1. Pharmacology of Local Anesthetics
John Yagiela, DDS, PhD
UCLA School of Dentistry

2. Pharmacology of Local Anesthetics
History
Definition
Physical properties
Mechanism of action
Pharmacokinetics
Adverse effects

3. 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

4. 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

5. History (3) 1921 Cartridge syringe marketed by Cook
1947 Aspirating syringe developed
1948 Lidocaine marketed
1959 Disposable needle introduced

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

7. Physical Properties (structure)3
Ester:
R —COO—R —N
R — Lipophilic aromatic residue. 1 2 1 R 4
R — Aliphatic intermediate connector. 2 R 3
R , R — Alkyl groups, occasionally 3 4
Amide:
R —NHCO—R —N 1 2
H. Constitute with N the hydrophilic
terminus. R 4
Example:
C H 2 5
H N—
—COO—(CH ) —N 2 2 2
C H 2 5
Exception:
Benzocaine, which lacks a substituted amino group

8. (Acid-base considerations)
Most local anesthetics are weak bases, pKa
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.

9. R-NH R-N + H+
acid base
base
acid
pH = pKa + log

10. (Henderson-Hasselbalch equation)
Alveolar mucosa O H C 5 2 O
COCH H N 2 C CH 5  + H N
COCH CH N H + H 2 2 2 H C 5 2
Cationic acid
Nonionized base
[1.0]
Base
Log
= pH – p K
Lipoid barriers
(nerve sheath) a
Acid
(Henderson-Hasselbalch equation)
Extracellular
Base Acid
[1.0]
fluid
For procaine (p K
= 8.9) a
at tissue pH (7.4)
Nerve membrane *
[3.1]
Base =
0.03
Axoplasm
Base Acid
[2.5]
Acid

11. Mechanism of Action Axonal membrane Mixed nerve
Local anesthetics interfere with propagation of the action potential by blocking the increase in sodium permeability during depolarization.
Mixed nerve

12. Membrane potential (mV)
+40
+20 30 g 2 Na 20
Membrane potential (mV)
-20
Ion conductance
(mmho/cm ) 10 g
-40 K
-60
-80 1 2 3 4
Time (msec)

13. Developing local anesthetic block40 A B C
Membrane potential (mV) D
–40
–80
Time (msec)

15. Movement of S4 Segments
Closed
Open

17. Local anesthetics block gating currents Time (msec) Benzocaine
0.0
0.5
1.0
1.5
Benzocaine
-10
1.5
Control
Na current (nA) +
Control
Benzocaine
-20
Gating current (nA)
-30
-1.5
0.0
0.5
1.0
1.5
Time (msec)

18. 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.

19. Critical length theory

20. Frequency dependent block}
100
Tonic 80
block } 60
Compound AP (% control) 40
Phasic
block 20 1 2 3 4
0.0
0.1
0.2
0.3
0.4
0.5
Minutes
Seconds
Time

21. 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 vascular-ity and local anesthetic and vasocon-strictor effects on local circulation.

22. 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 pseudo-cholinesterase activity may be highly sensitive to these drugs.

23. Amides are metabolized in the liver
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.

24. Local anesthetic metabolism
Ester
Hydrolysis
Hydrolysis
Amide CH 3 O R 3
N-dealkylation
NHC CH N
(and cyclization) R 4
Hydroxylation R 2
and conjugation R 1

25. Adverse Effects Side effects
CNS toxicity—Entry of local anesthe-tics 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.

26. CNS depression may cause hypoten-sion, respiratory depression, uncon-sciousness, 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.

27. Adverse Effects (2)
CVS derangement—High plasma titers may depress the cardiovasc-ular system directly. Blood pressure may fall because of arteriolar dilation, myocardial depression, and/or cardiac conduction disruption. Treat-ment includes patient positioning, IV fluids, and vasopressors. Cardiac asystole will require CPR.

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

29. 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.

30. 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.

31. Adverse Effects (5) Local toxic reactions
Selective destruction of skeletal muscle fibers. Epithelial damage from topical preparations. Local necrosis from vasoconstrictor actions.