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

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SECTION II
NEUROPHARMACOLOGY
reservoir. Relatively low doses of morphine result in an increase in
tonic contracture of the antral musculature (secondary to an inhibition
of local inhibitory neurons) and upper duodenum and reduced
resting tone in the musculature of the gastric reservoir (secondary to
inhibition of the motor neurons to the reservoir musculature), thereby
prolonging gastric emptying time and increasing the likelihood of
esophageal reflux. Passage of the gastric contents through the duodenum
may be delayed by as much as 12 hours, and the absorption
of orally administered drugs is retarded. Morphine and other agonists
usually decrease secretion of hydrochloric acid, although stimulation
sometimes is evident. Activation of opioid receptors on
parietal cells enhances secretion, but indirect effects, including
increased secretion of somatostatin from the pancreas and reduced
release of acetylcholine, appear to be dominant in most circumstances
(Kromer, 1988).
Intestine. Morphine reduces propulsatile activity in the small and
large intestine and diminishes intestinal secretions.
Propulsatile Activity. Opiate agonists suppress local neurogenic
networks that provide a rhythmic inhibition of muscle tone leading
to concurrent increases in basal tone in the circular muscle of the
small and large intestine. This results in enhanced high-amplitude
phasic contractions, which are nonpropulsatile. The upper part of
the small intestine, particularly the duodenum, is affected more than
the ileum. A period of relative atony may follow the hypertonicity.
The reduced rate of passage of the intestinal contents, along with
reduced intestinal secretion, leads to increased water absorption,
increasing viscosity of the bowel contents, and constipation. The
tone of the anal sphincter is augmented greatly, and reflex relaxation
in response to rectal distension is reduced. These actions, combined
with inattention to the normal sensory stimuli for defecation reflex
owing to the central actions of the drug, contribute to morphineinduced
constipation (Wood and Galligan, 2004).
The clinical relevance of the role of the peripheral opioid
receptors in regulating GI motility after systemic opioids is supported
by:
• The efficacy of peripherally limited opiate agonists such as loperamide
as anti-diarrheals
• The ability of peripherally limited opiate antagonists such as
methylnaltrexone to reverse the constipatory actions of systemic
opiate agonists
Direct delivery of opioids into the cerebral ventricles or into
the spinal intrathecal space could also inhibit GI propulsive activity
as long as the extrinsic innervation to the bowel is intact. Although
some tolerance develops to the effects of opioids on GI motility,
patients who take opioids chronically remain constipated.
Intestinal Secretions. In the presence of intestinal hypersecretion
that may be associated with diarrhea, morphine-like drugs inhibit the
transfer of fluid and electrolytes into the lumen by naloxone-sensitive
actions on the intestinal mucosa and within the CNS (Kromer, 1988).
Intestinal secretion arises from activation of enterocytes by local
cholinergic submucosal plexus secretomotor neurons. Opioids act
though μ/δ receptors on these secretomotor neurons to inhibit their
excitatory output to the enterocytes and thereby reduce intestinal
secretion.
Biliary Tract. Bile flow is regulated by the periodic contractions of
the sphincter of Oddi, which is relaxed by inhibitory innervation. This
inhibitory innervation is suppressed by opiates. After the subcutaneous
injection of 10 mg morphine sulfate, the sphincter of Oddi constricts,
and the pressure in the common bile duct may rise >10-fold
within 15 minutes; this effect may persist for 2 hours or more. Fluid
pressure also may increase in the gallbladder and produce symptoms
that may vary from epigastric distress to typical biliary colic.
Some patients with biliary colic experience exacerbation rather
than relief of pain when given opioids. Spasm of the sphincter of
Oddi probably is responsible for elevations of plasma amylase and
lipase that occur sometimes after morphine administration. All
opioids can cause biliary spasm. Atropine only partially prevents
morphine-induced biliary spasm, but opioid antagonists prevent or
relieve it. Papaverine, another alkaloid of the poppy that lacks opioid
activity, produces smooth muscle relaxation and is used therapeutically
for GI, urethral, and biliary colic and for other nonvisceral
conditions (e.g., embolism and angina pectoris) accompanied by
smooth muscle spasm.
Other Smooth Muscle
Ureter and Urinary Bladder. Voiding is a highly organized response
initiated by afferents activated by bladder filling and spinobulbospinal
reflex arcs, which lead to contraction of the bladder and a
reflex relaxation of the external urinary sphincter (Fowler et al.,
2008). Morphine inhibits the urinary voiding reflex and increases
the tone of the external sphincter with a resultant increase in the volume
of the bladder. In animal models, this effect is mediated by
MOR and DOR agonists. Stimulation of either receptor type in the
brain or in the spinal cord exerts similar actions on bladder motility
(Dray and Nunan, 1987). Tolerance develops to these effects of opioids
on the bladder. Clinically, opiate-mediated inhibition of micturition
can be of such clinical severity that catheterization
sometimes is required after therapeutic doses of morphine, particularly
with spinal drug administration. Importantly, in humans, the
inhibition of systemic opiate effects on micturition is reversed by
peripherally restricted antagonists (Rosow et al., 2007).
Uterus. If the uterus has been made hyperactive by oxytocics, morphine
tends to restore the tone, frequency, and amplitude of contractions
to normal.
Skin. Therapeutic doses of morphine cause dilation of cutaneous
blood vessels. The skin of the face, neck, and upper thorax frequently
becomes flushed. These changes may be due in part to the release of
histamine and may be responsible for the sweating and some of the
pruritus that commonly follow the systemic administration of morphine
(described later). Histamine release probably accounts for the
urticaria commonly seen at the site of injection. Though controversial,
it is not blocked by naloxone and thought not to be mediated by
opioid receptors. Itching is readily seen with morphine and meperidine
but to a much lesser extent with oxymorphone, methadone, fentanyl,
or sufentanil. This pruritus is a common and potentially
disabling complication of opioid use. It can be caused by systemic
as well as intraspinal injections of therapeutic doses of opioids, but
it appears to be more intense after epidural or intrathecal administration
(Ballantyne et al., 1988). The spinal effect, which is reversible
by naloxone, may reflect a disinhibition of itch-specific neurons that
have been identified in the spinal dorsal horn (Schmelz, 2002).
Immune System. The effects of opioids on the immune system are
complex. Opioids modulate immune function by direct effects on