Local Anesthetic Pharmacology

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Local Anesthetic Pharmacology

Steven L. Shafer, M.D.

Professor of Anesthesia, Stanford University

Adjunct Professor of Biopharmaceutical Science, UCSF


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Outline

History

Mechanism of Action

Properties that determine clinical effects

Classes

Toxicity Dosage Summary


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History: it all started with

cocaine Incas used cocaine as a topical anesthetic, dating back

to 3000 B.C.

1860: cocaine isolated coca leaves by PaoloMantegazza, who tested it on himself.

1860: cocaine formulated into Dr. Mariani's FrenchTonic, for which Dr. Mariani received a gold medal

from Pope Leo XIII. 1884: cocaine used for topical ophthalmic anesthesia

by Carl Koller (at the suggestion of Freud).


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1885 Advertisement


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History: more cocaine

1984: cocaine used for peripheral nerve block

(Halstead)

1886: John S. Pemberton invented Coca Cola,combining cocaine with Cola nitida extract (kola nut).

1898: cocaine first for spinal anesthetic (Bier) Personally developed PDPH, which he correctly diagnosed!


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Early 1900s

By 1900 the addictive properties of cocainewere well recognized.

1904: Fourneau develops stovaine,promptly forgotten

1905: Einhorn develops procaine,

introduced into clinical practice by Braun Einhorn called it novocaine, for new cocaine. Hedemonstrated that it had all the anesthetic effects,and none of the addictive potential.


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Modern local anesthetics

1932: Tetracaine

1943: Lidocaine (Lofgven and Lundquist)

1957: Mepivacaine

1960: Prilocaine

1963: Bupivacaine

1972: Etidocaine discovered 1973: Etidocaine lost

1996: Ropivacaine

1999: Levobupivacaine


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Mechanism of Action

Blocks the sodium channel Wide ranging effects on the nervous system

Local anesthetics blocks the channel from theintracellular side

Must enter the neuron to work

increased lipophilicity is associated with increased potency

Increased un-ionized fraction increases potency

The un-ionized molecule crosses the cell membraneAdding bicarbonate increases the un ionized fraction

Tetrodotoxin binds the sodium channel from theoutside


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Sodium Channels

Voltage gated ion channel

4 segments, each with 6

transmembrane helices

Central pore

http://courses.washington.edu/conj/membrane/nachan.htm


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Sodium Channels

A small machine with: Ion selector (very

specific for Na)

Voltage sensor

1 in each unit

Gate connected tovoltage sensor

Opens when voltagerises, letting Na+enter cell.

Inactivation gate

Closes when voltagegets to +30 mV,ending Na+ flux.

Selectivit

y Filter

Gate

Inactivationgate

Voltage

sensor

Outside

+++++

- - - - -

Inside

70-90mV at

rest

http://courses.washington.edu/conj/membrane/nachan.htm


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Sodium Channels:

Sequence of Events Each sensor moves at a slightly

different voltage.

When the transmembranepotential drops below 50, all

voltage sensors open. Relatively few ions pass, but the

ones that do rapidly raise thetransmembrane potential.

When the transmembranepotential rises to about +30 mV,

the inactivation gate closes,ending the sodium flux.

Outward potassium flux restoresthe resting potential.

Selectivit

y Filter

Gate

Inactivationgate

Voltage

sensor

Outside

+++++

- - - - -

Inside

70-90mV at

rest


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-100

-50

0

50

0 5 10 15

Milliseconds

T

ransmembran

epotential

(mV)

Resting RestingUndershoot

Depo

larization

Repolarization

Action Potential

Channel

Opens

ChannelCloses


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Site of Action

SelectivityFilter

Gate

Inactivation

gate

Voltagesensor

Outside

+++++

- - - - -

Inside

70-90

mV at

rest

Local Anesthetic


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Nerves

Small diameter nerves are more easily blockedthan large diameter nerves

For the same diameter, myelinated nerves willbe blocked before unmyelinated nerves.

