Page 758 - Basic _ Clinical Pharmacology ( PDFDrive )

744 SECTION VII Endocrine Drugs

Hypothalamus O
C NHC(CH )
3 3
CH 3

CH 3

GnRH
O N
– GnRH antagonists (1) H H
Finasteride
+/– GnRH agonists (2)
Receptor Inhibitors
Pituitary Flutamide, a substituted anilide, is a potent antiandrogen that has
gonadotrophs
been used in the treatment of prostatic carcinoma. Although not
a steroid, it behaves like a competitive antagonist at the androgen
receptor. It is rapidly metabolized in humans. It frequently causes
LH
mild gynecomastia (probably by increasing testicular estrogen
production) and occasionally causes mild reversible hepatic toxic-
ity. Administration of this compound causes some improvement
Testis
in most patients with prostatic carcinoma who have not had prior
endocrine therapy. Preliminary studies indicate that flutamide
– Ketoconazole, (3)
spironolactone is also useful in the management of excess androgen effect in
women.
Testosterone
F C
3
5α- – Finasteride O
Reductase (4)
O 2 N NH C CH CH 3
Dihydrotestosterone
CH 3
Flutamide, Flutamide
– – cyproterone, (5)
spironolactone
Bicalutamide, nilutamide, and enzalutamide are potent
Androgen-receptor complex
orally active antiandrogens that can be administered as a single
daily dose and are used in patients with metastatic carcinoma of
Androgen the prostate. Studies in patients with carcinoma of the prostate
response indicate that these agents are well tolerated. Bicalutamide is rec-
element
ommended (to reduce tumor flare) for use in combination with
a GnRH analog and may have fewer gastrointestinal side effects
than flutamide. A dosage of 150–200 mg/d (when used alone)
Expression of appropriate
genes in androgen-responsive cells is required to reduce prostate-specific antigen levels to those
achieved by castration, but, in combination with a GnRH analog,
FIGURE 40–6 Control of androgen secretion and activity and
some sites of action of antiandrogens: (1) competitive inhibition of 50 mg/d may be adequate. Nilutamide is administered in a dosage
GnRH receptors; (2) stimulation (+, pulsatile administration) or inhibi- of 300 mg/d for 30 days followed by 150 mg/d. The dosage of
tion via desensitization of GnRH receptors (–, continuous administra- enzalutamide is 160 mg/d orally.
tion); (3) decreased synthesis of testosterone in the testis; (4) decreased Cyproterone and cyproterone acetate are effective anti-
synthesis of dihydrotestosterone by inhibition of 5α-reductase; androgens that inhibit the action of androgens at the target
(5) competition for binding to cytosol androgen receptors. organ. The acetate form has a marked progestational effect that
suppresses the feedback enhancement of LH and FSH, leading
approved for this use in the United States. The dosage is 5 mg/d. to a more effective antiandrogen effect. These compounds have
Dutasteride is a similar orally active steroid derivative with a slow been used in women to treat hirsutism and in men to decrease
onset of action and a much longer half-life than finasteride. It is excessive sexual drive and are being studied in other conditions
approved for treatment of benign prostatic hyperplasia at a dosage in which the reduction of androgenic effects would be useful.
of 0.5 mg daily. These drugs are not approved for use in women Cyproterone acetate in a dosage of 2 mg/d administered con-
or children, although finasteride has been used successfully in the currently with an estrogen is used in the treatment of hirsutism
treatment of hirsutism in women and is approved for treatment of in women, doubling as a contraceptive pill; it has orphan drug
early male pattern baldness in men (1 mg/d). status in the United States.