Local Anaesthetics
Slides acknowledgment:
Dr Chris Keating
Modified and delivered by:
Dr. Shaymaa ElBahy
Objectives
• Understand basic chemistry of local
anaesthetics
• Understand how they work
• Investigate how their structural properties are
related to their pharmacological functions
Local anaesthetics are:
• Drugs that relieve pain in specific parts of
the body without causing the loss of
consciousness
• Drugs that reversibly block pain sensation
by blocking nerve conduction
Mechanism of action
Local anaesthetic
Na+ Inactivated voltage-gated sodium
channels
Mechanism of action
• Local anaesthetics reversibly bind to the
(inactivated) voltage gated sodium channels
present on neurons
✓ Blocks sodium channel gating
✓ Blocks action potential propagation and thus
nerve conduction
PROPAGATION
FAILURE
LOCAL ANAESTHETIC
Local anaesthetic effect upon action
potentials
Local
anaesthetics
block this
component of
action
potentials
History of local anaesthetics
• Cocaine (first local anaesthetic)
• Isolated from coca in 1880 (The
native inhabitants of Peru who
chewed the leaves of the coca
shrub for its psychotropic effects
knew of this plants numbing
effects on the mouth and tongue)
• Karl Koller
– Used cocaine in
ophthalmology
– Then dentistry
• In 1905 procaine (first synthetic
local anaesthetic developed)
Ideal properties of a local anaesthetic
– Specific and reversible action
– Non-irritant with no permanent damage
to tissues
– No systemic toxicity
– Rapid onset and long duration
– Active topically or by injection
Local anaesthetics: basic chemistry
General structure
LAs
grouped
into
AMIDES
or ESTERS
The general structure of local anaesthetic molecules consists
of i) an aromatic group (left) , ii) linked by an ester or amide
group to iii) an ionisable amine group (right)
General structure
If LA has
two “i”s in
it, then it
is an amide
Adapted from Rang and Dale, 7th Ed
Potency of local anaesthetics
Two important properties of local
anaesthetics determine their activity:
1) Lipid solubility (increases with number of
carbons on aromatic ring and/or amine
group). Higher lipid solubility means can use
lower dose and reduce toxicity risks
2) Ionization constant (pKa): determines the
proportion of ionised and unionised
anaesthetic in solution
• Lipid solubility determines potency, plasma
binding and duration of action of LA.
e.g.
anaesthetic Lipid potency % plasma duration
solubility protein
binding
Procaine low low 6% 60- 90 min
Tetracaine high high 80% 180- 600 min
• Local anaesthetics with lower pKa values
have faster onset of activity (greater
amount of unionised form can diffuse
across membrane)
pKa % free base Onset of
at pH 7.4 anaesthesia*
Lidocaine ~7.8 ~25% rapid
Mepivacaine 7.6 ~37% rapid
Bupivacaine 8.1 ~18% slow
• Local anaesthetics are weak bases (pKa > 7.4).
H+
Tertiary Form (B) Quarternary form (BH+)
• The proportion of the free base (B) and ionised
form (BH+) depends on the pH of the solution
and the pKa of the local anaesthetic.
Both the ionised (BH+) and unionised form (B) of
the local anaesthetic are necessary for activity
BH+ B + H+ pH = 7.4
Extracellular
Nav channel Na+
Na+
Plasma
membrane B
BH+
Blocked
Closed Open
Intracellular
H+ + B BH+
• Local anaesthetics block the inner region of the Na+
channel and block sodium ion conduction
Extra slide by Dr Majid for
In a nutshell… explanation
• Note that in the formulation, LA is present
predominantly as ionized
• When injected/applied, in the body in the
presence of physiological pH, LA is present
predominantly as unionized
– So it will easily cross the neuron membrane and will
go inside the neuron
• Inside the neuron, LA is predominantly present as
ionized
– So the ionized form will then block inactivated sodium
channels from the inside of the neuron and thus block
or slow down the conductance of nerve impulse
Note that LA is switching forms
between ionized and unionized
Pharmacological effects of local
anaesthetics
• Nerves: decrease and abolish conductance of
action potentials
• Vascular smooth muscle: vasodilation
• Cardiac muscle: decreased excitability.
