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P A R T 7  Drugs acting on the reproductive system

O estrogen receptor modulators Two available oestrogen receptor modulators are ralox- ifene ( Evista ) and toremifene ( Fareston ). The long-term effects of these two drugs are not yet known. Therapeutic actions and indications Oestrogen receptor modulators are not hormones but affect specific oestrogen receptor sites, stimulating some and blocking others. They were developed to produce some of the positive effects of oestrogen replacement while limiting the adverse effects. See Table 40.1 for usual indications for these drugs. Toremifene is dis- cussed in greater detail in Chapter 14, which discusses antineoplastic agents. Pharmacokinetics Administered orally, raloxifene is well absorbed from the GI tract and is metabolised in the liver. Excretion occurs through the faeces. It is known to cross the placenta and enter into breast milk. Contraindications and cautions Raloxifene is contraindicated in the presence of any known allergy to raloxifene to avoid hypersensitiv- ity reactions and during pregnancy and breastfeeding because of potential effects on the fetus or neonate. Caution should be used in people with a history of venous thrombosis or smoking because of an increased risk of blood clot formation if smoking and oestrogen are combined. Adverse effects Raloxifene has been associated with GI upset, nausea and vomiting. Changes in fluid balance may also cause headache, dizziness, visual changes and mental changes. Hot flushes, skin rash, oedema and vaginal bleeding may occur secondary to specific oestrogen receptor stimulation. Venous thromboembolism is a potentially dangerous side effect that has been reported. Clinically important drug–drug interactions Cholestyramine reduces the absorption of ralox- ifene. Highly protein-bound drugs, such as diazepam ( Valium ), ibuprofen ( Brufen ), indomethacin ( Indocin ) and naproxen ( Naprosyn ), may interfere with binding sites. Warfarin taken with raloxifene may decrease the prothrombin time (PT); people using this combination must be monitored closely.

Prototype summary: Oestradiol Indications: Palliation of moderate to severe vasomotor symptoms associated with menopause; prevention of postmenopausal osteoporosis; treatment of female hypogonadism, female castration, female ovarian failure; palliation of inoperable and progressing breast cancer and inoperable prostatic cancer. Actions: The most potent endogenous female sex hormone, responsible for oestrogen effects on the body. Pharmacokinetics: Route Onset Peak Duration PO Slow Days Unknown Topical preparations are not generally absorbed systemically. T 1/2 : Not known; with hepatic metabolism and excretion in the urine. Adverse effects: Corneal changes, photosensitivity, peripheral oedema, chloasma, hepatic adenoma, nausea, vomiting, abdominal cramps, bloating, breakthrough bleeding, change in menstrual flow, dysmenorrhoea, premenstrual-like syndrome. Prototype summary: Norethisterone Indications: Treatment of amenorrhoea, abnormal uterine bleeding due to hormonal imbalance; treatment of endometriosis; component of some hormonal contraceptives. Actions: Progesterone derivative that transforms the proliferative endometrium into a secretory endometrium; inhibits the secretion of pituitary FSH and LH, which prevents ovulation; inhibits uterine contractions. Pharmacokinetics: Route Onset Peak Duration PO Varies Unknown Unknown T 1/2 : Unknown, with hepatic metabolism and excretion in the faeces and urine. Adverse effects: Venous thromboembolism, loss of vision, diplopia, migraine headache, rash, acne, chloasma, alopecia, breakthrough bleeding, spotting, amenorrhoea, fluid retention, oedema, increase in weight.