Local anaesthetics
Dr. S. Parthasarathy
MD., DA., DNB, MD (Acu),
Dip. Diab. DCA, Dip. Software statistics
PhD (physio)
Mahatma Gandhi medical college and research
institute , puducherry – India
What is it ??
• A drug reversibly blocks the nerve conduction
beyond the point of application, if applied in
appropriate concentrations .
• Other drugs !!
• Quinidine, phenergan, TCADs --- no
History
• Koller is credited with introducing local
anesthetics into medical practice when he used
cocaine to numb the cornea before operating
on the eye.
• Isolation of cocaine by Neimann, in 1860
• Procaine was first synthesized in 1904,
• In lidocaine 1943 -- but the hierarchy is
History
ESTERS
AMIDES
The basic chemical structure- 3 parts:
• 1. Lipophilic group- an aromatic group, usually an
unsaturated benzene ring.
• 2. Intermediate bond- a hydrocarbon connecting
chain, either an ester (-CO-) or amide (-HNC-)
linkage. The intermediate bond determines the
classification of local anesthetic.
• 3. Hydrophilic group- a tertiary amine and proton
acceptor.
COO - ester
OR
CONH – amide
Amides
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•
•
•
•
•
•
Bupivacaine
Etidocaine
Levobupivacaine
Lidocaine
Mepivacaine
Prilocaine
Ropivacaine
Esters
Benzocaine
Chloroprocaine
Cocaine
Procaine
Tetracaine
Isomerism
• Many medications contain chiral molecules
which exist as stereoisomers.
• Chiral molecules are asymmetrical and the
direction of the configuration helps to
categorize the isomer. R and S
• Polarized light to right – D
• Polarized light to left - L
Bupi and ropi
• Bupivacaine is a long acting amide local anesthetic
that can be associated with significant toxicity issues.
• S-bupivacaine is almost as potent as the racemic
preparation but is less toxic. It takes larger doses of Sbupivacaine to cause cardiac arrest and seizure
activity than racemic preparations.
• Ropivacaine is a second local anesthetic that is a pure
S-ropivacaine.
Structure Activity Relationships
(Onset, Potency, Duration)
pLP=OPD
p = pKa = onset
L = lipophilicity = potency
P = protein binding = duration
Frequency dependent block
• Local anesthetics are prepared as a water soluble
hydrochloride salt and generally have a pH of 5-6.
• If the preparation contains epinephrine, the
solution must be acidic to create a stable
environment. pH of 3-4.
• . To enhance clinical onset, carbonated solutions
of epinephrine containing local anesthetics have
been used instead of HCL solutions.
pKa
• Because local anesthetics are weak bases,
increasing the pH (“alkalinization”) of solution
increases the ratio of base to cation.
• Henderson-Hasselbalch equation can be used
to quantitate the ratio:
• pKa(local anesthetic) – pH(solution) =
Log ([cation]/[base])
NH3 + HCl
= NH4+ + cl-
• pKa(local anesthetic) – pH(solution) =
Log ([cation]/[base])
• If pH is less , the cationic form is more
• If the pH is more the unionized form is more
Local anaesthetic
Exceptions to pKa
• Two notable exceptions are chloroprocaine and
benzocaine.
• Chloroprocaine has a high pKa and rapid
onset.
• Benzocaine does not exist in an ionized form
and exerts its effects by alternate mechanisms.
Lipophilic
Nerve cell membrane
Pharmacodynamics
• Analgesic effect has been reported following
intravenous lidocaine administration in many
acute and chronic conditions.
• Other than Na channels
• inhibition of G-protein coupled receptor
signaling
• Inhibit NGF
Differential blockade
• Bupivacaine and etidocaine are both potent,
long acting local anesthetics.
• Bupivacaine exhibits a more potent sensory
than motor block.
• Etidocaine exhibits an equally effective
sensory and motor block.
• Ropivacaine, on the other hand, exhibits a
potent sensory block similar to bupivacaine but
motor blockade appears less intense.
most common clinical use of local
anesthetics
•
•
•
•
•
Regional anesthesia and analgesia.
