Local Anaesthetics

Aaron Opoku Antwi, PhD.

Dept. of Pharmacology
Ist Floor, New Pharmacy Block
Anaesthesia
▷ Anaesthesia – reversible loss of sensation with
or without loss of consciousness.
▷ Local anaesthetics – agents which cause a
reversible loss of sensation for a limited region
of the body while maintaining consciousness.
Local anaesthetics
▷ Cocaine – first LA discovered; chewing leaves of
Erythroxylon coca had stimulatory effects and
numbed the tongue.
▷ Newer types discovered over the years.
▷ Drug is delivered directly to the target organ/site
○ systemic circulation diminishes/terminate its effect.
▷ High conc. can act on every type of fiber casing
both sensory and motor paralysis in applied area.
Local anaesthetics – Ideal Properties
▷ Not irritating to tissue or damaging to nerve
structure
▷ Low systemic toxicity
▷ Short onset of action
▷ Duration of action should be long enough for
completion of procedure
▷ Stable in solution and low allergenicity
 LAs: Nerve Fibre Blockade
▷ LA needs to cross nerve sheath and axon membrane.
▷ Differential sensitivity of types of nerve fibres depends
on fibre diameter, myelination, physiologic firing
rate, and anatomic location.
○ Smaller fibres are blocked more easily
○ myelinated fibres are blocked more easily than unmyelinated
fibres.
○ Fibers located in the periphery of a thick nerve bundle are
blocked sooner than those in the core - exposed earlier to
higher concentrations of the LA.
 LAs: Nerve Fibre Blockade
▷ Order of sensitivity

Type B and Type C  Recovery is in the reverse order

Type Aδ  Blockade of Type Aδ (sharp pain)

Type Aβ and Aγ and C fibres (dull pain) countributes

Type Aα most to the loss of pain sensation.

 LAs: General Uses
▷ Dental analgesia – for minor surgery (infiltration
anaesthesia).
▷ LA ointments used for pain relief from
haemorrhoids and anal fissure.
▷ Lozenges for mouth ulcers
▷ Eye drops containing oxybuprocaine, tetracaine for
tonometry or minor ophthalmic surgery.
▷ Component of ‘delay’ sprays and come condoms –
reduce sensation and delay ejaculation.
LAs: Chemistry
▷ Basic structure: Hydrophobic head (usually aromatic ring)
and hydrophilic side chain (usually tertairy amine) moeities with
an intermediate ester or amide linkage
 LAs: Chemistry
▷ Atypical LA – benzocaine
has no basic amine side chain.

▷ LAs are classified based on

type of linkage in its chemical
structure,
▷ Ester LAs
▷ Amide LAs
 LAs: Classification
▷ Esters
▷ Highly susceptible to metabolism by
tissue and sytemic esterases
▷ Rapidly inactivated; generally
shorter duration of action
▷ Higher risk of hypersensitivity
reactions
▷ Eg. Cocaine, benzocaine, procaine,
tetracaine (clue: no ‘I’ before
 LAs: Classification
▷ Amides
▷ Broken down by liver
amidases
▷ Fairly stable.
▷ Generally have longer plasma
half lives
▷ Eg. Lidocane, bupivacaine,
mepivacaine, ropivacaine
LAs: Chemistry
▷ 
LAs: Chemistry
▷ LAs are mainly but not completely, ionized
at physiological pH (7.14-7.34)
○ (except benzocaine pka 3.5) solely as
nonionized base under normal physiologic
conditions.
▷ reverse is true for higher pH (mainly
unionized forms exist).
LAs: Chemistry
▷ LAs are more effective at higher pH
○ greater proportion of unionized forms
○ diffuse faster across nerve sheath and axon
membrane to active site.
▷ This explains
○ alkalinization of LA solution to shorten onset
and improves effectiveness
○ ineffectiveness of LA is acidic wounds and
some infected tissues due to high acidity
LAs: Sructure Activity Relationship
▷ Smaller and more highly lipophilic LAs
○ have a faster rate of interaction with the Na channel
receptor
○ strong association with hydrophobic target sites (reduces
rate of degradation by tissue and liver enzymes)
▷ Lipid solubility increases potency, duration of
action and toxicity.
▷ Tetracaine, bupivacaine, and ropivacaine (all highly
lipid soluble) are potent agents with long duration of
action.
 Local anaesthetics: General properties
LA Lipid solubility Relative Duration
potency
Procaine <1 1 short

Mepivacaine 1 1.5 medium

Lidocaine 3 2 medium

Ropivacaine 14 8 long

Bupivacaine 28 8 long

Tetracaine 80 8 long
 LAs: Pharmacokinetics
▷ Absorption: Low molecular weight and highly
lipophilic LAs have a faster rate of diffusion
and interaction with Na channel.
▷ Systemic absorption (to be avoided) affected
by:
○ local blood flow
○ use of vasoconstrictor
LAs: Pharmacokinetics
▷ Benefits of addition of vasoconstrictor,
mainly epinephrine to LAs
○ Improved neuronal uptake/decrease in risk of
systemic toxicity
○ Longer duration
○ Lower anaesthetic dose requirement
○ Direct analgesic effect in spinal anaesthesia via
α2 stimulation
 LAs: Pharmacokinetics
▷ Metabolism and Excretion

