Local anesthetics drm

Definition
 Local anesthetics(LA) produce a transient
and reversible loss of sensation (analgesia)
in a circumscribed region of the body
without loss of consciousness.
 LA are drugs that block the sensation of pain
in the region where they are administered.
 Normally, the process is completely
reversible.

The anesthesia produced by LA is without
loss of consciousness or impairment of vital
central cardiorespiratory functions.
When applied directly to the peripheral
nervous tissue it blocks nerve conduction and
abolish all the sensations in that part
supplied by the nerve.
The clinically used LA have minimal local
irritant action and block sensory nerve
endings, nerve trunks, neuromuscular
junction, ganglionic synapse, and receptors
that function through increased net (nerve)
permeability.

Comparative features of general
and local anaesthesia

History
 1860: Albert Niemann isolated crystals from the coca
shrub –and called it “cocaine” –he found that it
reversibly numbed his tongue!
 Sigmund Freud became aware of the mood altering properties of
cocaine, and thought it might be useful in curing morphine addiction.
Freud obtained a supply of cocaine (from Merck) and shared it with his
friend Carl Koller, a junior intern in ophthalmology at the University of
Vienna
 1884: Following preliminary experiments using
conjunctival sacs of various animals species, Koller did
first eye surgery in humans using cocaine as local
anesthetic
 1905: German chemist Alfred Einhorn produced the first
synthetic ester-typelocal anesthetic -novocaine
(procaine) -retained the nerve blocking properties,
but lacked the powerful CNS actions of cocaine
 1943: Swedish chemist Nils Löfgren synthesizedthe first
amide-typelocal anesthetic -marketed under the
name of xylocaine(lidocaine)

Types of LA
 LA are used to abolish the sensation of pain in
a restricted area of the body
 The area is determined by the site and the
technique of administration of the anaesthetic
agent.
 LATypes depending on area are:
A. Surface orTopical Anaesthesia: Applied to the
mucous membrane, .e.g., conjunctiva, larynx,
throat, damaged skin surface, etc.
B. Infiltration Anaesthesia: Injected SC to
paralyze the sensory nerve endings around the
area to be rendered insensitive, e.g., an area to
be incised or for tooth extraction.

C. Nerve Block Anaesthesia:
Injected as close as possible to the nerve trunk
supplying the specific area to be anaesthetised.
i.e.minor operations on the limb are possible.
D. Spinal Anaesthesia: Injected into the subarachnoid
space, i.e., into the cerebrospinal fluid, to
paralyse the roots of the spinal nerves.This
method is used to induce anaesthesia for
abdominal or pelvic surgical operations.
E. Epidural Anaesthesia: This is a special type of nerve
block anaesthesia in which the drug is injected into the
epidural space. It is technically a more
difficult procedure.The roots of the
spinal nerves are anaesthetized.
F. Caudal Anaesthesia: This is smaller to epidural
anaesthesia where the injection is made through sacral
hiatus into the vertebral canal which contains the cauda

Uses
 Dentistry,
 Ophthalmology,
 Podiatry (treatment of disorders of the foot, ankle,
and leg)
 Minor surgical operations, including endoscopy,
 ENT operations
 Surgery of skin
 Labor pain
 Postoperative pain
 SkinTrauma
 Relieving pain in certain medical conditions such as
tumours growing in the spine.
 used topically for the temporary relief of pain from
insect bites, burns, and other surface wounds.

Chemical transmission of stimuli
occurring at synapse through NT
binding to their receptors
Electrical transmission of stimuli
occurring through axon by
movement of ion in and out

Events during an action
potential
An action potential is a temporary “all or nothing” changes in cell membrane potential

Changes inthe resting membrane
potential
Cell state Active receptors Potential
Resting potential Na/K Atphase pump active -70mV
Stimuli causes
Depolarization beyond
threshold potential (-55mV)
Voltage gated Na+ channel open
Na comes inside cell
+30mV
Repolarized state Voltage gated Na+ channel close
Voltage gated K+ channel open
K goes outside cell
+30 to -70mV
Hyperpolarized state Voltage gated K+ channel close slowly -90mV
Resting potential Na/K Atphase pump active -70mV

Mechanism of action
 LAs à block the voltage
gated Na+ channels during
depolarisation a Na+
permeability decreases a
consequently nerve
conduction is blocked.
 The sodium channel contains
specific amino acids that act
as a selectivity filter, only
allowing sodium ions to pass
through the channel.
 The amino acids that make up the selectivity
filter of an ion channel are referred to as the P region.