Topical
Infiltration
Blocks
Neuraxial etc
Other actions
• Blunt responses to tracheal instrumentation
• attenuating increases in intraocular pressure,
intracranial pressure, and intra-abdominal
pressure during airway instrumentation.
Other actions
• The primary site of action is the myocardium,
where decreases in electrical excitability,
conduction rate, and force of contraction occur.
• Depressed NMJ
• The local anesthetics depress contractions in
the intact bowel and in strips of isolated
intestine.
• also relax vascular and bronchial smooth
muscle,
Additives
• Carbonation of local anesthetics results
in a more rapid onset and a more profound degree of
conduction blockade, ph higher , More nonionized
form, speeder onset ,
CO2 released diffues inside – acidic- more ionized
better action
Less tachyphylaxix
• Sodabicarb
• 1 ml / 20 ml of lignocaine
• 0.1 ml /20 ml of bupivacaine
Additives
• Vasoconstrictors – epinephrine – 1 in 2 lakh – 5
mic/ ml.
• Mixtures of local anaesthetics –
• EMLA
• Ligno + bupi = OK but ??
• A solution containing 50% of the toxic dose of
local anesthetic A, and 50% of the toxic dose of
local anesthetic B, will have the same
implications as 100% of the toxic dose of either
local anesthetic alone.
Additives
• Glucose
• The specific gravity of hyperbaric (or ‘heavy’)
bupivacaine is 1.026 at 20 ◦C.
• The specific gravity of cerebrospinal fluid is
1.005 at 37 ◦C,
• Warming of the local anesthetic solutions can
also bring about a modified onset time
Additives
• Hyaluronidase, supplied as a white fluffy powder,
is used to facilitate the spread through connective
tissues following subcutaneous or intramuscular
injection.
Additives
•
•
•
•
Drug
Receptor
Uses
Opioids / mu and kappa Central ,periph
Clonidine 2-adrenoceptor
Central periphe
Ketamine
NMDA
Central
Duration of Action
. Local anesthetics are classified as follows:
• Short acting: procaine and chloroprocaine
• Moderate acting: lidocaine, mepivacaine, prilocaine
• Long acting: tetracaine, bupivacaine, etidocaine,
ropivacaine, levobupivacaine
Pharmacokinetics
Metabolism
• The metabolism : ester vs. amide.
• Ester local anesthetics undergo extensive hydrolysis
in the plasma by pseudocholinesterase enzymes
(plasma cholinesterase or butyrylcholinesterase). - rapid, resulting in water soluble metabolites which
are excreted in the urine.
• The ester that is an exception is cocaine. In addition
to ester hydrolysis cocaine is partially metabolized in
the liver (N-methylation).
Metabolism
Procaine and benzocaine are metabolized to paminobenzoic acid (PABA), which has been
associated with allergic reactions
When ester local anesthetics are placed in the CSF,
metabolism does not occur until there has been
vascular absorption of the local anesthetic. CSF does
not contain esterase enzymes.
Metabolism
• Amide local anesthetics are metabolized primarily by
microsomal P-450 enzymes in the liver (Ndealkylation and hydroxylation) and, to a lesser
extent, in other tissues.
• Most studied lignocaine
• Monoethyl glycine xylidide --- xylidine
Some drug interactions
Side effects
• The hydrolysis of all ester-linked local
anesthetics leads to the formation of paraaminobenzoic acid (PABA) or a substituted
PABA.
• True allergic reactions are associated with
amino ester-linked local anesthetics, not amino
amide-linked one
• Tissue Toxicity
• Myotoxicity and neurotoxicity
Cardiovascular Toxicity
• bupivacaine exhibits a much stronger binding
affinity to resting and inactivated sodium
channels than lidocaine
• Bupivacaine dissociates from sodium channels
during cardiac diastole much more slowly than
lidocaine
• Hence bupi cardiotoxicity is more dangerous
Methemoglobinemia
• The metabolism of prilocaine in the liver
results in the formation of O-toluidine, which
is responsible for the oxidation of hemoglobin
to methemoglobin.
• The methemoglobinemia associated with
prilocaine is spontaneously reversible or may
be treated by IV methylene blue.
