Michael H. Ossipov, Ph.D.Department of Pharmacology

Local/Regional Anesthetics

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

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)

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

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)

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)

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

Structure PKa % RN at PH 7.4

Onset in minutes

Mepivicaine 7.6 40 2 to 4

Etidocaine 7.7 33 2 to 4

Articaine 7.8 29 2 to 4

Lidocaine 7.9 25 2 to 4

Prilocaine 7.9 25 2 to 4

Bupivicaine 8.1 18 5 to 8

Procaine 9.1 2 14 to 18

•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

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

[1.0]

[2.5]

[1.0]

[3.1]

Structure

Structure

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

Mode of action

Mode of action

Mode of action

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 A-fibers.

Choice of local anesthetics

• Onset• Duration• Regional anesthetic technique• Sensory vs. motor block• Potential for toxicity

Clinical use Onset Duration Esters Procaine Slow Short Chloroprocaine Fast Short Tetracaine Slow Long Amides Lidocaine Fast Moderate Mepivacaine Fast Moderate Bupivacaine Moderate Long Ropivacaine Moderate Long Etidocaine Fast Long

Technique Appropriate drugsTopical Cocaine, tetracaine, lidocaineInfiltration Procaine, lidocaine, mepivacaine,

bupivacaine, ropivacaine,etidocaine

Peripheral nerve block Chloroprocaine, lidocaine,mepivacaine, bupivacaine,ropivacaine, etidocaine

Spinal Procaine, tetracaine, lidocaine,bupivacaine

Epidural Chloroprocaine, lidocaine,bupivacaine, ropivacaine,etidocaine

I.V. regional anesthesia Lidocaine

Choice of local anesthetics

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

Redistribution and metabolism

• Rapidly redistributed• More slowly metabolized and eliminated• Esters hydrolyzed by plasma cholinesterase• Amides primarily metabolized in the liver

Local anesthetic toxicity

• Allergy• CNS toxicity• Cardiovascular toxicity

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.

Systemic toxicity

• Results from high systemic levels• First symptoms are generally CNS

disturbances (restlessness, tremor, convulsions) - treat with benzodiazepines

• Cardiovascular toxicity generally later

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

Cardiovascular toxicity

• Depressed myocardial contractility• Systemic vasodilation• Hypotension• Arrhythmias, including ventricular fibrillation

(bupivicaine)

Avoiding systemic toxicity

• Use acceptable total dose• Avoid intravascular administration (aspirate

before injecting)• Administer drug in divided doses

Maximum safe doses of local anesthetics in adults

Anesthetic Dose (mg)

Procaine 500

Chloroprocaine 600

Tetracaine 100 (topical)

Lidocaine 300

Mepivicaine 300

Bupivacaine 175

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

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

•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

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

Uses of Local Anesthetics