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P A R T 7  Drugs acting on the reproductive system

metabolism. They are excreted in the urine. Oestrogens cross the placenta and enter breast milk. Contraindications and cautions Oestrogens are contraindicated in the presence of any known allergies to oestrogens and in people with idiopathic vaginal bleeding, breast cancer, any oestrogen-dependent cancer or with a history of thromboembolic disorders, including cerebrovascu- lar accident. Heavy smokers are at increased risk of thrombus and embolus development . Oestrogens are contraindicated during pregnancy due to the risk of serious fetal defects and should be avoided during breastfeeding because of possible effects on the neonate. Oestrogens should be used cautiously in people with metabolic bone disease because of the bone-conserving effect of oestrogen, which could exacer­ bate the disease ; with renal insufficiency, which could interfere with the renal excretion of the drug and increase the risk for potential adverse effects on fluid and electro- lyte balance ; and with hepatic impairment, which could alter the metabolism of the drug and increase the risk for the adverse effects, including those on the liver and gastrointestinal tract. Adverse effects Many of the most common adverse effects associated with oestrogens involve the genitourinary (GU) tract. They include breakthrough bleeding, menstrual irregu­ larities, dysmenorrhoea, amenorrhoea and changes in libido. Other effects can result from the systemic effects of oestrogens, including fluid retention, electrolyte dis- turbances, headache, dizziness, mental changes, weight changes and oedema. GI effects are also fairly common and include nausea, vomiting, abdominal cramps and bloating and colitis. Potentially serious GI effects, including acute pancreatitis, cholestatic jaundice and hepatic adenoma, have been reported with the use of oestrogens. Clinically important drug–drug interactions If oestrogens are given in combination with drugs that enhance their hepatic metabolism (e.g. barbiturates, rifampicin, tetracyclines, phenytoin), serum oestrogen levels may decrease. Whenever a drug is added to or removed from a drug regimen that contains oestrogens, the health professional should evaluate that drug for possible interactions and consult with the prescriber for appropriate dose adjustments. Oestrogens have been associated with increased therapeutic and toxic effects of corticosteroids, so people taking both drugs should be monitored very closely.

Smoking while taking oestrogens should be strongly discouraged because the combination with nicotine increases the risk for development of thrombi and emboli. Grapefruit juice can inhibit the metabolism of oestradiols, leading to increased serum levels. People should be discouraged from drinking large quantities of grapefruit juice if they are taking oestrogens. St John’s wort can affect the metabolism of oestrogens and can make oestrogen-containing contraceptives less effective. This combination should be discouraged. Other herbal and alternative therapies used for menopausal symptoms may interact with oestrogens. Progestogens Progestogens are used as contraceptives, most effectively in combination with oestrogens (Box 40.3 lists availa- ble contraceptives). They are used to treat primary and secondary amenorrhoea and functional uterine bleeding and as part of fertility programs. Like the oestrogens, some progestogens are useful in treating specific cancers with specific receptor-site sensitivity (see Chapter 14). See Table 40.1 for usual indications for each type of progestogen. The progestogens transform the proliferative endo- metrium into a secretory endometrium, inhibit the secretion of FSH and LH, prevent follicle maturation and ovulation, inhibit uterine contractions and may have some anabolic and oestrogenic effects. When they are used as contraceptives, the exact mechanism of action is not known, but it is thought that circulating progestogens and oestrogens “trick” the hypothalamus and pituitary, and prevent the release of gonadotropin- releasing hormone (GnRH), FSH and LH, thus prevent- ing follicle development and ovulation. The low levels of these hormones do not produce a lush endometrium that is receptive to implantation, and if ovulation and fertilisation were to occur, the chances of implantation would be remote. Pharmacokinetics The progestogens are well absorbed, undergo hepatic metabolism and are excreted in the urine. They are known to cross the placenta and to enter breast milk. Like oestrogens, progestogens are available in several forms. Etonogestrel, in addition to being available as a vaginal ring, NuvaRing, is available as a subdermal implant that may be left in place for up to 3 years and then must be removed. Another implant could be placed at that time. Levonorgestrel is available in combination-form oral contraceptives or as an intrauter- ine device. It is also used for emergency contraception as the “morning after” pill ( Levonelle, Postinor ).