Why preganglionic nerves are blocked before the smallerunmyelinated C fibers (pain nerves) in spinal anesthesia.

Nerves that fire frequently are preferentiallyblocked over nerves that fire infrequently.


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Nerve Sensitivity

1. Autonomic

2. Pain

3. Temperature

4. Touch

5. Proprioception6. Skeletal muscle tone


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Properties that govern clinical

effect Potency

Lipophilicity

Ionization (all are weak bases)

Rate of metabolism


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Rate of Onset Potency

Correlates closely with lipophilicity, with more lipophilic local anesthetics beingmore potent

Dose Increased dose, either by increasing volume or increasing concentration,

accelerates the rate of onset

Un-ionized fraction Adding bicarb accelerates the rate of onset

Epinephrine Reduces the rate at which the drug washes away

Elimination pharmacokinetics Rapidly eliminated drugs demonstrate rapid onset, because they are given in

relatively higher doses

For example, intrinsic rate of onset of succinylcholine is fairly slow, but therapid clearance permits administration of a huge overdose, which clinicallyresults in the rapid onset of drug effect.


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Potency, pKa, Lipophilicity

Drug pKa Octanol /H2OLow Potency

Procaine 8.9 100

Intermediate potency

Mepivacaine 7.7 130Prilocaine 8.0 129

Chloroprocaine 9.1 810

Lidocaine 7.8 366

High potency

Tetracaine 8.4 5822Bupivacaine 8.1 3420

Etidocaine 7.9 7320

Ropivacaine 8.1

Levobupivacaine 8.1 3420


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Addition of Bicarbonate

Lidocaine: 1 cc bicarb / 10 cc drug

Mepivacaine: 1 cc bicarb / 10 cc drug

Bupivacaine: 0.1 cc/10 cc Hard to not get precipitation

Levobupivacaine: same as bupivacaine


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Duration of Action

Rate of systemic absorption Tissue vascularity

Use of epinephrine

Rate of elimination Particularly for esters, which are metabolized locally

Dose

Potency

General groups: Short: Procaine, chloroprocaine

Intermediate: lidocaine, mepivicaine, prilocaine

Long acting: Tetracaine, bupivacaine, etidocaine, ropivacaine,levobupivacaine


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Metabolism

Amides

Primarily hepatic

Plasma concentrationmay accumulate with

repeated doses

Toxicity is dose

related, and may bedelayed by minutes or

even hours from time

of dose.

Esters

Ester hydrolysis in the plasma

by pseudocholinesterase

Almost no potential foraccumulation

Toxicity is either from direct

IV injection

tetracaine, cocaine

or persistent effects ofexposure

benzocaine, cocaine


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Systemic Absorption

Dose

Vascularity Intercostal > Caudal > Epidural > Brachial > Infiltration

pH Slower absorption if solution is alkaline, because more is bound into the

tissues.

Lipophilicity Slower absorption for more lipophilic drugs, again because more is

bound in the tissues

Epinephrine Decreases local blood flow, decreasing absorption


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Pharmacokinetics:

R and S Bupivacaine after epidural injection

S enantiomer

concentrations are much

higher. S is far more protein

bound, so the free

concentration is less.

Peak levels are 15-30

minutes after injection.

S-

R+

Peak

From Kees et al, Anesth Analg 1998,

86:361


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Pharmacokinetics:Ropivacaine and Bupivacaine after axillary block

175-225 mg given

Levels are similar

Peak levels are at 0.5-1.5hours, with median

around 1 hour.

Ropivacaine Bupivacaine

From Vilho, et al, Anesth Analg 1995 81:534


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Pharmacokinetics:Ropivacaine and Bupivacaine after intercostal block

Ropivacaine dotted line

Bupivacaine solid line

140 mg given

Levels are similar

Peak levels are at 20-30

minutes

From Kopacz, et al, Anesthesiology 1994 81:1139-1148


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Classes: The rule of i

Amides

Lidocaine

BupivacaineLevobupivacaineRopivacaineMepivacaineEtidocainePrilocaine

Esters

Procaine

Chloroprocaine

Tetracaine

Benzocaine

Cocaine


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Procaine (Novocaine)

N

NO

O

Ester Linkage

Slow onset, short duration, largely abandoned. Found in numerous drug

mixtures, though (e.g., Solu-Medrol, Penicillin), apparently to decrease

pain on injection.