Mechanism of action
 LA binds to the channel in an
area just beyond the selectivity
filter or P region.
 When the LA binds, it blocks
sodium ion passage into the cell
and thus blocks the formation
and propagation of the action
potential.
 This blocks the transmittance of
the message of “pain” or even
“touch” from getting to the
brain.
 The ability of a local anesthetic
to block action potentials
depends on:
 the ability of the drug to
penetrate the tissue surrounding
the targeted nerve and
 ability of the drug to access the
binding site on the sodium
channel.

 There are at least three conformations that
the sodium channel can form.
 (a) An open state:
 (b) A closed/inactive:The sodium channel is
now closed and inactive, it cannot open again
until the membrane has reached its resting
potential.
 (C) A closed/resting: The sodium channel is
now closed but able to open when a stimulus
reaches the threshold potential.

 The affinity of the LA for the binding site
has complex voltage and frequency dependant
relationships.
 Affinity depends on what state the sodium
channel is in as well as the specific drug being
tested.
 At resting states & when the membrane is
hyperpolarized- Bind with low affinity.
 When the membrane has been depolarized &
channel is open- bind with high affinity.
 when channel is in the “closed/inactive”
conformation - bind with high affinities, perhaps
stabilizing the inactive form of the receptor.

 Autonomic fibers are generally more
susceptible than somatic fibers.
 Among the somatic afferent order of
blockade is pain, temperature, sense, touch
and deep pressure sense.
Sensitivity to LA
Diameter
• the smaller diameter nerve fibers are more susceptible to the
action of LA than the larger diameter ones.
Type
• myelinated neurons are block earlier than nonmyelinated

Ideal Properties of LA
 Non-irritating to tissues and not causing any
permanent damage
 Low systemic toxicity
 Effective whether injected into the tissue or
applied locally to skin or mucous membranes
 Rapid onset of anaesthesia and short duration of
action
 Stable in solutions.
 Not interfere with healing of tissue.
 Have a vasoconstrictor action or compatible
with VC.

ADVERSE EFFECTS
 Systemic toxicity on rapid i.v. injection is related to the intrinsic
anaesthetic potency of the LA.
 Those rapidly absorbed but slowly metabolized are more toxic.
 CNS effects are light-headedness, dizziness, auditory and visual
disturbances, mental confusion, disorientation, shivering,
twitchings, involuntary movements, finally convulsions and
respiratory arrest.This can be prevented and treated by diazepam.
 Cardiovascular toxicity of LAs is manifested as bradycardia,
hypotension, cardiac arrhythmias and vascular collapse.
 Injection of LAs may be painful, but local tissue toxicity of LAs is
low. However, wound healing may be sometimes delayed.
 Vasoconstrictors should not be added for ring block of hands, feet,
fingers, toes, penis and in pinna.
 Bupivacaine has the highest local tissue irritancy.
 Hypersensitivity reactions like rashes, angioedema, dermatitis,
contact sensitization, asthma and rarely anaphylaxis occur.
 Often methylparaben added as preservative in certain LA solutions
is responsible for the allergic reaction.

CHEMISTRY
 Two important chemical properties that
determine activity:
 Lipid solubility: increases with extent of
substitution (no of carbons) on aromatic ring
and/or amino group
 Ionization constant (pK) –determines
proportion of ionized and non-ionized forms
of anesthetic

 Lipid solubility: determines, potency, plasma
protein binding and duration of action of local
anesthetics
Drug
Lipid
solubility
Relative
potency
Plasmaprotein
binding (%)
Duration
(minutes)
procaine 1 1 6 60-90
lidocaine 4 2 65 90-200
tetracaine 80 8 80 180-600
Local anesthetics are weak bases – proportion of free base (R-NH2) and
salt (R-NH +) forms depends on pH and pK of amino group.
Local anesthetics with lower pK have a more rapid onsetof action (more
uncharged form more rapid diffusion to cytoplasmic side ofNa+ channel)
Drug pK % free base
at pH 7.4
Onset of anesthesia
(min)
lidocaine 7.9 25 2-4
bupivacaine 8.1 18 5-8
procaine 9.1 2 14-18

