Pharmacology of Local
Anesthetics
John Yagiela, DDS, PhD
UCLA School of Dentistry
Pharmacology of Local
Anesthetics
History
Definition
Physical properties
Mechanism of action
Pharmacokinetics
Adverse effects
History
 500’s
Coca leaves first used by
Peruvians for psychotropic properties
 1850’s Cocaine isolated, hypodermic
needle developed
 1884
Sigmund Freud studies the
effects of cocaine
History (2)
 1884
Carl Koller introduces cocaine
into medical practice
 1884
Local anesthesia used in
dentistry by Halsted and Hall
 1905
Procaine synthesized by
Einhorn
History (3)
 1921
Cartridge syringe marketed by
Cook
 1947
 1948
 1959
Aspirating syringe developed
Lidocaine marketed
Disposable needle introduced
Definition
Local anesthetics are drugs that
reversibly depress nerve
conduction. "Caine" local
anesthetics act more selectively
than other agents.
Physical Properties (structure)
Ester:
R 1—COO—R 2 —N
R3
R4
Amide:
R 1—NHCO—R 2—N
R3
R4
R 1 — Lipophilic aromatic residue.
R 2 — Aliphatic intermediate connector.
R 3, R 4 — Alkyl groups, occasionally
H. Constitute with N the hydrophilic
terminus.
Example:
H2 N—
—COO—(CH 2) 2—N
C 2H 5
C 2H 5
Exception:
Benzocaine, which lacks a substituted amino group
(Acid-base considerations)
 Most local anesthetics are weak
bases, pKa 7.5-9.0.
 Usually prepared as a salt (e.g., with
HCl) to increase stability, water
solubility.
 When injected, 5%-40% is converted
to the nonionized free base.
R-NH+
R-N + H+
acid
base
base
pH = pKa + log
acid
Alveolar mucosa
H 2N
O
C 2H 5
COCH 2CH 2
N
O

H
H 2N
C2H5
COCH 2CH 2
N
+
C2H5
C 2H 5
Cationic acid
Log Base = pH – p Ka
Acid
+ H
Nonionized base
Lipoid barriers
[1.0]
(nerve sheath)
(Henderson-Hasselbalch equation)
Extracellular
fluid
Base
Acid
[1.0]
*
[3.1]
Acid
[2.5]
For procaine (p K a = 8.9)
at tissue pH (7.4)
Nerve membrane
Base =
0.03
Acid
Axoplasm
Base
Mechanism of Action
Axonal membrane
• Local anesthetics interfere with
propagation of the action potential
by blocking the increase in sodium
permeability during depolarization.
Mixed nerve
Membrane potential (mV)
+20
0
-80
30
gNa
-20
-40
1
20
gK
10
-60
0
2
Time (msec)
3
4
Ion conductance
(mmho/cm 2)
+40
Developing local anesthetic
block
Membrane potential (mV)
40
A
B
0
C
D
–40
–80
0
1
2
Time (msec)
3
Movement of S4 Segments
Closed
Open
Time (msec)
0.0
0.5
1.0
Local
anesthetics
1.5
0
block gating
currents
-10
Control
1.5
-20
-30
Control
Gating current (nA)
Na + current (nA)
Benzocaine
Benzocaine
0
-1.5
0.0
0.5
1.0
Time (msec)
1.5
Mechanism of Action (2)
Mixed nerve
• Local anesthetics provide pain relief by
blocking nociceptive fibers. Other fibers
are affected as well. Sensitivity to local
anesthetics depends on: fiber diameter,
fiber type, and degree of myelination.
Sensory modalities are affected in the
following order: pain, cold, warmth, touch,
and pressure.
Critical length theory
Compound AP (% control)
Frequency dependent block
100
}
80
60
Tonic
block
}
Phasic
block
40
20
0
0
1
2
3
Minutes
4
0.0
Time
0.1
0.
0.3
2Seconds
0.4
0.5
Pharmacokinetics
Absorption
• Local anesthetics are absorbed when
ingested. Some local anesthetics
may be absorbed in toxic amounts
after topical use. Absorption after an
injection depends on drug solubility
in lipid and in water, tissue vascularity and local anesthetic and vasoconstrictor effects on local circulation.
Pharmacokinetics (2)
Metabolism and excretion
• Esters are hydrolyzed by plasma and
liver esterases. Longer-acting esters
are often metabolized more slowly.
Sulfonamide therapy may be
neutralized by PABA liberation.
Patients with altered pseudocholinesterase activity may be
highly sensitive to these drugs.
• Amides are metabolized in the liver.
Patients with severe hepatic
damage or advanced congestive
heart failure may be unusually
sensitive to these drugs. Some
amides are partially excreted
unchanged in the urine.
Local anesthetic metabolism
Ester
Hydrolysis
Hydrolysis
CH 3
Amide
Hydroxylation
and conjugation
O
NHC CH
R1
R2
R3
N
R4
N-dealkylation
(and cyclization)
Adverse Effects
Side effects
• CNS toxicity—Entry of local anesthetics into the brain depression of CNS
pathways. The clinical picture may
include stimulation (e.g., excitement,
disorientation, increased heart rate
and respiration, tremors, and frank
convulsions) if inhibitory neurons
are affected initially.
• CNS depression may cause hypotension, respiratory depression, unconsciousness, and death. Treatment
includes supportive measures.
Excitement and convulsions may be
controlled with 5 mg dosess of
diazepam or 2 mg doses of midazolam.
Respiratory depression requires
oxygen and possibly rescue breathing.
Adverse Effects (2)
• CVS derangement—High plasma
titers may depress the cardiovascular system directly. Blood pressure
may fall because of arteriolar dilation,
myocardial depression, and/or
cardiac conduction disruption. Treatment includes patient positioning, IV
fluids, and vasopressors. Cardiac
asystole will require CPR.
Prevention of systemic
toxicity—Limit the amount of
drug employed. Use proper
injection techniques.
Adverse Effects (3)
Allergy
• Allergic reactions are rare,
especially with amide local
anesthetics. Urticarial rashes are
most common, but more serious
responses also occur. Mild skin
reactions are treated with
antihistamines; more serious
sequellae require epinephrine.
Adverse Effects (4)
Syncope
• The most common side effect of
dental injections. Must be treated
promptly since it may be dangerous
in its own right and has to be
differentiated from anaphylactic
shock.
Adverse Effects (5)
Local toxic reactions
• Selective destruction of skeletal
muscle fibers. Epithelial damage
from topical preparations. Local
necrosis from vasoconstrictor
actions.