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Chloroprocaine (Nesacaine)

N

NO

O

Ester Linkage

Cl

Rapid onset, rapid offset. Neurotoxic, so not used in spinal anesthesia


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Benzocaine (Hurricaine)

N

O

O

Ester Linkage

Only used topically. Associated with methemoglobinemia, particular as an mucosal spray.


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Tetracaine (Pontocaine)

N

O

O

Ester Linkage

N

Slow diffusion in tissues. Often found in topical preparations. Mostly used in anesthesia

for spinal blockade.


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Cocaine

N

O

O

Ester Linkage

O

O

Causes vasoconstriction (as do ropivacaine, bupivacaine, and levobupivacaine).

No reason to use. Use 4% lidocaine mixed with 1 ampule (10 mg) phenylephrine instead.


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Lidocaine (Xylocaine)

NN

O

Amide Linkage


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Bupivacaine

(Marcaine, Sensoricaine)

N

N

O

N N

O

S Bupivacaine R Bupivacaine

*

*

AKA: levobupivacaine, Chirocaine

Equipotent, but less cardiotoxicthan bupivacaine


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Levobupivacaine


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N

N

O

*

Ropivacaine (Naropin)

N

N

O

*

Only available as pure S isomer

Causes vasoconstriction

Less motor block than bupivacaine

Otherwise, equipotent anesthesia,but less cardiotoxic

S bupivacaine


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Mepivacaine

(Carbocaine, Polocaine)

N

N

O


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Etidocaine (Duranest)

N

N

O

Ive never seen it used it, but the profile looks good:

rapid onset, long effect. Achilles' heel is profound

motor block.


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Prilocaine

N N

O

Only amide missing a methyl

group here.


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Meperidine (Demerol)

Called pethidineeverywhere but NorthAmerica

Probably the strangest drugin anesthesia opioid, atropinic, local

anesthetic

blocks seretonin reuptake

leading to fatal interactionswith MAO inhibitors

toxic metabolite

Normeperidine

Negative inotrope

N

OO

Ester Linkage


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Tetrodotoxin


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Acute toxicity

Main concern is CNS and cardiac toxicity

CNS Tinnitus, dizziness, lightheadedness are early signs

Anxietydisorientationloss of consciousness seizures

respiratory arrest

Cardiac Hypotension

All local anesthetics are negative inotropes

PVC wide QRS Multiform vtach vfib, orPattern with bupivacaine

Bradycardiaasystole

Pattern with bupivacaine + lidocaine


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Acute Toxicity

With most drugs, CNS toxicity proceeds cardiac

toxicity, providing a warning of impending

disaster. Key response: maintain oxygenation and normal CO2!

With bupivacaine, CNS toxicity rapidly progresses

to cardiovascular collapse.

Pregnancy enhances the risk of cardiac toxicity.


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Acute toxicity

Risk of seizure and/or cardiovascular

collapse is increased by:

Cold temperature (slows metabolism) Metabolic or respiratory acidosis

Hypoxia


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Treatment of overdose

Airway:

100% oxygen

Intubate if necessary to ventilate

CNS:Break seizure with propofol, thiopental, or midazolam

Cardiovascular

Amiodarone has demonstrated efficacy. Use 300 mg

Lidocaine would be a particularly poor choice!Resuscitation difficult with bupivacaine, more frequently

successful in animal studies following ropivacaine andlevobupivacaine overdose.

