Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

Androgens should not be administered to male patients with carcinoma of the prostate or breast. Until more is known about the effects of these hormones on the central nervous system in developing children, they should be avoided in infants and young children.

Special caution is required in giving these drugs to children to produce a growth spurt. In most patients, the use of somatotropin is more appropriate (Chapter 37: Hypothalamic & Pituitary Hormones).

Care should be exercised in the administration of these drugs to patients with renal or cardiac disease predisposed to edema. If sodium and water retention occurs, it will respond to diuretic therapy.

Methyltestosterone therapy is associated with creatinuria, but the significance of this finding is not known.

Caution: Several cases of hepatocellular carcinoma have been reported in patients with aplastic anemia treated with androgen anabolic therapy. Colony-stimulating factors (Chapter 33: Agents Used in Anemias; Hematopoietic Growth Factors) should be used instead.

Androgen Suppression & Antiandrogens

Androgen Suppression

The treatment of advanced prostatic carcinoma often requires orchiectomy or large doses of estrogens to reduce available endogenous androgen. The psychologic effects of the former and gynecomastia produced by the latter make these approaches undesirable. As noted in Chapter 37: Hypothalamic & Pituitary Hormones, the gonadotropin-releasing hormone analogs such as goserelin, nafarelin, buserelin, and leuprolide acetate produce gonadal suppression when blood levels are continuous rather than pulsatile (see Chapter 37: Hypothalamic & Pituitary Hormones and Figure 40–5). Leuprolide acetate is injected subcutaneously daily in doses of 1 mg (or depot leuprolide is given once every month or every 3 months) for the treatment of prostatic carcinoma. Goserelin is administered once every 4 weeks as a subcutaneous slow-release injection. Although testosterone levels fall to 10% of their initial values after a month with either of these drugs, they increase significantly in the beginning. This increase is usually associated with a flare of tumor activity and an increase in symptoms. The combination of a GnRH agonist and flutamide, an androgen antagonist (or equivalent, see below), can prevent the initial stimulation and provide a more effective inhibition of androgenic activity.

Figure 40–5.

Control of androgen secretion and activity and some sites of action of antiandrogens. (1), competitive inhibition of GnRH receptors; (2), stimulation (+, pulsatile administration) or inhibition via desensitization of GnRH receptors (–, continuous administration); (3), decreased synthesis of testosterone in the testis; (4), decreased synthesis of dihydrotestosterone by inhibition

of 5-reductase; (5), competition for binding to cytosol androgen receptors.

GnRH antagonists have also been under study, since they would have the advantage of eliminating the surge of androgen secretion seen at the beginning of GnRH analog therapy. Most of the compounds studied have the capacity to release histamine and are unsuitable for use. However, newer agents with less histamine-releasing activity are being studied.

Antiandrogens

The potential usefulness of antiandrogens for the treatment of patients producing excessive amounts of testosterone has led to the search for effective drugs that can be used for this purpose. Several approaches to the problem, especially inhibition of synthesis and receptor antagonism, have met with some success.

Steroid Synthesis Inhibitors

Ketoconazole, used primarily for the treatment of fungal disease, is an inhibitor of adrenal and gonadal steroid synthesis, as described in Chapter 39: Adrenocorticosteroids & Adrenocortical Antagonists. It does not affect ovarian aromatase, but it reduces human placental aromatase activity. It displaces estradiol and dihydrotestosterone from sex hormone-binding protein in vitro and increases the estradiol:testosterone ratio in plasma in vivo by a different mechanism. However, it does not appear to be clinically useful in women with increased androgens because of the toxicity associated with prolonged use of the 400–800 mg/d required. The drug has also been used experimentally to treat prostatic carcinoma, but the results have not been encouraging. Men treated with ketoconazole often develop reversible gynecomastia during therapy; this may be due to the demonstrated increase in the estradiol:testosterone ratio.

Conversion of Steroid Precursors to Androgens

Several compounds have been developed that inhibit the 17-hydroxylation of progesterone or pregnenolone, thereby preventing the action of the side chain-splitting enzyme and the further transformation of these steroid precursors to active androgens. A few of these compounds have been tested clinically but have been too toxic for prolonged use.

Since dihydrotestosterone—not testosterone—appears to be the essential androgen in the prostate, androgen effects in this and similar dihydrotestosterone-dependent tissues can be reduced by an inhibitor of 5-reductase (Figure 40–5). Finasteride, a steroid-like inhibitor of this enzyme, is orally active and produces a reduction in dihydrotestosterone levels within 8 hours after administration that lasts for about 24 hours. The half-life is about 8 hours (longer in elderly individuals). Forty to 50 percent of the dose is metabolized; more than half is excreted in the feces. Finasteride has been reported to be moderately effective in reducing prostate size in men with benign prostatic hyperplasia and is approved for this use in the USA. The dosage is 5 mg/d. Its use in advanced prostatic carcinoma is under study. The drug is not approved for use in women or children, though it has been used successfully in the treatment of hirsutism in women and early male pattern baldness in men (1 mg/d).

