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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 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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 Acidification of urine: ionization & excretion of LA
 Ester-type hydrolyzed rapidly in ! blood (by pseudo-
choline-sterase) to inactive metabolites; short plasma t 1/2 (<
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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 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 > 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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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), 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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 Notes SE Plas Dura Onset Drug
-ma -tion
t1/2
Rarely used, CV & CNS, hr 1 M Medi -Coc
only as spray due to block um
for URT of amine
uptake
No longer CNS: < Short M -Pro
used restlessness 1hr
, shivering,
anxiety
CVS:
B.cardia, VD
& decrease
COP 18
Widely used + As hr 2 M Rapid Lid
IV in ventricular procaine
arrhythmia. but <
Mepivacaine is tendency
similar to CNS
spinal & corneal As Lid hr 1 Long V. Ametho
.anesthesia Slow c-
(tetrac
Widely used As Lid but hr 2 Long Slow -Bupivac
(long DOA). > CVS
Ropivacine is
similar, with
.less cardioTox
Widely used, No VD hr 2 M M -Priloc
not for obstetric MetHgemi
(neonatal a
.metHgemia 19
 Surface/topical anesthesia
 Local infiltration
 Peripheral nerve block
 Bier block (IV regional anesthesia)
 Epidural anesthesia
 Spinal anesthesia (subarachnoid)

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Spinal

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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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 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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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 long-

acting 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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