LOCAL

ANAESTHETICS
Lecture objectives
At the end of the lecture, students
should be able to:
 Classify different types of LA
 Explain the pharmacology of LA
 Compare the pharmacology of
different classes of LA
 Describe nerve factors affecting LA
effects
 Explain how the use of
vasoconstrictors affects LA effects
Pain management
 Peripherally-acting
 Act on peripheral pain receptors
 Prevent sensitisation and discharge of the
nociceptors during inflammation
 e.g. NSAIDs, aspirin
 Anaesthetic agents
 Block pain signal transmission
peripherally/centrally
 For short-term only (long-term→
complications)
 Centrally-acting (GA, opioids)
 Interact with specific receptors in the CNS
 Inhibit pain message and emotional
 INTRODUCTION
Local anaesthesia
• A transient loss of sensation in a
defined region w/o producing a
loss of consciousness.
• Reversibly depress excitation of
nerve endings; and
• Blockade of impulse conduction
along nerve axons from site of
pain stimulus to CNS
 Cocaine is found in the leaves of
Erythroxylon coca, a South American
shrub (high altitude in the Andes)
 Cocaine was introduced into clinical use
as a local anaesthetic in Germany in
1884.
 COCAINE
 is a potent inhibitor of catecholamine
uptake by noradrenergic nerve terminals
→ ↑ sympathetic nerve activity »»»
tachycardia, vasoconstriction, ↑ BP

 occurs also in the brain → effects closely

resembles that of amphetamine »»»
hyperactivity, tolerance, abuse, acute
poisoning !!!

»»» search for better LA with greater

efficacy & safety
 LOCAL ANAESTHETICS
 ESTER GROUP (allergic reaction)
Procaine (prototype)
Tetracaine (or amethocaine)
Benzocaine
Cocaine

 AMIDE GROUP
Lidocaine (or lignocaine) (prototype)
Mepivacaine
Bupivacaine
Prilocaine
Ropivacaine
Articaine
CLASSIFICATION BASED ON
DURATION OF ACTION:
1. Short-acting :
Procaine
2. Intermediate-acting:
Lidocaine
Mepivacaine
Cocaine
Prilocaine
3. Long-acting:
Tetracaine
Bupivacaine
Ropivacaine
 MECHANISM OF ACTION
 Primary MOA: Block action
potential generation by blocking
voltage-gated sodium channels
 Binds to its receptor within the Na
channel located intracellularly
 Blockade of Na channels by LA is
voltage- and time-dependent
 ‘Use-dependent’ block of sodium
channels-the more the channels
are opened, the greater the block
becomes.
 Na channels
1. Rested state** (predominates at more
–ve membrane potential)
2. Activated state (open state)
3. Inactive state (predominates at more
+ve membrane potential)

** lower affinity for LA receptor thus the

effect of LA is more marked in rapidly
firing axons than in resting fibres
Interaction of local anaesthetics with sodium channels. The blocking site within the
channel can be reached via the open channel gate on the inner surface of the
membrane by the charged species BH+ (hydrophilic pathway), or directly from the
membrane by the uncharged species B (hydrophilic pathway).
 Mechanism of action
(cont)cationic form of drugs have
 Charged,
higher affinity for LA receptor
 Note: Most LA are weak bases (exist
mainly in a protonated form at body
pH).
 LA penetrate the nerve in a non-ionised
(lipophilic) form, weak base
 once inside the axon, some ionised
molecules are formed → block the Na+
channels preventing the generation of
action potentials
Effects of Na channel
blockade
 Binding of LA to more and more Na
channels will result in:
 Increased threshold for excitation
 Slowed impulse conduction
 Declined rate of rise of action potential
 Decreased action potential amplitude
→ failure to generate action potential

 If Na current is blocked over a critical

length of the nerve → propagation of
impulse will be blocked
 NERVE FACTORS AFFECTING LA
EFFECTS
1. Firing frequency (high ff vs. low ff) –pain fibers
have high ff and long AP duration
2. Fibre diameter (Smaller fibers more susceptible) –
the distance over which such fibers can passively
propagate an electrical impulse is shorter
3. Myelination (Myelinated fibers more susceptible)
4. Fiber position in the nerve bundle (outer nerves
exposed to LA first) – in the extremities, sensory
fibers are located in the outer portion of the nerve
trunk
5. Tissue pH (low pH → ↓ LA infusion into nerve fibre)
Susceptibility
 Nociceptors>sympathetic>temperat
ure>etc>motor fibres
 Pharmacokinetics
 Administration: injection or topical
 Systemic absorption is determined
by:
 dose
 use of vasoconstrictor agent
 tissue perfusion
 site of injection
 drug-tissue binding
 physicochemical properties of
the drug
 Metabolism:

