Transcript local anesthetics

PAIN FOR THE POS
the anatomy, the chemistry and
everything else in between
Tissue injury produces a
biphasic response
•Peripheral sensation
•Excitatory neurotransmitters
•Chemical mediators of the
inflammatory response
(substance P, prostaglandins,
leukotrienes, bradykinin,
serotonin and histamine)
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Central sensation
Afferent traffic from the site of
injury and activation of
excitatory amino acid NMDA
receptors in the spinal cord
NSAIDS
• largely due to the inhibition of cyclooxygenase
which prevents the formation of prostglandins and
thromboxanes
• COX -1 present in all tissues
• COX- 2 produced primarily at the ssite of
inflamation
central sensitization
• afferent traffic from the site of injury and activation
of excitatory amino acid NMDA receptors in the
spinal cord
• amplification of afferent nocioceptive input by
expansion of receptive fields with in the CNS
the anatomy
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mixed nerves that contain both afferent
and efferent fibers
each axon is surrounded by
endoneurium -non neural glial cells
individual nerves are bundled into
fascicles and and surrounded by
perineurium -connective tissue
the entire peripheral nerve is wrapped
in epineurium composed of dense
connective tissue
nerve fiber classification
• size
• conduction velocity
• function
• the more myelin and the bigger the nerve the
faster the conduction velocity
nerve
A-alpha,
A-beta
A-delta
B
C
diameter
6-22
1-4
<3
0.31.3
myelin
+
+
+
-
conduction
location
fastes
t
muscles
a/e joints,
and
muscles propriocepti
on
6x
afferent
function
pain,
touch,
temp
slower
sensory
nerves
1.5 x
sympathetic
auto
sympathetic
auto,
pain,
temper
slower
5-10x
slowe
r
resting membrane
potential
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resting memnrane potential of most nerve
cells is - 60 to -90 mV.
cells at rest are more permeable to K+
ions and because the concentration of K+
is about 30 x greater inside the cell than
outside
depolarization
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when the cells are active, Na+ channels
are openedand the Na+ permeability
increases so the membrane potential
becomes less negative
if the membrane potential increases
enough additional Na+ channels open and
a wave is propagated along the axon
action of LA
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local anesthetics prevent the opening of
Na+ channels and prevent the membrane
potential from increasing sufficiently to
open additional Na+ channels
The problem is that the Na channels
need to be blocked from inside the cell!
acidic
alkaline
influenced by pH of surroundings
lipid insoluble
do not cross cell membranes
LA H +
lipid soluble
LA + H+
pKa
the pH at which the ratio of ionized to non-ionized
molecules is 1:1
dissociatic constant
ambient pH <
pKa
ambient pH>
pKa
weak acid
more ionized
more unionized
(lipid insoluble)
weak base
more ionized
more unionized
(lipid insoluble)
local anesthetics
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poorly soluble weak bases with pKa> 7.4 ( ie predominantly
ionized at a neutral pH
consist of a hydrophobic portion ( tertiary amine) and hydrophobic
portion (unsaturated amine ring) linked by ester or amide
modification of the chemical structure alter potency, rate of
metabolism and duration of action
lidocaine
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pK of lidocaine is 7.7(7.9)and the acid solution has a pH of 6 (
hydrochloride salt)
lidocaine hydrochloride solution in a syringe 99% of the total is in
the ionized form and 1% is in the non-ionized form.
once injected ....
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injected into the tissues, where the pH is 7.4 the ionized portion
drops to 76%
24% is now non-ionized or lipid soluble
able to diffuse passively down the concentration gradient across
the nerve cell membrane
through the cell membrane
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the pH is now 7.1
shifts the equilibrium between the
ionised and non- ionized form
86% of the total is now back towards
the ionized
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ionized form now means that it can pass into
and block the sodium channels
reduces the amount of non-ionized form on
the inside of the cell to increase the
concentration gradient across the cell
membrane
diffuses across the membrane in the
unionized form ( degree of ionization
depends on pKa of LA and pH of the
tissues in acidosis so the more LA in
ionized form, degree of penetration less)
mechanisms of blockade
• sodium channel blockade leads to
a
reduction in the action potential formation
and propagation
• animal studies suggest that there must be
a decrease in 50% of the action potential
before a loss of function is observed
frequency dependent block
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open sodium channels are more susceptible to local anesthetic binding than
those in a closed state
the higher the frequency of stimulation the more intense the block
nerves that carry high frequency impulses (sensory nerves) are more
susceptible to blockade than low frequency impulses (motor nerves)
do local anaesthetics block the
smallest fibers first?
