News, Views & Reviews. Repurposing of Drugs for Dermatologic Applications: Five Key Medications

well as generalized pruritus and chronic urticaria.²⁶ In addition to its antipruritic effects, doxepin possesses sedative activity that proves useful in alleviating these conditions. The overlap between dermatology and psychiatry is not insignificant: the estimated prevalence of psychiatric comorbidity in dermatologic outpatients exceeds 25%.²⁷ As many patients will balk at a referral to psychiatry,²⁸ dermatologists should be comfortable using drugs like doxepin to provide relief to patients suffering from psychocutaneous conditions leading to chronic pruritus.

Doxepin therapy starts at 10-25 mg nightly. Antipruritic and sedative effects begin shortly after treatment initiation, even at low doses; depending on patient response, the dose can be increased gradually by 10-25 mg every 2 weeks until a therapeutic maintenance dose providing adequate relief of symptoms is reached (usually 75-300 mg nightly). Complete therapeutic effect, including antidepressant activity, typically takes at least 2 weeks to emerge.²⁹ Potential adverse events with doxepin use relate to its off-target receptor effects. These include cardiotoxicity, orthostatic hypotension, increased seizure risk, excessive sedation, weight gain, confusion and delirium (especially in the elderly), dry mouth, blurred vision, acute glaucoma crisis, constipation, urinary retention, and sexual dysfunction.^26,29

Use of spironolactone began in 1954 as treatment for hyperaldosteronism. ³⁰ Since that time, it has been employed in the settings of hypertension (as a potassium-sparing diuretic), heart failure, ascites secondary to hepatic disease, and hypokalemia. In 1969, investigators discovered anti-androgenic activity of spironolactone in rats, thereby ushering in future dermatologic applications.³¹

As an anti-androgenic agent, spironolactone acts both centrally and peripherally, decreasing production of androgens as well as blocking their effects on target tissues. Specifically, it inhibits steroidogenesis via selective destruction of microsomal cytochrome P450 in the testes and adrenal glands, and acts competitively to block cytosolic receptors on target organs.³²

Today spironolactone is used off-label in dermatology to manage several androgen-dependent conditions. It is beneficial for acne because both increased androgen levels and heightened sensitivity of sebaceous glands to androgens contribute to disease through increased sebum production. Spironolactone has proven successful as monotherapy in women with cyclic or lateonset acne, and also serves as an adjunct to antibiotics when oral retinoids cannot be used. The dose range for acne is 50-200 mg daily.³³ In the setting of hirsutism, both central overproduction and peripheral sensitization to androgens leads to a shift from fine, non-pigmented vellus hair to thicker, pigmented, coarse terminal hair. In addition to seeking the underlying cause of the hirsutism (polycystic ovarian syndrome, idiopathic, neoplasm, etc.), daily administration of 50-200 mg of spironolactone has demonstrated efficacy.^32,33 Oral contraceptives may act synergistically to decrease unwanted hair.³⁴ Lastly, although scalp hair growth is not greatly androgen sensitive, spironolactone (50-200 mg daily) improves female pattern hair loss.^32,33 Patients may benefit from addition of 5% minoxidil to their treatment regimen.³⁵

Spironolactone’s anti-androgenic activity limits use in male patients due to the potential for development of gynecomastia and sexual side effects. In females it may cause breast enlargement and/or tenderness and menstrual changes, including postmenopausal bleeding. Orthostatic hypotension is a concern, especially in patients taking additional blood pressure medications. Severe hyperkalemia is rare in patients with normal renal function and those who are not simultaneously taking other potassium-elevating drugs (e.g., angiotensin-converting enzyme inhibitors). Mild gastrointestinal and neurologic side effects are common. Spironolactone is contraindicated in pregnancy owing to potential teratogenicity.^32,33

Following their discovery as natural fermentation products of Streptomyces aureofaciens, the tetracyclines were introduced into clinical medicine in the early 1950s.³⁶ Tetracyclines exert bacteriostatic activity by binding to the 30S subunit of the bacterial ribosome, thereby inhibiting bacterial protein synthesis. However, over 30 years ago investigators began to recognize that this class of antibiotics could therapeutically modulate other processes, including angiogenesis, cellular proliferation, inflammation, and immunity.^37,38 These numerous desirable properties have since been exploited and the tetracyclines have found widespread use in many dermatologic conditions.^37,39

Tetracyclines are commonly used in the treatment of acne, and it is now believed that tetracycline, minocycline, and doxycycline display antimicrobial, anti-inflammatory, and fatty acid/lipase-related activities to improve this condition.^40,41 For rosacea and related disorders, both anti-inflammatory and antiangiogenic effects of tetracyclines may affect disease course.⁴² Tetracycline and minocycline, alone or alongside nicotinamide, show efficacy in the setting of bullous dermatoses, specifically those involving the dermoepidermal junction, and may serve as alternatives to systemic corticosteroids.^37,39 For cutaneous sarcoidosis, 8 of 12 patients administered minocycline 200 mg daily for 12 months exhibited complete clearing of lesions, and 2 patients had partial responses.⁴³ COL-3, a chemically modified tetracycline, was both active and well-tolerated in a clinical trial investigating its use in AIDS-related Kaposi’s sarcoma.⁴⁴ Tetracyclines are also reported to be helpful in a number of neutrophilic dermatoses, such as Sweet’s syndrome and pyoderma gangrenosum; however, the level of evidence is limited and the observed effects need further characterization.^37,39

Although generally nontoxic and well-tolerated, significant adverse effects may occur with administration of tetracyclines. These include photosensitivity (especially with doxycycline), skin and nail discoloration (minocycline), gastrointestinal upset, vaginal candidiasis, and dizziness (minocycline). Less commonly, minocycline has been associated with more serious complications such as hypersensitivity syndrome reaction, serum sickness-like reaction, and immunologic conditions