Topical Corticosteroids

Structure of the Topical Corticosteroid Molecules

Hydrocortisone is considered the backbone of most TCS molecules ( Fig. 45.1 and Table 45.1 ). These molecules are formed by placing hydroxyl groups into the 11-β, 17-α, and 21 positions; ketone groups into the 3 and 20 positions; and a double bond into the 4 position of the glucocorticoid nucleus. The further addition or alteration of functional groups (hydroxy, hydrocarbon, ester, fluoro, chloro, acetonide, ketone) at certain positions can greatly affect the molecule’s pharmacokinetics (see Table 45.1 ).

The removal, replacement, or masking of hydroxyl groups changes a given molecule’s lipophilicity, solubility, percutaneous absorption, and glucocorticoid receptor (GCR)-binding activity. Replacement of the 21-hydroxy group in betamethasone with a chloro moiety creates clobetasol, which binds much more tightly to the GCR. Esterification or addition of acetonide groups masks hydroxyl groups. Esterification at the 17 position of betamethasone creates betamethasone-17-valerate, which binds much more tightly to GCR and is approximately 125 times more potent than betamethasone in the vasoconstriction assay. Esterification at the 21 position of betamethasone creates betamethasone-21-valerate, which binds less tightly to the GCR but significantly increases percutaneous absorption (and potency) by increasing the molecule’s lipophilicity. Acetonide groups are formed from the 16-α, 17-α dihydroxy groups of triamcinolone and fluocinolone. Triamcinolone acetonide binds much more tightly to GCR than triamcinolone, and fluocinolone acetonide penetrates human skin and hairless mouse skin 14 to 23 times faster than fluocinolone. Fluocinolone acetonide can be further esterified at the 21 position to create fluocinolone acetonide acetate (fluocinonide), which is even more potent.

A double bond in the 1 position increases glucocorticoid activity. Halogenation at the 6-α, 9-α, or 21 position increases potency according to the position and nature of the halogen atom. An additional fluorination (difluorasone diacetate-6-α) or chlorination further enhances the potency. Addition of a 16-α methyl, 16-β methyl, or 16-α hydroxy group reduces mineralocorticoid activity; thus, these functional groups are often incorporated into molecules containing 9-α or 6-α halogens such as dexamethasone, betamethasone, and triamcinolone.

Structural modifications also affect biotransformation. Enzymes in the epidermis cause de-esterification of TCS into inactive metabolites. Halogenation at the 21 position (clobetasol propionate) inhibits de-esterification at the 17 position and significantly increases potency. Halogenation at the 9-α position also reduces biotransformation.

Vehicle-Related Issues

The vehicle is a highly engineered balance of numerous chemicals, each serving a separate or overlapping purpose. Emollients are incorporated to retard transepidermal water loss, occlude the CS molecule, and increase the flexibility of the skin. Emulsifying agents are required to create oil-in-water preparations such as creams and lotions. Other chemicals act to stabilize emulsions and thicken the final preparation. Solvents are used in lotions, solutions, gels, and sprays to create a less viscous product. Humectants are necessary in all oil-in-water preparations to maintain the required water content.

The vehicle can indirectly alter a given preparation’s therapeutic and adverse actions by altering the pharmacokinetics of the TCS molecule. Q45.2 Solvents such as propylene glycol and ethanol, for example, affect the TCS molecule’s solubility in the vehicle and skin by affecting its percutaneous absorption. The net effect of the propylene glycol is to enhance potency through increasing the percutaneous absorption. Very occlusive vehicles also enhance a TCS molecule’s percutaneous absorption, probably by increasing the hydration of the stratum corneum. For this reason, a TCS molecule in an ointment vehicle tends to be more potent than the same concentration of the molecule in a cream or lotion. Emulsifiers help to distribute the drug evenly on the skin surface. The vehicle can also directly contribute to a TCS preparation’s therapeutic effects and adverse effects (AE) (see Adverse Effects and Therapeutic Guidelines sections) and ultimately determine a given TCS preparation’s acceptance by the patient. Foams are well accepted by patients, for example, but are more costly to produce because propellant technology is relatively complex and more expensive to manufacture.

