medicicine lectyure 3 la 20th nov 2012

7/30/2019 Medicicine Lectyure 3 LA 20th Nov 2012

1/72

Localanaethetics


2/72

outline

Introduction

History

mechanism of action and overview Classes of LA

Properties of a good LA

Clinical uses Adverse effects


3/72

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


4/72

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


5/72

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)


6/72

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


7/72

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


8/72

Chemistry

The esters are rapidly inactivated by esterases

Amides are more stable and have longer half

lives


9/72

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.


10/72

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.


11/72

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.


12/72

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.


13/72

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.


14/72

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.


15/72

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


16/72

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.


17/72

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).


18/72

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.


19/72

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


20/72

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.


21/72

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.


22/72

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


23/72

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.


24/72

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.


25/72

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.


26/72

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.


27/72

Classes of LA

ESTHERS

COCAINE

BENZOCAINE

TETRACANE

PROCAINE


28/72

AMIDES

LIDOCAINE

BUPIVACAINE

LEVOBUPIVACANE

ROPIVACAINE

ETIDOCAINE

MEPIVACAINE

PRILOCAINE

BENZOCAINE

Cinchocaine(dibucaine)

ARTICAINE


29/72

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.


30/72

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.


31/72

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.


32/72

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


33/72

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.


34/72

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


35/72

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.


36/72

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.


37/72

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.


38/72

Cervical plexus block is appropriate for surgery

of the neck.

Sciatic and femoral nerve blocks are useful for

surgery distal to the knee.


39/72

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.


40/72

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.


41/72

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.


42/72

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


43/72

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.


44/72

Control of cardiac arrhythmias-5

Procainamide and lidocaine are two of the

primary drugs for treating cardiac

arrhythmias.


45/72

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.


46/72

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.


47/72

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.


48/72

Continued exposure to high concentrations

results in general CNS depression and death

results from respiratory failure secondary to

medullary depression


49/72

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


50/72

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.


51/72

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


52/72

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.


53/72

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


54/72

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.


55/72

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.


56/72

Epinephrine plus cocaine, although still used

occasionally, is hazardous because the

catecholamine potentiates the cardiovascular

toxicity (e.g., arrhythmia, ventricularfibrillation) of cocaine.


57/72

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


58/72

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


59/72

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


60/72

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


61/72

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


62/72

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


63/72

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.


64/72

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


65/72

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.


66/72

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.


67/72

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.


68/72

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.


69/72

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).


70/72

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


71/72

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.


72/72

OTHER THERAPEUTIC USES OF LA

EPILEPSY

NEURODEGENERATIVE DISEASES

STROKE

NEUROPATHIC PAIN

MYOPATHIES

medicicine lectyure 3 la 20th nov 2012

Documents