Download بنام خداوند Useful drugs pharmacology in spinal anesthesia Dr

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Useful drugs pharmacology in
spinal anesthesia
Dr siamak yaghoubi
Anesthesiologist
intensivist
Clinical Pharmacology
• Successful use of regional anesthesia requires
knowledge of the pharmacologic properties
of the various local anesthetic drugs.
• Commonly used aminoester local anesthetics
include procaine, chloroprocaine, tetracaine,
and cocaine.
• Commonly used aminoamides include lidocaine,
mepivacaine, prilocaine, bupivacaine ,
ropivacaine, and etidocaine.
• The ester and amide local anesthetics differ in
their chemical stability, locus of
biotransformation, and allergic potential.
• Amides are extremely stable, whereas esters are
relatively unstable in solution.
• Aminoesters are hydrolyzed in plasma by
cholinesterase enzymes,
• but the amides undergo enzymatic degradation
in the liver.
• Two exceptions to this trend include cocaine, an
ester that is metabolized predominantly by
hepatic carboxylesterase,
• and articaine, an amide local anesthetic widely
used in dentistry that is inactivated by plasma
carboxylesterase-induced cleavage of a methyl
ester on the aromatic ring.
• p-Aminobenzoic acid is one of the
metabolites of ester-type compounds that
can induce allergic-type reactions in a small
percentage of patients.
• The aminoamides are not metabolized to paminobenzoic acid, and reports of allergic
reactions to these agents are extremely rare.
General Considerations
• Clinically important properties of the various
local anesthetics include potency, speed of
onset, duration of anesthetic action, and
differential sensory/motor blockade.
Anesthetic Potency
• Hydrophobicity appears to be a primary
determinant of intrinsic anesthetic potency
because the anesthetic molecule must
penetrate into the nerve membrane and bind
at a partially hydrophobic site on the Na+
channel.
• Clinically, however, the correlation between
hydrophobicity and anesthetic potency is not
as precise as in an isolated nerve.
Onset of Action
• The onset of conduction block in isolated nerves
is related to the physicochemical properties of
the individual agents.
• In vivo latency is also dependent on the dose or
concentration of local anesthetic used.
• For example, 0.25% bupivacaine possesses a
rather slow onset of action, but increasing the
concentration to 0.75% results in a significant
acceleration of its anesthetic effect.
Duration of Action
• The duration of action of the various local anesthetics
differs markedly.
• Procaine and chloroprocaine have a short duration of
action.
• Lidocaine, mepivacaine, and prilocaine produce a
moderate duration of anesthesia, whereas tetracaine,
bupivacaine, ropivacaine, and etidocaine have the longest
durations.
• For example, with procaine, the duration of brachial
plexus blockade is 30 to 60 minutes, but up to
approximately 10 hours of anesthesia (or at least
analgesia) is common for brachial plexus blockade with
bupivacaine or ropivacaine.
Factors Influencing Anesthetic Activity
in Humans
• Dosage of Local Anesthetic
• As the dosage of local anesthetic is increased,
the probability and duration of satisfactory
anesthesia increase and the time to onset of
block is shortened.
• The dosage of local anesthetic can be
increased by administering either a larger
volume or a more concentrated solution.
Addition of Vasoconstrictors
• Vasoconstrictors, usually epinephrine
(5 µg/mL or 1 : 200,000), are frequently
included in local anesthetic solutions to
decrease the rate of vascular absorption,
thereby allowing more anesthetic molecules
to reach the nerve membrane and thus
improve the depth and duration of
anesthesia, as well as to provide a marker for
inadvertent intravascular injection.
Site of Injection
• The most rapid onset but the shortest duration of action occurs after
intrathecal or subcutaneous administration of local anesthetics.
• The longest latencies and durations are observed after brachial plexus
blocks.
• For example, intrathecal bupivacaine will usually produce anesthesia
within 5 minutes that will persist for 3 to 4 hours.
