1. Local/Regional Anesthetics
Michael H. Ossipov, Ph.D.
Department of Pharmacology 4 1

2. General concepts
Cocaine isolated from Erythroxylon coca plant in Andes
Von Anrep (1880) discovers local anesthetic property, suggests clinical use
Koller introduces cocaine in opthalmology
Freud uses cocaine to wean Karl Koller off morphine
Halstead demonstrates infiltration anesthesia with cocaine
Rapidly accepted in dentistry 28 2

3. General concepts
Halstead (1885) shows cocaine blocks nerve conduction in nerve trunks
Corning (1885) demonstrates spinal block in dogs
1905: Procaine (NOVOCAINE) synthesized
analog of cocaine but without euphoric effects, retains vasoconstrictor effect
Slow onset, fast offset, ester-type (allergic reactions) 28 3

4. General concepts
First “modern” LA (1940s): lidocaine (lignocaine in UK; XYLOCAINE)
Amide type (hypoallergenic)
Quick onset, fairly long duration (hrs)
Most widely used local anesthetic in US today, along with bupivacaine and tetracaine 28 4

5. General concepts
Cause transient and reversible loss of sensation in a circumscribed area of the body
Very safe, almost no reports of permanent nerve damage from local anesthetics
Interfere with nerve conduction
Block all types of fibers (axons) in a nerve (sensory, motor, autonomic) 28 5

6. Local anesthetics: Uses
Topical anesthesia (cream, ointments, EMLA)
Peripheral nerve blockade
Intravenous regional anesthesia
Spinal and epidural anesthesia
Systemic uses (antiarrhythmics, treatment of pain syndromes) 29 6

7. Structure All local anesthetics are weak bases. They all contain:
An aromatic group (confers lipophilicity)
- diffusion across membranes, duration, toxicity increases with lipophilicity
An intermediate chain, either an ester or an amide; and
An amine group (confers hydrophilic properties)
– charged form is the major active form 30 7

8. Structure Formulated as HCl salt (acidic) for solubility, stability
PKa
% RN at PH 7.4
Onset in minutes
Mepivicaine
7.6 40
2 to 4
Etidocaine
7.7 33
Articaine
7.8 29
Lidocaine
7.9 25
Prilocaine
Bupivicaine
8.1 18
5 to 8
Procaine
9.1 2
14 to 18
Structure
Formulated as HCl salt (acidic) for solubility, stability
But, uncharged (unprotonated N) form required to traverse tissue to site of action
pH of formulation is irrelevant since drug ends up in interstitial fluid
Quaternary analogs, low pH bathing medium suggests major form active at site is cationic, but both charged and uncharged species are active 30 8

9. (Henderson-Hasselbalch equation)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 9

10. Structure 30 10

11. Structure 30 11

12. Mode of action Block sodium channels
Bind to specific sites on channel protein
Prevent formation of open channel
Inhibit influx of sodium ions into the neuron
Reduce depolarization of membrane in response to action potential
Prevent propagation of action potential 31 12

13. Mode of action 32 13

14. Mode of action 32 14

15. Mode of action 32 15

16. Sensitivity of fiber types
Unmyelinated are more sensitive than myelinated nerve fibers
Smaller fibers are generally more sensitive than large-diameter peripheral nerve trunks
Smaller fibers have smaller “critical lengths” than larger fibers (mm range)
Accounts for faster onset, slower offset of local anesthesia
Overlap between block of C-fibers and Ad-fibers. 31 16

17. Choice of local anesthetics
Onset
Duration
Regional anesthetic technique
Sensory vs. motor block
Potential for toxicity 36 17

18. Clinical use 37 18

19. Choice of local anesthetics38 19

20. Factors influencing anesthetic activity
Needle in appropriate location (most important)
Dose of local anesthetic
Time since injection
Use of vasoconstrictors
pH adjustment
Nerve block enhanced in pregnancy 39 20

