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.
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
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.
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.