Pharmacology of Local Pharmacology of Local AnestheticsAnesthetics

John Yagiela, DDS, John Yagiela, DDS, PhDPhD

UCLA School of UCLA School of DentistryDentistry

Pharmacology of Local Pharmacology of Local AnestheticsAnesthetics

HistoryHistoryDefinitionDefinitionPhysical propertiesPhysical propertiesMechanism of actionMechanism of actionPharmacokineticsPharmacokineticsAdverse effectsAdverse effects

HistoryHistory

500’s500’s Coca leaves first used Coca leaves first used by Peruvians for psychotropic by Peruvians for psychotropic propertiesproperties

1850’s1850’s Cocaine isolated, Cocaine isolated, hypodermic needle developedhypodermic needle developed

18841884 Sigmund Freud studies Sigmund Freud studies the effects of cocainethe effects of cocaine

History (2)History (2)

18841884 Carl Koller introduces Carl Koller introduces cocaine into medical practicecocaine into medical practice

18841884 Local anesthesia used Local anesthesia used in dentistry by Halsted and Hallin dentistry by Halsted and Hall

19051905 Procaine synthesized Procaine synthesized by Einhornby Einhorn

History (3)History (3)

19211921 Cartridge syringe Cartridge syringe marketed by Cookmarketed by Cook

19471947 Aspirating syringe Aspirating syringe developeddeveloped

19481948 Lidocaine marketedLidocaine marketed 19591959 Disposable needle Disposable needle

introducedintroduced

DefinitionDefinition

Local anesthetics are drugs Local anesthetics are drugs that reversibly depress that reversibly depress nerve conduction. "Caine" nerve conduction. "Caine" local anesthetics act more local anesthetics act more selectively than other selectively than other agents.agents.

Physical Properties Physical Properties (structure)(structure)

Ester:

Amide:

Example:

Exception: Benzocaine, which lacks a substituted amino group

R —COO—R —N

R —NHCO—R —N

1 2R

R3

4

21R

R3

4

H N— —COO—(CH ) —N2 2 2

C H2 5

C H2 5

R — Lipophilic aromatic residue.

R — Aliphatic intermediate connector.

R , R — Alkyl groups, occasionally H. Constitute with N the hydrophilic terminus.

1

2

3 4

(Acid-base considerations)(Acid-base considerations)

Most local anesthetics are weak Most local anesthetics are weak bases, pKbases, pKaa 7.5-9.0. 7.5-9.0.

Usually prepared as a salt (e.g., Usually prepared as a salt (e.g., with HCl) to increase stability, with HCl) to increase stability, water solubility.water solubility.

When injected, 5%-40% is When injected, 5%-40% is converted to the nonionized free converted to the nonionized free base.base.

R-NHR-NH++ R-N R-N + H+ H++

acidacid base base

pH = pKpH = pKaa + log + logbasebaseacidacid

O

COCHH N2

CCH22

H

H

2

N5

C 52

HC 52

HC 52

O

COCHH N2 CH22 N H + H+

Nonionized baseCationic acid

BaseAcid

Log = pH – pKa

(Henderson-Hasselbalch equation)

BaseAcid

0.03=

For procaine (pK = 8.9)at tissue pH (7.4)

a

Base Acid

Lipoid barriers (nerve sheath)

Extracellular fluid

Axoplasm Base Acid

*Nerve membrane

Alveolar mucosa

[1.0]

[2.5]

[1.0]

[3.1]

Mechanism of ActionMechanism of Action

Axonal membraneAxonal membrane•Local anesthetics interfere with Local anesthetics interfere with

propagation of the action propagation of the action potential by blocking the potential by blocking the increase in sodium permeability increase in sodium permeability during depolarizationduring depolarization.

Mixed nerveMixed nerve

Time (msec)1 2 3 4

+40

+20

0

-20

-40

-60

-80

30

10

20

Mem

bra

ne

pote

nti

al (

mV

)

gNa

gK

Ion

cond

uct

ance

(mm

ho/c

m ) 2

0

0 1 2 3

40

–80

–40

0

A

C

D

B

Mem

bra

ne p

ote

nti

al (m

V)

Time (msec)

Developing local Developing local anesthetic blockanesthetic block

Movement of S4 SegmentsMovement of S4 Segments

Closed Open

Na

h gate

+

OpenClosed

Outside Inside

Inactivated

2 31

0.0 0.5 1.51.0

0

-10

-20

-30

0

1.5

-1.5

Gati

ng

curr

ent

(nA

)

Time (msec)

Benzocaine

Control

Control

Benzocaine

Na

cu

rrent

(nA

)+

0.0 0.5 1.51.0

Time (msec)

Local Local anestheticsanesthetics

block gating block gating currentscurrents

Mechanism of Action (2)Mechanism of Action (2)

Mixed nerveMixed nerve• Local anesthetics provide pain relief by Local anesthetics provide pain relief by

blocking nociceptive fibers. Other blocking nociceptive fibers. Other fibers are affected as well. Sensitivity fibers are affected as well. Sensitivity to local anesthetics depends on: fiber to local anesthetics depends on: fiber diameter, fiber type, and degree of diameter, fiber type, and degree of myelination. Sensory modalities are myelination. Sensory modalities are affected in the following order: pain, affected in the following order: pain, cold, warmth, touch, and pressure.cold, warmth, touch, and pressure.