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small myelinated axons - gamma and delta are most sensitive
large myelinated - alpha and beta
least susceptible the small non-myelinated C fibers
nerve
A-alpha,
A-beta
A-delta
B
C
diameter
6-22
1-4
<3
0.31.3
myelin
+
+
+
-
conduction
location
fastes
t
muscles
a/e joints,
and
muscles propriocepti
on
6x
afferent
function
pain,
touch,
temp
slower
sensory
nerves
1.5 x
sympathetic
auto
sympathetic
auto,
pain,
temper
slower
5-10x
slowe
r
local anesthetic block of nerve
fibers
• depend on size and type of fibre
• frequency of membrane stimulation
• choice of local anesthetic
blockade is incomplete
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partially blocked fibers are further inhibited by repeated
stimulation
one local anesthetic binding site may be enough to account for the
resting and use dependent actions but the route to this single site
may be multiple pathways
clinically relevant rates of onset and recovery are governed by the
slow diffusion both in and out of the nerve as a whole NOT to the
faster binding to sodium channels
structure/ function characteristics
speed of onset
pKa
duration of action
related to
1) lipid solubility
2) protein binding - increases
the duration of action
potency
aromatic ring structure and
increase hydrocarbon length
determine lipid solubility
so what are these drugs?
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local anesthetics are agents that produce a reversible blockade
of neural transmission in autonomic, sensory and motor fibres
depending on the concentration applied through binding to fast
sodium channels in the axon membrane -preventing depoarization
and action potential propagation
O
C
R
O
N
R
esters
commonly used esters
• procaine
• chloroprocaine
• cocaine
• tetracaine
esters
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unstable in solution
rapidly hydrolysed by plasm cholinesterase
more commonly associated with allergies
esters
• Metabolized by pseudocholinesterase
• Hydrolysis occurs at the ester linkage and yields an
alcohol and para-aminobenzoic acid
• May be prolongs in people with liver disease,
neonates and atypical cholinesterase carriers
of the following local anesthetics ,
which is not an ester ?
• procaine
• lidocaine
• tetracaine
• cocaine
• all of the above
O
R
N
C
N
R
amides
commonly used amides
• lidocaine
• bupivacaine
• mepivacaine
• ropivacaine
lidocaine
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Rapid onset and medium duration of onset
Amide anesthetic and a class 1b anti- arrhythmic drug
Maximum dose 3 mg without epinephrine - 7 mg with epinephrine
Local infiltration, topical anesthesia, epidurals,
what the maximum lidocaine dose you can use in
20 kg boy using 1% lidocaine with epinephrine
• 6cc
• 8cc
• 10 cc
• 12 cc
• 14 cc
bupivicaine
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Amide anesthetic
Slow inset with a prolonged duration of action
Maximum safe dose 2.5 mg
Particularly cardiotoxic (it enters the Na channel fast but diffuses
out slowly
Spinal and epidural anesthesia, nerve blocks, local infiltration
with respect to lidocaine
• bupivicaine has a slower onset
• pKa is more acidic
• the maximum safety dose is under 500 mg
the adjustment of lidocaine dose
is necessary in the patient with
which one of the following
• hepatic insufficiency
• renal insufficiency
• patient with CHF
• respiratory insufficiency
• patient on propanolol
onset of action
• site and type of nerve
• proximity of the injection
• pKa of local anesthetic agents
• acidity of surroundings
systemic absorption
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decreased systemic absorption will have a greater margin of
safety
most important the site of injection
the dose
the physicochemical of the local anesthetic
greater the vascularity the faster the absorption the amount of fat
in the surrounding areas
potency
• the higher the lipid solubility, the
greater the potency
duration of action
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dose
local blood flow
intrinsic vasoactivity
vasoactive additives
protein binding
local drug metabolism
protein binding
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amide anesthetics are primarily protein bound
bupivicaine, levobupivicaine and ropivicaine are more than 90%
bound to1 alpha acid glycoproteins ( high affinity) and albumin (
high volume and low affinity)
free or unbound fraction of the local anesthetic is active
distribution
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organ blood flow
partition coefficients of local anesthesia between compartments
plasma protein binding
organ regional pharmacokinetics
children
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infants less than 6 months of age have decreased levels of
plasma proteins
adult levels of binding are reached about one year of age
alpha one glycoproteins increase with surgical stress, which in
