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Localanaethetics
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outline
Introduction
History
mechanism of action and overview Classes of LA
Properties of a good LA
Clinical uses Adverse effects
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defination
a local anesthetic is a drug that causes
reversible local anesthesia
The primary aim is to have a local analgesic
effect-inducing absence of pain sensation
Other local senses may be affected
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introduction
The property of electrical excitability is what
enables nerve cells to generate propagated
action potential
These are important for communication
Initiation of action potential is dependent on
voltage gated sodium channels which open
when membrane is depolarized
Local anaesthetics work by blocking sodium
channels
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Channel function may be modified in 2 ways
Blocking the channelreduces excitability
Modification of the gatingbehaviorsome drugs facilitate
opening(increase excitability while others
inhibit opening ,reducing excitability)
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history
Coca leaves have been chewed for their
psychotropic effects for many years by south
Americans
They also knew that it had numbing effect on
the mouth and tongue
Cocaine was isolated in the 1860
A synthetic substitute ,procaine was made in
1905
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chemistry
All contain an aromatic part linked by an
amide or an ester to a basic side chain
They are weak bases
They are mainly and not completely ionized at
physiologic PH
Ability to penetrate nerves sheath and axonmembrane is dependent on this
The ester or amide linkage is critical for
hydrolysis
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Chemistry
The esters are rapidly inactivated by esterases
Amides are more stable and have longer half
lives
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RECALL
Polarization: Charges are separated across the
plasma membrane, so the membrane has
potential.
Any time the value of the membrane potential
is other than 0 mV, in either the positive or
negative direction, the membrane is in a state
of polarization.
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the magnitude of the potential is directly
proportional to the number of positive and
negative charges separated by the membrane
the sign of the potential (+ or -) always
designates whether excess positive or excess
negative charges are present, respectively, on
the inside of the membrane.
At resting potential, the membrane is
polarized at -70 mV in a typical neuron.
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Depolarization: A reduction in the magnitude
of the negative membrane potential; the
membrane becomes less polarized than at
resting potential.
During depolarization the membrane
potential moves closer to 0 mV, becoming less
negative (for example, a change from -70 to -60 mV); fewer charges are separated than at
resting potential.
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M.O A
Local anesthetics bind reversibly to a specificreceptor site within the pore of the Na+ channelsin nerves and block ion movement through thispore.
When applied locally to nerve tissue inappropriate concentrations, local anesthetics canact on any part of the nervous system and on
every type of nerve fiber, reversibly blocking theaction potentials responsible for nerveconduction.
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M.O A.
Thus, a local anesthetic in contact with a nerve
trunk can cause both sensory and motor
paralysis in the area innervated.
These effects of clinically relevant
concentrations of local anesthetics are
reversible with recovery of nerve function and
no evidence of damage to nerve fibers or cellsin most clinical applications.
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M.O A
The application of a local anesthetic to a nervethat is actively conducting impulses will inhibitthe inward migration of Na.
This elevates the threshold for electricalexcitation, reduces the rate of rise of theaction potential, slows the propagation of theimpulse, and if the drug concentration issufficiently high, completely blocksconduction.
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The local anesthetics interfere with the the large,transient voltage-dependent rise in thepermeability of the membrane to Na which isfundamental to the generation of the action
potential. Almost all local anesthetics can exist as either
the uncharged base or as a cation.
The uncharged base is important for adequate
penetration to the site of action, and the chargedform of the molecule is required at the site ofaction
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The cation forms of local anesthetics appear
to be required for binding to specific sites in or
near the Na channels.
The presence of the local anesthetic at these
sites interferes with the normal passage of Na
through the cell membrane by stopping a
conformational change in the subunits of thevoltage-gated Na channel.
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FREQUENCY- AND VOLTAGE-DEPENDENCE OF LOCAL ANESTHETIC
ACTION
The degree of block produced by a given concentrationof local anesthetic depends on how the nerve has beenstimulated and on its resting membrane potential.
Nerves that are rapidly depolarizing are inherentlyparticularly susceptible to the effects of localanesthetics.
These frequency- and voltage-dependent effects oflocal anesthetics occur because the local anesthetic
molecule in its charged form gains access to its bindingsite within the pore only when the Na+ channel is in anopen state (depolarizing).
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differential sensitivity of nerve fibers to local anesthetics
Peripheral nerve functions are not equally
affected by local anaesthetics.
Generally, treatment with local anesthetics
causes the sensation of pain to disappear first,
followed by loss of the sensations of
temperature, touch, deep pressure, and finally
motor function.
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This differential blockade is a result of a
number of factors which include:
Size of the nerve
Presence and amount of myelin
Location of particular fibers within a nerve
bundle
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For conduction to be effectively blocked, the
local anesthetic must exert its effects over the
distance between several nodes of Ranvier.
