INTRODUCTION

Spironolactone is a potassium-sparing diuretic and selective aldosterone blocker used off-label in dermatology for treatment of acne and hirsutism in women.

HISTORY

Spironolactone received initial approval by the Food and Drug Administration (FDA) in 1960s. The effects of circulating androgens on the skin and hair are well known and studied (Choudhry, Hodgins, Van der Kwast, Brinkmann, & Boersma, 1992; Stewart, Downing, Cook, Hansen, & Strauss, 1992; Thiboutot, Gilliland, Light, & Lookingbill, 1999). It was first investigated as a treatment for acne because of its antiandrogen properties in a study published in the British Journal of Dermatology in 1984 (Goodfellow et al., 1984). Subsequent studies have supported its effectiveness in the treatment of acne and hirsutism, but not for hair loss (Burke & Cunliffe, 1985; Moghetti et al., 2000; Muhlemann, Carter, Cream, & Wise, 1986). Androgen hormones are produced in the adrenal glands and the gonads, but more potent forms of androgen are produced in the peripheral tissues from steroid precursors.

MECHANISM OF ACTION

When used for the treatment of acne and hirsutism, the mechanism of action of spironolactone is not completely understood. Spironolactone seems to affect androgen receptors in the sebaceous glands causing reduced sebum production and thereby causing an improvement in acne symptoms. Spironolactone also blocks the conversion of weaker androgens to more potent androgens in the peripheral tissues, which may also explain its benefit when treating hirsutism (George, Clarke, & Thiboutot, 2008).

AVAILABLE FORMS

Aldactone is the original branded preparation and is FDA approved for the management of primary aldosteronism, edematous conditions (e.g., congestive heart failure, cirrhosis, etc.), hypertension, and hypokalemia (Pfizer, 2008).

MANUFACTURER

Aldactone is made by Pfizer (New York, NY). However, this medication is available generically via multiple manufacturers and is very inexpensive for all patients with and without insurance (Pfizer, 2008).

PHARMACOLOGIC CLASS

Potassium-sparing diuretic and selective aldosterone blocker.

DERMATOLOGIC USES AND INDICATIONS

Spironolactone is not FDA approved for the treatment of acne or hirsutism. It should only be considered for the treatment of acne or hirsutism in select women when androgen sensitivity is suspected to be contributory or for women in which other acne treatments have been ineffective or insufficient. It is not indicated for women contemplating pregnancy, as the drug can cause feminization of the male fetus. Many dermatologist recommend prescribing an oral contraceptive with spironolactone to prevent pregnancy and achieve positive results at a lower dose (George et al., 2008; Thiboutot & Chen, 2003).

The first studies using spironolactone for its antiandrogen properties showed clinical improvement in 50% to 100% of women treated with spironolactone (Burke & Cunliffe, 1985; Goodfellow et al., 1984; Muhlemann et al., 1986). A study by Shaw (2000) examining treatment of women with spironolactone alone or in combination showed that 33% of women cleared their acne completely with spironolactone therapy whereas only 7% showed no improvement. Other studies have shown spironolactone to have a greater effect on hirsutism than finasteride (Erenus, Yucelten, Durmusoglu, & Gurbuz, 2000).

DOSAGES

The dosage of spironolactone for acne is 25-200 mg/day in one to two divided doses. A study that used 50 mg spironolactone twice a day on Days 5 through 21 of women's menstrual cycle had a high rate of success with low incidence of side effects (Harper, 2006).

The dosage of spironolactone for hirsutism is 50-200 mg/day in one to two divided doses (Harper, 2006).

CONTRAINDICATIONS

Spironolactone is contraindicated in patients with anuria, acute or chronic renal insufficiency, or hyperkalemia and should be used with caution in patients experiencing conditions that predispose them to electrolyte imbalances (e.g., excessive vomiting, severe hepatic impairment, and severe heart failure; Pfizer, 2008).

PREGNANCY

Spironolactone is a Category C medication, as fetal abnormalities have been noted in animal studies. It may be indicated in pregnancy when treating a primary medical indication, but its use is inappropriate for the management of acne or hirsutism in pregnant patients because of its possible effects on the sexual development of the fetus (Pfizer, 2008).