21. 40 21

22. 41 22

23. Redistribution and metabolism
Rapidly redistributed
More slowly metabolized and eliminated
Esters hydrolyzed by plasma cholinesterase
Amides primarily metabolized in the liver 42 23

24. Local anesthetic toxicity
Allergy
CNS toxicity
Cardiovascular toxicity 43 24

25. Allergy Ester local anesthetics may produce true allergic reactions
Typically manifested as skin rashes or bronchospasm. May be as severe as anaphylaxis
Due to metabolism to ρ-aminobenzoic acid
True allergic reactions to amides are extremely rare. 44 25

26. Systemic toxicity Results from high systemic levels
First symptoms are generally CNS disturbances (restlessness, tremor, convulsions) - treat with benzodiazepines
Cardiovascular toxicity generally later 45 26

27. CNS symptoms Tinnitus Lightheadedness, Dizziness
Numbness of the mouth and tongue, metal taste in the mouth
Muscle twitching
Irrational behavior and speech
Generalized seizures
Coma 46 27

28. Cardiovascular toxicity
Depressed myocardial contractility
Systemic vasodilation
Hypotension
Arrhythmias, including ventricular fibrillation (bupivicaine) 47 28

29. Avoiding systemic toxicity
Use acceptable total dose
Avoid intravascular administration (aspirate before injecting)
Administer drug in divided doses 48 29

30. Maximum safe doses of local anesthetics in adults49 30

31. Uses of Local Anesthetics
Topical anesthesia
- Anesthesia of mucous membranes (ears, nose, mouth, genitourinary, bronchotrachial)
- Lidocaine, tetracaine, cocaine (ENT only)
EMLA (eutectic mixture of local anesthetics)
cream formed from lidocaine (2.5%) & prilocaine (2.5%) penetrates skin to 5mm within 1 hr, permits superficial procedures, skin graft harvesting
Infiltration Anesthesia
- lidocaine, procaine, bupivacaine (with or w/o epinephrine)
- block nerve at relatively small area
- anesthesia without immobilization or disruption of bodily functions
- use of epinephrine at end arteries (i.e.; fingers, toes) can cause severe vasoconstriction leading to gangrene 2

32. Uses of Local Anesthetics
Nerve block anesthesia
- Inject anesthetic around plexus (e.g.; brachial plexus for shoulder and upper arm) to anesthetize a larger area
- Lidocaine, mepivacaine for blocks of 2 to 4 hrs, bupivacaine for longer
Bier Block (intravenous)
- useful for arms, possible in legs
- Lidocaine is drug of choice, prilocaine can be used
- limb is exsanguinated with elastic bandage, infiltrated with anesthetic
- tourniquet restricts circulation
- done for less than 2 hrs due to ischemia, pain from touniquet 2

33. Uses of Local Anesthetics
Spinal anesthesia
- Inject anesthetic into lower CSF (below L2)
- used mainly for lower abdomen, legs, “saddle block”
- Lidocaine (short procedures), bupivacaine (intermediate to long), tetracaine (long procedures)
- Rostral spread causes sympathetic block, desirable for bowel surgery
- risk of respiratory depression, postural headache 2

34. Uses of Local Anesthetics
Epidural anesthesia
- Inject anesthetic into epidural space
- Bupivacaine, lidocaine, etidocaine, chloroprocaine
- selective action of spinal nerve roots in area of injection
- selectively anesthetize sacral, lumbar, thoracic or cervical regions
- nerve affected can be determined by concentration
- High conc: sympathetic, somatic sensory, somatic motor
- Intermediate: somatic sensory, no motor block
- low conc: preganglionic sympathetic fibers
- used mainly for lower abdomen, legs, “saddle block”
- Lidocaine (short procedures), bupivacaine (intermediate to long), tetracaine (long procedures)
- Rostral spread causes sympathetic block, desirable for bowel surgery
- risk of respiratory depression, postural headache 2