4.5 Local anesthetics Flashcards
Local anesthetics
reversible loss of sensory perception, spedcifically of pain, in a restricted area of the body upon local injection or topical application, blocks the generation and conduction of impulse at all parts of neuron where it comes in contact, abolishes sensory and motor activity in a limited area without producing unconsciousness
local anesthetic structure
weak bases and have 3 structural domains. Hydrophobic (lipophilic group)–aromatic residue, hydrophilic group–amine, both are linked by ester or amide bond
LA block
Na channels, prolonging the inactivated state –> inhibit further activation, inhibit propogation of impulse through the nerve
LA suffix
caines
LA has a hydrophobic domain so
it enters cell
two types
ester local anesthetics or amide local anesthetics
ester local anesthetics
benzocaine, cocaine, procaine, chloroprocaine
amide local anesthetics
bupivacaine, lidocaine (most common), prilocaine, mepivacaine, ropivacaine
ester lined LA have
shorter duration of action (metabolized by cholinesterases), less intense analgesia, higher risk of hypersensitivity — hense rarely used for infiltration or nerve block, but are still used on mucous membranes
amide linked LA have
longer duration of action, more intense analgesia, less risk of hypersensitivity, no cross sensitivity with ester lined Las
LA short duration
Procaine, Chloroprocaine
LA intermediate duration
Lidocaine, Prilocaine, Mepivacaine
LA long duration
Bupivacaine, ropivacaine
Surface anesthetics (LA)
cocaine, lidocaine, tetracaine, benzocaine, oxetacaine (oxethazaine)
LA can be produced by cooling such as
application of ice, CO2 snow, ethyl chloride spray
Mechanism of LA
block nerve donduction by inhibiting voltage gated Na channel keeping it in the inactive form, increasing the thresholed for excitation and refractory period is prolonged. Las interact with the receptor situated within the voltage sensitive Na channesl and raise threshold of channels opening, i.e. Na permeability fails to increase in response to an impulse or stimulus (pain) 50-100X duration of normal closure
LA entry and binding
in basic environment, drug is non ionized to enter the cell, then inside the cell it has to be ionized again bc cell is a little acidic and the ionized form binds the receptor, binds at the activated and inactivated state but not in resting state (more the inactivated) on its inner aspect, hence blocks sodium current and slows recovery and propagation of action potentials —use dependant block –the more the channels are used the more will be the block
Modulated Receptor hypothesis
the different states of Na channels bind LA with different affinities –Las have higher affinity for the open and inactivated states than for the closed state —used dependent block—thus a resting nerve is rather resistant to blockade, and the block develops rapidly when the nerve is stimulated repeatedly
Tetrodotoxin/Saxitoxin
block Na outer gate
Scorpion venom
prevents inactivation causing massive depolarization
LA actions on nerves
blockage not only limited to loss of pain sensation, sensory and motor nerve fibers (high conc.) are both sensitive to LA, somatic as well as autonomic nerves are blocked – spinal anesthesia
blockage of autonomic nervsou system
motor n. block–>respiratory paralysis; autonomic block –>hypotension
sensitiveity of the nerve fiber ti the blockade is determine dby
the diameter and mylation of the fibers, smaller fibers are more sensitive than the larger fibers, non-mylinated fibers are blocked more easily than myelinated fibers –> differential functional blockade
small fibers blocked first
B and C > Adelta
block of modalitties
pain sensation first than other modality
fibers with high firing rate
more marked block
actions on modalities
sensory>motor. Adelta > A alpha
order of sensitivity to LA
B and C> A delta> Abeta and A gamma > Aalpha —- recovery in REVERSE order
block of autonomic fibers by LA
more succeptible than somatic fibers
somatic afferent blockade order is
pain-temperature-touch-deep pressure (differential blockade)
LA applied to tongue
bitter taste is lost followed by sweet and sour, and slaty taste last of all
nonmylinated and small diameter fibers
more intensely blocked – type B and C –pain and autonomic (slide 27)
nonionized part
responsible for crossing the lipid membrane
ionized part
responsible for binding to specific Na channel
absrobtion
most surface anesthtics are absorbed from the mucosa membranes and abraded arease—absorption through intact skin is poor
Ester linked LA metabolism
rapidly hydrolyzed by plasma pseudocholinesterase and the remaining by esterases in the liver,
after oral admin, both procaine and lidocaine
undergo extensive first pass metabolism so wont give orally, give thorugh IV
Amide lined LA metabolism
are degraded mainly in the liver by microsomal cyp-450 (dealkylation and hydroxylation)
Absorbpion dependent on
dosage, site of action, drug tissue binding, vasoconstrictor used