DRUG INTERACTIONS

Spironolactone should be used with caution in patients currently taking Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, aliskiren, cyclosporine, and Non-steroidal anti-inflammatory drugs (NSAIDs [e.g., ibuprofen]) because of the potential to reduce renal function and cause hyperkalemia. Spironolactone can also increase the blood levels of lithium, digoxin, and sotalol, increasing the risks for adverse effects and toxicity, as these agents have narrow blood level ranges for therapeutic use. Spironolactone has also shown to decrease the effect of warfarin, and patients on concomitant therapy may require more frequent monitoring of their coagulant response time (international normalized ratio; Pfizer, 2008).

ADVERSE REACTIONS

Menstrual irregularities, including intermenstrual spotting and increased menstrual flow, can occur during spironolactone therapy and may be dose related. Breast tenderness can also occur. Patients may experience symptoms of volume contraction such as hypotension, orthostasis, and exercise intolerance from the diuresis, all of which may necessitate medication discontinuation. Other common reactions patients may experience include rash, nausea, diarrhea, somnolence, and headache. Electrolyte imbalances can occur during therapy as well, most prominently hyperkalemia, hypomagnesaemia, and hyponatremia. These effects, however, are rare in healthy young women, and routine electrolyte measurement is discretionary, but it is recommended for older women with other medical problems or women concomitantly taking the oral contraceptive containing drosperinone (George et al., 2008). Typically, electrolytes should be monitored in 2-4 weeks after each dose titration and then at least annually during chronic therapy. Although most women do experience some degree of side effects, they are rarely significant enough to warrant discontinuing treatment (Harper, 2006).

Spironolactone carries an FDA black box warning concerning tumorigenic potential in chronic toxicity studies in rats. However, the clinical applicability of the animal research is questionable. According to the Centers for Disease Control, the average weight of an American woman is approximately 165 pounds (75 kg) (McDowell et al., 2008). The studies that support the tumorigenic potential of spironolactone were conducted in rats, each of which was given 10-500 mg/kg daily for 1-2 years. At the lowest dose of 10 mg/kg daily, this would be the equivalent of giving 750 mg/day to the average woman. Although such a dose seems improbable, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines require testing doses to be sufficiently higher than human doses to provide a safety window for therapeutic use. These doses are considered the maximum tolerated dose for toxicity and are predicted to produce a minimum toxicity effect over the course of the study (McDowell et al., 1997). However, the applicability of animal studies to humans is difficult and is left to individual clinical interpretation. It is also important to note that, as of July 2011, Pfizer has had no record of postmarketing reports concerning tumors or cancers with a definitive causal relationship to spironolactone use.

IMPLICATIONS FOR DERMATOLOGY NURSES

The prescriber should be aware of the teratogenicity potential of spironolactone and should counsel patients in whom pregnancy remains a possibility. For those women, oral contraception should be considered, and the patient should be counseled accordingly. For those who choose not to use oral contraceptives, barrier or other methods of contraception should be encouraged.

Blood pressure, symptoms of orthostasis, changes in menstrual patterns, and symptoms of breast tenderness should be monitored routinely at office visits during therapy. Quantitative assessment of circulating sex hormones is unnecessary unless a primary hyperandrogenism is suspected, which includes women who experience severe and sudden onset of acne, hirsutism, and irregular menses (Shaw, 2000).

Electrolytes should be monitored in select patients. A complete medication list must be elicited from the patient, including use of over-the-counter medications, to determine any potential interactions that may require special monitoring or counseling.

PATIENT INSTRUCTIONS

Patients need to be made aware of the black box warning and should be given enough objective information to make an informed decision whether spironolactone therapy is appropriate for them. Patients should plan to start the medication at a time and place when urinary frequency can be accommodated. They should be advised of the risks for hypovolemia and orthostasis and encouraged to maintain a consistent fluid intake. Although hyperkalemia is rare in young healthy women, patients should be counseled to avoid consuming large quantities of high-potassium foods and liquids, such as citrus fruits and melons as well as salt substitutes for seasoning foods. Spironolactone may be stopped at any time without any withdrawal concerns.

SUMMARY

Spironolactone is a potassium-sparing diuretic and selective aldosterone blocker that has found off-label use in dermatology for the treatment of acne and hirsutism in adult women. It is available generically and presents an attractive and inexpensive alternative to expensive proprietary medications because of its high efficacy and tolerability for use in select female patients. It has the added benefits of possibly enabling acne control with less reliance on antibiotics and may be effective in patients for whom other methods have either failed or were poorly tolerated. It can be used alone or in combination with other traditional acne medications to broaden treatment options. The dermatology nurse must be aware of the attached black box warning, the potential for teratogenicity, and the need to monitor for fluid and electrolyte imbalances and side effects.

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