Since the smallest nerves (C fibers) have no
myelin, they can be most easily blocked; thus,
sympathetic functions often are blocked soon
after a local anesthetic is applied to aparticular nerve bundle.
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Small myelinated nerves have correspondingly
short distances between nodes of Ranvier and
therefore are often blocked next.
These nerves sub serve temperature and
sharp pain sensation.
Larger nerves then become blocked,
accounting for the loss of function up to and
including motor innervations.
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In general, autonomic fibers, small
unmyelinated C fibers (mediating pain
sensations), and small myelinated Afibers (mediating pain and temperature
sensations) are blocked before the larger
myelinated A, A, and A fibers(mediating postural, touch, pressure, and
motor information
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prolongation of action by vasoconstrictors
The duration of action of a local anesthetic is
proportional to the time of contact with
nerve.
Sympathomimetic agents e.g. epinephrine are
added to local anaesthetics to delay
absorption of the anaesthetic from the site of
injection.
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By slowing absorption, these agents these
drugs reduce the anaesthetic systemic toxicity
and keep it in contact with nerve fibres longer,
thereby increasing the drugs duration ofaction.
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Administration of1% lidocaine with
epinephrine results in the same degree of
blockade as that produced by 2% lidocaine
without the vasoconstrictor.
Epinephrine can have and - adrenergic
effects and therefore caution is needed when
LA with this amine is given to patients withhypertension or myocardial dysfunction.
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The use of vasoconstrictors in local-anesthetic
preparations for anatomical regions with
limited collateral circulation could produce
irreversible hypoxic damage,
tissue necrosis,
gangrene
therefore is contraindicated.
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Classes of LA
ESTHERS
COCAINE
BENZOCAINE
TETRACANE
PROCAINE
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AMIDES
LIDOCAINE
BUPIVACAINE
LEVOBUPIVACANE
ROPIVACAINE
ETIDOCAINE
MEPIVACAINE
PRILOCAINE
BENZOCAINE
Cinchocaine(dibucaine)
ARTICAINE
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PROPERTIES OF AN IDEAL LOCAL
ANAESTHETIC AGENT
An important property of the ideal local
anesthetic is low systemic toxicity at an
effective concentration.
Onset of action should be quick, and duration
of action should be sufficient to allow time for
the surgical procedure.
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IdealLA.
The local anesthetic should be soluble in waterand stable in solution.
It should not deteriorate by the heat of
sterilization, it should be effective both when injected into
tissue and when applied topically to mucousmembranes.
Its effects should be completely reversible.
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Although the characteristics of an ideal localanesthetic are easily identifiable, synthesis of acompound possessing all these properties hasnot been accomplished.
The compounds used clinically fall short of theideal in at least one aspect.
However, the judicious choice of a particular
agent for a particular need will permit thepractitioner to employ local anesthesia effectivelyand safely.
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CLINICAL USES
Topical anesthesia-1
Local anesthetics are used extensively on themucous membranes in the nose, mouth,
tracheobronchial tree, and urethra. The vasoconstriction produced by some local
anesthetics, cocaine especially, adds a veryimportant advantage to their use in the noseby preventing bleed-ing and inducing tissueshrinkage
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Caution should be exercised because when
the tracheobronchial tree and larynx are
anesthetized, normal protective reflexes,
which prevent pulmonary aspiration of oral orgastric fluids and contents, are lost.
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Infiltration Anesthesia-2
Infiltration anesthesia is the injection of local
anesthetic directly under the skin
The duration of infiltration anesthesia can be
approximately doubled by the addition of
epinephrine (5 g/mL) to the injection
solution
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Epinephrine-containing solutions should not,
however, be injected into tissues supplied by
end arteriesfor example, fingers and toes,
ears, the nose, and the penis.
the resulting vasoconstriction may cause
gangrene.
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The advantage of infiltration anesthesia and
other regional anesthetic techniques is that it
can provide satisfactory anesthesia without
disrupting normal bodily functions.
The chief disadvantage of infiltration
anesthesia is that relatively large amounts of
drug must be used to anesthetize relativelysmall areas.
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Nerve Block Anesthesia-3
Injection of a local anesthetic into or aroundindividual peripheral nerves or nerve plexusesresults in greater areas of anesthesia
Brachial plexus blocks are particularly usefulfor procedures on the upper extremity andshoulder.
Intercostal nerve blocks are effective foranesthesia and relaxation of the anteriorabdominal wall.
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Cervical plexus block is appropriate for surgery
of the neck.
Sciatic and femoral nerve blocks are useful for
surgery distal to the knee.
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Other useful nerve blocks prior to surgical
procedures include
blocks of individual nerves at the wrist and at
the ankle,
blocks of individual nerves such as the
median or ulna at the elbow,
blocks of sensory cranial nerves.