turn will decrease the free fraction of anesthetic
patient status
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age
immature enzyme pathways
decreased hepatic blood flow
impaired hepatic enzymes
elimination
• ester anesthetics are eliminated by
plasma cholinesterases
• amide anesthetics are dependent
on clearance by the liver
• hepatic extraction, hepatic
perfusion, hepatic metabolism and
protein binding are going to
influence the rate of clearance
Methemoglobinemia
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prilocaine is metabolized to O-toluidine
result is a hemoglobin that is less able to bind oxygen
fetal hemoglobin is much more sensitive to the metabolite
appear cyanotic and cause interference with the pulse oxymetry
duration of action
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dose
local blood flow
intrinsic vasoactivity
vasoactive additives
protein binding
local drug metabolism
epinephrine
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prolongation of local block
increased intensity if the block
decreased systemic absorption of local anesthetic
antagonizing inherent vasodilation of local anesthetics
bicarbonate
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pH of local anesthetic solutions commercially prepared ranges
from 3.9 to 6.47
less than 3% of the commercial preparations exist as the lipid
soluble neutral form
rationalization to increase the lipid soluble form
why not at Mac? onset of the block is only five minutes faster
α 2 adrenergic agonists
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clonidine produces analgesia via supraspinal and spinal
adrenergic receptors
it also has direct inhibitory effects on peripheral nerve conduction
may be synergistic if given intrathecaly
not approved in Canada for routine use
lipid
relative
potency
protein
binding
duration
Pka
onset
procaine
low
0.5
6
short
8.9
slow
bupivicaine
high
4
96
long
8.1
slow
7.7
rapid
8.1
med
lidocaine
med
1
64
mediu
m
ropivacaine
med
3
95
long
•the more potent the agents, with
greater lipid solubility and
protein binding will result in
lower systemic absorption
tachyphylaxis
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repeated injections of the same dose of local anesthetics leads to
a decreasing effacy
dependance on the dosing interval, if the dosing interval is short
enough that pain does not develop neither does the tachyphalxis.
the opposite is also true
allergies
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true allergic reactions to local anesthetics are rare and usually
involve type 1 or Type IV reactions
anaphylaxis to amides is rare
increased allergic reactions to esters most likely the result of the
metabolism to PABA
may also be the result of additives methylparaben and
metabisulfite
with respect to local
anesthetics
• lidocaine allergy prohibits the use of procaine
QuickTime™ and a
GIF decompressor
are needed to see this picture.
CNS
CVS
tingling around the mouth
tinnitus, visual disturbance
light headedness
tremor, agitation
slurred speech
muscle twitching
coma
respiratory arrest
myocardial depression
resistant cardiac
arrhythmias
ventricular arrest
CNS TOXICITY
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readily cross the blood brain barrier
anesthetic potency for generalized CNS toxicity
approximately parallels the action potential
blocking potential
acidosis and increased PO2 may worsen increase
the risk of toxicity (decrease the plasma protein
binding)
seizures produce hypoventilation and a metabolic
acidosis which may worsen the CNS toxicity
cardiovascular toxicity
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decrease in the rate of depolarization in the fast conduction
tissues f the purkinjie fibers and ventricular muscle
decreased availability of fast sodium channels in cardiac
membranes
high concentration of dose dependent negative inotropic action on
cardiac muscle
comparative cardiovascular
toxicity
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ratio of the dosage of bupivicaine to lidocaine
fatal ventricular arrythmias may occur more often with bupivicaine
than with lidocaine
pregnant patients may be more sensitive to cardiotoxic effects of
bupivicaine
acidosis and hypoxia enhance the cardiotoxic effects
factors that predispose to toxicity
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peak levels in plasma and rate of rise are important
toxic doses
site of injection - effected by blood flow and tissue vascularity
vasoconstrictor additives - lowers maximal blood concentration
fraction of unbound ( active drug ) in the plasma
what system is most
commonly affected by
lidocaine toxicity
• cardiovascular
• neurological
• respiratory
• musculoskeletal
• renal
with respect to local
anesthetics
• cardiac side effects present prior to neurological
side effects
• toxicity is increased with epinephrine
• toxicity is more likely in renal failure patients
so what would you do?