• However, when bupivacaine is administered for brachial plexus
blockade, the onset time is approximately 20 to 30 minutes, and the
duration of anesthesia (or at least analgesia) averages 10 hours.
• These differences in the onset and duration of anesthesia and analgesia
are due in part to the particular anatomy of the area of injection, which
will influence the rate of diffusion and vascular absorption and, in turn,
affect the amount of drug used for various types of regional anesthesia.
• The addition of sodium bicarbonate to local
anesthetic solutions has also been reported to
decrease the onset time of conduction blockade.
• An increase in the pH of the local anesthetic
solution increases the amount of drug in the
uncharged base form, which should enhance the
rate of diffusion across the nerve sheath and
nerve membrane and result in a more rapid
onset of anesthesia.
Mixtures of Local Anesthetics
• Mixtures of local anesthetics for regional anesthesia
are sometimes used in an effort to compensate for
the short duration of action of certain rapidly acting
agents such as chloroprocaine and lidocaine and the
long latency of longer-acting agents such as tetracaine
and bupivacaine.
• Mixtures of chloroprocaine and bupivacaine
theoretically offer significant clinical advantages
because of the rapid onset and low systemic toxicity
of chloroprocaine and the long duration of action of
bupivacaine; however, clinical results in studies of
combinations have been mixed.
• There are many choices of drugs to produce
spinal anesthesia:
• procaine (Novocain),
• lidocaine (Xylocaine),
• mepivacaine (Carbocaine),
• tetracaine (Pontocaine),
• ropivacaine (Naropin),
• levobupivacaine (Chirocaine),
• These drugs provide a duration of spinal
anesthesia ranging from 45 to 400 minutes
and offer two clinical lengths of action:
shorter (<90 minutes) and
• longer (>90 minutes).
• Procaine is one of the oldest spinal anesthetics and
originally replaced cocaine as the drug of choice for
spinal anesthesia early in the 20th century.
• It is used for brief spinal anesthesia (<1 hour) but
appears to be used less frequently than lidocaine for
shorter spinal anesthesia because of three primary
clinical differences.
• It is associated with:
• a higher frequency of nausea (unexplained cause),
• a relatively high anesthetic failure rate,
• and a slower time to recovery.
• It is often used as a hyperbaric drug in a dose
ranging between 50 and 150 to 200 mg in a
10% concentration.
• The reason that some anesthesiologists
continue in their use of procaine is the lower
frequency of back and leg pain after its use
than with lidocaine.
• Lidocaine is also often chosen for shorter procedures
that can be completed in 1.5 hours or less.
• It has measurable effect in less than 5 minutes and is
most commonly used as the 5% solution in 7.5%
dextrose; however, many continue exploring reducing
the concentration of the drug during spinal
anesthesia.
• It is not clear that reducing the concentration of
lidocaine affects the incidence of the back and leg
pain (called transient neurologic symptoms and
formerly called transient radicular irritation) that
follows its use for spinal anesthesia.
• Transient neurologic symptoms develop most
frequently after ambulatory procedures,
especially in patients placed in the lithotomy
or knee arthroscopy positions.
• Although many continue attempts to link
these symptoms with subclinical neurologic
injury, the evidence for such an association
remains elusive.
• My use of lidocaine for spinal anesthesia is
directed by the following suggestions.
• Limit the dose to 60 to 70 mg, inject the dose
at a rate exceeding 0.2 mL/sec, keep the
needle aperture directed cephalad, and limit
use of the drug for continuous spinal
techniques as much as practical.
• Mepivacaine is another drug useful for spinal
anesthesia and is being applied in settings in
which lidocaine was used in the past.
• The drug-mass ratio for mepivacaine and
lidocaine is approximately 1.3 : 1, suggesting
that mepivacaine can be used for spinal
anesthesia in a 30- to 60-mg dose and
typically in the 2% concentration.