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Local anesthetic is never intentionally injected
into the nerve; this would be painful and
could cause nerve damage.
Instead, the anesthetic agent is deposited as
close to the nerve as possible.
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Higher concentrations of local anesthetic will
provide a more rapid onset of peripheral
nerve block, but the potential for systemic
toxicity and direct neural toxicity limits use ofhigh concentrations.
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Spinal Anesthesia-4
Spinal anesthesia follows the injection of localanesthetic into the cerebrospinal fluid (CSF) inthe lumbar space.
For a number of reasons, including the abilityto produce anesthesia of a considerablefraction of the body with a dose of localanesthetic that produces negligible plasma
levels, spinal anesthesia remains one of themost popular forms of anesthesia
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In most adults, the spinal cord terminatesabove the second lumbar vertebra; betweenthat point and the termination of the theca
sac in the sacrum, the lumbar and sacral rootsare bathed in CSF.
Thus, in this region there is a relatively largevolume of CSF within which to inject drug,
thereby minimizing the potential for directnerve trauma.
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Control of cardiac arrhythmias-5
Procainamide and lidocaine are two of the
primary drugs for treating cardiac
arrhythmias.
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UNDESIRED EFFECTS OF LOCAL
ANESTHETICS
In addition to blocking conduction in nerve
axons in the peripheral nervous system, local
anesthetics interfere with the function of all
organs in which conduction or transmission ofimpulses occurs.
Thus, they have important effects on the CNS,
autonomic ganglia, neuromuscular junctions,and all forms of muscle.
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The danger of such adverse reactions is
proportional to the concentration of local
anesthetic achieved in the circulation.
In general, in local anesthetics with chiral
centers, the S-enantiomer is less toxic than
the R-enantiomer.
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Central Nervous System-1
Local anaesthetics given in initially high
concentrations result in CNS stimulation
(presumably due to suppression of inhibitory
neurons), producing restlessness and tremorthat may progress to clonic convulsions.
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Continued exposure to high concentrations
results in general CNS depression and death
results from respiratory failure secondary to
medullary depression
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Airway control and ventilatory support are
essential features of treatment in the late
stage of intoxication.
Benzodiazepines or rapidly acting
barbiturates administered intravenously are
the drugs of choice for both the prevention
and arrest of convulsions
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Cardiovascular System-2
Cardiac toxicity is generally the result of druginduced depression of cardiac conduction
Following systemic absorption; local
anesthetics decrease electrical excitability,conduction rate, and force of contraction.
Most local anesthetics also cause arteriolardilation.
These effects may progress to hypotensionand cardiac arrest.
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Hypersensitivity-3
Some individuals are hypersensitive to local
anesthetics, displaying allergic dermatitis or a
typical asthmatic attack.
Hypersensitivity seems to occur more
frequently with local anesthetics of the ester
type
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The ester-type local anesthetics aremetabolized to p-aminobenzoic acidderivatives.
These metabolites are responsible for allergicreactions in a small percentage of the patientpopulation.
Amides are not metabolized to p-aminobenzoic acid, and allergic reactions toamide local anesthetics are extremely rare.
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However , although the amides are essentiallyfree of allergic responses, solutions of suchagents may contain preservatives such as
methylparaben that may provoke an allergicreaction.
Local anesthetic preparations containing avasoconstrictor also may elicit allergic
responses due to the sulfite added as anantioxidant.
ESTERS
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ESTERS
Cocaine
Cocaine hydrochloride remains useful
primarily because of the vasoconstriction it
provides with topical use.
Toxicity prohibits its use for other than topical
anesthesia.
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Cocaine has a rapid onset of action (1 minute)
and a duration of up to 2 hours, depending on
the dose or concentration.
Lower concentrations are used for the eye,
while the higher ones are used on the nasal
and pharyngeal mucosa.
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Epinephrine plus cocaine, although still used
occasionally, is hazardous because the
catecholamine potentiates the cardiovascular
toxicity (e.g., arrhythmia, ventricularfibrillation) of cocaine.
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Cardiovascular effects are related to bothcentral and peripheral sympatheticstimulation.
Initial bradycardia appears to be related tovagal stimulation; this is followed bytachycardia and hypertension.
Larger doses are directly depressant to themyocardium, and death results from cardiacfailure
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Cocaine is readily absorbed from mucousmembranes, so the potential for systemic toxicityis great.
The CNS is stimulated, and euphoria and corticalstimulation (e.g., restlessness, excitement)frequently result.
Over dosage leads to convulsions followed by
CNS depression. The cortical stimulation it produces is responsible
for the drugs abuse.
