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

OH
N
1115
NH 2
CH 2
OH
OH
Dopamine
N
H
N
Quinagolide
O
S
O
N
improved adherence to therapy due to decreased side effects.
Therapy is initiated at a dose of 0.25 mg twice a week or 0.5 mg
once a week. If the serum prolactin remains elevated, the dose can
be increased to a maximum of 1.5-2 mg two or three times a week
as tolerated; the dose should not be increased more often than once
every 4 weeks.
Cabergoline induces remission in a significant number of
patients with prolactinomas, and a trial of drug discontinuation is
advocated for the subset of patients with normalization of prolactin
and disappearance of a detectable pituitary lesion on MRI scanning.
At higher doses, cabergoline is used in some patients with
acromegaly and is now under investigation for patients with
Cushing’s disease due to corticotrope adenomas (Chapter 42).
Adverse Effects. Compared to bromocriptine, cabergoline has a
much lower tendency to induce nausea, although it still may cause
hypotension and dizziness. Cabergoline has been linked to valvular
heart disease, an effect proposed to reflect agonist activity at the
serotonin 5-HT 2B
receptor. A similar effect has been seen with pergolide
(see later). Thus echocardiographic assessment seems appropriate
for patients receiving chronic therapy with cabergoline,
particularly those on higher doses (Colao et al., 2008b).
Quinagolide. Quinagolide (NORPROLAC) is a non-ergot
D 2
agonist (Figure 38–6) with a t 1/2
(22 hours) between
those of bromocriptine and cabergoline. Quinagolide is
administered once daily at doses of 0.1-0.5 mg/day. It
is not approved by the FDA but has been used extensively
in Europe and Canada.
Pergolide. Pergolide (PERMAX), an ergot derivative FDA-approved
for treatment of Parkinson disease, also was used off label to treat
hyperprolactinemia. In part due to concerns of valvular heart disease,
pergolide has been withdrawn from the market.
O
Br
H
N
N
O
O
OH
N
Bromocriptine
N
CH
O
Therapy of Growth Hormone Deficiency
The pharmacology of somatotropic hormone deficiency
is focused on GH because prolactin is not used clinically.
Replacement therapy is well established in GHdeficient
children and is gaining wider acceptance for
GH-deficient adults. Several other indications are also
approved, as described later. More recently, recombinant
human IGF-1 has been approved for use in patients
with mutations in the GH receptor that impair its action,
as well as in GH-deficient children who develop antibodies
against the recombinant hGH preparation.
Although once marketed, a synthetic GHRH analog is
no longer available.
Recombinant Human Growth Hormone. Humans do not
respond to GH from nonprimate species. In earlier
times, GH for therapeutic use was purified from human
cadaver pituitaries; it thus was available in very limited
quantities and in the mid-1980s was linked to the
transmission of Creutzfeldt-Jakob disease. Currently,
human GH is produced by recombinant DNA technology,
thereby providing virtually unlimited amounts
of the hormone while eliminating the risk of disease
transmission associated with the pituitary-derived
preparations.
Somatropin refers to the many GH preparations
whose sequences match that of native GH (ACCRETROPIN,
GENOTROPIN, HUMATROPE, NORDITROPIN, NUTROPIN, OMNI-
TROPE, SAIZEN, SEROSTIM, TEV-TROPIN, VALTROPIN, and
O
O
Cabergoline
Figure 38–6. Dopamine receptor agonists used in the treatment of prolactinomas. The structures of dopamine, the predominant regulator
of prolactin secretion, and of dopaminergic agonists that are used to inhibit prolactin secretion are shown. Bromocriptine and
cabergoline are ergot derivatives, whereas quinagolide is not. The β-phenylethylamine region of structural similarity between dopamine
and the agonists is shown in red.
NH
N
N
NH
CHAPTER 38
INTRODUCTION TO ENDOCRINOLOGY: THE HYPOTHALAMIC-PITUITARY AXIS