Both free base and ionized forms of local
anesthetic are necessary for activity:
local anesthetic enters nerve fibre as neutral free
base and the cationic form blocks conduction by
interacting at inner surface of the Na+ channel

SARs of Local Anesthetics
All LA contain 3 structural components:
an aromatic ring(usually substituted)
a connecting group which is either an ester
(e.g., novocaine) or an amide(e.g. lidocaine)
an ionizable amino group

 All local anesthetics have an amine on
one end to an aromatic ring on the other
 The amine end is hydrophilic, and the
aromatic end is lipophilic.
 The two groups are connected by mostly an
ester or an amide group and less commonly
by ether or ketones
 •Thus two main classes of local anesthetics
exist:Amides and Esters
 They have pka in range of 7.5 to 9.5
SARs of LA

Lipophilic group
 Lipophilicity is important to penetrate the lipid
layer and reach the binding site on the inside of
the cell.
 The aromatic ring is believed to interact with the
local anesthetic binding site in π-π interaction or π –
cation interaction.
 Presence of electron withdrawing group in ortho or
para position decreases Lipophilicity but still
increases activity for only ester group.
 Presence of e- withdrawing halogens in ortho
position only can decrease duration of action by
making the ester more Likely for a nucleophilic attack

 Lipophilic substituent's and electron-donating
substituent's in the para position increases activity.
 Electron-donating groups on the aromatic ring created a
resonance effect between the carbonyl group and the
ring, resulting in the shift of electrons from the ring to
the carbonyl oxygen.
 As the electronic cloud around the oxygen increased, so
did the affinity of the molecule with the receptor
For amide only, presence of di-ortho substituted group prevent breakdown
of amide and thus increase it’s stability in both liquid
formulation and the body enzymes

Linker group
 Linker group has short alkynene (-CH2-) chain
containing few carbon atoms and functional
group such as Amides or Esters.
 No of carbon atoms in the linker is increased, the
lipid solubility, protein binding, duration of
action, and toxicity increases.
 Increasing the length of alkylene chain increases
the pKa which reduces potency because more
drug get ionized outside the membrane and thus
can’t penetrate into the binding site.
 Amides are more stable than esters and thus
have longer half-lives than esters

 The binding affinity and stability of the
anesthetic molecule is affected by the linker as
well as the functional groups on the aromatic
ring.
 Placement of small alkyl groups (branching)
around ester group (hexylcaine/meprylcaine) or
the amide function also hinder hydrolysis, and
hence, increase in duration of action.
 Modifi cations also affect the duration of action
and toxicity. In general, amides (X= N) are more
 resistant to metabolic hydrolysis than esters (X =
O).Thioesters (X = S) may cause dermatitis.

Hydrophilic portion
 The amino alkyl group is not necessary for local
anaesthetic activity, but it is used to form water
soluble salts such as HCl salts.
 Tertiary amines are more useful agents.
 The secondary amines appear to have a longer
duration of action, but they are more irritating.
Primary amines are not active/cause irritation.
 The tertiary amino group may be diethyl amino,
piperidine, or pyrolidino, leading to a product that
exhibit same degree of activity, essentially.
 The more hydrophilic morpholino group usually
leads to diminished potency.
 In general, the local anaesthetic drug should have
increased lipid solubility and lower pKa values that
leads to rapid onset and lower toxicity.

Vasoconstrictors Used in
Combination with LA
 In clinical practice, a solution of LA (except
cocaine) often contains a vasoconstrictor
(epinephrine, norepinephrine or
phenylepinephrine).
 The vasoconstrictor serves dual purpose by
decreasing the rate of absorption.
 It not only localizes the anaesthetic at the
desired site, but also limits the rate at which it is
absorbed into the circulation.
 The vasoconstrictor prolongs the action and
lowers the systemic toxicity of local
anaesthetics.