- ester-linked LA (e.g., procaine)

rapidly hydrolysed by plasma
cholinesterase to produce p-
aminobenzoic acid derivatives
»»» short t1/2
- amide-linked LA (e.g., lignocaine,
prilocaine) metabolised mainly by N-
dealkylation in the liver (metabolites
often active)
»» longer activity
 Vasoconstrictor

Effects of vasoconstrictors:
 increase in the effect of LA
 decrease in the toxicity of LA
 increase in the duration of the effect of LA

Note:
Vasoconstrictors must not be used for
producing
ring-block of an extremity (e.g. finger or
toe)
Reason: ????
 METHODS OF ADMINISTRATION
1. Surface anaesthesia
Topical application to external or
mucous surface. LA must be able to
penetrate tissues. Relatively high
concentrations used, when large areas
are anaesthetised - systemic toxicity
may occur.
 2. Infiltration
anaesthesia
Injected directly into the tissues to act on
local nerve endings, usually with a
vasoconstrictor (adrenaline).
 3. Nerve block
(neuraxial)
spinal anaesthesia (intrathecal block)
 drugs is injected into the cerebrospinal
fluid in the subarachnoid space

epidural anaesthesia
 anaesthetic is injected outside the dura

infiltration of anaesthetic around a

single nerve (e.g. dental anaesthesia)
or nerve trunks
Epidural Anaesthesia
Spinal Anaesthesia
 4. Intravenous regional
anaesthesia
LA is injected i.v. into an exsanguinated
limb. A tourniquet prevents the agent
reaching the systemic circulation.
 ADVERSE EFFECTS
1. Acute toxicity: resulting from actions on
CNS and cardiovascular system
2. Hypersensitivity reactions:
usually allergic dermatitis, but
occasionally also an acute anaphylactic
reaction.
3. Toxicity of vasoconstrictor agents:
- ischaemic tissue damage
- systemic toxicity (increase in BP)
4. Specific to particular drugs
eg prilocaine – methemoglobinemia, not
for obstertric analgesia
 Toxicity
 Two major forms of LA toxicity:
 Systemic toxicity- due to escape of
LA into systemic circulation
 Direct neurotoxicity from the local
effects of the drugs when administered
close to the spinal cord and other major
nerve trunks (>> lidocaine → transient
neuropathic symptoms e.g for spinal
anaesthesia)
 LA depress other excitable
tissues:
 BRAIN (CNS)
 HEART
 smooth muscle
 neuromuscular junction
1. CNS: the most dangerous
- low concentrations: sleepiness,
light-headedness, visual and auditory
disturbances
- early symptoms of LA toxicity:
tongue numbness, metallic taste
- stimulation of CNS
(anxiety, restlessness, visual disturbances,
agitation, tremor→ convulsion &
respiratory depression)
- depression of CNS and coma
(respiratory centre and vasomotor centre)
 2. Cardiovascular system
- myocardial depression
(reduction of contractility via the reduction of Na+
entry )
- vasodilation
→ directly via the vascular smooth muscle
→ indirectly via the decreased tone of
the sympathetic system
 fall in blood pressure may be life-threatening
Exception: cocaine
→ inhibits noradrenaline reuptake
 increases sympathetic activity
(vasoconstriction, tachycardia, increase BP)
3. Smooth muscle
Slight spasmolytic activity
(decrease in the tonus of smooth
muscle)
4. Neuromuscular
junction:
Decrease in the depolarisation and
contraction
(LA affects the postsynaptic ion
transports)
 AMIDE-LINKED LA
LIDOCAINE (lignocaine)
Lidocaine is the prototype

Indications:
 All types of LA ( infiltration, nerve block,
topically)
 Also used as an antiarrhythmic agent
 Produces anaesthesia of only short
duration when used without a
vasoconstrictor
Pharmacokinetics:

 Duration of action of about 90

minutes.
 Penetrates tissue readily
 Rapid onset
 Dealkylated in the liver, metabolites
retain LA activity.
Toxicity

-ventricular fibrillation or cardiac arrest

(massive overdosage)

-CNS effects (signs of central depressions,

including drowsiness, sedation, and ataxia,
although tremor and/or convulsions
may occur)

-Intermediate in toxicity: twice as toxic as

procaine but much less toxic than more
potent agents, e.g. tetracaine.
 ESTER-LINKED LA
PROCAINE
 Procaine is the prototype

 Indications: infiltration and nerve block

local anaesthesia (not effective for the
surface anaesthesia).
 Procaine is rapidly metabolized by
esterase enzymes and, since it is
metabolized minorly by the liver, may be
used in patients liver dysfunction.
 one of the least toxic of currently available
local anaesthetics (rapidly inactivated in
the blood by esterase enzymes)
 incidence of allergy is greater than that
seen with amide-type agents (patients
with procaine allergy may also be allergic
to other esters, especially tetracaine)
 Procaine should not be used in patients
taking sulfonamides. WHY?
Adverse effects:
 Acute toxicity
 Allergy
 Vasodilation