Download Local Anesthetics

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LA: Reversibly block impulse conduction
along nerve axons & other excitable
membrane that utilize Na+ channels for
Action Potential generation.
Uses: block pain sensation (nociception)
from specific area of ! body.
Cocaine was ! 1st LA isolated from Coca
plant as an ophthalmic anesthetic; Its
chronic use: psychological dependence
(addiction).
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Followed by procaine &
then Lidocaine (Lid) which is ! most
widely used LA.
What characteristics of LAs make
them ideal agents for anesthesia?
As ropivacaine
1- Rapid onset,
2- Long Duration of Action,
3- Reversible & selective blockade of
sensory nerves without motor blockade,
4- Minimal local tissue irritation & no
systemic toxicities.
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Chemistry of LA
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Weak base & available as salts to
increase solubility & stability.
Consist of lipophilic gp (aromatic ring):
memb penetration ++ intermediate
chain via an ester or amide to ionizable
gp: for channel blockade .
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• Absorption esp systemic: depends on:
1- dosage,
2- site of inj, (VASCULARITY): IV >
tracheal > intercostals > paracervical >
epidural > brachial plexus > sciatic > SC
3- drug-tissue binding,
4- local bld flow,
5- use of Vasoconstrictors (epinephrine/
phenylephrine) &
6- ! physiochemical property of ! drug.
Absorption in highly vascular area is >
poor perfused tissue.
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Epinephrine/ VC:
Slow ! removal & reduce systemic absorption of
LA from inj site by decreasing bld flow &
cause higher local tissue conc of ! drug &
prolong conduction blockade.
+ reduce CNS & systemic tox.
Used with short/ intermediate duration of
action: (procaine, Lid & mepivacaine).
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VCs are < effective in prolonging anesthetic
action of more lipid-soluble, long-acting drugs
(bupivacaine & ropivacaine) which are highly
tissue-bound.
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Distribution
! Amide LAs are widely distributed
after IV bolus inj.
Initial rapid phase into highly
perfused organs,
then a slower phase to moderately
perfused organs.
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Metabolism & Excretion
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Acidification of urine: ionization &
excretion of LA
Ester-type hydrolyzed rapidly in ! bld
(by pseudo-choline-sterase) to inactive
metabolite; short plasma t1/2 (< 1 min).
! amide linkage is hydrolyzed by liver
cyto P450 with diff rate (prilocaine
(fastest) > Lid > mepivacaine >
ropivacaine > bupivacaine (slowest).
All converted to water-soluble
metabolites & excreted in urine.
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Toxicity from amide-type LA
occur in hepatic D.
Ex: elimination t1/2 of Lid from
1.6 hr in normal pat to > 6 hr in
liver disease pat.
amide LA also affected by enz
inhibitors.
 Reduced hepatic bld flow:
decrease their elimination.
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MOA
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Block ! Initiation & propagation of AP
by preventing voltage-gated Na+
channels.
Activity is PH-dependent, increased
at alkaline PH. Its penetration to
Na+ chs is very poor at acid PH.
Inflamed tissues (acidic): resis to LA.
Elevated extracellular Ca2+
antagonizes ! action of LA by Ca2+ w
increase! surface potential on !
membrane.
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Structure- Activity Characteristics of LA:
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Smaller & more lipophilic LA: ! Faster
rate of interaction with Na+ chs.
Potency is +vely correlated with lipid
solubility.
Lid, procaine, & mepivacaine are >
water-soluble than tetracaine,
bupivacaine, & ropivacaine that are
more potent & have longer DOA.
Long acting (bupivacaine ) also bind
more extensively to plasma proteins &
can be displaced by other drugs.
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Other actions on nerves:
1- Loss of sensation from site of painful
stimuli
2- Motor paralysis during surgery
Disadvantages
 In Spinal anesthesia, motor paralysis:
impair respiratory activity &
AN blockade: hypotension & urinary
retention (catheterization).
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1- Effect on fiber diameter:
LA block conduction in small-diameter
nerve fibers > readily than in large
fibers.
 Pain sensation is blocked > readily than
other sensory modalities.
 Motor axons (large diameter), are
relatively resistance.
 LAs block conduction in ! following order:
small myelinated (nociceptive
impulses), non- myelinated (C-fibers),
large myelinated axons.
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2- Effect on firing frequency
Blockade by LA is > at higher
frequencies of depolarization.
 Sensory (esp pain) fibers have High
firing rate & long AP duration. while
Motor fibers fire at a slower rate & have
shorter AP duration.
