LOCAL ANESTHETICS

dr. Hori Hariyanto, SpAn

Introduction
The 1st local anesthetic, cocaine, was introduced to clinical
medicine by Carl Koller in (1884) as a topical anesthetic for
the cornea.
The 1st synthetic local anesthetic, procaine, was introduced by
Einhorn (1905).
Prototype of local anesthetic, lidocaine, synthesized by
Lofgren (1943).
Local anesthetics are drugs that block nerve conduction when
applied to nerve tissue in appropriate concentrations.
Local anesthetics produce transient and reversible loss of
sensory, motor, and autonomic function in regionalized area
of the body without producing loss of consciousness.
Carl Koller

Theories of Local Anesthetics

Neuron, unlike most other types of tissue, have membrane-bound,
voltage-gated sodium and potassium channel that produce membrane
depolarization following chemical, mechanical, or electrical stimuli.
Resting membrane potential
It happens when a neuron is not sending a signal.
Resting membrane potential is about 70 mV.
At rest, potassium channel is more permeable than sodium
channel (more sodium inside and more potassium inside)
intracellular is relatively negative than extracellular.

Theories of Local Anesthetics

Action potential
Action potential occurs when a neuron sends signal.
If the depolarization exceeds a treshold level (about -55 mV), sodium
channel is activated and it cause a sudden and spontaneous influx of
sodium ions and generating action potential. This action potential is
normally conducted as is an impulse along the nerve axon.
If the treshold level can not be achieved, no action potential will be
generated (all or none).
Repolarization
Increase of sodium permeability in the channel causes a relative excess of
cations intracellularly, resulting in a reversal of membrane potential to +
35 mV.
A subsequent rapid in sodium permeability (caused by inactivation of
voltage-gated sodium channels) along with a transient increase in
potassium conductance through voltage-gated potassium channels (more
potassium exit the cell) return the membrane to its resting potential.

Action Potential

Action
Potential

Action
Potential

Mechanism of Action
Local anesthetics produce conduction blockade of neural impulses
by preventing passage of sodium ions through selective sodium
channels in nerve membranes.
Sodium channels are membrane-bound proteins that are composed
of one large -subunit, through which sodium ions pass, and one or
two smaller -subunit. Voltage-gated sodium channels exist in three
states resting, activated (open), and inactivated.
Most local anesthetics bond to -subunit and block voltage-gated
sodium channel from inside the cell, preventing subsequent channel
activation and interfering with large transient sodium influx
associated with membrane depolarization.

Mechanism of Action
Failure of sodium channel permeability to increase slows the rate of
depolarization such that treshold potential is not reached and an
action potential is not generated along the nerve membrane.
Local anesthetics do not alter the resting membrane potential or
treshold level, but it slows the rate of depolarization.
Local anesthetics have much greater affinity for the channel in the
activated and inactivated state than in the resting state.
Not all nerve fibers are equally affected by local anesthetics.
Sensitivity to blockade is determined by axonal diameter, degree of
myelination, and various other anatomic and physiologic factors.
In spinal nerves, sensitivity to local anesthetics is autonomic >
sensory > motor.

Structure-activity Relationship
Local anesthetic consist of:
Lipophylic group (unsaturated benzene ring)
Hydrophylic group (tertiary amine and proton acceptor)
This two groups are separated by a
hydrocarbon connecting chain, that
includes an ester or amide linkage.

Local anesthetic are poorly soluble in water and therefore are

marketed as water soluble hydrochloride salts (pH 6). It is
contributing to the stability of local anesthetics.
An acidic pH is also important if local anesthetics solutions contain
epinephrine, because epinephrine is unstable in alkaline pH.

Structure-activity Relationship
Potency : The ability of local anesthetic molecule to penetrates
membranes, a hydrophobic.
Correlates with lipid solubility.
Cm (minimum blocking concentration) : Minimum concentration of
local anesthetic that will block nerve impulse conduction.
Onset of action correlates with lipid solubility and pK a.
Duration of action correlates with lipid solubility and protein
binding (1- acid glycoprotein).

Classification of Local Anesthetics

Local anesthetics

Esters

Amides

Procaine
Cocaine
Chlorprocaine
Tetracaine

Lidocaine
Mepivacaine
Bupivacaine
Ropivacaine

Local
Anesthetics

Classification of Nerve Fibers

Fiber Type

Diameter
(mm)

Conduction
(m/s)

Sensitivity
of Local
Anesthetic

Myelination

Function

12-20

70-120

Yes

Propioception
Large motor

5-12

30-70

++

Yes

Small motor
Touch pressure
Proprioception

3-6

15-30

++

Yes

Muscle tone

2-5

12-30

++

Yes

Pain
Cold
temperature
Touch
Sharp pain

Classification of Nerve Fibers

Fiber Type

Diameter
(mm)

Conduction
(m/s)

Sensitivity
of Local
Anesthetic

Myelination

Function

<3

3-14

+++

Some

C
(Dorsal root)

