Transcript Local_Anesthetics

Local Anesthetics
By
S.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)
R3
Ester:
R 1—COO—R 2 —N
R 1 — Lipophilic aromatic residue.
R4
R3
Amide:
R 1—NHCO—R 2—N
R4
R 2 — Aliphatic intermediate connector.
R 3, R 4 — Alkyl groups, occasionally
H. Constitute with N the hydrophilic
terminus.
Example(procaine):
C 2H 5
H2 N—
—COO—(CH 2) 2—N
C 2H 5
Exception:
Benzocaine, which lacks a substituted amino group
Esters
Amides
Amides
(Acid-base considerations)
• Most local anesthetics are weak bases, pKa 7.59.0.
• 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-NH+
R-N + H+
acid
base
Alveolar mucosa
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
Mechanism of Action
• Axonal membrane
Local 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
MYEL
IN
DIAMETER
, uM
CONDUC
TION
VELOCIT
Y
M·SEC-1
Afferent to and efferent
from muscles and joints
Yes
6-22
10-85
FUNCTION
CLINICAL
SENSITIVIT
TO BLOCK
A fibers
Aα
Motor and
proprioception
Aβ
+
++
Aγ
Efferent to muscle
spindles
Yes
3-6
15-35
Muscle tone
++
Aδ
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
++++
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
++++
C fibers
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
Ester
Hydrolysis
Hydrolysis
CH 3
Amide
Hydroxylation
and conjugation
O
NHC CH
R1
R2
R3
N
R4
N-dealkylation
(and cyclization)
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.