine
Infiltration Anaesthesia
for minor surgical procedures
Amide LAs - moderate duration
of action are commonly used
(lignocaine, prilocaine and
mepivacaine
Procaine has a short duration
(15-30 min),
Infiltration Anaesthesia
lignocaine, mepivacaine and
prilocaine - moderate duration
(70-140 min)
Bupivacaine has the longest
duration (~200 min).
adrenaline (1 in 200,000) will
increase the quality and
prolong the duration
minor nerve blockade (e.g. ulnar,
radial or intercostal
major blockade of deeper nerves
or trunks with a wide dermatomal
distribution (e.g. brachial plexus
blockade
Extradural Anaesthesia
epidural space between the dura mater
and the periosteum lining the vertebral
canal.
Blocks intradural spinal nerve roots.
quality and extent volume & total dose
of the drug
spread of LA more extensive in elderly
pregnant, obesse
Bupivacaine (0.5%) or lignocaine (1.5-
2.0%) are usually used
Spinal Anaesthesia
directly into the CSF produces
spinal anaesthesia.
faster onset of action & smaller
dose is required.
Spinal similar clinical effect with a
dose ~10 times smaller than
extradural
Intravenous Local
Anaesthesia -IVRA
useful method of providing analgesia
for minor surgical procedures.
LAs injected into a vein of a limb
previously exsanguinated and
occluded by a tourniquet
Bupivacaine and etidocaine should
never be used for IVRA !
Toxicity of Local
Anaesthetic Agents
systemic and localized toxic
reactions accidental intravascular
intrathecal injection
excessive dose of the LA
CNS and the CVS
CNS toxicity
light- headedness, dizziness and
circumoral paraesthesia - precede
visual and/or auditory disturbances
such as difficulty focusing and
tinnitus (ringing in the ears).
convulsions
Cardiovascular toxicity
occurs at doses and blood
concentrations which are higher
than those required to produce
CNS toxicity.
LA exert both direct effect on the
heart & periph blood vessels.
Management of Acute
Toxicity
airway maintained
oxygen
ventilation if apnoea occurs.
Convulsions should be treated
with anticonvulsant drugs such
as thiopentone (150-250mg
I.V.) or diazepam (10-20 mg
I.V.) repeated as necessary.
Management of Acute
Toxicity
Profound hypotension and brady -
arrhythmias - IV atropine (0.5-1.5mg)
and colloid or crystalloid infusions
adrenaline may be required for
severe hypotension or bradycardia.
ventricular fibrillation due to
bupivacaine toxicity, CPR continued
for at least 60mins. Bretyllium may
facilitate cardioversion
Practical Use of Local Anaesthetic
Agents
Example 1
A 70 kg male is scheduled for axillary
block. The anaesthetist decides to use 30
mls of solution. He only has 2% plain
lignocaine available. What should he do?
A 2% solution contains 20mg/ml
lignocaine. The toxic dose of lignocaine is
3mg/kg without adrenaline added and
7mg/kg with adrenaline.
The maximum safe dose of lignocaine for
this patient is 210mg without and 490 mg
with adrenaline.
Example 1…
30mls of 2% plain lignocaine gives
600mg. The anaesthetist must therefore
dilute the lignocaine and add adrenaline
to it.
20 mls of 2% plain lignocaine contains
400 mg lignocaine which can be made up
to a 30 ml solution with 10 mls N. Saline.
The adrenaline is 1:1000 i.e. 1mg/ml and
he requires 1:200,000 i.e. 5
microgram/ml. Therefore for every 20mls
of local anaesthetic solution he should
add 0.1ml of 1:1000 solution; a total of
0.15mls for his 30ml mixture.
Example 2
A 6 year old child weighing 20kg is
scheduled for hernia repair. The
anaesthetist wishes to supplement general
anaesthesia with an ilioinguinal block. He
only has 0.5% plain bupivacaine. What
should he do? Ideally he would wish to use
at least 10mls of solution. The maximum
dose of bupivacaine which can be given is
2mg/kg ie. 40mg.
Example 2……
10 ml of 0.5% solution should be
diluted with 10ml normal saline to
give 20ml 0.25% solution. 10 ml of
this solution should be used to
produce an ilioinguinal block
Maximum Safe Dose
Plain With
Solution Adrenaline
mg/kg mg/kg
Prilocaine 6 9
Lignocaine 3 7
Bupivacain 2 2
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