Epinephrine/Phenylephrine
LA causes vasodialation so some amount can be absorbed and less drug will be available at the site of cation so you need more frequent administration to provide the persistent pain control—so using EPI will decrease absorption allwing more neuronal uptake and more anesthesia, so less is required bc more amount of drug remains in the tissues, leading to decrease in systemic toxicity —>provides a relativley bloodless field for surgery
EPI/Phenylephrine actions with LA
prolongs the duration of anesthesia bc more of drug will remain in tissue, reduces the requirement of LA, and reduces the systemic toxicity of LA
Combination contraindicated in
end artery orgains – fingers, toes, pinna, tip of penis—never use vasoconstirtors with end artery organs
Time and onset of blockade is related to
the pKa of LA, those with lower pKa (7.6 to 7.8) eg Lidocaine, Mepivacaine are fasting (as 30-50% LA remains unionized base at pH 7.4 and in this form, penetrates the axon), Those with higher pKa (8.1-8.9) are slow acting (as only 15% or less is unionized at pH 7.4) eg procaine, Tetracaine, Bupivacaine
pKa of most Las is in the range of
8 to 9 hence larger percentage of them will be charged –LA activity is storngly pH dependent –increased at alkaline extracellular pH
inflammed tissues are often acidic thus
somewhat resitant to local anesthetic agents. Inflammation lowers pH of the tissue, blood flow to the inflamed area is increased, LA is removed more rapidly from the side, Inflammatory products may oppose LA action
Procain Poetncy
1
Procaine DA
short
Cocaine Potency
2
Cocaine DA
medium
Tetracaine Potency
16
Tetracaine DA
long
long DA
tetracaine, bupivacaine, ropivacaine
medium duration
lidocaine, mepivacaine, prilocaine, cocaine
potency of 16
tetracaine, bupivacaine, ropivacaine
Clinical Pharmacology of Las
temporary but complete analgesia
usual routes
infiltration, surface anesthesia, nerveblock, subarachnoid spinal anesthesia, epidural anesthesia, intravenous regional anesthesia
Choice of LA drugs depends on duration
short/intermediate –> lidocainte , >3hrs –>Bupivacaine
Duration can be prolonged by
vasoconstrictors Epinephrine/phenylephrine
Combination with vasoconstrictors contraindicated in procedures of
end artery organs – fingers, toes, hands, feet, penis, pinna
use of Las during pregnancy
pregnant women are more succeptible to LA bc inferior vena cava compression during pregnancy leads to engorgement of the vertebral system and a decrease in the capacity of subarachnod space– dec dose required for neverblock, dec dose required for toxicity
LA on CVS
cardiac depressants, Las cause fall in BP due to sympathetic blockade and direct vascualr SM relaxation, cocaine as a sympathomimetic action and is the only local anesthetic agent causing vasoconstriction
most caridotoxic drug
Bupivacaine
what is the only LA causing vasoconstriction
Cocaine
LA on CNS
all Las are capable of producing sequence of stimulation followed by depression
Lidocaine causes
drowsiness, then excitation, follwed by depression
most serious toxic reactions due to Las
convulsions (from excessive blood concentrations)
Cocaine
produces CNS stimulation – affects mood and behaviour, only LA that causes vasoconstriction, used for ocular tracheobronchial anesthesia (topical anesthesia)
Procaine
not a popular LA noadays due to its low potency, slow onset and short D/A
Procaine is metabolized to
PABA hence it inhibits the action of sulfonamides (larger doses required), PABA is incorporated into folate path but sulfonamide blocks this incorporation, but increased amount can overcome this block leading to sulfonamide failure
Tetracaine
ester of PABA and is effective topical LA, more potent and longer d/a than procaine, commonly used for spinal anesthesia, (epi added to prolon d/a), also incorporated in sevaral topical anesthetic preparations
Lidocaine
most commonly used LA, has intermediate d/a, in addition to its use in infiltration and regional nerve blocks, also commonly used for spinal, epidural and topical anesthesia, and also as an antiarrhytmic agent – class 1 b sodium channel blocker
lidocane compared to procaine
more rapid onset, more intense and more prolonged d/a
lidocaine adverse effects
drowsiness, tinnitus, dizziness, dysgeusia, twitching
Bupivacaine
potent agent capable of producing prolonged anesthesia, long duration of action plus its tendency to provide more sensory than motor block have made it popular drug for providing prolonged analgesia during labor or postoperative period in obstetrics
Bupivacaine used for
infiltration, spinal, and epidural anesthesia
what is more cardiotoxic
Bupivacaine is more cardiotoxic thatn lidocaine (ventriclar arrhythmia, myocardial depression) than lidocaine
etidocaine
chemically similar to Lidocaine, but ahs more prolonged action, used ro regional blocks, including epidural anesthesia, limited role in obstetrics and same cardiotxicity as Bupivacaine, no longer marketed in the US
Mepivacaine
