1. Local anesthetics (LAs) reversibly block sodium channels in excitable membranes, blocking nerve impulse conduction. They are used for pain control and anesthesia. 2. LAs have various administration methods including infiltration, peripheral nerve blocks, epidural/spinal anesthesia, and intravenous regional anesthesia. 3. Toxicity from LAs can affect the central nervous system, cardiovascular system, and cause allergic reactions. Long-acting LAs like bupivacaine are more cardiotoxic. Prilocaine can cause methemoglobinemia in infants.

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Prepared by : Dr Alia Alshanawani
College of Medicine, KSU.

2.  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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3.  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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4. 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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8. • 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)8

9.  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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10.  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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11. METABOLISM & EXCRETION
 Acidification of urine: ionization & excretion of LA
 Ester-type hydrolyzed rapidly in ! blood (by pseudo-
choline-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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12. 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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13. 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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14.  Smaller & more lipophilic LA: ! Faster rate of
interaction with Na+ channels.
 Potency is +vely correlated with lipid solubility.
Lid, procaine, & mepivacaine are > water-
soluble 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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Structure- Activity Characteristics of LA:

15. 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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16. 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), non-
myelinated (C-fibers), large myelinated axons.
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17. 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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18. PROPERTIES OF LAS
Drug Onset Dura
-tion
Plas
-ma
t1/2
SE Notes
Coc- Medi
um
M 1 hr CV & CNS,
due to block
of amine
uptake
Rarely used,
only as spray
for URT
Pro- M Short <
1hr
CNS:
restlessness
, shivering,
anxiety
CVS:
B.cardia, VD
& decrease
COP
No longer
used
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19. Lid Rapid M 2 hr As
procaine
but <
tendency
to CNS
Widely used +
IV in ventricular
arrhythmia.
Mepivacaine is
similar
Ametho
c-
(tetrac
V.
Slow
Long 1 hr As Lid spinal & corneal
anesthesia.
Bupivac
-
Slow Long 2 hr As Lid but
> CVS
Widely used
(long DOA).
Ropivacine is
similar, with
less cardioTox.
Priloc- M M 2 hr No VD
MetHgemi
a
Widely used,
not for obstetric
(neonatal
metHgemia. 19

20. 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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21. EPIDURAL
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Spinal

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23. 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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24. 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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25.  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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26. 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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27. 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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28.  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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29. 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 long-
acting LA.
 Ropivaciane: CV & CNS tox, but < than
Bupivacaine.
 Cocaine blocks Norepinephrine uptake: VC &
HTN + cardiac arrhythmia & ischemia.
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30. 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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