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

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

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

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

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

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

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

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

(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

Structure 30 10

Structure 30 11

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

Mode of action 32 13

Mode of action 32 14

Mode of action 32 15

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

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

Clinical use 37 18

Choice of local anesthetics 38 19

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

40 21

41 22

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

Local anesthetic toxicity Allergy CNS toxicity Cardiovascular toxicity 43 24

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

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

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

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

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

Maximum safe doses of local anesthetics in adults 49 30

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

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

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

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