Text Book Reading
LOCAL
ANESTHESIA
Pandhu Suprobo
Pembimbing
dr Wiwi Jaya SpAn KIC
1
■ Barash Clinical Anesthesia 8th edition 2017
Page 1432 to 1469
■ Hadzic ‘s Texbook of Regional Anesthesia and Acute Pain
Management 2018
Page 124 to 138
2
HISTORY
■ sixteenth century used by Incan society,
“the cocaine paste”
■ 1884, Koller and Gartner producing
topical cocaine anesthesia
■ 1884 William Halsted using cocaine to
produce mandibular nerve block
■ 1898 August Bier. Cocaine spinal
anesthesia was used to treat cancer
■ 1904 Einhorn. Introduce Procaine, the
first synthetic ester LA,
■ in 1948 amide LA lidocaine was found
3
■ Local anesthetics provide anesthesia and analgesia
by blocking the transmission of pain sensation along
nerve fibers.
■ The key target of local anesthetics is the voltage-
gated sodium channel
4
Action Potential
■ resting membrane potential of −60 to −70 mV by
active transport and passive diffusion of ions
■ sodium–potassium pump (Na + -K + -ATPase)
■ When stimulus is sufficient to depolarize a patch of
membrane, the signal can be transmitted as a wave of
depolarization
5
6
Structure of Sodium channel
■ Na channels exist as
tetramers
■ contain one larger α-
subunit and one or two
smaller β-subunits,
■ The α-subunit, the site
of ion conduction and
LA binding, has four
homologous domains
7
Anatomy of Nerve
■ Nerves contain both afferent
and efferent fibers bundled
into one or more fascicles
■ 3 layers :
endoneurium
perineurium
epineurium
8
Anatomy of Nerve
■ Nerves divided into
Myelinated and Un
myelinated nerve
fibers
■ Myelin made by
Schwann cells in
the PNS and by
oligodendrocytes in
the CNS
9
Nerve Classification
■ Nerve fibers are commonly classified according to their size, conduction,
velocity, and function.
■ Larger nerve size and myelinated faster conduction velocity ,
better intrinsic electric
conductance.
rapid impulse transmission via
saltatory
conduction.
10
Nerve Classification
■ small diameter increases sensitivity to local anesthetics.
the larger, the slower conduction
■ Larger unmyelinated fibers are less sensitive than smaller
unmyelinated fibers.
■ Small unmyelinated C fibers are relatively resistant
compared to larger myelinated fibers.
11
12
13
Physiology
■ In the absence of a stimulus, voltage-gated sodium
channels are in the resting
■ Activation of voltage- gated Na channels causes a change
in the conformation of the channel, allowing an influx of
Na ions and generating an action potential.
■ Sodium ions rush through the opened pore.
14
Molecular mechanism of LA
■ Local anesthetics reversibly bind
the intracellular portion of
voltage-gated sodium channels
■ “resting,” “open,” and
“inactivated,” first described by
Hodgkin and Huxley.
■ Na channels open briefly,
allowing extracellular Na ions to
flow into the cell, (depolarization)
■ After a few milliseconds, Na
channels inactivate then return
to the resting
conformation(repolarization)
15
16
17
■ Local anesthetics disrupt the transmission of
action potentials along nerve fibers.
■ The degree of nerve blockade depends on the
local anesthetic concentration and volume.
■ A sufficient volume is needed to suppress the
regeneration of nerve impulse
18
Pharmacology and
Pharmacodynamics
■ Local anesthetics consist of ;
1.a lipophilic group (usually an aromatic benzene
ring)
2.ester or amide linkage
3. a hydrophilic group (usually a tertiary amine)
19
■ All LAs contain an
aromatic ring and an
amine at opposite ends
of the molecule,
separated by a
hydrocarbon chain, and
either an ester or an
amide bond.