Critical length theoryCritical length theory

Frequency dependent Frequency dependent blockblock

}Time

SecondsMinutes

100

80

60

40

20

0

Com

pound

AP

(% c

ontr

ol)

Tonicblock

Phasicblock

}

0 1 2 3 4 0.0 0.1 0.2

0.3 0.4 0.5

PharmacokineticsPharmacokinetics

AbsorptionAbsorption•Local anesthetics are absorbed when Local anesthetics are absorbed when

ingested. Some local anesthetics ingested. Some local anesthetics may be absorbed in toxic amounts may be absorbed in toxic amounts after topical use. Absorption after an after topical use. Absorption after an injection depends on drug solubility injection depends on drug solubility in lipid and in water, tissue vascular-in lipid and in water, tissue vascular-ity and local anesthetic and vasocon-ity and local anesthetic and vasocon-strictor effects on local circulation.strictor effects on local circulation.

Pharmacokinetics (2)Pharmacokinetics (2)

Metabolism and excretionMetabolism and excretion•Esters are hydrolyzed by plasma Esters are hydrolyzed by plasma

and liver esterases. Longer-acting and liver esterases. Longer-acting esters are often metabolized more esters are often metabolized more slowly. Sulfonamide therapy may slowly. Sulfonamide therapy may be neutralized by PABA liberation. be neutralized by PABA liberation. Patients with altered pseudo-Patients with altered pseudo-cholinesterase activity may be cholinesterase activity may be highly sensitive to these drugs.highly sensitive to these drugs.

•Amides are metabolized in Amides are metabolized in the liver. Patients with severe the liver. Patients with severe hepatic damage or advanced hepatic damage or advanced congestive heart failure may congestive heart failure may be unusually sensitive to be unusually sensitive to these drugs. Some amides these drugs. Some amides are partially excreted are partially excreted unchanged in the urine.unchanged in the urine.

Local anesthetic Local anesthetic metabolismmetabolism

NHC

CH 3O

CH N

R1R2

R3

Hydroxylationand conjugation

N-dealkylation(and cyclization)

R4

Hydrolysis

Hydrolysis

AmideAmide

EsterEster

Adverse EffectsAdverse Effects

Side effectsSide effects•CNS toxicity—Entry of local anesthe-CNS toxicity—Entry of local anesthe-

tics into the brain depression of CNS tics into the brain depression of CNS pathways. The clinical picture may pathways. The clinical picture may include stimulation (e.g., excitement, include stimulation (e.g., excitement, disorientation, increased heart rate disorientation, increased heart rate and respiration, tremors, and frank and respiration, tremors, and frank convulsions) if inhibitory neurons are convulsions) if inhibitory neurons are affected initially. affected initially.

•CNS depression may cause hypoten-CNS depression may cause hypoten-sion, respiratory depression, uncon-sion, respiratory depression, uncon-sciousness, and death. Treatment sciousness, and death. Treatment includes supportive measures. includes supportive measures. Excitement and convulsions may be Excitement and convulsions may be controlled with 5 mg dosess of controlled with 5 mg dosess of diazepam or 2 mg doses of midazolam. diazepam or 2 mg doses of midazolam. Respiratory depression requires Respiratory depression requires oxygen and possibly rescue breathing.oxygen and possibly rescue breathing.

Adverse Effects (2)Adverse Effects (2)

•CVS derangement—High plasma CVS derangement—High plasma titers may depress the cardiovasc-titers may depress the cardiovasc-ular system directly. Blood pressure ular system directly. Blood pressure may fall because of arteriolar may fall because of arteriolar dilation, myocardial depression, dilation, myocardial depression, and/or cardiac conduction disruption. and/or cardiac conduction disruption. Treat-ment includes patient Treat-ment includes patient positioning, IV fluids, and positioning, IV fluids, and vasopressors. Cardiac asystole will vasopressors. Cardiac asystole will require CPR.require CPR.

Prevention of systemic Prevention of systemic toxicity—Limit the toxicity—Limit the amount of drug amount of drug employed. Use proper employed. Use proper injection techniques.injection techniques.

Adverse Effects (3)Adverse Effects (3)

AllergyAllergy•Allergic reactions are rare, Allergic reactions are rare,

especially with amide local especially with amide local anesthetics. Urticarial rashes are anesthetics. Urticarial rashes are most common, but more serious most common, but more serious responses also occur. Mild skin responses also occur. Mild skin reactions are treated with reactions are treated with antihistamines; more serious antihistamines; more serious sequellae require epinephrine.sequellae require epinephrine.

Adverse Effects (4)Adverse Effects (4)

SyncopeSyncope•The most common side effect The most common side effect

of dental injections. Must be of dental injections. Must be treated promptly since it may treated promptly since it may be dangerous in its own right be dangerous in its own right and has to be differentiated and has to be differentiated from anaphylactic shock.from anaphylactic shock.

Adverse Effects (5)Adverse Effects (5)

Local toxic reactionsLocal toxic reactions•Selective destruction of Selective destruction of

skeletal muscle fibers. skeletal muscle fibers. Epithelial damage from Epithelial damage from topical preparations. Local topical preparations. Local necrosis from vasoconstrictor necrosis from vasoconstrictor actions.actions.