Eff t f B i i I


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Effects of Bupivacaine Isomers on

Cardiac Sodium Channels

Dextrobupivacaine

Has faster onset of action thanlevobupivacaineHas greater affinity for cardiac sodium

channels

Has a slower offset time


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Effects of Levobupivacaine and Racemic

Bupivacaine in Anesthetized Pigs

Levobupivacaine

Dose (mg)

0.00

20.00

40.00

60.00

80.00

100.00

120.00

140.00

25% Difference

47% Difference

In

creaseinQRS(ms)

Bupivacaine

0.375 0.75 1.5 3.0 7.04.0

Morrison SG, et al. Anesth Analg 2000;90:1308-1314.

I t l D f B i i d


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Incremental Doses of Bupivacaine and

Levobupivacaine in Sheep: CV Effects

Baseline Multiform VT

0 1 2 3 4 225 226 227 228 229 240 241 242 243

Bupivacaine, 200 mg IV for 3 min

Baseline Wide QRS

Time(sec)

0 1 2 3 4 300 301 302 303 304 375 376 377 378 379

Levobupivacaine, 200 mg IV for 3 min

Time

(sec)

Huang YF, et al. Anesth Analg 1998;86:797-804.

l ff


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Central Nervous System Effects:

Convulsant Dose

Mean 95% CI

Dose(mg)

0

20

40

60

80

100

120

140

Levobupivacaine

(n=7)

Bupivacaine

(n=7)

Gennery BA, et al. Semin Anesth 2000 (in press).


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Neurotoxicity

Chloroprocaine Low pH and presence of metabisulfite

Not recommended for spinal anesthesia

Lidocaine Initially seen with formulation in 10% dextrose

Now seen with all formulations

No longer used for spinal anesthesia

Bupivacaine appears free of neurotoxicity


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Allergies

AmidesTrue allergies to amide

anesthetics are

EXCEEDINGLY rare

Esters

Uncommon

Allergic reactions areprobably related to

PABA.

Common ingredient in

sun-screen.

May also be related to

topical benzocaine

exposure.


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PABA

para-aminobenzoic acid

N

O

O

Note structural

similarity to procaine


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Allergies

Allergies to local anesthetics are commonly reported by patients.

True allergies to local anesthetics of either class are rare.

Most allergic responses that have been carefully evaluated are: Psychogenic

Reactions to preservatives (e.g., metabisulfite) or latex

cardiovascular response to epinephrine.

The exception is long-term exposure to benzocaine in topicalpreparations, which has resulted in numerous reports of contactdermatitis.


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Methemoglobinemia

10%: clinical anoxia

60%: stupor, coma, and death.

Documented with benzocaine, prilocaine Associated with benzocaine and prilocaine

Treat with methylene blue, 1-2 mg/kg givenover 5 minutes

Faster administration may exacerbatemethemoglobinemia


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Drug Interactions

Local anesthetic toxicities are ADDITIVE Divide lidocaine dose / 4 to convert to bupivacaine

equivalents Keep lidocaine / 4 + bupivacaine less than 3 mg/kg


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Dosing Guidelines

(nerve block)

Drug Onset Local custom Duration

Maximum With epinephrineAmides

Lidocaine Rapid 4.5 mg/kg 7 mg/kg 900 mg withepi 1-2 h

Mepivacaine Medium 6 mg/kg not given 750 mg 2-3 h

Etidociaine Rapid 6 mg/kg 8 mg/kg N/A 4 - 8 h

Prilocine Medium 8 mg/kg 8 mg/kg N/A 1-2 h

Bupivacaine Slow 2.5 mg/kg 3 mg/kg 200 mg 4 - 12 h

Ropivacaine Slow 4 mg/kg No effect N/A 4 - 9 h

Levobupivacaine Slow 2 mg/kg (!) not given 300 mg 4 - 8 h

Esters

Procaine Rapid 10 mg/kg 15 mg/kg N/A 15-30 min

Chloroprocaine Very rapid 10 mg/kg 15 mg/kg 10 mg/kg 30-60 min

Tetracaine Slow 1.5 mg/kg 2.5 mg/kg N/A 3 h

Per Package Insert


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Complete Dosing Guideline

(From VA National Formulary)

Microsoft Excel

Worksheet

(Double click on Excel icon to get spreadsheet.)

Documents

Local Anesthetic Pharmacology