Local

Anaesthetics

Classification
2 groups.
Classified according to the structure of
intermediate chain, which is either an amide
or an ester.

Esters

Amides

Cocaine

Lignocaine

Benzocaine

Bupivacaine

Tetracaine

Levobupivacaine

Procaine

Ropivacaine

Amethocaine

Prilocaine

 Amide undergo hepatic metabolism

Esters are metabolised by plasma cholinesterase.
Cerebrospinal fluid lacks esterase resolution of
neuraxial blockade with ester local anaesthetic agents
depends on systemic uptake of the drug. ( This
explains how even though they have a short half-life
they will have a prolonged duration of action if given
intrathecally)
Breakdown of esters para-aminobenzoic acid (PABA)
PABA = ALLERGEN
Amides = preferred agents in clinical practice as have
more predictable action and extremely low rate of
allergic reactions.

Structure-Activity
relationship
Lipophilic aromatic group (benzene ring) on
one end
Facilitates the binding of the drug to the sites
on the Na channel

Hydrophilic tertiary group (tertiary amide) on

other end
Linked by either an ester or amide chain

 The intermediate chain

Basis for classification of local anaesthetics
Determines how drugs are metabolised
Esters are broken down by plasma
cholinesterase
Amides are metabolised via the hepatic
microsomal enzyme system

 Modification of basic local anaesthetic structure will

change the characteristics of these drugs i.e. lipid
solubility, duration of onset, rate of metabolism, duration
of action and potency
Structural changes are usually made by:
Changing the number of carbon atoms on the lipophilic
benzene rings by
Adding a propyl group to the piperidine nitrogen atom of
bupivacaine ropivacaine (less potent and less motor blockade)
Using only L-isomer

Lengthening the interlinking chain

 All local anaesthetics (with the exception of

lignocaine) are chiral, as they possess an
asymmetric carbon
There are two stereo-isomers, S/left and
R/right.
Bupivacaine is a racemic mixture (both
isomers are present in equal amounts)
Levobupivacaine and ropivacaine have only
the S/left isomer and so are less cardiac and
neurotoxic

Bupivacaine vs. Ropivacaine vs.

Levobupivacaine

Lignocaine

Mechanism of Action

Classical mechanism

Newer Theories

Sodium channel blockers

Ion channel involvement

Receptor involvement
Transient receptor
potential vanilloid
subtype-1 channels

 Sodium channel blockers

Normal impulse conduction relies on the depolarisation of nerve
tissue by means of Na influx through ion-specific channels
Neutral non-ionised fraction of the local anaesthetic crosses the
cell membrane of the nerve. Here in a lower pH (6.9 vs. 7.4), the
local anaesthetic becomes ionised
The ionised fraction now binds to an intracellular binding site
(located on the sixth helix of domains 1, 3, and 4) on the inner
aspect of the Na channel and therefore prevents the influx of Na,
depolarisation and impulse propagation
This causes the lipid membrane to become impermeable to Na.
An action potential will not be generated, and conduction of the
impulse will cease.

 Ion channel involvement

Voltage-dependent K channels are possibly
blocked, which may explain why local
anaesthetics broaden the action potential
Voltage-dependent Ca channels may also be
blocked

 Receptor Involvement
Gq protein coupled receptors may be blocked
by local anaesthetics, suggesting an
intracellular target for the anti-inflammatory
effects of local anaesthetic drugs

 Transient receptor potential vanilloid subtype-1 channels

New evidence suggests that permanently charged local anaesthetic drugs may
gain entry to the intra-cellular milieu via the so-called transient receptor
potential vanilloid subtype-1 channels (TRPV 1)
Once opened, these channels are nonselective for the passage of mono- and
divalent cations, as well as anomalously large charged molecules. The
challenge is to deliver these large charged molecules into the cytoplasm
Currently available local anaesthetic drugs do have some ability to open the
TRPV 1 channels, their action is of limited clinical value
If a drug can be produced to open these channels, a far more potent and
prolonged impulse will be produced.
The addition of a specific TRPV 1 opener, such as capsaicin or heat, enhances
the entry of the charged local anaesthetic compounds by decreasing channel
selectivity for the large compounds. Once in the cytoplasm, blockade of the
Na channel completes the mechanism of action.

