Page 742 - Basic _ Clinical Pharmacology ( PDFDrive )

728 SECTION VII Endocrine Drugs

TABLE 40–2 Properties of some progestational agents.

Activities 1
Route Duration of Action Estrogenic Androgenic Antiestrogenic Antiandrogenic Anabolic
Progesterone and derivatives
Progesterone IM 1 day − − + − −
Hydroxyprogesterone IM 8–14 days sl sl − − −
caproate
Medroxyprogesterone IM, PO Tabs: 1–3 days; − + + − −
acetate injection: 4–12 weeks
Megestrol acetate PO 1–3 days − + − + −
17-Ethinyl testosterone derivatives
Dimethisterone PO 1–3 days − − sl − −
19-Nortestosterone derivatives
Desogestrel PO 1–3 days − − − − −
Norethynodrel PO 1–3 days + − − − −
Lynestrenol 2 PO 1–3 days + + − − +
Norethindrone PO 1–3 days sl + + − +
Norethindrone acetate PO 1–3 days sl + + − +
Ethynodiol diacetate PO 1–3 days sl + + − −
l-Norgestrel 2 PO 1–3 days − + + − +
1 Interpretation: + = active; – = inactive; sl = slightly active. Activities have been reported in various species using various end points and may not apply to humans.
2
Not available in USA.

synthesized in the ovary, testis, and adrenal cortex from circulating Pharmacokinetics
cholesterol. Large amounts are also synthesized and released by the Progesterone is rapidly absorbed following administration by any
placenta during pregnancy. route. Its half-life in the plasma is approximately 5 minutes, and
In the ovary, progesterone is produced primarily by the corpus
luteum. Normal males appear to secrete 1–5 mg of progesterone small amounts are stored temporarily in body fat. It is almost
completely metabolized in one passage through the liver, and for
daily, resulting in plasma levels of about 0.03 mcg/dL. The level that reason it is quite ineffective when the usual formulation is
is only slightly higher in the female during the follicular phase administered orally. However, high-dose oral micronized proges-
of the cycle, when only a few milligrams per day of progesterone terone preparations have been developed that provide adequate
are secreted. During the luteal phase, plasma levels range from progestational effect.
0.5 mcg/dL to more than 2 mcg/dL (Figure 40–1). Plasma levels In the liver, progesterone is metabolized to pregnanediol and
of progesterone are further elevated and reach their peak levels in conjugated with glucuronic acid. It is excreted into the urine
the third trimester of pregnancy.
as pregnanediol glucuronide. The amount of pregnanediol in
the urine has been used as an index of progesterone secretion.
Synthetic Progestins This measure has been very useful despite the fact that the pro-
A variety of progestational compounds have been synthesized. portion of secreted progesterone converted to this compound
Some are active when given by mouth. They are not a uniform varies from day to day and from individual to individual. In
group of compounds, and all of them differ from progesterone in addition to progesterone, 20α- and 20β-hydroxyprogesterone
one or more respects. Table 40–2 lists some of these compounds (20α- and 20β-hydroxy-4-pregnene-3-one) also are found.
and their effects. In general, the 21-carbon compounds (hydroxy- These compounds have about one-fifth the progestational
progesterone, medroxyprogesterone, megestrol, and dimethis- activity of progesterone in humans and other species. Little is
terone) are the most closely related, pharmacologically as well known of their physiologic role, but 20α-hydroxyprogesterone
as chemically, to progesterone. A new group of third-generation is produced in large amounts in some species and may be of
synthetic progestins has been introduced, principally as compo- some importance biologically.
nents of oral contraceptives. These “19-nor, 13-ethyl” steroid The usual routes of administration and durations of action of
compounds include desogestrel (Figure 40–4), gestodene, and the synthetic progestins are listed in Table 40–2. Most of these
norgestimate. They are claimed to have lower androgenic activity agents are extensively metabolized to inactive products that are
than older synthetic progestins. excreted mainly in the urine.