CLASSIFICATION
 Local anaesthetics are generally classified into the
following groups:
1. Natural agents: Cocaine
2. Synthetic nitrogenous compounds
a. Derivatives of benzoic acid
b. Derivatives of para-amino benzoic acid
i. Freely soluble: Procaine, Amethocaine.
ii. Poorly soluble: Benzocaine, Orthocaine
c. Derivatives of acetanilide: Lignocaine,
Mepivacaine, Bupivacaine,
d. Derivatives of quinoline: Cinchocaine,
dimethisoquin
3. Synthetic non-nitrogenous agents: Benzyl alcohol,
propanediol
4. Miscellaneous drugs with local action: Clove oil,
phenol, chlorpromazine and certain antihistamines,
for example, diphenhydramine

 On the basis of chemical structure, local
anaesthetics are classifi ed as follows:
I. Benzoic acid derivatives
CLASSIFICATION

II. p-Amino benzoic acid derivatives

III. Anilide derivatives (2,6 Xylidines)

Benzoic acid derivatives
 Cocaine
 Cocaine is the first local anaesthetic discovered;
it is an alkaloid obtained from the leaves of
Erythroxylon cocca.
 In 1884, a German surgeon demonstrated
the successful use of cocaine to
anesthetize the cornea during eye surgery.
 Cocaine has inherent vasoconstrictor
properties thus requires no additional
epinephrine.
 Toxic manifestations include excitation,
dysphoria, tremor, seizure activity,
hypertension, tachycardia, myocardial
ischemia, and infarction.

 Cocaine is used primarily for nasal surgeries,
although its abuse potential has resulted in a
decrease in use.
 When cocaine was compared with lidocaine/
phenylephrine for nasal intubations, the
results were the same with less toxicity in the
lidocaine/ phenylephrine group.
 it is still employed topically as a 1% or 2%
solution for the anaesthesia of the ear, nose,
throat, rectum, and vagina because of its
intense vasoconstrictive action.

Hexylcaine hydrochloride
 It is regarded as
an all-purpose
soluble local
anaesthetic agent.
 The onset and
duration of action
is almost similar
to that of
lignocaine.
 It is mainly used
as surface
anaesthetic .
Cyclomethycaine Sulphate
 It is extensively used as an effective
topical anaesthetic in thermal and
chemical burns ; in dermatological
lesions, sunburn and skin abrasions ;
in urology, gynaecology, obstetrics
and anaesthetic procedures.
 Used to relieve pain from damaged
skin, mucous membrane of rectum,
vagina, and urinary bladder.

II. Para amino benzoic acid
derivatives
 Procaine
 First synthetic local anaesthetic
introduced in 1905.
 Has the advantage of lacking of local
irritation, minimal systemic toxicity,
longer duration of action, and low cost.
 Effectively used for causing anaesthesia
by infi ltration, nerve block, epidural
block, or spinal anaesthesia.

 pKa of procaine is 8.9
 Has low lipid solubility and the ester group is unstable in
basic solutions.
 Available in 0.25% to 10% with pHs adjusted to 5.5 to 6.0
for chemical stability.
 Also included in some formulations of penicillin G to
decrease the pain of intramuscular injection.
 It is very quickly metabolized in the plasma by
cholinesterases and in the liver via ester hydrolysis by a
pseudocholinesterase.
 The in vitro elimination half-life is : 60 sec.
 Ester hydrolysis produces PABA- responsible for the
allergic reactions common to the ester anesthetics.
 Not used topically because of its inability to pass through
lipid membranes.

Chloroprocaine
 The 2 chloride substitution on the aromatic ring is an
electron-withdrawing functional group.
 The carbonyl carbon is now a stronger electrophile and
 more susceptible to ester hydrolysis.
 It has a more rapid metabolism than procaine.
 The in vitro plasma half-life is approx 25 seconds.
 The 2-chloro-4- aminobenzoic acid metabolite precludes
this from being used in patients allergic to PABA.
 very short duration of action means that this drug can be
used in large doses for conduction block (with rapid onset
and short duration of action.)
 used for cutaneous or mucous membrane infiltration for
surgical procedures, epidural anesthesia (without
preservatives) and for peripheral conduction block.

Tetracaine
 Addition of the butyl side chain on the para nitrogen increases the
lipid solubility of the drug and enhances the topical potency.
 10 times more toxic and potent than procaine
 The plasma half-life is 120 to 150 seconds.
 Duration of action is twice than that of procaine.
 WhenTopically applied topically requires 30 to 45 minutes to
confer topical anesthesia.
 Metabolism is similar to procaine yielding parabutyl aminobenzoic
acid and dimethylaminoethanol and conjugates excreted in the
urine.
 The pKa of the dimethylated nitrogen is 8.4 and is formulated as a
HCl salt with a pH of 3.5 to 6.0.
 It is an all-purpose local anaesthetic drug used frequently in
surface, infiltration block, caudal, and spinal anaesthesia.

