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Unformatted text preview: Local Anesthetics
Brendan Astley MD
October 2008 Local Anesthetics
Local Used at multiple sites throughout the body: Epidural
Peripheral nerve blocks
IV (Bier Block)
Skin sites locally Amides and Esters
Amides Lidocaine (Xylocaine)
Tetracaine (Pontocaine) Mechanism of Action
Mechanism 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.
every Mechanism of Action (cont’d)
Mechanism 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 Mechanism of Action
Mechanism Benzocaine…. Does not exist in a charged form how does it
Most likely by expanding the lipid membrane of
the axon and therefore inhibiting the transport
mechanisms of Na and K ions.
mechanisms General Structure
General 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
Lipid Most lipid soluble: Increased lipid solubility also equals greater potency and
longer duration of action.
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
pKa 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
Not Αα− Motor with fast conduction 70-120m/s, diameter
12-20mm, myelinated and not very sensitive to local
Aα- Type Ia and Ib- proprioception fast conduction
again 70-120m/s, same diameter as above, a little
more sensitive to LA, myelinated
Aβ- 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
Not Aγ - motor (muscle spindle) smaller diameter
3-6mm, slower conduction 15-30m/s same LA
sensitivity as type Ia and Ib fibers
Αδ- 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
Not B fibers- Preganglionic autonomic fibers, <3mm diameter, 314m/s conduction speed and very sensitive to LA. Some
C fibers- Type IV fibers in the dorsal root, pain warm and cold
fiberstemp. 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
fibersat .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 Bupivacaine, Etidocaine and RopivacaineBupivacaine,
very 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
ESTERS Chloroprocaine and Procaine- have low
potency and lipid solubility and also low
duration and protein binding.
Cocaine- has intermediate potency and
Cocainesolubility and intermediate duration and
Tetracaine- has high potency and lipid
Tetracainesolubility along with a long duration of action
and high protein binding
and Plasma protein binding
Plasma What protein are LAs bound??? Mostly α1-acid glycoprotein
Mostly -acid To a lesser degree albumin Absorption
Absorption 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? 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
Rate Intravenous > tracheal > intercostal > caudal >
paracervical > epidural> brachial plexus >
sciatic > subcutaneous
Any vasoconstrictor present??
High tissue binding also decreases the rate of
Metabolism Amides… N-dealkylation and hydroxylation
P-450 enzymes, liver, slower process than esterase activity
Prilocaine has a metabolite…. o-toluidine
o-toluidine This causes methemoglobin to form (Benzocaine can also
cause methemoglobin to form)
Treated with methylene blue 1-2mg/kg over 5 minutes Reduces methemoglobin Fe3+ to hemoglobin Fe2+ Metabolism
Metabolism Esters… Procaine and benzocaine are metabolized to… Pseudocholinesterase
PABA (p-aminobenzoic acid) allergy risk Tetracaine intrathecal has it’s action
terminated No esterase activity intrathecally therefore
absorption into bloodstream terminates it’s action
absorption Clinical Uses
Clinical Esters Benzocaine- Topical, duration of 30 minutes to 1
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
Tetracaine- Spinal, topical, 3mg/kg max., 1.5-6
hours duration Clinical Uses
Clinical 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
nerve Systemic Toxicity
Systemic Blockage of voltaged-gated Na channel affects
action potential propagation throughout the
body…therefore the potential is present for
Mixtures of LA have additive affects
i.e. a 50% toxic dose of lidocaine and a 50% toxic
dose of bupivicaine have 100% the toxic affect of
either Systemic Toxicity
Systemic Neurological 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.
seizures Local anesthetic toxicity
Local Seizure treatment: Thiopental 1-2mg/kg abruptly terminates seizure
Benzos and hyperventilation…decrease CBF and
therefore drug exposure. These raise the threshold
of local anesthetic-induced seizures
of Chloroprocaine injected intrathecally can
cause prolonged neurotoxicity. This is likely
due to a preservative no longer used with this
agent. (Sodium bisulfate)
agent. Local anesthetic toxicity
Local Repeated doses of 5% lidocaine and .5% tetracaine
may be responsible for cauda equina syndrome
following infusion through small bore catheters in
Pooling of drug around the cauda equina resulted in
permanent neurological damage
Animal studies suggest that neuro damage is:
perservative free chloroprocaine may be neurotoxic Local anesthetic toxicity
Local 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 Lidocaine intrathecally
Outpatient status Local anesthestic toxicity
Local Respiratory center may be depressed
(medullary)…postretrobulbar apnea syndrome
Lidocaine depresses hypoxic respiratory drive
Direct paralysis of phrenic or intercostal
nerves LA cardio toxicity
LA All LA’s depress spontaneous Phase IV
depolarization and reduce the duration of the
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 LA cardio toxicity
LA 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.
Making LA cardio toxicity
LA 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 LA toxicity treatment
LA Supportive care: intubation, vasopressors, appropriate
defibrillation, fluids, stop injection of LA, anything
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
Epi and vasopresin should likely both be used in the
resusitation efforts (animal model data from A & A)
resusitation Lipid, Not Propofol, Treats Bupivacaine Overdose
Guy Weinberg, MD, Paul Hertz, MD, and Janet Newman, MD Department of Anesthesiology, University of Illinois, Chicago, IL, [email protected]
To the Editor:
Mayr et al. (1) recently reported the comparative efficacies of epinephrine, vasopressin, and a combination of the two drugs in a porcine model of bupivacaine overdose. They used a single
5 mg/kg IV bolus of bupivacaine, applied advanced cardiac life support 1 min after asystole, and administered drugs 2 min later and at 5-min intervals thereafter. Monophasic
countershocks were applied as dictated by rhythm disturbance. Rates of survival were 5/7 for vasopressin, 4/7 for epinephrine, 7/7 in the combined treatment group, and 0/7 in controls.
