Keratolytic & Destructive Agents

KERATOLYTIC & DESTRUCTIVE AGENTS

SALICYLIC ACID

Salicylic acid has been extensively used in dermatologic therapy as a keratolytic agent. The mechanism by which it produces its kera-tolytic and other therapeutic effects is poorly understood. The drug may solubilize cell surface proteins that keep the stratum corneum intact, thereby resulting in desquamation of keratotic debris. Salicylic acid is keratolytic in concentrations of 3–6%. In concentrations greater than 6%, it can be destructive to tissues.

Salicylism and death have occurred following topical applica-tion. In an adult, 1 g of a topically applied 6% salicylic acid preparation will raise the serum salicylate level not more than 0.5 mg/dL of plasma; the threshold for toxicity is 30–50 mg/dL. Higher serum levels are possible in children, who are therefore at a greater risk for salicylism. In cases of severe intoxication, hemo-dialysis is the treatment of choice . It is advisable to limit both the total amount of salicylic acid applied and the frequency of application. Urticarial, anaphylactic, and erythema multiforme reactions may occur in patients who are allergic to salicylates. Topical use may be associated with local irritation, acute inflammation, and even ulceration with the use of high concentrations of salicylic acid. Particular care must be exercised when using the drug on the extremities of patients with diabetes or peripheral vascular disease.

PROPYLENE GLYCOL

Propylene glycol is used extensively in topical preparations because it is an excellent vehicle for organic compounds. It has been used alone as a keratolytic agent in 40–70% concentrations, with plas-tic occlusion, or in gel with 6% salicylic acid.

Only minimal amounts of a topically applied dose are absorbed through normal stratum corneum. Percutaneously absorbed pro-pylene glycol is oxidized by the liver to lactic acid and pyruvic acid, with subsequent utilization in general body metabolism. Approximately 12–45% of the absorbed agent is excreted unchanged in the urine.

Propylene glycol is an effective keratolytic agent for the removal of hyperkeratotic debris. It is also an effective humectant and increases the water content of the stratum corneum. The hygro-scopic characteristics of propylene glycol may help it to develop an osmotic gradient through the stratum corneum, thereby increas-ing hydration of the outermost layers by drawing water out from the inner layers of the skin.

Propylene glycol is used under polyethylene occlusion or with 6% salicylic acid for the treatment of ichthyosis, palmar and plan-tar keratodermas, psoriasis, pityriasis rubra pilaris, keratosis pilaris, and hypertrophic lichen planus.

In concentrations greater than 10%, propylene glycol may act as an irritant in some patients; those with eczematous dermatitis may be more sensitive. Allergic contact dermatitis occurs with propylene glycol, and a 4% aqueous propylene glycol solution is recommended for the purpose of patch testing.

UREA

Urea in a compatible cream vehicle or ointment base has a soft-ening and moisturizing effect on the stratum corneum. It has the ability to make creams and lotions feel less greasy, and this has been utilized in dermatologic preparations to decrease the oily feel of a preparation that otherwise might feel unpleasant. It is a white crystalline powder with a slight ammonia odor when moist.

Urea is absorbed percutaneously, although the amount absorbed is minimal. It is distributed predominantly in the extracellular space and excreted in urine. Urea is a natural product of metabo-lism, and systemic toxicities with topical application do not occur.

Urea increases the water content of the stratum corneum, pre-sumably as a result of the hygroscopic characteristics of this natu-rally occurring molecule. Urea is also keratolytic. The mechanism of action appears to involve alterations in prekeratin and keratin, leading to increased solubilization. In addition, urea may break hydrogen bonds that keep the stratum corneum intact.

As a humectant, urea is used in concentrations of 2–20% in creams and lotions. As a keratolytic agent, it is used in 20% con-centration in diseases such as ichthyosis vulgaris, hyperkeratosis of palms and soles, xerosis, and keratosis pilaris. Concentrations of 30–50% applied to the nail plate have been useful in softening the nail prior to avulsion.

