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

1114 provides a highly effective alternative for use in patients who have
not responded to SST analogs, either as sole therapy or as a temporizing
measure while waiting for radiation therapy to achieve its full
effect; it also is receiving increased scrutiny as first-line therapy.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Therapy of Prolactin Excess. The therapeutic options
for patients with prolactinomas include transphenoidal
surgery, radiation, and treatment with DA receptor agonists
that suppress prolactin production via activation
of D 2
receptors. The surgical success rates are 75% for
microadenomas and 33% for macroadenomas. Given
these results, D 2
receptor agonists are widely recognized
as the treatment of choice for most patients
(Gillam et al., 2006).
Dopamine Receptor Agonists
These agents generally decrease both prolactin secretion
and the size of the adenoma, thereby improving
both the endocrine abnormalities and neurological
symptoms caused directly by the adenoma (including
visual field deficits). Over time, especially with cabergoline,
the prolactinoma may decrease in size to the
extent that the drug can be discontinued without recurrence
of the hyperprolactinemia. Some experts therefore
recommend treatment with a dopamine receptor agonist
for a minimum of 2 years, followed by a trial of
dopamine agonist withdrawal in patients who have
responded to dopamine agonist therapy with normalization
of prolactin and disappearance of the tumor on
MRI scanning (Gillam et al., 2006).
Patients with prolactinomas who wish to become
pregnant comprise a special subset of hyperprolactinemic
patients because drug safety during pregnancy
becomes an important consideration. The dopamine
agonists described here relieve the inhibitory effect of
prolactin on ovulation and permit most patients with
prolactinomas to become pregnant. Clinical experience
also indicates that many patients can discontinue the
dopaminergic agonist during pregnancy without clinically
significant tumor growth. Although drug therapy
ideally is discontinued before pregnancy to avoid any
fetal exposure, most experts discontinue therapy after
pregnancy is confirmed and carefully follow for symptoms
or signs of pituitary mass effect throughout gestation.
Because of its greater track record, bromocriptine
generally is recommended for fertility induction in
patients with hyperprolactinemia. Substantial clinical
use with cabergoline has not revealed adverse maternal
or fetal effects (Colao et al., 2008a), but most
endocrinologists still prefer bromocriptine in this setting.
Although not definitive, there are data linking
quinagolide with fetal abnormalities (reviewed by
Gillam et al., 2006), and it should not be used when
pregnancy is intended.
Bromocriptine. Bromocriptine (PARLODEL) is the
dopamine receptor agonist against which newer agents
are compared.
Chemistry. Bromocriptine is a semisynthetic ergot alkaloid
(Figure 38–6) that interacts with D 2
receptors to inhibit spontaneous
and TRH-induced release of prolactin; to a lesser extent, it also activates
D 1
receptors.
Absorption, Distribution, and Elimination. Although a large fraction
of the oral dose of bromocriptine is absorbed, only 7% of the
dose reaches the systemic circulation because of a high extraction
rate and extensive first-pass metabolism in the liver. Bromocriptine
has a relatively short elimination t 1/2
(between 2 and 8 hours) and
thus is usually administered in divided doses (see Adverse Effects).
To avoid the need for frequent dosing, a slow release oral form is
available outside of the U.S. Bromocriptine may be administered
vaginally (2.5 mg once daily), reportedly with fewer gastrointestinal
side effects.
Therapeutic Uses. Bromocriptine normalizes serum prolactin levels
in 70-80% of patients with prolactinomas and decreases tumor
size in >50% of patients, including those with macroadenomas.
Typically, bromocriptine does not cure the underlying adenoma,
and hyperprolactinemia and tumor growth recur upon cessation of
therapy.
Adverse Effects. Frequent side effects of bromocriptine include nausea
and vomiting, headache, and postural hypotension, particularly
on initial use. Less frequently, nasal congestion, digital vasospasm,
and CNS effects such as psychosis, hallucinations, nightmares, or
insomnia are observed. These adverse effects can be diminished by
starting at a low dose (1.25 mg) administered at bedtime with a
snack. After 1 week, a morning dose of 1.25 mg can be added. If
clinical symptoms persist or serum prolactin levels remain elevated,
the dose can be increased gradually, every 3-7 days, to 5 mg two or
three times a day as tolerated. Patients often develop tolerance to the
adverse effects of bromocriptine. Those who do not respond to
bromocriptine or who develop intractable side effects often respond
better to cabergoline. At higher concentrations, bromocriptine is used
in the management of acromegaly, as noted earlier, and at still higher
concentrations is used in the management of Parkinson’s disease
(Chapter 22).
Cabergoline. Cabergoline (DOSTINEX) is an ergot derivative
with a longer t 1/2
(~65 hours), higher affinity, and
greater selectivity for the D 2
receptor (approximately
four times more potent) than bromocriptine. It undergoes
significant first-pass metabolism in the liver, and the precise
oral availability is not known.
Therapeutic Uses. Cabergoline is FDA-approved for the treatment
of hyperprolactinemia and has become the preferred drug in
most settings for this disorder. Its greater efficacy in decreasing
serum prolactin in patients with hyperprolactinemia may reflect