• In many aspects, mepivacaine is slightly
longer-acting lidocaine, with variable reports
of lower or equivalent rates of transient
neurologic symptoms.
• When longer-acting agents for spinal anesthesia
are desired, four drugs are available:
• tetracaine, bupivacaine, ropivacaine, and
levobupivacaine.
• Tetracaine:
• This drug has an onset of 5 to 10 minutes and is
selected for procedures lasting up to 2 to 3
hours when epinephrine is added and up to 5
hours for lower extremity procedures when
phenylephrine (0.5 mg) is added as a
vasoconstrictor.
• Bupivacaine spinal anesthesia is commonly carried out with 0.75% and
0.5% solutions in dextrose, as well as with isobaric forms of the drug, the
0.5% and the 0.75% plain solutions.
• The clinical difference between 0.5% tetracaine and 0.75% bupivacaine
as hyperbaric solutions is minimal, although more bupivacaine is used
than tetracaine.
•
It appears that when “isobaric” 0.5% and 0.75% bupivacaine are
compared, the mass of drug (milligram dose) injected is more important
in determining the eventual block height than the volume of isobaric
drug administered.
• Bupivacaine is appropriate for procedures lasting up to 2 to 2.5 hours.
• Ropivacaine is an amide local anesthetic that is frequently
used for epidural anesthesia because of experimental
evidence of less effect on the cardiac conduction system
than occurs with bupivacaine.
• With spinal anesthesia, this difference is minimal because
small doses are administered.
• When compared with bupivacaine, it is estimated to
require 1.8 to 2 times the dose to produce a similar clinical
effect.
• Many believe that it is clinically indistinguishable from
bupivacaine when the dose of drug administered is of a
mass to produce an equal effect.
• Levobupivacaine is the isolated (S)-enantiomer of bupivacaine and
is available for use as a spinal anesthetic.
• Clinical data suggest that this drug is converted to bupivacaine
when used for spinal anesthesia, and for doses ranging from 4 to
12 mg, a volunteer study suggests little clinical difference between
levobupivacaine and racemic bupivacaine.
• In 80 patients undergoing elective hip replacement and receiving
isobaric levobupivacaine (3.5 mL of a 0.5% solution) or isobaric
bupivacaine (3.5 mL of a 0.5% solution), their clinical efficacy was
judged equivalent.
• In a clinical situation in which systemic toxicity is a minimal issue
(or the typical spinal anesthetic), the advantage of
levobupivacaine over bupivacaine appears to be more theoretical
than real.
Spinal Anesthetic Additives
• Some physicians are concerned that the use of additives, particularly
vasoconstrictors, may be risky.
• The concept is that epinephrine and phenylephrine have such potent
vasoconstrictive action that they place the blood supply of the spinal
cord at risk.
• There are no human data supporting this theory. Kozody and colleagues
have shown that administering subarachnoid epinephrine (0.2 mg) or
phenylephrine (5 mg) does not decrease spinal cord blood flow in dogs.
• These traditional vasoconstrictors are not the only adrenergomimetic
agents being studied.
• Clonidine, an α2-agonist, prolongs the motor block associated with
tetracaine spinal anesthesia in dogs as much as epinephrine does while
prolonging sensory blockade for an even longer interval.
• The mechanism for this prolongation may involve vasoconstriction and
antinociception from α-adrenergic stimulation.
• Another drug investigated for spinal use as an
additive is neostigmine.
• This acetylcholinesterase inhibitor inhibits the
breakdown of acetylcholine and thereby induces
analgesia.
• It also prolongs and intensifies the analgesia
through release of nitric oxide in the spinal cord.
• Despite the side effect of nausea and
prolongation of motor block when combining it
with local anesthetics, it is slowly gaining
acceptance clinically.
• The interaction of various vasoconstrictors and
local anesthetics is better understood.
