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Local Anesthetics (■ BASIC PHARMACOLOGY OF LOCAL ANESTHETICS…
Local Anesthetics
■ BASIC PHARMACOLOGY OF LOCAL ANESTHETICS
Pharmacodynamics
A. Mechanism of Action: Slows, then blocks action potential propagation
Sodium channel isoforms
1. Membrane potential: blockade of voltage-gated Na channels--> reduce influx of Na--> preventing depo of membrane--> blocking conduction of action potential
;
important: cannot block EC, must pass membrane and block either from inside or through membrane
Channel blockade: block voltage-dependent Na channels
4. Other effects:
High [ ] of EC K+ may enhance LA activity
Elevated EC Ca2+ may antagonize it
B. Structure-Activity Characteristics of Local Anesthetics
C. Neuronal Factors Affecting Block
Differential block
Intrinsic susceptibility of nerve fibers
Smaller fibers blocked more easily than larger (most important)
myelinated fibers blocked more easily than unmyelinated fibers
(second most important)
Blockade more marked at higher frequencies of depolarization: Activated pain fibers fire rapidly--> pain sensation appears to be selectively blocked by LAs
Anatomic arrangement: Fibers located in periphery of a thick nerve bundle blocked sooner than those in core--> sensory block will occur in sequence from proximal to distal
Pharmacokinetics
B. Distribution
Systemic
Localized
C. Metabolism and Excretion
Metabolism of ester: plasma cholinesterases (pseudocholinesterases)
amides metabolized: in liver, in part by cytochrome P450 isozymes
Acidification of urine promotes ionization of LAs--> more excretion
A. Absorption:
readily absorbed into blood from injection site--> duration of local action limited unless blood flow to area reduced:
administration of a vasoconstrictor (u an α-agonist sympathomimetic) w/ local anesthetic agent
;
-
Cocaine an important exception bc it has intrinsic sympathomimetic action (inhibits norepi reuptake)
longer-acting agents (eg, bupivicaine, ropivicaine, tetracaine) also less dependent on coadministration of vasoconstrictors
Surface activity: a property of certain local anesthetics, esp benzocaine, lidocaine,
and tetracaine: available as gels, used in minor surgeries (dental), skin and cosmetics
more lipid soluble--> more potent, longer duration of action
Application to a highly vascular area--> more rapid absorption--> higher blood levels
Chemistry
Most consist of a lipophilic group connected by an
intermediate chain via an ester or amide
to an ionizable group (
amine
:
can pass BBB
)
ester: procaine (Novocaine) (short acting, potency:1), Cocaine (medium, p:2, surface action), Tetracaine (Pontocaine) (long, p:16), Benzocaine
amide: Mepivacaine (medium, 2), lidocaine (Xylocaine) (medium, 4), Articaine (medium), Bupivacaine (Marcaine) (long, 16), Ropivacaine (long), Prilocaine (Citanest)
are weak bases
, u made
available clinically
as
salts to incr solubility & stability
; In the body, exist either as uncharged base or as a cation;
pKa of most in range of 7.5–9.0--> charged, cationic form will constitute larger percentage
at physiologic pH; An
exception: benzocaine (pKa around 3.5)--> nonionized base under normal physiologic conditions
ionized form blocks more but passes less through membrane
in bacterial oral infections (strep viridans)--> acidic enviro--> lidocaine ineffective; must use antibiotics prior
■ COMMONLY USED LOCAL ANESTHETICS & THEIR APPLICATIONS
AMIDES: analgesia via topical, or injection (perineural, epidural, subarachnoid). rarely IV
BUPIVACAINE:
spinal anesthesia in C-section (injection, in serum dextrose)
Neuropathic pain and OA, etc (Transdermal patch)
long-duration
procedures like PRILOCAINE, ROPIVACAINE, MEPIVACAINE, LEVOBUPIVACAINE
ETIDOCAINE
LIDOCAINE: most used in clinic;
Cardiac arrhythmia: first choice in V arrhythmias
;
most important: Dental anesthesia
:
Lidocaine
(2%)
w/ adrenaline
(1:80,000): standard LA used in dentistry which produces good soft tissue and pulpal anesthesia and also
reduce post extraction bleeding
;
short-duration procedures epidural, spinal anesthesia
also Neuropathic and etc
pain (Transdermal patch)
duration: 0.5-1h
sometimes used w/ cephalosporines which is very dangerous and may cause heart block
enhances muscle relaxants
used in hemorrhoids
PRILOCAINE: in Iran as Lidocaine P (Lidocaine + Prilocaine)
ARTICAINE
ESTERS: Analgesia, topical only for cocaine and benzocaine
CHLOROPROCAINE
COCAINE: first LA, as a topical ophthalmic anesthetic
; procedures requiring high surface activity and vasoconstriction
PROCAINE: very short procedures;
in penicllin G: reduces pain and incr rate of absorption but less duration of action
TETRACAINE
:
spinal, epidural anesthesia; duration 2-3h
used in eye drops
BENZOCAINE: (surface use only)
■ CLINICAL PHARMACOLOGY OF LOCAL ANESTHETICS
Clinical Block Characteristics
B. Intentional Use of Systemic Local Anesthetics
A. Effect of Added Vasoconstrictors
Toxicity
A. Systemic Toxicity
CNS toxicity:
light-headedness, Sedation, restlessness, nystagmus,most important: tonic-clonic convulsions, High doses lead to respiratory depression, coma and death
(all: CNS excitation)
cocaine: inhibit DA reuptake--> incr DA in NA and PFC-->mood elevation
Cardiotoxicity
exception of cocaine, all LAs: vasodilators
Na block
-->
heart block and other disturbances
of cardiac electrical function at high plasma levels of LAs
cocaine abuse: severe HTN w/ cerebral hemorrhage, cardiac arrhythmias, and MI
Reversal of
bupivacaine toxicity: cardiovascular
(collapse) toxicity of bupivacaine overdose difficult to treat, has caused
fatalities in healthy young adults.
Prilocaine metabolized to o-toluidine products--> capable of converting Hb to methemoglobin
B. Localized Toxicity
Neural injury:
In high [ ]s, LAs may cause a local neurotoxic action (histologic damage and permanent impairment of function)
Transient neurologic symptoms (TNS)
Treatment:
Convulsions: diazepam or thiopental
Hyperventilation w/ oxygen helpful