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

ful anti-nausea and anti-emetic drugs (Cameron et al., 2003); however,
caution is warranted due to the propensity of metoclopramide to
cause tardive dyskinesia (Chapter 46).
Cardiovascular System. In the supine patient, therapeutic
doses of morphine-like opioids have no major effect
on blood pressure or cardiac rate and rhythm. Such
doses can, however, produce peripheral vasodilation,
reduced peripheral resistance, and an inhibition of
baroreceptor reflexes. Thus, when supine patients
assume the head-up position, orthostatic hypotension
and fainting may occur. The peripheral arteriolar and
venous dilation produced by morphine involves several
mechanisms:
• morphine-induced release of histamine from mast
cells, leading to vasodilation (reveresed by naloxone
only partially blocked by H 1
antagonists)
• blunting of the reflex vasoconstriction caused by
increased P CO2
High doses of MOR agonists, such as fentanyl and
sufentanil, used as anesthetic induction agents, have
only modest effects upon hemodynamic stability, in
part because they do not cause release of histamine
(Monk et al., 1988).
Effects on the myocardium are not significant in normal individuals.
In patients with coronary artery disease but no acute medical
problems, 8-15 mg morphine administered intravenously
produces a decrease in O 2
consumption, left ventricular enddiastolic
pressure, and cardiac work; effects on cardiac index usually
are slight. In patients with acute myocardial infarction, the cardiovascular
responses to morphine may be more variable than in normal
subjects, and the magnitude of changes (e.g., the decrease in blood
pressure) may be more pronounced (Roth et al., 1988). Anesthetic
induction doses (described later) of the MOR result in a centrally
mediated increase in vagal outflow to the heart, leading to an
atropine-sensitive bradycardia.
Morphine may exert its well-known therapeutic effect in the
treatment of angina pectoris and acute myocardial infarction by
decreasing preload, inotropy, and chronotropy, thus favorably altering
determinants of myocardial O 2
consumption and helping to relieve
ischemia. It is not clear whether the analgesic properties of morphine
in this situation are due to the reversal of acidosis that may stimulate
local acid-sensing ion channels (McCleskey and Gold, 1999) or to a
direct analgesic effect on nociceptive afferents from the heart.
When administered before experimental ischemia, morphine
has been shown to produce cardioprotective effects. Morphine can
mimic the phenomenon of ischemic preconditioning, where a short
ischemic episode paradoxically protects the heart against further
ischemia. This effect appears to be mediated through receptors signaling
through a mitochondrial ATP-sensitive K + channel in cardiac
myocytes; the effect also is produced by other GPCRs signaling
through Gi (Fryer et al., 2000). Some researchers suggest that
opioids can be anti-arrhythmic and anti-fibrillatory during and after
periods of ischemia (Fryer et al., 2000), although other data suggest
that opioids can be arrhythmogenic (McIntosh et al., 1992).
Morphine-like opioids should be used with caution in patients
who have decreased blood volume because these agents can aggravate
hypovolemic shock. Morphine should be used with great care in
patients with cor pulmonale because deaths after ordinary therapeutic
doses have been reported. The concurrent use of certain phenothiazines
may increase the risk of morphine-induced hypotension.
Cerebral circulation is not affected directly by therapeutic
doses of opiates. However, opioid-induced respiratory depression
and CO 2
retention can result in cerebral vasodilation and an increase
in cerebrospinal fluid pressure. This pressure increase does not occur
when PCO 2
is maintained at normal levels by artificial ventilation.
Nevertheless, opioids produce changes in arousal that can obscure
the clinical course of patients with head injuries.
Motor Tone. At therapeutic doses required for analgesia, opiates
have little effect upon motor tone or function. However, high doses
of opioids, as used for anesthetic induction, produce muscular rigidity
in humans. Thus, rigidity of the chest wall and masseter severe
enough to compromise respiration and intubation is not uncommon
during anesthesia and routinely requires the use muscle relaxants.
Myoclonus, ranging from mild twitching to generalized
spasm, is an occasional side-effect, which has been reported with all
clinical opiate agonists; while it may be observed at lower therapeutic
doses, it is particularly prevalent in hospice patients receiving
high doses (Lyss et al., 1997). The increased muscle tone is certainly
mediated by a central effect although the mechanisms of its effects
are not clear. High doses of spinal opiates can increase motor tone,
possibly through an inhibition of inhibitory interneurons in the ventral
horn of the spinal cord. Alternately, intracranial delivery can initiate
rigidity in animal models possible reflecting on increased
extrapyramidal activity. As already indicated, both actions are
reversed by opiate antagonists.
GI Tract. Opiates have important effects upon all aspects of GI function.
It is estimated that 40-95% of patients treated with opioids
develop constipation and that changes in bowel function can be
demonstrated even with acute dosing (Benyamin et al., 2008).
Opioid receptors are densely distributed in enteric neurons between
the myenteric and submucosal plexi and on a variety of secretory
cells. The more prominent expression of the action mediated by these
receptors will be reviewed in the next sections. Importantly, the presence
of opioids can obscure recognition of the diagnosis or clinical
course in patients with acute abdominal conditions.
Esophagus. The esophageal sphincter is under control by brainstem
reflexes that activate cholinergic motor neurons originating in the
esophageal myenteric plexus. This system regulates passage of material
from the esophagus to the stomach and prevents regurgitation;
conversely, it allows relaxation in the act of emesis. Morphine inhibits
lower esophageal sphincter relaxation induced by swallowing and by
esophageal distension. This effect is believed to be centrally mediated,
as peripherally restricted opiates such as loperamide do not alter
esophageal sphincter tone (Sidhu and Triadafilopoulos, 2008).
Stomach. Movement of a meal though the stomach reflects the coordinated
contractions of the antrum and the resting tone of the gastric
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CHAPTER 18
OPIOIDS, ANALGESIA, AND PAIN MANAGEMENT