By comparison, we reported that injecting a 20% lipid emulsion in combination with cardiac massage leads to successful return of normal hemodynamics in 9/9 dogs after a bolus injection
of 10 mg/kg bupivacaine (2). Lipid infusion in 6 of these dogs was delayed for 10 min to approximate a clinical scenario. A normal rhythm was established in all 9 dogs within 5 min; no
electrical counter shock was required. No control animal demonstrated return of BP or HR.
Dogs and pigs may differ in terms of susceptibility to bupivacaine cardiac toxicity; the porcine and canine models may not be completely comparable for this and other reasons. However,
we and others (3) believe the rapid return of normal rhythm and hemodynamics in both dogs and rats following massive bupivacaine overdose (twice the dose used in Mayr’s study),
indicates superior efficacy of lipid rescue for bupivacaine toxicity to drugs, such as epinephrine and vasopressin that are components of the generic ACLS protocol for cardiopulmonary
arrest (4). Perhaps Dr. Mayr will consider comparing combined epinephrine/vasopressin with lipid rescue in the porcine model of bupivacaine cardiac toxicity.
Mayr et al. (1) also incorrectly cite us as indicating that "....a lipid infusion such as propofol increases the dose of bupivacaine required to induce cardiac arrest, and, therefore, this strategy
has been suggested as a potential means to improve outcomes from such toxicity." We have never recommended use of propofol for treating bupivacaine overdose, and strongly suspect
that its use in cardiac arrest will impede resuscitation.
W e have recommended treating bupivacaine-associated cardiac arrest by injecting a 1 mL/kg bolus of 20% lipid emulsion (such as Intralipid) and starting an infusion of 0.25 mL/kg/min
for 10 min, while continuing basic life support (5). The bolus could be repeated every 5 min, two or three times if needed. The upper dose limit of 20% lipid emulsion is not known, but a
total of more than 8 mL/kg is not likely to be needed, nor successful if lower doses are not. Note that this protocol will deliver a significant volume load (several hundred mL in an adult).
The standard formulation of propofol is 10% lipid and 1% propofol. Therefore, gram quantities of propofol would accompany our recommended regimen and only half the dose of lipid,
the necessary ingredient, would be delivered.
Propofol is not an acceptable treatment for bupivacaine overdose.
Mayr VD, Raedler C, Wenzel V, et al. A comparison of epinephrine and vasopressin in a porcine model of cardiac arrest after rapid intravenous injection of bupivacaine. Anesth Analg
2004; 98: 1426–31.[Abstract/Free Full Text]
Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003; 28: 198–202. [ISI]
Groban L, Butterworth J. Lipid reversal of bupivacaine toxicity: has the silver bullet been identified? Reg Anesth Pain Med 2003; 28: 167–9. [ISI][Medline]
Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: advanced challenges in resuscitation: section 2: toxicology in ECC. The American Heart
Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000; 102 (suppl 8): I223–8. [Medline]
Weinberg G. Lipid rescue: caveats and recommendations for the "Silver Bullet" [letter]. Reg Anesth Pain Med 2004; 29: 74–5. Response
Viktoria D. Mayr, MD, Claus Raedler, MD, Volker Wenzel, MD, Karl H. Lindner, MD, and Hans-Ulrich Strohmenger, MD Univ. Klinik f. Anaesthesie u. Allg. Intensivmedezin,
Innsbruck, Austria, [email protected]
W e would like to thank Weinberg et al. for their interest in our work, as well as for their constructive comments. First, we sincerely apologize for having incorrectly cited Weinberg et al.
by confounding propofol and intralipid; we completely agree with their statement that propofol administration cannot be recommended for managing a bupivacaine overdose. When
indicating in the Discussion section that "... a lipid infusion such as propofol increases the dose of bupivacaine required to induce cardiac arrest, and therefore, this strategy has been
suggested as a potential means to improve outcomes from such toxicity," we did not suggest to use propofol for treating bupivacaine toxicity, nor that Dr. Weinberg et al. used propofol for
treating bupivacaine toxicity. We share the same opinion that usage of propofol in cardiac arrest may impede resuscitation. With our statement about a "lipid infusion such as propofol...",
we only wanted to state the reason why we did not use propofol but isoflurane and nitrous oxide to maintain anesthesia in our experiment. Instead of saying "... a lipid infusion such as
propofol...", it would have been better to state "... as propofol is a lipid infusion which may increase the dose of bupivacaine required to induce cardiac arrest..." Second, beneficial lipid
effects during massive bupivacaine overdose as described by Weinberg et al. resulted in impressive outcome data. However, their conclusion drawn in the letter that these results indicate
the superiority of this treatment regime in comparison to advanced cardiac life support including epinephrine and vasopressin has not been proven. The comparative investigation of the
epinephrine/vasopressin combination and the lipid rescue protocol in the same animal model of bupivacaine cardiac toxicity can only provide reliable information in this respect. True Allergic Reactions to LA’s
True Very uncommon
Esters more likely because of p-aminobenzoic
Methylparaben preservative present in amides
is also a known allergen
is Local Anesthetic Musculoskeletal
Local Cause myonecrosis when injected directly into
When steroid or epi added the myonecrosis is
Regeneration usually takes 3-4 weeks
Ropivacaine produces less sereve muscle
injury than bupivacaine
injury Drug Interactions
Drug Chloroprocaine epidurally may interfere with the analgesic
effects of intrathecal morphine
Opioids and α2 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
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 Clinical Anesthesiology, Morgan and Mikhail ...
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