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Properties of LAs
Drug Onset Dura Plas
tion
ma
t1/2
Coc-
M
M
Pro-
M Short
1 hr
SE
Notes
CV & CNS
Rarely used,
only as spray
for URT
< CNS:
No longer
1hr restlessness used
, shivering,
anxiety
CVS:
B.cardia &
decrease
COP
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Lid
Rapid
M
As
procaine
but <
tendency
to CNS
As Lid
Widely used +
IV in ventricular
arrhythmia.
Mepivacaine is
similar
spinal & corneal
anesthesia.
Bupivac Slow Long 2 hr
-
As Lid but
> CVS
Priloc-
No VD
MetHgemi
a
Widely used
(long DOA).
Ropivacine is
similar, with
less cardioTox.
Widely used,
not for obstetric
(neonatal
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metHgemia.
Long
Ametho V.
cSlow
(tetrac
M
M
2 hr
1 hr
2 hr
Classification: Six Placement Sites
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Surface/topical anesthesia
Local infiltration
Peripheral nerve block
Bier block (IV regional anesthesia)
Epidural anesthesia
Spinal anesthesia (subarachnoid)
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Epidural
Spinal
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Clinical pharm
Effective analgesia in specific regions of !
body.
Route of administration:
1- Topical/ surface application (nasal
mucosa, wound margins)
2-Inj in ! vicinity of peripheral nerve endings
(infiltration) & major nerve trunks (blocks)
3- Inj into ! epidural or subarachnoid spaces
surrounding ! spinal cord.
4- IV regional anesthesia (Bier block) for
surgery < 60 min in limbs.
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Local Infiltration:
Extravascular placement of ! LA in !
region to be anesthetized
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Peripheral Nerve Block:
LA inj into tissues around individual
nerves or nerve plexuses (e.g. brachial
plexus).
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DOA
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Short: proc- & chloropro- caine
Intermediate: Lid, mepiva- & prilo- caine
Long-acting: tetra-, bupiva-, & ropivacaine.
DOA can be prolonged by increasing !
Dose/ adding VC agent.
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To increase onset of LA: + Na-bicarbonate to
LA sol.
 Repeated inj of LA: tachyphylaxis
(extracellular acidosis)
 Pregnancy increase LA tox.
 Topical LA: eye, ENT & for cosmetic surgery.
Properties:
1- rapid penetration across ! skin/ mucosa &
2- low tendency to diffuse away from ! site of
application.
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Cocaine bec of excellent penetration & local VC
used for (ENT) procedures. Has irritating effect
so NOT used in ophthalmic procedure.
Other topical: Lid + VC, tetracaine, pramoxine,
dibucaine, benzocaine, & dyclonine.
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OTHER USES:
 LAs have membrane-stabilizing effects;
Both IV Lid & po (mexiletine, tocainide)
used to Tr pat with neuropathic pain
syndrome: (uncontrolled, rapid, sensory
fiber firing).
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Systemic LA: as adjuncts to
TCA (amitriptyline) &
anticonvulsant (carbamazepine)
combination.
Systemic toxicity: CNS & CV system.
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Toxicity
A- CNS:
1- All LAs at low conc: sleepiness, light
headiness, visual & auditory
disturbances & restlessness.
Early symp: tongue numbness + metallic
taste.
Rare, but High plasma conc.: nystagmus &
muscular twitching, then tonic-clonic
convulsions. Followed by generalized
CNS depression (apnea).
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Convulsions: excessive LA level in !
bld. If large dose of LA is required: Rx
pre-medication with BDZs prophylaxis.
2- For cocaine: widely abuse drug,
severe CV toxicity; HTN, arrhythmia, &
myocardial Failure.
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B- Neurotox: direct neuronal tox. With
excessive high conc. Chloroprocaine &
Lid are > neurotoxic than others in
spinal anes.,: transient irritation
(neuropathic symptoms).
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C- CVS: direct effect on ! hrt & smooth
muscle & indirect effect on ! ANS.
 Depress strength of cardiac contraction,
ECG changes & cause arteriolar
dilatation;; hypotension.
 Cocaine blocks Norepinephrine uptake:
VC & HTN + cardiac arrhythmia &
ischemia.
 Bupivacaine is > cardiotoxic than other
long-acting LA.
 Ropivaciane: CV & CNS tox, but < than
Bupivacaine.
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D- Hematologic effects:
Large dose of prilocaine: accumulation of
Oxidizing Agent (o- toluidine) that
convert Hg to metHg.;; cyanosis &
chocolate-colored. Not recommended in
infants. (Benzocaine can also cause
metHg).
Rx: IV methylene blue/ ascorbic acid.
E- Allergic rxs: (Not e amides)
Ester-type LAs are metabolized to P-ABA
derivatives; allergic rxs.
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