Benzocaine
 unique local anesthetic because it does not contain a tertiary amine.
 The pKa of the aromatic amine is 3.5 ensuring that it is uncharged at
physiological pH.
 It is not water soluble but is ideal for topical applications.
 The onset of action is 30 sec. and DOA action is 10 to 15 min.
 Used for endoscopy, bronchoscopy, and topical anesthesia.
 It is available as a 20% solution topical spray, in a 1% gel for mucous
membrane application, and a 14% glycerin suspension for topical use in
the outer ear.
 Toxicity can occur when the topical dose exceeds 200 to 300 mg
resulting in methemoglobinemia.
 Infants and children are more susceptible to this and
methemoglobinemia
 has been reported
 It is used to get rid of the pain caused by wounds, ulcers, and in mucous
surface.
 It is nonirritant and nontoxic.

III. Anilides
 Agents of this class are more stable to
hydrolysis.
 They are more potent, have lower frequency
of side effects, and induce less irritation than
benzoic acid derivatives.
Lidocaine
2-(Diethylamino)-2′, 6′-acetoxylidide
 Potent local anesthetic.
 Twice as active as procaine hydrochloride in
the same concentrations.
 First amino amide synthesized in 1948
and has become the most popular

 has a rapid onset of action (IV - 45 to 90 sec).
 more lipid solubility than procaine, pka = 7.8
 Produces eutectic mixture with prilocaine
 has moderate DOA (1-2 hrs) (Due to ortho methyl group)
 also used as Class IB Antiarrhythmic agent
 has local vasodilating action, but usually used with
vasoconstrictor adrenaline to prolong the activity.
 used for infiltration, peripheral nerve and plexus blockade,
and epidural anesthesia.
 Toxicity increases in patients with liver disease and acidosis,
which decreases plasma protein binding of drug.
 CNS toxicity is low with seizure activity reported with high
doses.
 The cardiac toxicity: bradycardia, hypotension, and
cardiovascular collapse, which may lead to cardiac arrest
and death.

 The liver is responsible for most of the metabolism of
lidocaine and any decrease in liver function will decrease
metabolism.
 It is primarily metabolized by de-ethylation of the tertiary
nitrogen to form monoethylglycinexylidide (MEGX).
 The amide functional group is fairly stable because of the
steric block provided by the ortho methyl groups although
amide hydrolysis products are reported.

Prilocaine
 The pKa of the secondary amine is 7.9 and commercial
preparations have a pH of 5.0 to 5.6.
 only one ortho substitution on the aromatic ring, making
it more susceptible to amide hydrolysis and giving it a
shorter duration of action than lidocaine.
 used for intravenous regional anesthesia as the risk of
CNS toxicity is low because of the quick metabolism.
 available as a solution for nerve block or infiltration in
dental procedures.
 The solution of prilocaine HCl is specifically used for such
patients who cannot tolerate vasopressor agents,
patients having cardiovascular disorders, diabetes,
hypertension, and thyrotoxicosis.

 The metabolism of prilocaine in the liver yields o-toluidine,
which is a possible carcinogen.
 Metabolites of o-toluidine are also believed to be responsible
for the methemoglobinemia.
 To decreaseit, strictly adhere to Max recommended dose.
 Metabolism of prilocaine is extensive with less than 5% of a
dose excreted unchanged in the urine.

Etidocaine
 Differs from lidocaine :
1. addition of an alkyl chain
2. the extension of one ethyl group on the tertiary amine to a
propyl group.
 The additional lipophilicity gives a quicker onset, longer half-life,
and an increased potency compared with lidocaine.
 most potent amino amide local anesthetic
 used for epidural anesthesia, infiltrative, topical anesthesia, and for
peripheral nerve or plexus block.
 It blocks large fast-conducting neurons quicker than the sensory
neurons. Used when A and C nerve fibers are being anesthetized
for long surgical procedures (2 hours).
 It has the same potential for cardiac toxicity as bupivacaine and the
decreased reports probably are results of the decreased use of
Etidocaine.