lipid rescue
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mechanism by which it works is still uncertain
carnatine deficiency
bupivicaine interfers with carnatine dependent mitochondrial lipid
transport
anesthesiology V 105 No 1, July 2006
things to remember
• local anesthetics block the generation, propagation
and oscillations of electrical impulses in electrally
excitable tissue
• work on the inside of the sodium channel
• more potent and longer acting are more lipid
soluble, increased protein binding, less systemic
absorption, but more risk of systemic toxicity
• efficacy
may be increased by addition of opioids,
epinephrine
Patient controlled
analgesia
• Superior pain relief with less medication
• Less daytime sedation
• Decreased delay between requests and the
administration
• Improved postoperative function
• Accommodation for diurnal changes in drug
requirements and a wider range of analgesic needs
• Improved continous incremental titration
• High patient acceptance
• Improved sleep patterns
• Earlier mobilization
Disadvantages to PCA
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Requires mental alertness
Ability to push the button
remember....
backs come in all shapes and
sizes
bbc website, june 4 2007, spencer tunik
Spinal anesthetics
• The level of anesthesia
• The volume of solution
• The concentrating of the the agent
• The speed of the injection
• The position of the patient
• The presence of increased intraabdominal pressure
Spinals
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The reversible interruption begins caudally and proceeds
in a cephalic direction
Autonomic is lost before sensory which is lost before
motor function
Motor block requires the highest drug concentration as
the heavily myelinated fibers are the most resistant to the
block and the first to which the motor function returns
Autonomic block is two or more dermatomes above the
sensory level, motor block two dermatomes below
classification
• Saddle block sensory anesthesia involving the
lower lumbar and sacral segments
• Lower spinal - skin anesthesia at T 10
• Misdial at the costal margin ( T6)
• High spinal - at or above T4
postdural puncture
headache
• common complication of spinal anesthesia
• risk is less with epidurals but when accidental
meningeal puncture occurs incidence is 50%
• elevation of the head rapidly leads to a severe
frontal occipital headache
• cranial nerve symptoms, nausea and vomiting may
be present
other complications
• hearing loss
• total spinal
• neurologic injury (3:100,000- 1: 1000), however the
block may not always be the cause
• persistent parasthesia
• limited motor weakness
• paraylisis or cauda equina syndrome do occur but
very rare
a patient receives a spinal anesthetic. the
surgeon requests the patient to be placed in
trendelenburg position and the patient
becomes hypotensive
• anaphylactic
• sympathetic block
• injection of anesthetic into a spinal artery
• aorta/IVC injury
Transient neurological
symptoms
• pain, dysethesia in both legs or buttocks after spinal
anesthesia
• all local anesthetics, but highest risk with lidocaine
• outpatient, lithotomy ? obesity
• resolves within 72 hours but has lasted up to six
months
Epidurals
• Epidural
space is identified by the passage of
needle from an area of high resistance to an area
of low resistance major sites of action of epidural
injected local anesthetics are the spinal nerve roots
• Accidental dual puncture
• Intravascular injection
• Hypotension
• High spinal
• Epidural abscess and hecatomb
• peripheral nerve blockade provides longer and
more localized pain relief than neuraxial techniques
• larger volumes may increase the success but the
total milligram dose must be lower
• higher concentrations increase the motor blockade
• the absorption of drug and duration of of
anesthesia may vary with dose, drug, location and
the presence of vasoconstricitors
• duration depends on blood supply to the region
equivalent doses
• epidural space 3-4 hours
• 12 -14 hours in the arm
• 24 - 36 hours in the sciatic nerve
• addition of epinephrine
• blockade techniques associated with reliable
proximity of nerves to bones are easiest to perform
I Can Eat Big Bowls of Spaghetti
•
intercostal nerve block
•
caudal
•
epidural
•
brachial plexus
•
sciatic/femoral
•
subcutaneous
dr. Mark Banks,
2003
Anesthesiology Review, Third
edition Edited by Ronald J. Faust
Clinical Anesthesia, Fifth Edition
Edited by Paul Barash