DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

580 intravascular injection easier to detect and modifies the effect of
sympathetic blockade during epidural anesthesia.
For each anesthetic agent, a relationship exists between the
volume of local anesthetic injected epidurally and the segmental
level of anesthesia achieved. For example, in 20- to 40-year-old,
healthy, nonpregnant patients, each 1-1.5 mL of 2% lidocaine will
give an additional segment of anesthesia. The amount needed
decreases with increasing age and also decreases during pregnancy
and in children.
The concentration of local anesthetic used determines the
type of nerve fibers blocked. The highest concentrations are used
when sympathetic, somatic sensory, and somatic motor blockade are
required. Intermediate concentrations allow somatic sensory anesthesia
without muscle relaxation. Low concentrations will block only
preganglionic sympathetic fibers. As an example, with bupivacaine
these effects might be achieved with concentrations of 0.5%, 0.25%,
and 0.0625%, respectively. The total amounts of drug that can be
injected with safety at one time are approximately those mentioned
earlier in the chapter under “Nerve Block Anesthesia” and
“Infiltration Anesthesia.” Performance of epidural anesthesia
requires a greater degree of skill than does spinal anesthesia. The
technique of epidural anesthesia and the volumes, concentrations,
and types of drugs used are described in detail in standard texts on
regional anesthesia (e.g., Cousins et al., 2008).
A significant difference between epidural and spinal anesthesia
is that the dose of local anesthetic used can produce high
concentrations in blood following absorption from the epidural
space. Peak concentrations of lidocaine in blood following injection
of 400 mg (without epinephrine) into the lumbar epidural
space average 3-4 μg/mL; peak concentrations of bupivacaine in
blood average 1 μg/mL after the lumbar epidural injection of 150 mg.
Addition of epinephrine (5 μg/mL) decreases peak plasma concentrations
by ~25%. Peak blood concentrations are a function of the
total dose of drug administered rather than the concentration or
volume of solution following epidural injection (Covino and
Vassallo, 1976). The risk of inadvertent intravascular injection is
increased in epidural anesthesia, as the epidural space contains a
rich venous plexus.
Another major difference between epidural and spinal anesthesia
is that there is no zone of differential sympathetic blockade
with epidural anesthesia; thus, the level of sympathetic block is
close to the level of sensory block. Because epidural anesthesia
does not result in the zones of differential sympathetic blockade
observed during spinal anesthesia, cardiovascular responses to
epidural anesthesia might be expected to be less prominent. In
practice this is not the case; the potential advantage of epidural
anesthesia is offset by the cardiovascular responses to the high concentration
of anesthetic in blood that occurs during epidural anesthesia.
This is most apparent when, as is often the case, epinephrine
is added to the epidural injection. The resulting concentration of
epinephrine in blood is sufficient to produce significant β 2
adrenergic
receptor-mediated vasodilation. As a consequence, blood pressure
decreases, even though cardiac output increases due to the positive
inotropic and chronotropic effects of epinephrine (Chapter 12). The
result is peripheral hyperperfusion and hypotension. Differences
in cardiovascular responses to equal levels of spinal and epidural
anesthesia also are observed when a local anesthetic such as
SECTION II
NEUROPHARMACOLOGY
lidocaine is used without epinephrine. This may be a consequence
of the direct effects of high concentrations of lidocaine on vascular
smooth muscle and the heart. The magnitude of the differences
in responses to equal sensory levels of spinal and epidural anesthesia
varies, however, with the local anesthetic used for the
epidural injection (assuming no epinephrine is used). For example,
local anesthetics such as bupivacaine, which are highly lipid
soluble, are distributed less into the circulation than are less lipidsoluble
agents such as lidocaine.
High concentrations of local anesthetics in blood during
epidural anesthesia are especially important when this technique is
used to control pain during labor and delivery. Local anesthetics
cross the placenta, enter the fetal circulation, and at high concentrations
may cause depression of the neonate. The extent to which they
do so is determined by dosage, acid-base status, the level of protein
binding in both maternal and fetal blood, placental blood flow, and
solubility of the agent in fetal tissue. These concerns have been lessened
by the trend toward using more dilute solutions of bupivacaine
for labor analgesia.
Epidural and Intrathecal Opiate Analgesia. Small quantities of
opioid injected intrathecally or epidurally produce segmental analgesia
(Yaksh and Rudy, 1976). This observation led to the clinical
use of spinal and epidural opioids during surgical procedures and
for the relief of postoperative and chronic pain (Cousins and
Mather, 1984). As with local anesthesia, analgesia is confined to
sensory nerves that enter the spinal cord dorsal horn in the vicinity
of the injection. Presynaptic opioid receptors inhibit the release
of substance P and other neurotransmitters from primary afferents,
while postsynaptic opioid receptors decrease the activity of
certain dorsal horn neurons in the spinothalamic tracts
(Willcockson et al., 1986; see also Chapters 8 and 18). Since conduction
in autonomic, sensory, and motor nerves is not affected
by the opioids, blood pressure, motor function, and non-nociceptive
sensory perception typically are not influenced by spinal opioids.
The volume-evoked micturition reflex is inhibited, as manifested
by urinary retention. Other side effects include pruritus, nausea,
and vomiting in susceptible individuals. Delayed respiratory
depression and sedation, presumably from cephalad spread of opioid
within the CSF, occur infrequently with the doses of opioids
currently used.
Spinally administered opioids by themselves do not provide
satisfactory anesthesia for surgical procedures. Thus, opioids have
found the greatest use in the treatment of postoperative and chronic
pain. In selected patients, spinal or epidural opioids can provide
excellent analgesia following thoracic, abdominal, pelvic, or lower
extremity surgery without the side effects associated with high
doses of systemically administered opioids. For post-operative analgesia,
spinally administered morphine, 0.2-0.5 mg, usually will provide
8-16 hours of analgesia. Placement of an epidural catheter and
repeated boluses or an infusion of opioid permits an increased duration
of analgesia. Many opioids have been used epidurally.
Morphine, 2-6 mg, every 6 hours, commonly is used for bolus injections,
while fentanyl, 20-50 μg/hour, often combined with bupivacaine,
5-20 mg/hour, is used for infusions. For cancer pain, repeated
doses of epidural opioids can provide analgesia of several months’
duration. The dose of epidural morphine, e.g., is far less than the