▷ Ester types – rapidly hydrolyzed in blood by

circulating butyrylcholinesterase to inactive
metabolites (half-life of procaine less than a minute.)
▷ Amide types – metabolized by liver microsomal
enzymes via hydroxylation and N-dealkylation
▷ Greater risk of toxicity in hepatic disease.
 LAs: Mechanism of Action
▷ Inhibit action potential conduction in sensory nerves
by blocking voltage gated Na channels.
▷ Bind reversibly to specific site deep within Na channel
pore – Easily reached by unprotonated forms
▷ It is however the protonated form that interacts with
Na channels – charged forms of the drugs are the active
forms.
▷ Protonation (of diffused uncharged forms) easily occurs
at tissue pH.
LAs: Mechanism of Action
LAs: MOA – Use dependence
▷ Resting nerve is much less sensitive to LA
than a repetitively stimulated one (frequency
and voltage dependence).
▷ Charged LA gains access to binding site
(within channel pore) when it is in open state.
▷ LA binds more tightly to and stabilizes channel
in inactivated state (prevents opening of H gate
and Na entry).
LAs: MOA – Use dependence
LAs: Adverse Effects
▷ Toxicity arises mainly from ‘escape’ of LAs into
systemic circulation.
▷ CNS effects: agitation, confusion, tremors
progressing to convulsions and respiratory
depression, coma.
▷ CVS effects: myocardial depression and
vasodilatation, leading to fall in BP, cardiac arrest
 LAs: Adverse Effects
▷ Hypersensitivity Reactions:
allergic dermatitis, rashes,
anaphylaxis
▷ Risk is much higher with an
ester type than with an amide
because of PABA, a metabolite
of esters.
▷ There is cross-reactivity within
a class
LAs: Adverse Effects
▷ Transient Neurological Symptoms
(TNS) - syndrome of transient pain of
lower back, limbs, buttocks, thighs, or
calves typically after spinal anaesthesia
Lidocaine (Xylocaine, Lignocaine)
▷ Rapid onset, moderate duration and good
penetration.
▷ Widely used for local anaesthesia
▷ Also used intravenously for treating ventricular
dysrhythmias though no longer as first choice
▷ By injection or topically as a gel or aerosol.
▷ Useful in all local anaesthesia techniques
▷ Hypoallergenic
Bupivacaine
▷ Slow onset but long duration.
▷ It is often used for epidural blockade (e.g. to
provide continuous epidural blockade during
labour and spinal anaesthesia.
▷ Greater cardiotoxicity than lidocaine
▷ S(–) enantiomer of bupivacaine, levobupivacaine
is less cardiotoxic.
▷ Not suited for ambulatory surgery/outpatient
(long duration – delayed recovery)
Mepivacaine
▷ Rapid onset and good penetration similar to
lidocaine
▷ Less vasodilatation (may be administered without
a vasoconstrictor).
▷ Slowly metabolized by the fetus
○ poor choice for epidural anesthesia in the
parturient woman
Prilocaine
▷ No vasodilator activity
▷ Lower risk of typical systemic toxicity (useful in
IV regional anaesthesia)
▷ Can cause methaemoglobinaemia (due to
accumulation of one of its metabolites, ortho-
toluidine, an oxidizing agent.
▷ Widely used; not preferred for obstetric analgesia
because of risk of neonatal methaemoglobinaemia.
EMLA
▷ Eutectic Mixture of Local Anesthetics
▷ Formulation of 2.5% lidocaine and 2.5%
prilocaine, permits anesthetic penetration of the
keratinized layer of skin, producing localized
numbness.
▷ It is commonly used in pediatrics to anesthetize
the skin prior to venipuncture for intravenous
catheter placement.
▷ Anaesthetic prior to venipuncture, skin harvesting
etc.
 Others
▷ Cocaine: Rarely used; causes vasoconstriction; limited
use due to potential for abuse.
▷ Procaine: The first synthetic agent poor penetration, No
longer used, prototypic ester type.
▷ Tetracaine: Used mainly for spinal and corneal
anaesthesia. Slow onset and long acting
▷ Articaine: Used in dentistry; contains an amide linkage it
also has an ester group on a side chain. Can induce
prolonged numbness (paraesthesia) that outlasts the
presence of the drug in the body.
Others
▷ Benzocaine: unusual local anaesthetic of very
low solubility. Mainly for surface anaesthesia (dry
powder to dress painful skin ulcers, or as throat
lozenges).
▷ Ropivacaine: less cardotoxicity; Newer long
acting local anaesthetics.
Other Na channel blockers
▷ Tetrodotoxin: produced by a marine bacterium and
accumulates in the tissues of a poisonous pacific
fish, the puffer fish.
▷ Saxitoxin: produced by a marine microorganism
(micro algae) and in jellyfish contaminated by the
algae.
▷ Both TTX and STX are unsuitable for clinical use
as local anaesthetics, being expensive to obtain
from their exotic sources and poor at penetrating
tissues because of their very low lipid solubility
 LAs: Various techniques
▷ Surface Anaesthesia: Nose, mouth, bronchial tree
(usually in spray form), cornea. (tetracaine, lidocaine
benzocaine)
▷ Infiltration anaesthesia: Direct injection into tissues
to reach nerve branches and terminals. Used in minor
surgery (dental, wound stitching etc). vasoconstrictor
required. (lidocaine, procaine, bupivacaine)
▷ Nerve block anaesthesia: LA is injected close to nerve
trunks to produce a loss of sensation peripherally; Used
for surgery, dentistry, analgesia (lidocaine,
bupivacaine, mepivacaine)
 LAs: General Uses
▷ Spinal anaesthesia: LA injected into the subarachnoid
space (containing cerebrospinal fluid) to act on spinal
roots and spinal cord; mainly lidocaine
▷ Epidural Anaesthesia: LA injected into epidural
space, blocking spinal roots Used as for spinal
anaesthesia; also for painless childbirth. (lidocaine,
bupivacaine, tetracaine)
▷ Intravenous regional anaesthesia: LA injected
intravenously distal to a pressure cuff to arrest blood
flow; Used for limb surgery. (lidocaine, prilocaine)