Physicochemical Properties
Property

Effect

pKa

The closer the pKa is to normal pH the faster

the onset of action

Lipid
solubility

Higher solubility = slower onset of action

Higher solubility = increased potency

Protein
binding

Higher binding = prolonged effect

Isomerism

L(S) enantiomers = less potent, less toxic

Nerve
Anatomy

Smaller diameter = easier blockade

Myelinated = easier blockade
Increased activity = easier blockade

Local factors

Sites of injection (peripheral vs. neuraxial)

Increased local blood flow = decreased
duration of action
Addition of vasoconstrictors = decreased
onset time and increased duration of action

 Degree of ionisation
Local anaesthetics are weak bases that exist in equilibrium
between the lipid-soluble non-ionised form and the ionised
hydrophilic form. When these fractions are present in equal []
the pH is known as the dissociation constant or pKa of the drug
Environmental pH (serum and intracellular pH) as well as the
pKa of the drug, determines the amount of local anaesthetic
that exists in either the ionised or non-ionised form.
Since local anaesthetic drugs bind to the intracellular aspect of
the Na channel, they need to cross the cell-membrane. To
accomplish this, they must be non-ionised. Therefore, the [] of
the non-ionised fraction is the most important

 The closer the pKa of a specific drug is to

serum pH, the larger the non-ionised fraction
will be, resulting in increased intracellular
drug []. Therefore more drug is available
leading to a higher degree of binding to the
Na channel and faster onset of action

 Lipid solubility
Increased lipid solubility hastens crossing of
the membrane, but also results in increased
sequestration of non-ionised drug in the myelin
sheaths and lipid compartments
Net result = slower onset of action, but
increased duration of action (because of local
anaesthetic that is stored in lipid tissue)

 Lipid solubility also confers a higher potency

The higher [] gradient across the membrane
driving more of the drug intracellularly
The increased affinity of the more lipid-soluble
drug for the Na channel
The ability to alter the conformation of the Na
channel by direct effects on the lipid
membrane

 Plasma protein binding

Increased protein-binding is associated with
increased duration of action (bupivacaine is 95
% protein bound and ropivacaine 94 %)
Prolonged duration of action is related to the
degree of protein binding onto extracellular
and membranous proteins

 Enantiomers
Enantiomers have different effects on the
pharmacodynamics, pharmacokinetics and
systemic toxicity of a drug
All currently available agents are racemic
mixtures, with the exception of lignocaine
(achiral), ropivacaine (S-enantiomer) and
levobupivacaine (S-enantiomer).
R- enantiomers seem to have greater
therapeutic efficacy and potential systemic
toxicity

 Nerve anatomy
Higher-activity nerves are easier to block
Myelinated nerves are easier to block
Smaller-diameter myelinated nerves
(B fibre type nerves), responsible for
preganglionic autonomic conduction are the
most sensitive to local anaesthetics
Thicker nerve fibres A (motor) and A
(pressure and proprioception) are more difficult
to block

 Site of action
site of action influences the efficacy of local
anaesthetics
e.g. peripheral, neuraxial
At the site where infection is present

 Regional blood flow

regional blood flow to the area of blockade will
determine the rate of uptake of LAs into systemic
circulation
Higher blood flow assists removal of drug from the
area and shortens the duration of action but it also
increases the chance of systemic toxicity as the
systemic concentration will rise more rapidly
Vasoconstriction and adrenaline decrease blood
flow prolong DOA

 Patient factors
Hyperkalaemia causes an increase in RMP and
thereby an increase in inactive receptors. This
may increase local anaesthetic toxicity
Low pH in tissues may delay absorption
Foetuses and neonates have lower levels of
1-acid glycoprotein thus increasing the free
fraction of local anaesthetic

