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

494
SECTION II
NEUROPHARMACOLOGY
indirect effects upon dopaminergic and noradrenergic modulatory
projections into the parventricular and supraoptic hypothalamus
(Gimpl and Fahrenholz, 2001).
Miosis. Illumination of the pupil activates a reflex arc, which through
local circuitry in the Edinger Westphal nucleus, activates parasympathetic
outflow through the ciliary ganglion to the pupil, producing
constriction. MOR opiates induce pupillary constriction (miosis) in
the awake state and block pupillary reflex dilation during anesthesia.
The parasympathetic outflow is locally regulated by GABAergic
interneurons. Opiates are believed to block the GABAergic interneuronmediated
inhibition (Larson, 2008). At high doses of agonists, the
miosis is marked, and pinpoint pupils are pathognomonic; however,
marked mydriasis will occur with the onset of asphyxia. While some
tolerance to the miotic effect develops, addicts with high circulating
concentrations of opioids continue to have constricted pupils.
Therapeutic doses of morphine increase accommodative power and
lower intraocular tension in normal and glaucomatous eyes.
Seizures and Convulsions. In older children and adults, moderately
higher doses of opiates produce EEG slowing. In the newborn, morphine
has been shown to produce epileptiform activity (Young and
da Silva, 2000) and occasionally seizure activity. While increased
jaw and chest wall rigidity routinely occur at doses used for anesthesia
induction, frank seizures and convulsions typically occur only
at doses far in excess of those required to produce even profound
analgesia. Myoclonus and seizures have been reported particularly
in opioid tolerant patients on high doses of morphine-like opiates,
including fentanyl, as encountered in hospice and terminal stages of
pain therapy (Vella-Brincat and Macleod., 2007). However, seizures
that are produced by some agents such as meperidine may occur at
doses only moderately higher than those required for analgesia,
especially in children, particularly with repeated delivery.
Several mechanisms are most certainly involved in these excitatory
actions:
• Inhibition of inhibitory interneurons. Morphine-like drugs excite
certain groups of neurons, especially hippocampal pyramidal
cells, probably from inhibition of the release of GABA by
interneurons (McGinty, 1988).
• Direct stimulatory effects. Opiates may interact with receptors
coupled through both inhibitory and stimulatory G-protein, with
the inhibitory coupling but not the excitatory coupling showing
tolerance with continued exposure (King et al., 2005).
• Actions mediated by non-opioid receptors. The metabolites of
several opiates have been implicated in seizure activity, notably
morphine-3-glucuronide (from morphine) and normeperidine
(from meperidine) (Seifert and Kenendy, 2004; Smith, 2000).
A special case is the withdrawal syndrome from an opiatedependent
state in the adult and in the infant born to an opiatedependent
mother. Withdrawal in these circumstances, either by
antagonists or abstinence, can lead to prominent EEG activation,
tremor, and rigidity. Approaches to the management of such activation
are controversial. Re-narcotization with a tapering dose and
management of symptoms with anticonvulsants and anesthetics has
been suggested (Farid et al., 2008). Anticonvulsant agents may not
always be effective in suppressing opioid-induced seizures
(Chapter 21).
Cough. Morphine and related opioids depress the cough reflex at least
in part by a direct effect on a cough center in the medulla and this can
be achieved without altering the protective glottal function. There is
no obligatory relationship between depression of respiration and
depression of coughing, and effective antitussive agents are available
that do not depress respiration (antitussives are discussed later
in the chapter). Suppression of cough by such agents appears to
involve receptors in the medulla that are less sensitive to naloxone
(an opioid antagonist) than those responsible for analgesia (Chung
and Pavord, 2008).
Cough is a protective reflex evoked by airway stimulation. It
involves rapid expression of air against a transiently closed glottis.
The reflex is complex, involving the central and peripheral nervous
systems as well as the smooth muscle of the bronchial tree. Irritation
of the bronchial mucosa causes bronchoconstriction, which in turn
stimulates cough receptors (which probably represent a specialized
type of stretch receptor) located in tracheobronchial passages.
Afferent conduction from these receptors is via fibers in the vagus
nerve; central components of the reflex probably include several
mechanisms or centers that are distinct from the mechanisms
involved in the regulation of respiration.
Nauseant and Emetic Effects. Nausea is the prodomal
sensation that is a common feature of gastric upset that
is associated with reduced gastric motility and
increased secretions. Vomiting, the motor sequela of
nausea, is a complex reflex characterized by simultaneous
contractions of inspiratory-expiratory respiratory
muscle, increased stomach pressure, relaxation
of the esophageal sphincter, and retrograde reflex
propulsion of gastric contents. Nausea and vomiting
produced by morphine-like drugs are side-effects
caused by direct stimulation of the chemoreceptor
trigger zone for emesis in the area postrema of the
medulla. Apomorphine is a structural analog of morphine
that has no opioid action but has prominent
emetogenic actions.
Nausea and vomiting are relatively uncommon in recumbent
patients given therapeutic doses of morphine, but nausea occurs in
~40% and vomiting in 15% of ambulatory patients given 15 mg of the
drug subcutaneously. This suggests that a vestibular component is
also operative. Indeed, the nauseant and emetic effects of morphine
are markedly enhanced by vestibular stimulation, and morphine and
related synthetic analgesics produce an increase in vestibular sensitivity.
A component of nausea is likely due to the gastric stasis that
occurs postoperatively and that is exacerbated by analgesic doses of
morphine (Greenwood-Van Meerveld, 2007). All clinically useful
agonists produce some degree of nausea and vomiting. Careful, controlled
clinical studies usually demonstrate that, in equianalgesic
dosage, the incidence of such side effects is not significantly lower
than that seen with morphine. Antagonists to the 5-HT3 receptor have
supplanted phenothiazines and drugs used for motion sickness as the
drugs of choice for the treatment of opioid-induced nausea and vomiting.
Gastric prokinetic agents such as metoclopramide also are use-