Local Anesthetics 08 Oct

7/27/2019 Local Anesthetics 08 Oct

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Local Anesthetics

by

Brendan Astley MDOctober 2008


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Local Anesthetics

Used at multiple sites throughout the body:

Epidural

Spinal

Peripheral nerve blocks

IV (Bier Block)

Skin sites locally


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Amides and Esters

Chloroprocaine

(Nesacaine)

Cocaine (crack)

Procaine

Tetracaine (Pontocaine)

Lidocaine (Xylocaine)

Bupivacaine (Marcaine)

Etidocaine (Duranest) Mepivacaine

(Carbocaine)

Prilocaine (Citanest) Ropivacaine


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Mechanism of Action

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.


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Mechanism of Action (contd)

If the resting potential encounters the properchemical, mechanical or electrical stimuli to reducethe membrane potential to less than -55 mV then anaction potential is produced that allows the influx ofsodium ions. LA act here to block the Na influx.

The influx allows the membrane potential to furtherincrease to +35mV temporarily.

Sodium and potassium channels along with thesodium/potassium pump eventually returning a givenaxon back to its resting membrane potential after anaction potential.


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Mechanism of Action

Benzocaine.

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.


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General Structure

A lipophilic groupusually a benzene ring

A Hydrophilic groupusually a tertiary amine

These are connected by an intermediate chainthat includes an ester or amide linkage

LAs are weak bases


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Lipid solubility

Most lipid soluble:

Tetracaine

Bupivicaine

Ropivacaine

Etidocaine Increased lipid solubility also equals greater potency and

longer duration of action.

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???


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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


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Not all Axons are equal

Aa- Motor with fast conduction 70-120m/s, diameter12-20mm, myelinated and not very sensitive to localanesthetic

Aa- Type Ia and Ib- proprioception fast conductionagain 70-120m/s, same diameter as above, a littlemore 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 Ibfibers


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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.


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B fibers- Preganglionic autonomic fibers,


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AMIDES

Bupivacaine, Etidocaine and Ropivacaine-

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

binding.


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ESTERS

Chloroprocaine and Procaine- have lowpotency and lipid solubility and also lowduration and protein binding.

Cocaine- has intermediate potency andsolubility and intermediate duration andprotein binding

Tetracaine- has high potency and lipidsolubility along with a long duration of actionand high protein binding


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Plasma protein binding

What protein are LAs bound???

Mostly a1-acid glycoprotein

To a lesser degree albumin


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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 oil-

water emulsion

An occlusive dressing placed for 1 hour will penetrate 3-

5mm and last about 1-2 hours.

Typically 1-2 grams of drug per 10cm2 of skin


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Rate of systemic absorption

Intravenous > tracheal > intercostal > caudal >

paracervical > epidural>brachial plexus >

sciatic > subcutaneous

Any vasoconstrictor present??

High tissue binding also decreases the rate of

absorption


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Metabolism

Amides

N-dealkylation and hydroxylation

P-450 enzymes, liver, slower process than esterase activity

Prilocaine>lidocaine>mepivacaine>ropivacaine>bupivacaine

Prilocaine has a metabolite. 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+


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Metabolism

Esters

Pseudocholinesterase

Procaine and benzocaine are metabolized to

PABA (p-aminobenzoic acid) allergy risk

Tetracaine intrathecal has its action

terminated by

No esterase activity intrathecally therefore

absorption into bloodstream terminates its action


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Clinical Uses

Esters

Benzocaine- Topical, duration of 30 minutes to 1hour

Chloroprocaine- Epidural, infiltration andperipheral 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


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Clinical Uses

Bupivacaine- Epidural, spinal, infiltration, peripheralnerve block, 3mg/kg max., 1.5-8 hours duration

Lidocaine- Epidural, spinal, infiltration, peripheralnerve 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


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Systemic Toxicity

Blockage of voltaged-gated Na channel affects

action potential propagation throughout the

bodytherefore the potential is present for

systemic toxicity.

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 ofeither drug


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Systemic Toxicity

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.


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Local anesthetic toxicity

Seizure treatment:

Thiopental 1-2mg/kg abruptly terminates seizureactivity

Benzos and hyperventilationdecrease CBF andtherefore drug exposure. These raise the thresholdof local anesthetic-induced seizures

Chloroprocaine injected intrathecally can

cause prolonged neurotoxicity. This is likelydue to a preservative no longer used with thisagent. (Sodium bisulfate)


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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


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Transient Neurological Symptoms

This is associated with dysethesia, burning pain andaching in lower ext, buttocks.

Follows spinal anesthesia with variety of agents

(lido), attributed to radicular irritation and resolves in1 week usually

Risk factors include Lidocaine intrathecally

Lithotomy position Obesity

Outpatient status


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Local anesthestic toxicity

Respiratory center may be depressed

(medullary)postretrobulbar apnea syndrome

Lidocaine depresses hypoxic respiratory drive

(PaO2)

Direct paralysis of phrenic or intercostal

nerves


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LA cardio toxicity

All LAs depress spontaneous Phase IVdepolarization and reduce the duration of therefractory period

Myocardial contractility and conductionvelocity are depressed at higher concentrations

All LAs except cocaine cause smooth muscle

relaxation and therefore vasodilation (art)whick can lead to brady, heart block andhypotensioncardiac arrest.


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LA cardio toxicity

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.


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LA cardio toxicity

Levo-bupivacaine (S isomer) is no longeravaliable in the US but had a cardiovascularprofile similar to ropivacaine.

Ropivacaine has a larger therapeutic index andit is 70% less likely to cause severe cardiacdsyrhythmias than bupivacaine

Also ropviacaine has greater CNS tolerance The improved safety profile is due to a lower

lipid solubility


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LA toxicity treatment

Supportive care: intubation, vasopressors, appropriatedefibrillation, fluids, stop injection of LA, anythingelse.

IntralipidBolus 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)


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True Allergic Reactions to LAs

Very uncommon

Esters more likely because of p-aminobenzoic

acid (allergen)

Methylparaben preservative present in amides

is also a known allergen


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Local Anesthetic Musculoskeletal

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


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Drug Interactions

Chloroprocaine epidurally may interfere with the analgesiceffects of intrathecal morphine

Opioids and a2agonists potentiate LAs

Propranolol and cimetidine decrease hepatic blood flow and

decrease lidocaine clearance Pseudocholinesterase inhibitors decrease Ester LA metabolism

Dibucaine (amide LA) inhibits pseudocholinesterase used todetect abn enzyme

Sux and ester LA need pseudochol. for metabolism thereforeadminstering both may potentiate their activity

LA potentiate nondepolarizing muscle relaxant blockade


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Other agents with LA properties

Meperidine

TCAs (amitriptyline)

Volatile anesthetics

Ketamine

Tetrodotoxin (blocks Na channels from theoutside of the cell membrane) Animal studies

suggest that when used in low doses withvasoconstrictors it will significantly prolongduration of action of LA.


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Bibliography

Clinical Anesthesiology, Morgan and Mikhail

Documents

Local Anesthetics 08 Oct