0.4-12

0.5-2

++++

No

Pain
Warm and cold
temperature
Touch

C
(Sympatheti
c)

0.3-13

0.7-2.3

++++

No

Postganglioni
c sympathetic
fibers

Preganglionic
autonomic

Physiochemical Properties of Local Anesthetics

Generic

Chain
Structure

Lipid
Solubility

pKa

Protein
Binding

Maximum Dose
(mg/kg)

Lidocaine

Amide

++

7.8

++

4.5

Bupivacaine

Amide

++++

8.1

++++

Ropivacaine

Amide

++++

8.1

++++

Cocaine

Ester

++

8.7

++

Procaine

Ester

8.9

12

Tetracaine

Ester

++++

8.2

+++

Pharmacokinetics
Absorption
Mucous membrane
Dermal, eg EMLA (eutetic mixture of local anesthetic, 1:1 mixture of
5% lidocaine and 5% priloaine).
Depth of penetration, duration of action, and amount of drug
absorbed depend on: application time, dermal blood flow, keratin
thickness, and total dose administered.

Pharmacokinetics

Absorption
Systemic absorption depends on blood flow, which is determined by:
Site of injection
Propotionate to the vascularity of site of injection.
Intravenous > tracheal > intercostal > caudal > paracervical > epidural >
brachial plexus > sciatic > subcutaneous.
Presence of vasoconstrictor
Addition of epinephrine causes vasoconstriction at the site of
administration.
Less absorption increases neuronal uptake, enhances the quality of
analgesia, prolongs the duration of action, and limits toxic side effects.
Local anesthetic agent
High tissue bound local are more slowly absorbed.

Pharmacokinetics

Metabolism and Excretion

1. Esters
.
.
.
.

Metabolized by pseudocholinesterase (plasma cholinesterase).

Ester hydrolysis is very rapid.
Water-soluble metabolites excreted in the urine.
p-aminobenzoic acid (PABA) associated with allergic reaction
specifically to procaine and benzocaine.
. In CSF which is lack of esterase enzymes, the termination of
action is depends on their absorption into the blood stream.
. Genetic abnormality of pseudocholinesterase will predispose
patients to systemic toxicity due to disruption of metabolic rate.

Pharmacokinetics

Metabolism and Excretion

2. Amides
Metabolized by microsomal P-450 enzymes in the liver.
The rate of metabolism depends on the specific agent (prilocaine
> lidocaine > mepivacaine > ropivacaine > bupivacaine).
Decreases of hepatic function and liver blood flow will reduce the
metabolic rate and predispose patients to systemic toxicity.
Excreted in the urine.
Prilocaine
metabolites
and
benzocaine
may
cause
methemoglobinemia.

Pharmacokinetics

Allergic reaction

Toxicity
of Local
Anesthetics

Local toxicity

Systemic toxicity

True allergic reaction are rare.

Mostly occur as a manifestation of systemic
toxicity due to adverse reaction (overdose).
Ester > amide (PABA metabolites).
The preservatives of local anesthtetic may
also induce allergic reaction.
Rare
Local anesthetic pressure (large amount).
Contamination
Intraneuronal injection
Accidental high dose subarachnoid injection
Due to accidental intravascular injection
excess plasma concentration.
Less often due to systemic absorption from
tissue injection sites.
dose injected,
mmmmDepends on
vascularity
vasoconstrictor

Pharmacokinetics

Systemic Toxicity
1. Central Nervous System

Sign of local anesthetic toxicity in awake patient.

Early sympoms: circumoral numbness, tongue paresthesia, dizziness.
Sensory : tinnitus, blurred vision.
Excitatory sign: restlessness, vertigo, agitation, nervousness,
paranoia.
CNS depression: slurred speech, drowsiness, seizure and coma.

Pharmacokinetics

Systemic Toxicity
2. Cardiovacular System
Usually occur during general anesthesia
It reflex the ability of local anesthetics to block cardiac Na channel.
High plasma concentration can produce.
Direct myocardial depression and impair cardiac conduction.
Cardiac dysrrythmia or circulatory collapse
Hypotension due to relaxation of arterial smooth muscle.

Lidocaine > Ropivacaine > Bupivacaine.

3. Respiratory System
Depresses hypoxic drive.
Postretrobulbar apnea syndrome (injection of local anesthetic into
optic nerve sheath, with spread to cerebrospinal fluid).

Toxic Effects
Lidocaine plasma concentration
(g.ml-1)

30

25

20
15
10
5
0

CVS depression
Respiratory arrest
Coma
Convulsions
Unconsciousness
Muscular twitching
Visual disturbance
Lightheadedness
Numbness of tongue

Clinical Uses

Regional anesthesia
Topical anesthesia
Antidysrhythmia
Blunting the response to tracheal stimulation.
Lidocaine effective to block bronchoconstriction reflex during
intubation.

Spinal Anesthesia

Block
Anesthesia
Nerve detector

Thank You