• Traditionally, epinephrine was thought to
prolong tetracaine spinal anesthesia but not
bupivacaine or lidocaine spinal anesthesia.
• This theory was postulated because of
differences in the vasodilatory action of the local
anesthetic drugs; plain lidocaine and
bupivacaine cause vasodilation, whereas plain
tetracaine does not.
• Since that time it has become clearer that twodermatome regression in the middle to high thoracic
dermatomes may be misleading when measuring
spinal anesthetic duration in the lower thoracic and
lumbar dermatomes.
• Some data indicate that lidocaine spinal anesthesia is
prolonged by epinephrine when measured by twodermatome regression in the lower thoracic
dermatomes and by occurrence of pain at the
operative site for procedures carried out at the level
of the lumbosacral dermatomes.
• When epinephrine has been compared with
phenylephrine as a means of prolonging spinal anesthesia,
conflicting information has resulted.
• Concepcion and coworkers compared epinephrine (0.2
and 0.3 mg) and phenylephrine (1 and 2 mg) added to
tetracaine and did not find a difference in increased
duration with the two vasoconstrictors.
• Caldwell and associates used larger doses of
vasoconstrictors, epinephrine at 0.5 mg and
phenylephrine at 5 mg, and showed that phenylephrine
prolonged tetracaine spinal anesthesia significantly more
than epinephrine did .
• Phenylephrine has been shown to prolong lidocaine spinal
anesthesia, but it appears that the length of prolongation
is more similar to that produced with epinephrine rather
than significantly longer.
• The duration of bupivacaine spinal anesthesia does not
appear to be prolonged by phenylephrine.
• Whichever local anesthetic solution and additives are
selected for subarachnoid injection, special care should be
taken to ensure that the clinician knows what substance is
being injected and that all procedures have been carried
out aseptically
Hypobaric and Isobaric Spinal
Anesthesia
• The density of any solution is the weight in grams of
1 mL of the solution at a standard temperature.
• Specific gravity is the ratio of the density of a solution
to the density of water.
• Baricity is a ratio comparing the density of one
solution to another.
• If the other solution happens to be water, the baricity
will be the same as the specific gravity.
• To make a drug hypobaric to CSF, it must be less
dense than CSF, with a baricity appreciably less than
1.0000 or a specific gravity appreciably less than
1.0069 (the mean value of the specific gravity of CSF).
A common method of formulating a hypobaric
solution is to mix tetracaine in a 0.1% to 0.33%
solution with sterile water.
This makes the baricity of the solution less than
0.9977 and allows clinically useful anesthesia to be
induced.
In the prone position for anorectal procedures or in
the lateral position for hip repairs, 4 to 6 mg of a
selected hypobaric dilution is often adequate.
There is evidence that the rate of injection (0.02
versus 0.5 mL/sec) of hypobaric (0.2%) tetracaine
influences spread of the drug.
• Another method of formulating a hypobaric-like
solution is to use warmed 0.5% bupivacaine.
• Data show that 0.5% bupivacaine warmed to 37°C as
opposed to 4°C demonstrates hypobaric
characteristics when the block is administered to
sitting patients.
• The investigators suggest that warmed bupivacaine
provides more predictable cephalad spread of the
sensory level than a cold or room-temperature drug
does.
• Another drug that has been investigated as a
“clinically” hypobaric spinal drug is 2%
lidocaine.
• Its physiochemical characteristics make it
more similar to an isobaric than a hypobaric
drug; however, some clinicians have found it
useful in situations generally reserved for
hypobaric techniques.
• When isobaric spinal anesthesia is planned, the
drugs most often chosen across the globe are
bupivacaine, ropivacaine, and levobupivacaine
(in 0.5% or 0.75% concentrations).
• Another drug that can be used is tetracaine.
• It is formulated into an isobaric solution by
diluting the niphanoid tetracaine crystals
(20 mg) with CSF and then injecting the selected
mass of drug in an isobaric fashion.
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