Download Local Anesthetics

Local Anesthetics
Local Anesthetics
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Used at multiple sites throughout the body:
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Epidural
Spinal
Peripheral nerve blocks
IV (Bier Block)
Skin sites locally
Amides and Esters
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Lidocaine (Xylocaine)
Bupivacaine (Marcaine)
Etidocaine (Duranest)
Mepivacaine
(Carbocaine)
Prilocaine (Citanest)
Ropivacaine
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Chloroprocaine
(Nesacaine)
Cocaine (crack)
Procaine
Tetracaine (Pontocaine)
Mechanism of Action
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Local anesthetics work in general by binding to
sodium channel receptors inside the cell and thereby
inhibiting action potentials in a given axon. They
work the best when the axon is firing.
The Cell membrane consists of ion pumps, most
notably the Na/K pump that create a negative 70mV
resting potential by pumping 2 K+ intracellular for
every 3 Na+ it pumps extracellular.
Mechanism of Action (cont’d)
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If the resting potential encounters the proper
chemical, mechanical or electrical stimuli to reduce
the membrane potential to less than -55 mV then an
action potential is produced that allows the influx of
sodium ions. LA act here to block the Na influx.
The influx allows the membrane potential to further
increase to +35mV temporarily.
Sodium and potassium channels along with the
sodium/potassium pump eventually returning a given
axon back to it’s resting membrane potential after an
action potential.
Mechanism of Action
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Benzocaine….
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Does not exist in a charged form how does it
work?
Most likely by expanding the lipid membrane of
the axon and therefore inhibiting the transport
mechanisms of Na and K ions.
General Structure
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A lipophilic group…usually a benzene ring
A Hydrophilic group…usually a tertiary amine
These are connected by an intermediate chain
that includes an ester or amide linkage
LAs are weak bases
Lipid solubility
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Most lipid soluble:
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Increased lipid solubility also equals greater potency and
longer duration of action.
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Tetracaine
Bupivicaine
Ropivacaine
Etidocaine
Why?
Because it has less of a chance of being cleared by blood flow
Decreased lipid solubility means a faster onset of action.
What else effects onset of action???
pKa
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Local anesthetics with a pKa closest to physiological
pH will have a higher concentration of nonionized
base that can pass through the nerve cell membrane,
and generally a more rapid onset.
The charged cation form more avidly binds to the
Na+ channel receptors inside the cell membrane.
pKa > 7.4 more cations, pKa < 7.4 more anions
Not all Axons are equal
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Aa- Motor with fast conduction 70-120m/s, diameter
12-20mm, myelinated and not very sensitive to local
anesthetic
Aa- Type Ia and Ib- proprioception fast conduction
again 70-120m/s, same diameter as above, a little
more sensitive to LA, myelinated
Ab- Touch pressure and proprioception, smaller
diameter 5-12mm and slower conduction 30-70m/s,
myelinated and as sensitive to LA as type Ia and Ib
fibers
Not all Axons are equal
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Ag- motor (muscle spindle) smaller diameter
3-6mm, slower conduction 15-30m/s same LA
sensitivity as type Ia and Ib fibers
Ad- Type III fibers, pain, cold temperature and
touch, smaller diameter 2-5mm, 12-30m/s,
more sensitive to LA than the above fibers and
myelinated.
Not all Axons are equal
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B fibers- Preganglionic autonomic fibers, <3mm diameter, 314m/s conduction speed and very sensitive to LA. Some
myelination.
C fibers- Type IV fibers in the dorsal root, pain warm and cold
temp. and touch, .4-1.2mm in diameter, slow conduction again
at .5-2m/s, very sensitive to LA, not myelinated.
C fibers- Postganglionic sympathetic fibers, smaller diameters
at .3-1.3mm, slow conduction at .7-2.3m/s, very sensitive to
LA and no myelination.
In general this all means that the autonomic nerves are blocked
before the sensory nerves which are blocked before the motor
nerves.
AMIDES
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Bupivacaine, Etidocaine and Ropivacainevery high potency and lipid solubility, very
long duration and protein binding also.