 Hepatic impairment decreases metabolism of the drug

Drug interaction e.g. cimetidine will prolong the elimination
half-life of lignocaine
Physiological changes in pregnancy have the following effect:
More rapid onset of blockade as less plasma proteins are available
Prolonged exposure to progesterone causes increased tissue
sensitivity
Engorged epidural veins result in increased absorption with a
higher risk of cardiovascular toxicity
Placental transfer is affected by maternal free drug [], degree of
ionisation and metabolism, while the low foetal pH causes ion
trapping

Esters

Lipid
Solubility

pKa @ 25

% protein
binding

Potency

Cocaine

0.6

8.7

5.8

Procaine

0.02

8.9

5.8

Tetracaine

4.1

8.6

75

Amides

Lipid
solubility

pKa @ 25

% protein
binding

Potency

Lignocaine

2.9

7.7

64

Ropivacaine

6.1

8.1

94

3.5

Bupivacaine

27

8.1

95

16

LBupivacaine

27

8.1

95

16

Etidocaine

141

7.1

94

16

Prilocaine

0.9

7.9

55

0.5

Additives
Many additives in an attempt to increase the
duration of onset or prolong the duration of
effect
Adrenaline, Opioids (fentanyl, morphine), 2
agonists ( e.g. clonidine) prolong duration of
action
Alkalinisation shortens onset of action and
favours spread of epidural block

EMLA cream
A eutectic mixture composed of two
compounds
Lidocaine 2.5 % and Prilocaine 2.5 %
Only effective if applied for 60 minutes prior
to procedure
Do not use in G6PD deficiency
Can methaemoglobinaemia

Maximum Doses of LAs

Without
Adrenaline

With Adrenaline

Bupivacaine

2 mg/kg

2 mg/kg

Ropivacaine

2 mg/kg

2 mg/kg

L-Bupivacaine

2 mg/kg

2 mg/kg

Lignocaine

IV 1-1.5 mg/kg

IV 1-1.5 mg/kg

SC or IM 3-5 mg/kg

7 mg/kg

Topical 5 mg/kg

5 mg/kg

Biers
block 0.5
1.5
mg/kg
mg/kg

0.5 mg/kg
mg/kg
1.5

Cocaine

* Caution * Debate*
Some authors have advocated up to 9 mg/kg
lignocaine for topicalisation of the airway prior to
fibre-optic intubation
Lignocaine has a complex pharmacokinetic profile
and plasma levels may me unpredictable
Other authors have expressed the opinion that only
2 % lignocaine should be used for topicalisation
and the dose should not exceed 5 mg/kg
We only have 2 % available

Complications
Local Anaesthetic drug itself
Procedure related

Immediate

Intermediate

Toxic reactions
Motor paralysis
Hypotension
Urinary retention
Respiratory distress
Pain on injection

Late
Neurological
damage
- nerve trauma
- anterior spinal
artery
syndrome
- arachnoiditis
- pressure on
spinal
cord

Local Anaesthetic Toxicity

Systemic and local effects
Nerves: direct neurotoxicity (cauda equina
syndrome) and transient neurological
symptoms
Muscles: Direct damage in area of infiltration
e.g. eye blocks
Systemic targets: CNS and CVS

Clinical signs and symptoms of

toxicity

CNS

CVS

Initial phase
- Circumoral paraesthesia
- Tinnitus
- Confusion

Initial phase
- Hypertension
- Tachycardia during the CNS
excitation phase

Excitatory phase
- Convulsions

Excitatory phase
- Myocardial depression
- Decreased cardiac output
- Hypotension

Anaphylactic Rxn

* Anaphylactic reactions (Type I IgE- mediated

immune reaction) can occur.
* PABA is a breakdown product of ester local
anaesthetics
* cross-sensitivity exists for all of the esters,
and these drugs should be avoided in patients
with sensitivity to PABA-containing substances
like sunscreen