Fluorouracil is a fluorinated pyrimidine antimetabolite that resembles uracil, with a fluorine atom substituted for the 5-methyl group. Its systemic pharmacology is described in Chapter 54. Fluorouracil is used topically for the treatment of multiple actinic keratoses.
Approximately 6% of a topically applied dose is absorbed—an amount insufficient to produce adverse systemic effects. Most of the absorbed drug is metabolized and excreted as carbon dioxide, urea, and α-fluoro-β-alanine. A small percentage is eliminated unchanged in the urine. Fluorouracil inhibits thymidylate synthetase activity, interfering with the synthesis of DNA and, to a lesser extent, RNA. These effects are most marked in atypical, rapidly proliferating cells.
Fluorouracil is available in multiple formulations containing 0.5%, 1%, 2%, 4%, and 5% concentrations (Carac, Efudex, Fluoroplex, Tolak). The response to treatment begins with erythema and progresses through vesiculation, erosion, superficial ulceration, necrosis, and finally reepithelialization. Fluorouracil should be continued until the inflammatory reaction reaches the stage of ulceration and necrosis, usually in 3–4 weeks, at which time treatment should be terminated. The healing process may continue for 1–2 months after therapy is discontinued. Local adverse reactions may include pain, pruritus, a burning sensation, tenderness, and residual postinflammatory hyperpigmentation. Excessive exposure to sunlight during treatment may increase the intensity of the reaction and should be avoided. Allergic contact dermatitis to fluorouracil has been reported, and its use is contraindicated in patients with known hypersensitivity.
Ingenol mebutate (Picato) is derived from the sap of the Euphorbia peplus plant and has recently been approved for the topical treatment of actinic keratoses. The mechanism by which ingenol mebutate induces keratinocyte cell death is unknown. For the treatment of actinic keratoses on the face and scalp, the 0.015% gel should be applied once daily for 3 consecutive days. For actinic keratoses on the trunk and extremities, the 0.05% gel should be applied to the affected area daily for 2 consecutive days. Local skin reactions are to be expected with crusting, swelling, vesiculation, and possible ulceration. Caution must be taken to prevent eye exposure. Patients must wash their hands well after applying the gel and avoid transfer of the drug to the periocular area during and after application.
A topical 3% gel formulation of the nonsteroidal anti-inflammatory drug diclofenac (Solaraze) has shown moderate effectiveness in the treatment of actinic keratoses. The mechanism of action is unknown. As with other NSAIDs, anaphylactoid reactions may occur with diclofenac, and it should be given with caution to patients with known aspirin hypersensitivity (see Chapter 36).
Aminolevulinic acid (ALA) is an endogenous precursor of photo-sensitizing porphyrin metabolites. When exogenous ALA is provided to the cell through topical applications, protoporphyrin IX (PpIX) accumulates in the cell. When exposed to light of appropriate wavelength and energy, the accumulated PpIX produces a photodynamic reaction resulting in the formation of cytotoxic superoxide and hydroxyl radicals. Photosensitization of actinic keratoses using ALA (Levulan Kerastick) and illumination with a blue light photodynamic therapy illuminator (BLU-U) is the basis for ALA photodynamic therapy.