Download Local Anesthetics

Prepared by : Dr Alia Alshanawani
College of Medicine, KSU.
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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/ faster onset,
2- Long Duration of Action,
3- Reversible & selective blockade of sensory
nerves without motor blockade,
4- Minimal local tissue irritation & no systemic
toxicities (cardiac & CNS).
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CHEMISTRY OF LA
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 of injected LA, 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 blood flow,
5- use of Vasoconstrictors (epinephrine/ phenylephrine) &
6- ! physiochemical property of ! drug.
Absorption in highly vascular area (trachea, intercostal) is
> poor perfused tissues (dermis & SC fat).
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Epinephrine/ VC:
Slow ! removal & reduce systemic absorption of LA from
inj site by decreasing blood flow (upto 30%) &
cause higher local tissue conc. of ! drug & prolong
conduction blockade.
+ reduce CNS & systemic tox.
Used with short/ intermediate duration of action:
(procaine, Lid & mepivacaine).

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 (brain, kidney, liver & heart),
then a slower phase to moderately perfused
organs (Muscle, GIT).
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METABOLISM & EXCRETION




Acidification of urine: ionization & excretion of LA
Ester-type hydrolyzed rapidly in ! blood (by pseudocholine-sterase) to inactive metabolites; short plasma
t1/2 (< 1 min).
! amide linkage is hydrolyzed by liver cytochrome P450
with different rates order (prilocaine (fastest) > Lid >
bupivacaine (slowest).
All ester & amide LAs converted to more 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 increase 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
Block ! Initiation & propagation of action potential
(AP) by preventing voltage-gated Na+ channels.
 Activity is PH-dependent, increased at alkaline PH.
Its penetration to Na+ channels is very poor at acid
PH. Inflamed tissues (acidic): resistance to LA.


Elevated extracellular Ca2+ antagonizes ! action of
LA by Ca2+ which increase ! surface potential on !
membrane.
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Structure- Activity Characteristics of LA:

Smaller & more lipophilic LA: ! Faster rate of
interaction with Na+ channels.
Potency is +vely correlated with lipid solubility.
Lid, procaine, & mepivacaine are > watersoluble than tetracaine, bupivacaine, &
ropivacaine that are > potent & have longer
DOA.
 Long acting (bupivacaine ) also bind more
extensively to plasma proteins & can be
displaced by other protein-bound drugs.

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Other actions of LA on nerves:
1- Loss of sensation from site of painful stimuli
2- Motor paralysis during surgery; desirable; but
also limit ! ability of patient to cooperate in
obstetric delivery.
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. (bec electrical
impulse is shorter)
 Pain sensation is blocked > readily than other
sensory modalities.
 Motor axons (large diameter), are relatively
resistance.
 LAs block conduction in ! following order:
small myelinated (pain impulses), nonmyelinated (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-
Pro-
Medi
um
M
M Short
1 hr
SE
Notes
CV & CNS, Rarely used,
due to block only as spray
of amine
for URT
uptake
<
CNS:
No longer
1hr restlessness used
, shivering,
anxiety
CVS:
B.cardia, VD
& 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
metHgemia. 19
Long
Ametho V.
cSlow
(tetrac
M
M
2 hr
1 hr
2 hr
METHODS OF ADMINISTRATION:
SIX PLACEMENT SITES
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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DURATION OF ACTION
Short: proc- & chloropro- caine
 Intermediate: Lid, mepiva- & prilo- caine
 Long-acting: tetra-, bupiva-, & ropiva- caine.


duration can be prolonged by increasing ! Dose/
adding VC agent.
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To increase onset of LA: + Na-bicarbonate to LA sol; LA
become > lipid soluble.
 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.



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, dibucaine,
benzocaine, & dyclonine.
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OTHER USES:
 LAs have membrane-stabilizing effects; Both IV
Lid & po (mexiletine, tocainide) used to Tr
patients with neuropathic pain syndrome:
(uncontrolled, rapid, sensory fiber firing).

Systemic LA: as adjuncts to TCA (amitriptyline) &
anticonvulsant (carbamazepine).

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.

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.
 Bupivacaine is > cardiotoxic than other longacting LA.
 Ropivaciane: CV & CNS tox, but < than
Bupivacaine.
 Cocaine blocks Norepinephrine uptake: VC &
HTN + cardiac arrhythmia & ischemia.
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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 with amides)
Ester-type LAs are metabolized to P-ABA
derivatives; allergic rxs.
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