Lidocaine, Prilocaine and Mepivacaine- have
intermediate potency and lipid solubility and
intermediate duration of action and protein
binding.
ESTERS
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Chloroprocaine and Procaine- have low
potency and lipid solubility and also low
duration and protein binding.
Cocaine- has intermediate potency and
solubility and intermediate duration and
protein binding
Tetracaine- has high potency and lipid
solubility along with a long duration of action
and high protein binding
Plasma protein binding
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What protein are LAs bound???
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Mostly a1-acid glycoprotein
To a lesser degree albumin
Absorption
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Mucous membranes easily absorb LA
Skin is a different story…
It requires a high water conc. for penetration and a
high lipid concentration for analgesia
Which LAs can we use for this?
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EMLA cream- 5% lidocaine and 5% prilocaine in an oilwater emulsion
An occlusive dressing placed for 1 hour will penetrate 35mm and last about 1-2 hours.
Typically 1-2 grams of drug per 10cm2 of skin
Rate of systemic absorption
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Intravenous > tracheal > intercostal > caudal >
paracervical > epidural> brachial plexus >
sciatic > subcutaneous
Any vasoconstrictor present??
High tissue binding also decreases the rate of
absorption
Metabolism
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Amides…
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N-dealkylation and hydroxylation
P-450 enzymes, liver, slower process than esterase activity
Prilocaine>lidocaine>mepivacaine>ropivacaine>bupivacai
ne
Prilocaine has a metabolite….
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o-toluidine
This causes methemoglobin to form (Benzocaine can also
cause methemoglobin to form)
Treated with methylene blue 1-2mg/kg over 5 minutes
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Reduces methemoglobin Fe3+ to hemoglobin Fe2+
Metabolism
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Esters…
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Procaine and benzocaine are metabolized to…
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Pseudocholinesterase
PABA (p-aminobenzoic acid) allergy risk
Tetracaine intrathecal has it’s action
terminated by…
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No esterase activity intrathecally therefore
absorption into bloodstream terminates it’s action
Clinical Uses
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Esters
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Benzocaine- Topical, duration of 30 minutes to 1
hour
Chloroprocaine- Epidural, infiltration and
peripheral nerve block, max dose 12mg/kg,
duration 30minutes to 1 hour
Cocaine- Topical, 3mg/kg max., 30 minutes to one
hour
Tetracaine- Spinal, topical, 3mg/kg max., 1.5-6
hours duration
Clinical Uses
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Bupivacaine- Epidural, spinal, infiltration, peripheral
nerve block, 3mg/kg max., 1.5-8 hours duration
Lidocaine- Epidural, spinal, infiltration, peripheral
nerve block, intravenous regional, topical, 4.5mg/kg
or 7mg/kg with epi, 0.75-2 hours duration
Mepivacaine- Epidural, infiltration, peripheral nerve
block, 4.5mg/kg or 7mg/kg with epi, 1-2 hours
Prilocaine- Peripheral nerve block (dental), 8mg/kg,
30 minutes to 1 hour duration
Ropivacaine- Epidural, spinal, infiltration, peripheral
nerve block, 3mg/kg, 1.5-8 hours duration
Systemic Toxicity
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Blockage of voltaged-gated Na channel affects
action potential propagation throughout the
body…therefore the potential is present for
systemic toxicity.
Mixtures of LA have additive affects
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i.e. a 50% toxic dose of lidocaine and a 50% toxic
dose of bupivicaine have 100% the toxic affect of
either drug
Systemic Toxicity
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Neurological
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Symptoms include cicumoral numbness, tongue
paresthesia, dizziness, tinnitus, blurred vision,
restlessness, agitation, nervousness, paranoia,
slurred speech, drowsiness, unconsciousness.
Muscle twitching heralds the onset of tonic-clonic
seizures with respiratory arrest to follow.
Local anesthetic toxicity
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Seizure treatment:
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Thiopental 1-2mg/kg abruptly terminates seizure
activity
Benzos and hyperventilation…decrease CBF and
therefore drug exposure. These raise the threshold
of local anesthetic-induced seizures
Chloroprocaine injected intrathecally can
cause prolonged neurotoxicity. This is likely
due to a preservative no longer used with this
agent. (Sodium bisulfate)
Local anesthetic toxicity
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Repeated doses of 5% lidocaine and .5% tetracaine
may be responsible for cauda equina syndrome
following infusion through small bore catheters in
spinal anesthetics.
