Download General Anesthetics - Department of Pharmacology

Local/Regional Anesthetics
Michael H. Ossipov, Ph.D.
Department of Pharmacology
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
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•
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•
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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
•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
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
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
Structure
Structure
Mode of action
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•
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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 largediameter 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.
Choice of local anesthetics
•
•
•
•
•
Onset
Duration
Regional anesthetic technique
Sensory vs. motor block
Potential for toxicity
Clinical use
Esters
Procaine
Chloroprocaine
Tetracaine
Amides
Lidocaine
Mepivacaine
Bupivacaine
Ropivacaine
Etidocaine
Onset
Duration
Slow
Fast
Slow
Short
Short
Long
Fast
Fast
Moderate
Moderate
Fast
Moderate
Moderate
Long
Long
Long
Choice of local anesthetics
Technique
Topical
Infiltration
Peripheral nerve block
Spinal
Epidural
I.V. regional anesthesia
Appropriate drugs
Cocaine, tetracaine, lidocaine
Procaine, lidocaine, mepivacaine,
bupivacaine, ropivacaine,
etidocaine
Chloroprocaine, lidocaine,
mepivacaine, bupivacaine,
ropivacaine, etidocaine
Procaine, tetracaine, lidocaine,
bupivacaine
Chloroprocaine, lidocaine,
bupivacaine, ropivacaine,
etidocaine
Lidocaine
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
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•
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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
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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
Procaine
Chloroprocaine
Tetracaine
Lidocaine
Mepivicaine
Bupivacaine
Dose (mg)
500
600
100 (topical)
300
300
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
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
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
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