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

antipsychotic agent. That clonazepam and propranolol have significant
cortical activity and are ineffective for other forms of EPS,
points to an extrastriatal origin for akathisia symptoms.
The rare neuroleptic malignant syndrome (NMS) resembles a
very severe form of parkinsonism, with signs of autonomic instability
(hyperthermia and labile pulse, blood pressure, and respiration rate),
stupor, elevation of creatine kinase in serum, and sometimes myoglobinemia
with potential nephrotoxicity. At its most severe, this syndrome
may persist for more than a week after the offending agent is discontinued,
and is associated with mortality. This reaction has been associated
with various types of antipsychotic agents, but its prevalence may
be greater when relatively high doses of potent agents are used, especially
when they are administered parenterally. Aside from cessation
of antipsychotic treatment and provision of supportive care, including
aggressive cooling measures, specific pharmacological treatment is
unsatisfactory, although administration of dantrolene and the dopaminergic
agonist bromocriptine may be helpful. While dantrolene also is
used to manage the syndrome of malignant hyperthermia induced by
general anesthetics, the neuroleptic-induced form of hyperthermia
probably is not associated with a defect in Ca 2+ metabolism in skeletal
muscle. There are anecdotal reports of NMS with atypical antipsychotic
agents, but this syndrome is now rarely seen in its full presentation.
Hyperprolactinemia results from blockade of the
pituitary actions of the tuberoinfundibular dopaminergic
neurons; these neurons project from the arcuate
nucleus of the hypothalamus to the median eminence,
where they deliver DA to the anterior pituitary via the
hypophyseoportal blood vessels. D 2
receptors on lactotropes
in the anterior pituitary mediate the tonic
prolactin-inhibiting action of DA. Correlations between
the D 2
potency of antipsychotic drugs and prolactin elevations
are excellent. With the exception of risperidone
and paliperidone, atypical antipsychotic agents show
limited (asenapine, iloperidone, olanzapine, quetiapine,
ziprasidone) to almost no effects (clozapine, aripiprazole)
on prolactin secretion.
The hyperprolactinemia from antipsychotic drugs is rapidly
reversible when the drugs are discontinued. Hyperprolactinemia can
directly induce breast engorgement and galactorrhea. Approximately
33% of human breast cancers are prolactin-dependent in vitro, a factor
of potential importance if the prescription of these drugs is contemplated
in a patient with previously detected breast cancer. By
suppressing the secretion of gonadotropins and sex steroids, hyperprolactinemia
can cause amenorrhea in women and sexual dysfunction
or infertility in men. The development of amenorrhea is of
concern as it represents low serum estradiol levels and ongoing risk
for bone density loss. The development of amenorrhea becomes a
sensitive marker for sex hormone levels, and should prompt clinical
action, while asymptomatic measurable increases in serum prolactin
levels do not necessarily merit any intervention. Dose reduction can
be tried to decrease serum prolactin levels, but caution must be exercised
to keep treatment within the antipsychotic therapeutic range.
When switching from offending antipsychotic agents is not feasible,
bromocriptine can be employed. There is also anecdotal evidence
that aripiprazole augmentation may be effective.
All DA antagonist antipsychotic drugs possess antiemetic
properties by virtue of their actions at the medullary chemoreceptor
trigger zone (Figure 46–4). The D 2
partial agonists aripiprazole (and
bifeprunox), however, can be associated with nausea. For aripiprazole
this effect was noted in clinical trials of oral medication for
acute mania, bipolar maintenance, or schizophrenia (nausea incidence
15% for aripiprazole vs. 11% for placebo; vomiting incidence
11% for aripiprazole vs. 6% for placebo), and also in studies of pediatric
bipolar mania in patients ages 10-17 (nausea incidence 11%)
and in acute IM trials for agitation in schizophrenia or acute mania
(nausea incidence 9%). Bifeprunox possessed a level of intrinsic DA
agonism that was slightly greater than that for aripiprazole (25-28%),
but was significant enough to cause clinical problems with nausea
and vomiting, that a 10-day titration from an initial starting dose of
0.125 mg was necessary to reach the proposed effective dosage range
of 10-30 mg (Glick and Peselow, 2008).
H 1
Receptors. Central antagonism of H 1
receptors is associated
with two major adverse effects: sedation and
weight gain via appetite stimulation. Examples of sedating
antipsychotic drugs include low-potency typical
agents such as chlorpromazine and thioridazine, and the
atypical agents clozapine and quetiapine. The sedating
effect is easily predicted by their high H 1
receptor affinities
(Table 16–2). Some tolerance to the sedative properties
will develop, a fact that must be kept in mind
when switching patients to nonsedating agents.
There is an extended-release quetiapine preparation available,
with markedly reduced C max
compared to the immediate-release form.
Immediate-release quetiapine generates peak serum levels > 800 ng/mL
within 2 hours of ingestion, while the extended release preparation
has C max
~50% lower, with peak serum levels seen 4-8 hours after
ingestion. In clinical practice the onset of sedation for extendedrelease
quetiapine is delayed for at least 3 hours after oral administration,
and subjectively the sedation is much less profound than
with the immediate-release form (Mamo et al., 2008).
Rapid discontinuation of sedating antihistaminic antipsychotic
drugs is inevitably followed by significant complaints of rebound
insomnia and sleep disturbance. If discontinuation of sedating
antipsychotic treatment is deemed necessary, except for emergency
cessation of clozapine for agranulocytosis, the medication should be
tapered slowly over 4-8 weeks, and the clinician should be prepared
to utilize a sedative when the end of the titration is reached. Generous
dosing of another antihistamine (hydroxyzine), or the anticholinergic
antihistamine diphenhydramine are reasonable replacement sedative
medications, but others can used, including benzodiazepines,
non-benzodiazepine hypnotics that act at specific benzodiazepine
sites (e.g., zolpidem, eszopiclone), and sedating antidepressants (e.g.,
trazodone). Sedation may be useful during acute psychosis, but excessive
sedation can interfere with patient evaluation, may prolong emergency
room and psychiatric hospital stays unnecessarily, and is poorly
tolerated among elderly dementia and delirium patients, so appropriate
caution must be exercised with the choice of agent and the dose.
Weight gain is a significant problem during long-term use of
antipsychotic drugs and represents a major barrier to medication
adherence, as well as a significant threat to the physical and emotional
CHAPTER 16
PHARMACOTHERAPY OF PSYCHOSIS AND MANIA
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