intermediate acting LA
Mepivacaine causes
less drowsiness and sedation than lidocaine
Mepivacaine is more toxic to
neonate hence not used in obstetrics
Mepivacaine action
rapid onset of action as lidocane (3-5 min) but duration of actin is lightly longer than lidocaine in the absence of a co-administered vasoconstrictor
Mepivacaine topical anesthetic
not as effective for topical anesthetic, used for nerve block and spinal anesthesia
Prilocaine
intermediate-acting, onset of action is slightly more delayed than lidocaine, DA is comparable
Prilocaine difference form lidocaine
causes little vasodilation hence can be sued without vasoconstrictor, large Vd, hence lows CNS toxicity making it suitable for intravenous regional block
what drug causes methemoglobinemia
Prilocaine _ so use its limited in obstetrical nestesia (may lead to the complication in the newborn), not used topically or for subarachnoid anesthesia
EMLA
eutectic mixture of Lidocaine and prilocaine, anesthetizes up to 5mm
Eutectic
this mixture of two or more substances that melt at the lower temperature is called eutectic mixture
EMLA has been showne to
provide reduced pain on venipuncture, provide topical anesthesia to intact skin, nosignificant local or systemic toxicity has been reported
Surface (topical) anesthesia
produced by topical application of surface anesthetics to mucous membranes and abraded skine, only superficial layer is anesthesized – eg lidocaine
Infiltration anesthesia
injection of Las under the skin in the area of operation bloks sensory nerve endings onset of anesthesia is rapid (immediate), minimally effective concentratino of LA should be used to avoid toxicity from overdosage – eg. Lidocaine, Bupivacaine
Conduction block
LA is injected around nerve truns so that area distal to injectin is anesthetized and paralzyed –field block and nerve block
conduction block – field block
produced by injecting the LA subcutaneously in a manner that all nerves coming to a particualr field are blocked, large area can be anesthetized with less drug compared to infultration, the same concentration of LA as for infiltration is ued for field block
conduction block – nerve block
produced by injection of LA around anatomically localized nerve trunks or plexus, muslce supplied by injected nerve/plexes, latency of anestesia depends on the drug and the area to be covred by diffusion (lidocaine anestehtizes intercostal neves within 3 minutes but brachial plexus block may take 15 min, nerve block lasts longer than field block or infiltration anesthesia
spinal anesthesia
LA is injected in the subarachnoid space btw L3-5, or L4-5, i.e. below the lower end of the spinal cord (protect SC from dammage), produces extensive and profound anesthesia with a minimum amount of drug
spinal anesthesia into subarachnoid spase has
rapid onset and with proper drug selection duration of anesthesia may last from 1 to 4 hours, used for surgeries on the lower limbs, pelvis, lower abdomen, prostatectomy, fracture setting, obstetric procedrues-cesarean section, site of action of spinal anesthesia - spinal nerve roots, spinal ganglia, LAs used for spinal anesthesia are Lidocaine, Tetracaine, Bupivacaine, Dibucaine
Epidural anesthesia
procedure involves the same area of the body as does spinal anesthesia; LA drug is deposited outside the dura, much larger amount of the drug is required in comparison to spinal anesthesia, depending on the site of injection epidural anesthesia can be divided into 3 categories a) thoracic, b) lumbar, c) caudal, specially useful in obstetrics
advantage of epidural over spianl anesthesia
is the ability to maintain continuous anesthesia after placement of an epidural catheter, thus making it suitable for procedures of long duration
LA used for epidural anestehsia
Lidocaine and Bupivacaine
Bupivacaine at low concentratiosn with epidural anesthesia
minimizes the pain without significantly affecting motor fucntion, allowing the parturient woman to ambulate
CNS adverse effects
restlessness, disorientation, confusion, tremors, convulsions and general CNS depression (death occurs from respiratory failure secondary to medulary paraylsis)
CVS adverse effects
bradycardia, arrhythmia, conduction block (AV block, intraventricular block), hyptension, vascular collapse, death —> Bupivacaine most cardiotoxic
Hypersensitivities advers effects
especially with ester lined Las via PABA formation
resuscitation from LA
difficult, correction of acidosis (due to resp paralysis or inc motor activity) – hyperventilation/NaHCO3, Epinephrin/atropine/bretylium used to correct cvs commplications, can be minimized with use of vasoconstrictors epinephrine and lidocaine, allergic rxn ester type
Tetradotoxin (puffer fish) and Saxitoxin (algea toxin, “red tide”)
block activated sodium channels in both cardiac and nerve cell membrane – and decrease influx
Ciguatoxin (exotic fish) and Batrachotoxin (frogs)
bind to activated sodium channel and cause increased activation (prolonged Na influx)