Prolong the effective refractory period
• CNS: increased excitability followed by
depression
Influence of nerve fibre diameter
PROPAGATION
FAILURE
LOCALANAESTHETIC
LOCALANAESTHETIC
Local anaesthetics preferentially block smaller diameter
nerve fibres
Nerve fibre susceptibility to local
anaesthetic block
Fibre type Associated with Diameter Myelinated Conduction Blocked by LA
(µm) velocity
(m/s)
Type A: Proprioception; 12- 20 YES 70- 120 +
Alpha (α) motor functions FAST SLOW
Beta (β) Light touch; 5- 12 YES 30- 70 ++
pressure; muscle
spindle receptors
Gamma (γ) Muscle spindles 3- 6 YES 15- 30 ++
stretch
Delta (δ) Fast Pain; mechanical 2- 5 YES 12- 30 +++
stimuli; Cold
Type B: Preganglionic fibres <3 Light 3- 15 ++++
Autonomic
Type C: Slow pain; warm
temperature;
0.3- 2 No 0.5- 2
SLOW FAST
++++
Sensory mechanical stimuli
Summary of nerve fibre responses to
local anaesthetics
Generally:
✓ Local anaesthetics preferentially block
conduction in small diameter nerve fibres
✓ Better at blocking unmyelinated C-fibres
✓ Aδfibres and C fibres mediate nociceptive
impulses; therefore LA block pain sensation
more readily than other sensory functions (e.g.
touch, proprioception)
✓ BUT: other sensory modalities will be affected
over increased exposure time
QUESTION
• Patient X presents at an ER clinic with a severely
inflamed finger, and in great pain. The doctor
finds that localised injections of a local
anaesthetic don’t have much effect on pain relief
in this patient. Why? What factors should the
doctor look for in his choice of local anaesthetic?
Hints: Inflamed tissue will contain a cocktail of
inflammatory mediators such as ATP,
prostaglandins, 5-HT, and H+ ions.
QUESTION
• In dentistry, lidocaine injections often contain
epinephrine. Why do you think this is, and
why are adverse cardiac effects a risk with
local anaesthesia?
• Hints: LA are mainly removed from sites of
application via the systemic circulation. What
effect does epinephrine have on small blood
vessels? LA block ALL Na channels.
Duration of action of local
anaesthetics
• Only cocaine has its own vasoconstrictor
activity
– Noradrenaline uptake inhibitor
• Most other injections contain epinephrine
– Counteract/oppose the vasodilating properties
of LA
– Remains in contact with nerve (prolongs
actions of LA)
– Reduces systemic toxicity and side effects of
LA (such as unwanted actions on CNS and
heart)
Effect of adrenaline on anaesthesia
Local adrenaline Duration of
anaesthetic anaesthesia
Lidocaine (2%) 5- 10 min
Lidocaine (2%) 1: 100, 000 60 min
• Concentration of epinephrine (adrenaline) in
preparations can vary and is usually expressed
in ug per ml
• Above example 1:100,000 = 1 g : 100,000 ml
(10 ug/ml)
Data: university British Columbia & Cook Waite
Metabolism of local anaesthetics occurs
at the ester or amide links
• Esters (Metabolised in the plasma)
✓ Most ester-linked LA are quickly metabolized by
non specific esterases in plasma
• Amides (Metabolised in the liver)
✓ Amide-linked LA are more stable with longer
plasma half lives. Metabolized by
✓ oxidative dealkylation/oxygenation by
monooxygenase &
✓ hydroxylation by carboxylesterase
Clinical use of local anaesthetic agents
• Infiltration: use in minor surgery (e.g. Inradermal))
• Topical anaesthesia: use in nose, mouth, bronchial
tree
• Spinal anaesthesia: use in surgery (when GA can’t
be used?)
• Epidural: use in spinal anaesthesia and childbirth
• Nerve block: use in surgery , analgesia, dentistry
• Intravenous regional block: use in limb surgery
Adverse drug reaction (ADRs) of
local anaesthetics
• CNS
– Initially stimulation, tremors and even
convulsions
• Due to block of inhibitory neurons
• Treat with benzodiazepines
– Higher concentration leads to depression
• Death from respiratory depression
• Need to maintain airways
• Cardiovascular
– Decreased excitability of myocardium
– Decreased cardiac output
– Also some vasodilatation
– Occasionally CV collapse and death
Lidocaine and procainamide used as anti-
arrhythmics
Mechanism and symptoms of acute local
anesthetic toxicity
nAch, nicotinic acetylcholine; NMDA, N‐methyl‐D‐aspartate.
[Link]
Management of acute local anesthetic toxicity
[Link]
Summary
• Local anaesthetics act by blocking inactivated
voltage gated sodium channels and prevent action
potential generation in nerve fibres
• Generally block action potentials conduction in
small diameter nerve fibres more readily than large
diameter fibres
• Comprise of many similar drugs, but they contain
subtle differences in structure that allow their
pharmacological use to be tailored for different
medical situations
