Dermatologic Pharmacology: Retinoids, Topicals & Skin Biologics
Retinoids, topicals, and targeted skin drugs — each mechanism and its classic catch
Retinoids
Isotretinoin. Oral 13-cis-retinoic acid, a vitamin A derivative acting through nuclear retinoic acid receptors, triggers sebocyte apoptosis, shrinking sebaceous glands and sharply cutting sebum. It also normalizes follicular keratinization and indirectly reduces Cutibacterium acnes. It is reserved for severe nodulocystic or scarring acne and acne that fails oral antibiotics; a 4–6-month course often brings lasting remission.
Teratogenicity. Retinoids disrupt cranial neural crest development: microtia or anotia, cleft palate, conotruncal heart defects, thymic hypoplasia, hydrocephalus, and frequent miscarriage. The iPLEDGE program requires two contraceptive methods from 1 month before until 1 month after therapy, two negative pregnancy tests before the first dose, monthly tests with 30-day prescriptions, and tests at the end of treatment and 1 month after stopping; blood donation is barred during and for a month after treatment.
Other adverse effects. Most mirror hypervitaminosis A: nearly universal cheilitis and dry skin, hypertriglyceridemia (which can precipitate pancreatitis), elevated transaminases, myalgias, reduced night vision, and mood changes that warrant monitoring. Lipids and liver enzymes are followed, and vitamin A supplements are avoided.
Isotretinoin plus a tetracycline raises the risk of idiopathic intracranial hypertension (headache, papilledema); never prescribe them together.
Topical retinoids and acitretin. Tretinoin (all-trans retinoic acid) and adapalene (RAR-β/γ selective, sold over the counter) normalize follicular keratinization and are first-line comedolytics; they irritate and photosensitize, so they are applied at night. Oral acitretin treats pustular, palmoplantar, and erythrodermic psoriasis. Alcohol re-esterifies it to etretinate, which is stored in fat for years.
| Feature | Isotretinoin | Acitretin |
|---|---|---|
| Main use | Severe nodulocystic acne | Pustular, palmoplantar, erythrodermic psoriasis |
| Key toxicities | Cheilitis, ↑ triglycerides, ↑ transaminases, pseudotumor with tetracyclines | Mucocutaneous dryness, ↑ lipids, hepatotoxicity, hair loss |
| Contraception after stopping | 1 month | 3 years (etretinate) |
Topical Anti-inflammatory and Antiproliferative Agents
Corticosteroids. Seven potency classes run from superpotent clobetasol propionate (class 1) to hydrocortisone (class 7). Potent agents are used for short courses (about 2 weeks) on thick plaques, palms, and soles; low-potency agents such as hydrocortisone or desonide suit the face, eyelids, groin, skin folds, and infants, where absorption is high. Local effects include atrophy, striae, telangiectasia, perioral dermatitis, and acneiform eruptions; occlusion or extensive use can suppress the HPA axis.
Calcineurin inhibitors. Tacrolimus ointment and pimecrolimus cream bind FKBP12, and the complex inhibits calcineurin, preventing NFAT-driven IL-2 transcription and T-cell activation. They do not thin the skin, so they are steroid-sparing for atopic dermatitis of the face, eyelids, and folds. Application-site burning is common, and a boxed warning cites a theoretical malignancy risk.
Calcipotriene and PUVA. Calcipotriene (calcipotriol), a vitamin D analog, binds the vitamin D receptor to slow keratinocyte proliferation and promote differentiation in psoriasis; it is often combined with a steroid, and overuse can cause hypercalcemia. In PUVA, oral psoralen (methoxsalen) intercalates into DNA and forms cross-links when UVA activates it, treating psoriasis, vitiligo, and mycosis fungoides at the cost of cataracts (eye protection required), photoaging, and dose-dependent cutaneous squamous cell carcinoma and melanoma. Narrowband UVB, which needs no psoralen, has largely replaced it.
Imiquimod and 5-fluorouracil. Imiquimod is a TLR7 agonist that induces IFN-α, TNF-α, and IL-12, provoking a local immune attack on anogenital warts, actinic keratoses, and superficial basal cell carcinoma. Topical 5-fluorouracil is converted to FdUMP, which inhibits thymidylate synthase and destroys dividing dysplastic keratinocytes, making it field therapy for actinic keratoses. Both cause brisk redness, erosion, and crusting.
Acne and Hair Agents
Benzoyl peroxide and azelaic acid. Benzoyl peroxide releases oxygen radicals that kill C. acnes without inducing resistance and is mildly comedolytic, so it accompanies any antibiotic regimen; it bleaches hair and fabric. Azelaic acid is antibacterial and comedolytic and inhibits tyrosinase, treating acne, rosacea, and post-inflammatory hyperpigmentation or melasma; it is safe in pregnancy.
Oral acne agents. Doxycycline blocks the 30S ribosome and also inhibits matrix metalloproteinases and neutrophil chemotaxis. It treats inflammatory acne and rosacea but causes photosensitivity, pill esophagitis, and tooth discoloration (avoided under age 8 and in pregnancy); courses are limited to about 3–4 months alongside benzoyl peroxide. Minocycline instead causes blue-gray pigmentation, vertigo, and drug-induced lupus or autoimmune hepatitis. Spironolactone blocks androgen receptors to treat hormonal acne and hirsutism in women; it can cause hyperkalemia, menstrual irregularity, and breast tenderness and is avoided in pregnancy because it can feminize a male fetus.
Minoxidil. This ATP-sensitive K+ channel opener dilates arterioles and prolongs the anagen phase. Topical or low-dose oral minoxidil treats androgenetic alopecia and causes hypertrichosis; as a full-dose oral antihypertensive it causes reflex tachycardia, fluid retention, and pericardial effusion, so it is paired with a β-blocker and a diuretic.
Targeted Biologics and JAK Inhibitors
Dupilumab. This antibody against IL-4 receptor α blocks signaling by both IL-4 and IL-13, the core Th2 cytokines. It treats moderate-to-severe atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyps; conjunctivitis and keratitis are its signature adverse effects.
Omalizumab. This anti-IgE antibody binds free IgE so it cannot load FcεRI on mast cells and basophils. It treats chronic spontaneous urticaria that persists despite high-dose H1 antihistamines, as well as allergic asthma; anaphylaxis is rare.
JAK inhibitors. In alopecia areata and vitiligo, CD8+ T cells attack follicles or melanocytes under IFN-γ and IL-15 signals that run through JAKs. Oral baricitinib and ritlecitinib treat severe alopecia areata, and topical ruxolitinib cream treats nonsegmental vitiligo; the class carries warnings for serious infection, zoster, and thrombosis.