Receptor Inhibitors

Cyproterone and cyproterone acetate are effective antiandrogens that inhibit the action of androgens at the target organ. The acetate form has a marked progestational effect that suppresses the feedback enhancement of LH and FSH, leading to a more effective antiandrogen effect. These compounds have been used in women for the treatment of hirsutism and in men to decrease excessive sexual drive and are being studied in other conditions in which the reduction of androgenic effects would be useful. Cyproterone acetate in a dosage of 2 mg/d administered concurrently with an estrogen is used in the treatment of hirsutism in women, doubling as a contraceptive pill; it has orphan drug status in the USA.

Flutamide, a substituted anilide, is a potent antiandrogen that has been used in the treatment of prostatic carcinoma. Though not a steroid, it behaves like a competitive antagonist at the androgen receptor. It is rapidly metabolized in humans. It frequently causes mild gynecomastia (probably by increasing testicular estrogen production) and occasionally causes mild reversible hepatic toxicity. Administration of this compound causes some improvement in most patients who have not had prior endocrine therapy. Preliminary studies indicate that flutamide is also useful in the management of excess androgen effect in women.

Bicalutamide and nilutamide are potent orally active antiandrogens that can be administered as a single daily dose and are used in patients with metastatic prostate carcinoma. Studies in patients with carcinoma of the prostate indicate that they are well tolerated. Bicalutamide is recommended for use in combination with a GnRH analog (to reduce tumor flare) and may have fewer gastrointestinal side effects than flutamide. A dosage of 150–200 mg/d (when used alone) is required to reduce prostate-specific antigen levels to those achieved by castration, but, in combination with a GnRH analog, 50 mg/d may be adequate. Nilutamide is approved for use following surgical castration in a dosage of 300 mg/d for 30 days followed by 150 mg/d.

Spironolactone, a competitive inhibitor of aldosterone (see Chapter 15: Diuretic Agents), also competes with dihydrotestosterone for the androgen receptors in target tissues. It also reduces 17-

hydroxylase activity, lowering plasma levels of testosterone and androstenedione. It is used in dosages of 50–200 mg/d for the treatment of hirsutism in women and appears to be as effective as finasteride, flutamide, or cyproterone in this condition.

Chemical Contraception in Men

Although many studies have been conducted, an effective oral contraceptive for men has not yet been found. For example, various androgens, including testosterone and testosterone enanthate, in a dosage of 400 mg per month, produced azoospermia in less than half the men treated. Minor adverse reactions, including gynecomastia and acne, were encountered. Testosterone in combination with danazol was well tolerated but no more effective than testosterone alone. Androgens in combination with a progestin such as medroxyprogesterone acetate were no more effective. However, preliminary studies indicate that the intramuscular administration of 100 mg of testosterone enanthate weekly together with 500 mg of levonorgestrel daily orally can produce azoospermia in 94% of men.

Cyproterone acetate, a very potent progestin and antiandrogen, also produces oligospermia; however, it does not cause reliable contraception.

At present, pituitary hormones—and potent antagonist analogs of GnRH—are receiving increased attention. A GnRH antagonist in combination with testosterone has been shown to produce reversible azoospermia in nonhuman primates.

Gossypol

Extensive trials of this cottonseed derivative have been conducted in China. This compound destroys elements of the seminiferous epithelium but does not alter the endocrine function of the testis in a major fashion.

In Chinese studies, large numbers of men were treated with 20 mg/d of gossypol or gossypol acetic acid for 2 months, followed by a maintenance dosage of 60 mg/wk. On this regimen, 99% of men developed sperm counts below 4 million/mL. Preliminary data indicate that recovery (return of normal sperm count) following discontinuance of gossypol administration is more apt to occur in men whose counts do not fall to extremely low levels and when administration is not continued for more than 2 years. Hypokalemia is the major adverse effect and may lead to transient paralysis. The drug has also been tried as an intravaginal spermicide contraceptive.

Katzung PHARMACOLOGY, 9e > Section VII. Endocrine Drugs > Chapter 40. The Gonadal Hormones & Inhibitors >

Preparations Available1

Estrogens

Conjugated estrogens (Premarin)

Oral: 0.3, 0.625, 0.9, 1.25, 2.5 mg tablets

Parenteral: 25 mg/5 mL for IM, IV injection

Vaginal: 0.625 mg/g cream base

Dienestrol (Ortho Dienestrol, DV)

Vaginal: 10 mg/g cream

Diethylstilbestrol diphosphate (Stilphostrol)

Oral: 50 mg tablets

Parenteral: 50 mg/mL injection

Esterified estrogens (Menest, Estratab)

Oral: 0.3, 0.625, 1.25, 2.5 mg tablets

Estradiol cypionate in oil (generic, Depo-Estradiol Cypionate)

Parenteral: 5 mg/mL for IM injection

Estradiol (generic, Estrace)

Oral: 0.5, 1, 2 mg tablets

Vaginal: 0.1 mg/g cream

Estradiol transdermal (Estraderm, others)