Mepivacaine
 Available in 1% to 3% solutions
 Indicated for infiltration anesthesia, dental procedures,
peripheral nerve block, or epidural block.
 The onset of anesthesia is rapid, ranging from about 3 to 20
minutes for sensory block.
 The duration of action is signifi cantly longer than that of
lidocaine, even without adrenaline.
 It is of particular importance in subjects showing contraindication
to adrenaline.
 Mepivacaine is rapidly metabolized in the liver.
 Less than 5% to 10% of the administered dose is found
unchanged in the urine.
 The primary metabolic products are the N-demethylated
metabolite and the 3 and 4 phenolic metabolites excreted as their
glucuronide conjugates.

Bupivacaine
 It is a long-acting local anaesthetic .
 A potent amide type local anestheticused mostly
parenterally
 It has rapid onset of action and higher lipid solubility
and lower hepatic degradation and thus longer
duration of action (6-8 hrs) than the structurally
similar lidocaine, pKa = 8.1
 When the methyl on the cyclic amine of mepivacaine
is exchanged for a butyl group the lipophilicity,
potency and the duration of action all increase.
 about four times more potent than Mepivacaine and
lidocaine

 Highly bound to plasma proteins (95%)
 Thus the free concentration may remain low until all
of the protein binding sites are occupied.
 After that point, the plasma levels of bupivacaine rise rapidly
and patients may progress to overt without ever showing
signs of CNS toxicity.
 Cardiac toxicity due toaaffinity to cardiac tissues and its ability
to depress electrical conduction and predispose the heart to
reentry types of arrhythmias.
 It exists in racemic form. The R isomer has greater affinity for
Voltage gated Na+ channels and is linked with cardiotoxicity
 The S isomer, called levobupivacaine, is clinically used as it has
lower cardiotoxicity and CNS toxicity
 Levobupivacaine is available in solution for
epidural administration, peripheral nerve block
administration, and infiltration anesthesia.

Ropivacaine
 Ropivacaine is the propyl analog of mepivacaine (methyl)
and bupivacaine (butyl).
 The pKa of the tertiary nitrogen is 8.1, and it displays the
same degree of protein binding as bupivacaine (94%).
 It displays less cardiotoxicity.The shortened alkyl chain
gives it approximately
 One third of the lipid solubility of bupivacaine.
 Long-acting amide-type local anesthetic
 With inherent vasoconstrictor activities, so it does not
require the use of additional vasoconstrictors.
 Undergoes extensive metabolism with only 1% of a dose
excreted unchanged in the urine
 It is approved for epidural, nerve block, infiltration, and
intrathecal anesthesia.
1-propyl-N-(2, 6-dimethyl phenyl)-2-piperidin carboxamide

IV. Miscellaneous class
Phenacaine
 Structurally, it is related to anilides in that the
aromatic ring is attached to a sp2 carbon through a
nitrogen bridge.
 It is one of the oldest synthetic local anaesthetic.
 It is used mainly for producing local anaesthesia of
the eye.
Pramoxine
 It is a surface anesthetic, which possesses very low
degree of toxicity and sensitization.
 It is applied locally as 1% solution in rectal surgery,
itching, and minor burns.
 Structurally, it is unrelated to any of the amide type
agents, simple ether linkage fulfils this function, and
thus, exhibits the local anaesthetic activity.

Dibucaine
 It is the most potent toxic and long-acting local anaesthetics
 Topical amide anesthetic available in OTC creams and
ointments used to treat minor conditions such as sunburns
and hemorrhoids.
 Has been found to be highly toxic when taken orally, inducing
seizures, coma, and death in several children who accidentally
ingested it.
Dimethisoquin
 It is a surface anaesthetic used as an ointment or lotion for
relief from irritation, itching, pain, or burning.

Articaine
 Articaine has a secondary nitrogen with a pKa of 7.8.
 It contains an aromatic thiophene ring bioisostere of the phenyl
ring found in most other amide anesthetics.
 The log P of a benzene ring is 2.13 and the thiophene ring log P is
1.81,
 Although the thiophene ring has less lipid solubility than a phenyl
ring, articaine is a lipid-soluble compound due to the
propylamine, the branched methyl and the substitutions on the
thiophene ring.
 The onset of action is similar to lidocaine’s onset of action.
 Available in a 4% solution with epinephrine for use in infiltration
and nerve block anesthesia.
 The rapid plasma metabolism and reported inactivity of the
carboxylic acid metabolite make articaine a potentially safer
anesthetic agent when multiple or large doses are necessary

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