PODOPHYLLUM RESIN & PODOFILOX

Podophyllum resin, an alcoholic extract of Podophyllum peltatum, commonly known as mandrake root or May apple, is used in the treatment of condyloma acuminatum and other verrucae. It is a mixture of podophyllotoxin, α and β peltatin, desoxypodophyl-lotoxin, dehydropodophyllotoxin, and other compounds. It is soluble in alcohol, ether, chloroform, and compound tincture of benzoin.

Percutaneous absorption of podophyllum resin occurs, par-ticularly in intertriginous areas and from applications to large moist condylomas. It is soluble in lipids and therefore is distrib-uted widely throughout the body, including the central nervous system.

The major use of podophyllum resin is in the treatment of condyloma acuminatum. Podophyllotoxin and its derivatives are active cytotoxic agents with specific affinity for the microtubule protein of the mitotic spindle. Normal assembly of the spindle is prevented, and epidermal mitoses are arrested in metaphase. A 25% concentration of podophyllum resin in compound tincture of benzoin is recommended for the treatment of condyloma acuminatum. Application should be restricted to wart tissue only, to limit the total amount of medication used and to prevent severe erosive changes in adjacent tissue. In treating cases of large condy-lomas, it is advisable to limit application to sections of the affected area to minimize systemic absorption. The patient is instructed to wash off the preparation 2–3 hours after the initial application, because the irritant reaction is variable. Depending on the indi-vidual patient’s reaction, this period can be extended to 6–8 hours on subsequent applications. If three to five applications have not resulted in significant resolution, other methods of treatment should be considered.

Toxic symptoms associated with excessively large applications include nausea, vomiting, alterations in sensorium, muscle weak-ness, neuropathy with diminished tendon reflexes, coma, and even death. Local irritation is common, and inadvertent contact with the eye may cause severe conjunctivitis. Use during preg-nancy is contraindicated in view of possible cytotoxic effects on the fetus.

Pure podophyllotoxin (podofilox) is approved for use as either a 0.5% solution or gel (Condylox) for application by the patient in the treatment of genital condylomas. The low concentration of podofilox significantly reduces the potential for systemic toxicity. Most men with penile warts may be treated with less than 70 μL per application. At this dose, podofilox is not routinely detectedin the serum. Treatment is self-administered in treatment cycles of twice-daily application for 3 consecutive days followed by a 4-day drug-free period. Local adverse effects include inflammation, ero-sions, burning pain, and itching.

SINECATECHINS

Sinecatechins 15% ointment (Veregen) is a prescription botanical drug product of a partially purified fraction of the water extract of green tea leaves from Camellia sinensis containing a mixture of catechins. Sinecatechins ointment is indicated for the topical treat-ment of external genital and perianal warts in immunocompetent patients 18 years and older. The mechanism of action is unknown. Sinecatechins ointment should be applied three times daily to the warts until complete clearance, not to exceed 16 weeks of therapy.

FLUOROURACIL

Fluorouracil is a fluorinated pyrimidine antimetabolite that resembles uracil, with a fluorine atom substituted for the 5-methyl group. 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 syn-thetase 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%, and 5% concentrations. 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 contrain-dicated in patients with known hypersensitivity.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

A topical 3% gel formulation of the nonsteroidal anti-inflamma-tory drug diclofenac (Solaraze) has shown moderate effectiveness in the treatment of actinic keratoses. The mechanism of action isunknown. As with other NSAIDs, anaphylactoid reactions may occur with diclofenac, and it should be given with caution to patients with known aspirin hypersensitivity .

AMINOLEVULINIC ACIDS

Aminolevulinic acid (ALA) is an endogenous precursor of photo-sensitizing porphyrin metabolites. When exogenous ALA is pro-vided to the cell through topical applications, protoporphyrin IX (PpIX) accumulates in the cell. When exposed to light of appro-priate 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.

Treatment consists of applying ALA 20% topical solution to individual actinic keratoses followed by blue light photodynamic illumination 14–18 hours later. Transient stinging or burning at the treatment site occurs during the period of light exposure. Patients must avoid exposure to sunlight or bright indoor lights for at least 40 hours after ALA application. Redness, swelling, and crusting of the actinic keratoses will occur and gradually resolve over a 3- to 4-week time course. Allergic contact dermatitis to methyl ester may occur.