Transdermal: patches with 0.025, 0.0375, 0.05, 0.075, 0.1 mg/d release rates

Estradiol valerate in oil (generic)

Parenteral: 10, 20, 40 mg/mL for IM injection

Estrone aqueous suspension (generic, Kestrone 5)

Parenteral: 5 mg/mL for injection

Estropipate (generic, Ogen)

Oral: 0.625, 1.25, 2.5, 5 mg tablets

Vaginal: 1.5 mg/g cream base

Ethinyl estradiol (Estinyl)

Oral: 0.02, 0.05, 0.5 mg tablets

Progestins

Hydroxyprogesterone caproate (generic, Hylutin) Parenteral: 125, 250 mg/mL for IM injection

Levonorgestrel (Norplant)

Kit for subcutaneous implant: 6 capsules of 36 mg each

Medroxyprogesterone acetate (generic, Provera) Oral: 2.5, 5, 10 mg tablets

Parenteral (Depo-Provera): 150, 400 mg/mL for IM injection

Megestrol acetate (generic, Megace)

Oral: 20, 40 mg tablets; 40 mg/mL suspension

Norethindrone acetate (generic, Aygestin)

Oral: 5 mg tablets

Norgestrel (Ovrette) (See also Table 40–3)

Oral: 0.075 mg tablets

Progesterone (generic)

Oral: 100 mg capsules

Topical: 8% vaginal gel

Parenteral: 50 mg/mL in oil for IM injection

Androgens & Anabolic Steroids

Fluoxymesterone (generic, Halotestin)

Oral: 2, 5, 10 mg tablets

Methyltestosterone (generic)

Oral: 10, 25 mg tablets; 10 mg capsules; 10 mg buccal tablets Parenteral: 200 mg/mL injection

Nandrolone decanoate (Deca-Durabolin, others) Parenteral: 100, 200 mg/mL in oil for injection

Oxandrolone (Oxandrin)

Oral: 2.5 mg tablets

Oxymetholone (Androl-50)

Oral: 50 mg tablets

Stanozolol (Winstrol)

Oral: 2 mg tablets

Testolactone (Teslac)

Oral: 50 mg tablets

Testosterone aqueous (generic, others)

Parenteral: 25, 50, 100 mg/mL suspension for IM injection

Testosterone cypionate in oil (generic, others) Parenteral: 100, 200 mg/mL for IM injection

Testosterone enanthate in oil (generic)

Parenteral: 200 mg/mL for IM injection

Testosterone propionate in oil (generic, Testex) Parenteral: 100 mg/mL for IM injection

Testosterone transdermal system

Patch (Testoderm): 4, 5, 6 mg/24 h release rate Patch (Androderm): 2.5, 5 mg/24 h release rate

Gel (Androgel): 25, 50 mg total

Testosterone pellets (Testopel)

Parenteral: 75 mg/pellet for parenteral injection (not IV) Antagonists & Inhibitors

(See Also Chapter 37: Hypothalamic & Pituitary Hormones)

Anastrozole (Arimidex)

Oral: 1 mg tablets

Bicalutamide (Casodex)

Oral: 50 mg tablets

Clomiphene (generic, Clomid, Serophene, Milophene) Oral: 50 mg tablets

Danazol (generic, Danocrine)

Oral: 50, 100, 200 mg capsules

Dutasteride (Avodart)

Oral: 0.5 mg tablets

Exemestane (Aromasin)

Oral: 25 mg tablets

Finasteride

Oral: 1 mg tablets (Propecia); 5 mg tablets (Proscar)

Flutamide (Eulexin)

Oral: 125 mg capsules

Fulvestrant (Faslodex)

Parenteral: 50 mg/mL for IM injection

Letrozole (Femara)

Oral: 2.5 mg tablets

Mifepristone (Mifeprex)

Oral: 200 mg tablets

Nilutamide (Nilandron)

Oral: 50, 150 mg tablets

Raloxifene (Evista)

Oral: 60 mg tablets

Tamoxifen (generic, Nolvadex)

Oral: 10, 20 mg tablets

Toremifene (Fareston)

Oral: 60 mg tablets

1 Oral contraceptives are listed in Table 40–3.

Chapter 41. Pancreatic Hormones & Antidiabetic Drugs

Katzung PHARMACOLOGY, 9e > Section VII. Endocrine Drugs > Chapter 41. Pancreatic Hormones & Antidiabetic Drugs >

The Endocrine Pancreas

* Deceased.

The endocrine pancreas in the adult human consists of approximately 1 million islets of Langerhans interspersed throughout the pancreatic gland. Within the islets, at least four hormone-producing cells are present (Table 41–1). Their hormone products include insulin, the storage and anabolic hormone of the body; islet amyloid polypeptide (IAPP, or amylin), whose metabolic function remains undefined; glucagon, the hyperglycemic factor that mobilizes glycogen stores; somatostatin, a universal inhibitor of secretory cells; and pancreatic peptide, a small protein that facilitates digestive processes by a mechanism not yet clarified.

Table 41–1. Pancreatic Islet Cells and Their Secretory Products.