Benzocaine
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Benzocaine
Benzocaine is a PABA derivative used primarily fortopical application to skin and mucous membranes.
Its low aqueous solubility allows it to stay at the site ofapplication for long periods.
Its minimal rate of absorption after topicaladministration is associated with a low incidence ofsystemic toxicity.
Benzocaine is contraindicated in patients with known
sensitivity to ester-linked anesthetics or PABA-containing compounds.
Chloroprocaine
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Chloroprocaine
Chloroprocaine hydrochloride is obtained fromaddition of a chlorine atom to procaine, which resultsin a compound of greater potency and less toxicitythan procaine itself.
This local anesthetic is hydrolyzed very rapidly bycholinesterase and therefore has a short plasma half-life.
Because it is broken down rapidly, Chloroprocaine iscommonly used in obstetrics.
It is believed that the small amount that might get tothe fetus continues to be rapidly hydrolyzed, so theremay be no residual effects on the neonate.
Procaine
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Procaine
Procaine hydrochloride is readily hydrolyzed byplasma cholinesterase, although hepaticmetabolism also occurs.
It is not effective topically but is employed for
infiltration, nerve block, and spinal anesthesia. It has a relatively slow onset and short (1hour)
duration of action.
All concentrations can be combined with
epinephrine. It is available in dental cartridges with
Phenylephrine as the vasoconstrictor.
Tetracaine
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Tetracaine
Tetracaine hydrochloride is an ester of PABA thatis an effective topical local anesthetic agent andalso is quite commonly used for spinalanesthesia.
Epinephrine is frequently added to prolong theanesthesia.
Tetracaine is considerably more potent and moretoxic than procaine and cocaine.
It has approximately a 5-minute onset and 2 to 3hours of action.
AMIDES
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AMIDES
Lidocaine hydrochloride is the mostcommonly used local anesthetic.
It is well tolerated, and in addition to its use
in infiltration and regional nerve blocks, it is commonly used for spinal and topical
anesthesia and as an antiarrhythmic agent.
Lidocaine has a more rapidly occurring, moreintense,and more prolonged duration ofaction than does procaine.
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Bupivacaine hydrochloride (Marcaine)
has long action, and some nerve blocks last
more than 24 hours;
this is often an advantage for post-operative
analgesia. Its use for epidural anesthesia in obstetrics has
attracted interest because it can relieve the pain
of labor at concentrations as low as 0.125% whilepermitting some motor activity of abdominal
muscles to aid in expelling the fetus
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The lower concentration minimizes thepossibility of cardiac toxicity.
Fetal drug concentrations remain low, and drug-
induced neurobehavioral changes are notobserved in the newborn.
Bupivacaine also is approved for spinalanesthesia and is approximately four times more
potent and more toxic than mepivacaine andlidocaine.
It can be used with or without epinephrine.
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Levobupivacaine hydrochloride
is the S-enantiomer of Bupivacaine.
It too has long action.
Animal studies show that it has less CNS and
cardiac toxicity than does Bupivacaine.
It also is slightly more motor sparing than is
Bupivacaine.
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Ropivacaine
is a recently developed long- acting amide-
linked local anesthetic.
Its duration of action is similar to that of
bupivacaine, but it is slightly less potent andrequires higher concentrations to achieve the
same degree of block.
Its primary advantage over Bupivacaine is itslesser degree of cardio toxicity.
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Etidocaine hydrochloride
although chemically similar to lidocaine, has amore prolonged action.
It is used for regional blocks, including epidural
anesthesia. It exhibits a preference for motor rather than
sensory block
therefore, its use in obstetrics is limited,
although fetal drug concentrations remain low. It can be used with or without epinephrine.
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Mepivacaine hydrochloride
is longer acting than lidocaine and has a morerapid onset of action (35 minutes).
Topical application is not effective.
It has been widely used in obstetrics, but its usehas declined recently because of the earlytransient neurobehavioral effects it produces.
Adverse reactions associated with mepivacaineare generally similar to those produced by other
local anesthetics. It can be used with epinephrine (dental use
only).
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Prilocaine hydrochloride
is an amide anesthetic whose onset of actionis slightly longer than that of lidocaine .
Prilocaine is 40% less toxic acutely than
lidocaine, making it especially suitable forregional anesthetic techniques.
It is metabolized by the liver toorthotoluidine, which when it accumulates,can cause conversion of hemoglobin tomethemoglobin
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Oxygen transport is impaired in the presence
of methemoglobinemia.
Treatment involves the use of reducing agents,
such as methylene blue, given intravenously,to reconvert met hemoglobin to hemoglobin.
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OTHER THERAPEUTIC USES OF LA
EPILEPSY
NEURODEGENERATIVE DISEASES
STROKE
NEUROPATHIC PAIN
MYOPATHIES