20
■ Aminoesters are hydrolyzed by plasma
cholinesterases and
Aminoamides are degraded by hepatic
carboxylesterases
■ Local anesthetics are weak bases that usually
carry a positive charge at the tertiary amine
21
Amida
Ester
22
LA POTENCY
■ More lipid-soluble More readily permeate nerve
membranes and Greater affinity to Na channels more potent
■ More lipid-soluble = water insoluble highly protein bound in
blood,
less readily removed by the bloodstream more slowly
“washed out” from
nerves the longer duration of action
■ Chemical structure
23
■ Lipid Solubility facilitates passage through the lipid
membrane barriers.
help binding to the sodium channel
■ Lipid solubility of local anesthetics can be strenghten by adding
composition of alkyl substitution on the amide and the
benzene
groups
24
LA ONSET
■ The pKa is the pH at which the fraction of ionized and nonionized
drug is equal
■ The lower pKa the more local anesthetic base can diffuse the
shorter the onset of the nerve block
■ When pKa closest to physiological pH a greater fraction of
nonionized base more readily permeates the nerve cell membrane
(more rapid onset)
■ Less lipid-soluble agents generally have a faster onset
25
PH
26
27
28
LA DURATION
■ Highly lipid-soluble local anesthetics a longer duration
of action,
more slowly diffuse from a lipid-rich environment to
the aqueous
bloodstream
■ The usage of vasoconstrictor
Antagonizing inherent vasodilating effects of local
anesthetics,
Decreasing systemic absorption and intraneural
clearance
■ Closely related to pharmacokinetic of LA
29
30
LA Pharmacokinetics
■ Absorption
1. the site of injection,
intravenous (or intraarterial) > tracheal > intercostal >
paracervical > epidural >
brachial plexus > sciatic > subcutaneous.
2 Presence of vasoconstrictors
3. More lipid-soluble local anesthetics that are highly tissue bound
are also more
slowly absorbed
4. The vascularity of the tissue
31
32
LA Pharmacokinetics
■ Elimination
Determined by their chemical linkage.
Aminoesters are hydrolyzed by plasma cholinesterases
aminoamides are transformed by hepatic
carboxylesterases and cytochrome P450 enzymes
33
LA Pharmacokinetics
■ Distribution
1. Tissue perfusion
the lung extracts significant amounts of local anesthetic;
arterial injections more toxic than venous injections
right-to-left shunts are more susceptible to toxic
2. Tissue/blood partition coefficient
Increasing lipid solubility greater plasma protein binding , greater
tissue uptake
from an aqueous compartment.
3. Tissue mass.
34
LA Pharmacokinetics
■ Excretion
■ 1. Esters
■ metabolized by pseudocholinesterase (plasma cholinesterase or
butyrylcholinesterase). Ester hydrolysis is very rapid, and the water-
soluble metabolites are excreted in the urine.
■ Procaine and benzocaine are metabolized to p -aminobenzoic acid
(PABA) anaphylactic reactions.
■ 2. Amides
■ —Amide local anesthetics are metabolized (N-dealkylation and
hydroxylation) by microsomal P-450 enzymes in the liver.
slower than ester hydrolysis
35
Drug Interaction
Alteration
■ Succinylcholine and esters LA
■ Histamine (H 2 ) receptor blockers and β blockers
■ Choline esterase inhibitor
■ Potentiation
■ Opioid
■ Alfa 1 and 2 adrenergic agonist
36
EFFECTS ON ORGAN SYSTEM
Neurological
■ include circumoral numbness, tongue paresthesia, dizziness,
tinnitus, and blurred vision.
■ Excitatory signs include restlessness, agitation, nervousness,
garrulousness, and a feeling of “impending doom.”
■ tonic–clonic seizures.
■ The excitatory reactions are thought to be the result of selective
blockade of inhibitory pathways.
■ Potent, highly lipid-soluble local anesthetics produce seizures
37
EFFECTS ON ORGAN SYSTEM
Cardiovascular
■ depress myocardial automaticity (spontaneous phase IV
depolarization).
■ Myocardial contractility and conduction velocity result from
direct cardiac muscle membrane changes (ie, cardiac Na
channel blockade)
■ Arteriolar vasodilation inhibition of nitric oxide
■ Major cardiovascular toxicity usually requires about three
times the local anesthetic concentration in blood
38
Immunological
■ Esters appear more likely to induce a true allergic
reaction a known allergen PABA
■ Amides often contain methylparaben , which has
a chemical structure vaguely similar to that of
PABA
39
Respiratory
■ phrenic and intercostal nerve paralysis or
depression of the medullary respiratory center
Apnea can result from
Hematological
■ Lidocaine mildly depresses normal blood
coagulation (reduced thrombosis and decreased
platelet aggregation) and enhances fibrinolysis
40
“KNOWLEGDE WILL ENLIGHTEN THE SOUL”
( Ali Bin Abi Thalib)
TERIMAKASIH
41