Toxicity
• IV > tracheal > intercostal > caudal
> paracervical > epidural >
brachial > sciatic > subcutaneous
Treatment of Systemic Toxicity from Local
Anesthetics
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•
•
•
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Prevention
aspiration for blood,
use of a small test dose of local anesthetic
slow injection
fractionation of the rest of the dose of local
anesthetic
Treatment of systemic toxicity is
primarily supportive
• Injection of local anesthetic should be stopped.
• Oxygenation and ventilation should be
maintained
• If needed intubate and ventilate
• Midaz, thio if seizures , ephedrine IVF
• IV lipid for bupi
• Can we give propofol??
Neural Toxicity of Local Anesthetics
• local anesthetic–induced injury to Schwann
cells, inhibition of fast axonal transport,
disruption of the blood-nerve barrier,
decreased neural blood flow disruption of cell
membrane integrity
• radiculopathy to be approximately 0.03% and
of paraplegia to be approximately 0.0008%.
Myotoxicity
• Toxicity to skeletal muscle is an uncommon
side effect of local anesthetic injection.
Individual local
anaesthetics --Some
pearls
Cocaine
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•
•
•
•
Sympathetic stimulation
Vasoconstriction
Temperature rise
Local 10% solution and paste
Brompton mixture with heroin for terminally
ill
Procaine
•
•
•
•
•
Very short acting– no toxicity
weak drug
Vasodilator
Suxa
PABA – allergic reaction
• No longer in use
Cinchocaine (dibucaine)
• Dibucaine number
• Scoline apnea
Lidocaine
• is also used in ointment, jelly, viscous, and
aerosol preparations for a variety of topical
anesthetic procedures.
IVRA
Anti arrythmic
Pain relief - IV
inherent potency, rapid onset, moderate
duration of action, and topical anesthetic activity
Mepivacaine
• similar to that of lidocaine
• It is ineffective as a topical anesthetic agent.
• The metabolism of mepivacaine is greatly
prolonged in the fetus and newborn; not
employed for obstetric anesthesia
Drug doses and toxic doses
• Procaine
• 7 mg/kg; not to exceed 350-600 mg
• Chloroprocaine
• Without epinephrine: 11 mg/kg; not to exceed
800 mg total dose
With epinephrine: 14 mg/kg; not to exceed
1000 mg
• Prilocaine
• Body weight <70 kg: 8 mg/kg; not to exceed
500 mg
Body weight >70 kg: 600 mg
• Ropivacaine
• 5 mg/kg; not to exceed 200 mg for minor
nerve block
• Lidocaine
• Without epinephrine: 4.5 mg/kg; not to exceed
300 mg
• Lidocaine with epinephrine With epinephrine: 7
mg/kg
• Bupivacaine
• Without epinephrine: 2.5 mg/kg; not to exceed
175 mg total dose
• Bupivacaine with epinephrine
• With epinephrine: Not to exceed 225 mg total
dose
What does a local do ??
1.
2.
Local anesthetic is deposited near a nerve.
A portion of the local anesthetic is removed
due to tissue binding and circulation.
3.
If the local anesthetic is an ester, a portion
of the deposited local anesthetic will be
removed by local hydrolysis, in addition to
tissue binding and circulation.
4.
The remaining local anesthetic penetrates
the nerve sheath.
What does a local do ??
• 5. Local anesthetic penetrates the axon
membranes and axoplasm.
• This step is dependent on pKa and
lipophilicity.
• 6. Local anesthetic binds to Na+ channels
preventing their opening by inhibiting
conformational changes
• 7.Local anesthetics may also bind to the
channel pore and block the passage of Na+.
What does a local do ??
• 8.During
incomplete.
onset,
impulse
Partially
blockade
blocked
fibers
is
are
inhibited by repetitive stimulation. The reverse
is true during recovery.
• 9. The primary route for local anesthetics is the
hydrophobic route, within the axon membrane.
What does a local do ??
• 10. Clinical onset of blockade is due to the
slow diffusion of local anesthetic molecules
into the nerve, NOT by binding to ion channels
and inhibition of impulse propagation, which
occurs at a faster rate. Recovery occurs in
reverse.
• LA s have no role in RMP.
• Individual detailing of local anaesthetics are
not done in the hope
• That the individual postgraduates will read
Thank you all