local anesthetics by s.bohlooli, phd. schematic diagram of a primary afferent neuron mediating pain
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Local Anesthetics
ByS.Bohlooli, PhD
Schematic diagram of a primary afferent neuron mediating pain
Definition
• Local anesthetics are drugs that reversibly depress nerve conduction. "Caine" local anesthetics act more selectively than other agents.
Physical Properties (structure)
Ester:
Amide:
Example(procaine):
Exception: Benzocaine, which lacks a substituted amino group
R —COO—R —N
R —NHCO—R —N
1 2R
R3
4
21R
R3
4
H N— —COO—(CH ) —N2 2 2
C H2 5
C H2 5
R — Lipophilic aromatic residue.
R — Aliphatic intermediate connector.
R , R — Alkyl groups, occasionally H. Constitute with N the hydrophilic
terminus.
1
2
3 4
Esters
Amides
Amides
(Acid-base considerations)
• Most local anesthetics are weak bases, pKa 7.5-9.0.
• 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.
R-NHR-NH++ R-N R-N + H+ H++
acidacid basebase
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
Alveolar mucosa
[1.0]
[2.5]
[1.0]
[3.1]
Mechanism of Action
• Axonal membraneLocal anesthetics interfere with propagation of the
action potential by blocking the increase in sodium permeability during depolarization.
Functional and structural features of the Na+ channel
Movement of S4 Segments
Closed Open
Mechanism of Action
• 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• Degree of myelination.
– Sensory modalities are affected in the following order: pain, cold, warmth, touch, and pressure.
Table 14-1. Susceptibility to Block of Types of Nerve Fibers
CONDUCTION BIOPHYSICAL CLASSIFICATI
ON
ANATOMIC LOCATION MYELIN
DIAMETER, uM
CONDUCTION
VELOCITY
M·SEC-1
FUNCTION CLINICAL SENSITIVITTO BLOCK
A fibers
A α Afferent to and efferent from muscles and joints
Yes 6-22 10-85 Motor and proprioception
+
A β ++
A γ Efferent to muscle spindles
Yes 3-6 15-35 Muscle tone ++
A δ Sensory roots and afferent peripheral nerves
Yes 1-4 5-25 Pain, temperature, touch
+++
B fibers Preganglionic sympathetic Yes <3 3-15 Vasomotor, visceromotor, sudomotor, pilomotor
++++
C fibers
Sympathetic Postganglionic sympathetic
No 0.3-1.3 0.7-1.3 Vasomotor, visceromotor, sudomotor, pilomotor
++++
Dorsal root Sensory roots and afferent peripheral nerves
No 0.4-1.2 0.1-2 Pain, temperature, touch
++++
SOURCE: Adapted from Carpenter and Mackey, 1992, with permission.
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 vascularity and local anesthetic and vasoconstrictor effects on local circulation.
Pharmacokinetics (2)
• Metabolism and excretion– Esters are hydrolyzed by plasma and liver
esterases. Longer-acting esters are often metabolized more slowly. • Patients with altered pseudo-cholinesterase activity
may be highly sensitive to these drugs.
– 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.
Local anesthetic metabolism
NHC
CH 3O
CH N
R1R2
R3
Hydroxylationand conjugation
N-dealkylation(and cyclization)
R4
Hydrolysis
Hydrolysis
AmideAmide
EsterEster
Adverse Effects
• Side effects– CNS toxicity —Entry of local anesthetics 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.
– CNS depression may cause:• Hypotension, • Respiratory depression, • Unconsciousness• 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.
Adverse Effects (2)
– Cardiovascular derangement —High plasma titers may depress the cardiovascular system directly. Blood pressure may fall because of arteriolar dilation, myocardial depression, and/or cardiac conduction disruption. Treatment includes patient positioning, IV fluids, and vasopressors. Cardiac asystole will require CPR.
Prevention of systemic toxicity—Limit the amount of drug
employed. Use proper injection techniques.
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 sequela require epinephrine.
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.
Adverse Effects (5)
• Local toxic reactions– Selective destruction of skeletal muscle fibers.
Epithelial damage from topical preparations. Local necrosis from vasoconstrictor actions.
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