Transcript ไม่มีชื่อเรื่องภาพนิ่ง

Local Anesthetics
Agents,Action,Misconceptions
Lecture Objectives
Review the mechanism of
action , pharmacodynamics ,
phamacokinetics , toxicity , and
common misconceptions about
local anesthetics.
General considerations
- All local anesthetics [ LA ] contain an
aromatic ring at one end of the molecule
and an amine at the other , separated by
hydrocarbon chain.
- LAs segregate into esters and amides,
based on the chemical link between the
aromatic moiety and hydrocarbon chain.
Electrophysiology , Na channel ,
and LA action.
- Local anesthesia results when LAs
bind Na channels in nerves , inhibiting the
Na permeability that underlies action
potential.
- Na channels can exist in at least 3
conformations : resting , open , and
inactivated .
- LAs will bind to many different sites ;
thus, the molecular mechanism by which
LAs produce spinal or epidural analgesia
may include LA binding to targets other
than Na channels.
- Other chemicals also bind and Na
channels , including tetrodotoxin and
other toxins , calcium channel blockers ,
a adrenergic agonists , volatile general
anesthetics, and meperidine.
2
LA Pharmacodynamics
- Potency, duration of action , speed of
onset,and tendency for differential block.
LA potency
- The larger,more lipophilic LAs permeate
nerve membranes more readily and bind
Na channels with greater affinity.
LA Duration : regulated by protein binding?
- It is a misconception that the duration of
regional anesthesia directly relates to LA
protein binding.
- More lipid soluble LAs are less relatively
water- insoluble and, therefore, highly
protein - bound.
- It is more logical to state that LA duration
of action relates to LA lipid solubility.
LA Speed of Onset : Controlled by pKa ?
- At any pH , percentage of LA molecule
present in the uncharged form is largely
responsible for membrane permeability
decrease with increasing pKa.
- One should consider the two LAs of
fastest onset in the clinic : eticocaine and
chloroprocaine.
Differential Sensory Nerve Block
- All LAs will block myelinated or unmyelinated fibers of smaller diameter at lower
concentration than are required to block
larger fibers of the same type.
- Bupivacaine and ropivacaine are
relatively selective for sensory fibers ;
adequate sensory analgesia , with little or
no motor block.
Other Factor Influencing LA Activity.
- A variety of factor influence the quality
of regional anesthesia, including LA dose,
site of administration, additives , temp. ,
and pregnancy.
- In general , the fastest onset and
shortest duration of anesthesia occurs
with spinal or subcutaneous injections ;
a slower onset and longer duration are
obtain with plexus blocks.
- Epinephrine is frequently added to LA
solution in a 1 :200,000 dilution.
- Other popular LA additives include
clonidine, opioids, neostigmine, hyaluronidase, and NaHCO3.
- LAs more potently block action potential at basic pH , where there are increase
amount of LA in the uncharged form,than
at more acid pH.
- Some clinical studies show that the
addition of sodium bicarbonate to LAs
speeds the onset of nerve blocks.
- The potency of LAs increase in vitro
and in vivo with cooling in some circumstances, but not in others.
- Spread of epidural or spinal anesthesia
increase during pregnancy.
- Pregnancy appears to increase the
susceptibility of nerves to LAs.
LA Concentrations, Protein Binding,
Metabolism, and Phamacokinetics.
- Peak LA concentrations vary by the site
of injection.
- After plexus, epidural, or intercostal
blocks, the latter consistenly produced
the greatest peak LA concentrations.
- The least potent, shortest-acting LAs
are less protein-bound than the more
potent, longer-persisting agents.
- For esters metabolism , the primary step
is ester hydrolysis , catalyzed by plasma
pseudocholinesterase.
- For amides metabolism , undergo nearly
exclusive metabolism by the liver.
- Ester metabolism can, theoretically, be
slowed by cholinesterase deficiency or
long-term cholineserase inhibition
- Amide clearance is highly dependent on
hep.blood flow, hep.extraction and enz.
function.
Toxic Side Effects of LAs
CNS Side Effects.
- More potent LA consistently produce
seizure at lower blood concentration
and lower doses than less potent LAs
- Both elevated pCO2 and acidosis
decrease the LA convulsive dose.
CV Toxicity.
- Occur when blood concentration is at
least 3 times that producing seizure.
- There are reports of simultaneous CNS
and CV toxicity with bupivacaine and
related agents.
- The bupivacaine R[+] isomer binds
cardiac Na channels more avidly than
the S [-] isomer , forming the basis for the
development of ropivacaine and levobupivacaine.
Allergic Reaction to LAs.
- Uncommon.
- True anaphylaxis has been documented
with esters, particularly those which are
metabolized directly to PABA.
- Anaphylaxis to amide anesthetic is
much less common.
Neurotoxic Effect of LAs.
- 2-chloroprocaine occasionally produce
cauda equina syndrome when large
doses were accidentally injected into
spinal fluid.
- Presently, there is controversy regardling
whether lidocaine produces persisting
sacral deficit and whether it may be
associated with an excessive incidence
of transient radicular irritation after SPB.
Treatment of LA Toxicity.
- Essential treatment of LA-induced seizure
should include maintaining the airway
and providing oxygen.
- Seizures may be terminated with IV
thiopental , BZP, or a paralytic dose of
succinyl choline followed by tracheal
intubation.
- Hypotension may be treated by IV fluid
and vasopressors.