Pooling of drug around the cauda equina resulted in
permanent neurological damage
Animal studies suggest that neuro damage is:
Lido=tetracaine>bupivacaine>ropivacaine. Also
perservative free chloroprocaine may be neurotoxic
Local anesthetic toxicity
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Transient Neurological Symptoms
This is associated with dysethesia, burning pain and
aching in lower ext, buttocks.
Follows spinal anesthesia with variety of agents
(lido), attributed to radicular irritation and resolves in
1 week usually
Risk factors include
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Lidocaine intrathecally
Lithotomy position
Obesity
Outpatient status
Local anesthestic toxicity
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Respiratory center may be depressed
(medullary)…postretrobulbar apnea syndrome
Lidocaine depresses hypoxic respiratory drive
(PaO2)
Direct paralysis of phrenic or intercostal
nerves
LA cardio toxicity
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All LA’s depress spontaneous Phase IV
depolarization and reduce the duration of the
refractory period
Myocardial contractility and conduction
velocity are depressed at higher concentrations
All LA’s except cocaine cause smooth muscle
relaxation and therefore vasodilation (art)
whick can lead to brady, heart block and
hypotension…cardiac arrest.
LA cardio toxicity
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Major cardiovascular toxicity usually results
from 3 times the blood concentration of LA
that causes seizures.
Therefore cardiac collapse is usually the
presenting sign under GA.
R isomer of bupivacaine avidly blocks cardiac
sodium channels and dissociates very slowly.
Making resuscitation prolonged and difficult.
LA cardio toxicity
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Levo-bupivacaine (S isomer) is no longer
avaliable in the US but had a cardiovascular
profile similar to ropivacaine.
Ropivacaine has a larger therapeutic index and
it is 70% less likely to cause severe cardiac
dsyrhythmias than bupivacaine
Also ropviacaine has greater CNS tolerance
The improved safety profile is due to a lower
lipid solubility
LA toxicity treatment
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Supportive care: intubation, vasopressors, appropriate
defibrillation, fluids, stop injection of LA, anything
else….
Intralipid…Bolus 1cc/kg of 20% intralipid,
0.25cc/kg/min of 20% intralipid for 10 minutes
Bolus can be repeated every 5 minutes up to a
maximum of 8cc/kg of 20% intralipid
Cardiac support should be continued as ACLS
dictates
Epi and vasopresin should likely both be used in the
resusitation efforts (animal model data from A & A)
True Allergic Reactions to LA’s
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Very uncommon
Esters more likely because of p-aminobenzoic
acid (allergen)
Methylparaben preservative present in amides
is also a known allergen
Local Anesthetic Musculoskeletal
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Cause myonecrosis when injected directly into
the muscle
When steroid or epi added the myonecrosis is
worsened
Regeneration usually takes 3-4 weeks
Ropivacaine produces less sereve muscle
injury than bupivacaine
Drug Interactions
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Chloroprocaine epidurally may interfere with the analgesic
effects of intrathecal morphine
Opioids and a2 agonists potentiate LA’s
Propranolol and cimetidine decrease hepatic blood flow and
decrease lidocaine clearance
Pseudocholinesterase inhibitors decrease Ester LA metabolism
Dibucaine (amide LA) inhibits pseudocholinesterase used to
detect abn enzyme
Sux and ester LA need pseudochol. for metabolism therefore
adminstering both may potentiate their activity
LA potentiate nondepolarizing muscle relaxant blockade
Other agents with LA properties
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Meperidine
TCAs (amitriptyline)
Volatile anesthetics
Ketamine
Tetrodotoxin (blocks Na channels from the
outside of the cell membrane) Animal studies
suggest that when used in low doses with
vasoconstrictors it will significantly prolong
duration of action of LA.
Bibliography
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Clinical Anesthesiology, Morgan and Mikhail