Role of Condition of Skin in Percutaneous Absorption

The condition of the skin also affects bioavailability. Penetration of the applied drug correlates inversely with the thickness of the stratum corneum. Penetration increases with inflamed or diseased skin, and with increased hydration of the stratum corneum, relative humidity, and temperature. The stratum corneum may also act as a reservoir for TCS for up to 5 days; this retention is TCS concentration and formulation dependent.

Mechanism of Action

Atopic Dermatitis

TCS are first-line treatments for AD in all age groups; their efficacy is well established in randomized, controlled clinical trials. For adults, moderate-potency TCS is used for flares on the trunk and extremities; typically, control of the disease occurs after 2 to 3 weeks of twice-daily therapy. To finish treatment or to treat early recurrences, a lower potency of the TCS can be used twice daily (see Therapeutic Guidelines section). Fluticasone propionate 0.05% cream applied once daily was as effective as twice-daily treatment in a multicenter, randomized study. Prophylactic treatment with mometasone furoate cream twice weekly for 6 months was effective (90% disease free) in an open-label study of 68 patients; however, one patient developed skin atrophy. Desoximetasone 0.25% spray has been shown to be an effective treatment option for adults with AD, especially with itch being a major symptom. Within 1 week of starting treatment there was a significant reduction in pruritus after twice daily application. Throughout the study period of 4 weeks the reduction in pruritus was sustained and no AE occurred. Quality of life was also improved with use of desoximetasone 0.25% spray.

For children with AD, lower-potency TCS are recommended (see Therapeutic Guidelines section). Twice-daily desonide hydrogel 0.05%, flucocinolone acetonide 0.01% in peanut oil, hydrocortisone butyrate 0.1% lipocream, and once-daily fluticasone proprionate 0.05% lotion have been shown to be effective and safe for up to 1 month in children down to 3 months of age. Occasionally, intermediate-potency TCS are necessary for reasonably short courses. Betamethasone valerate 0.1% ointment applied for 3 days followed by vehicle for 4 days was as effective as hydrocortisone 1% cream applied for 7 days in an 18-week randomized, double-blinded, parallel-group study of 174 children. Mometasone furoate 0.1% cream once daily was significantly more effective than twice-daily hydrocortisone valerate 0.2% cream in a 3-week multicenter, randomized, evaluator-blinded, parallel-group study with 219 children aged 2 to 12 years. These children had failed to respond to at least 7 consecutive days of a topical hydrocortisone preparation. No treatment-related atrophy was noted in either group.

Compliance with TCS may be a very significant issue in AD patients. Adherence to regimens varies significantly, although patients may report near perfect usage.

Ceramide-based barrier creams, pimecrolimus cream, and tacrolimus ointment can augment the benefit of TCS therapy of AD in both adults and children. (see Chapter 48 .)

Discoid Lupus Erythematosus

Fluocinonide 0.05% cream and topical tacrolimus 0.3% in clobetasol propionate 0.05% ointment have been shown to be effective in treating individuals with discoid lupus erythematosus.

Granuloma Annulare

Superpotent TCS alone or high-potency TCS under occlusion are effective treatments for localized granuloma annulare. Occlusive TCS preparations (such as flurandrenolide tape) and intralesional TCS treatment (such as 5–10 mg/mL triamcinolone acetonide) are also effective.

Lichen Planus—Cutaneous.

Localized cutaneous lichen planus (LP) generally responds to TCS. Fluocinonide in an adhesive base produced good to partial responses in 16 of 20 cutaneous LP patients treated in a randomized, double-blind, placebo-controlled study. TCS are also useful in the treatment of lichen planopilaris.

Lichen Planus—Oral

Oral erosive LP can be effectively treated with TCS in gels, ointments, inhalers, and rinses. Dexamethasone elixir or solution and prednisolone oral solution to be used as rinses are currently available. Mometasone furoate 1% microemulsion mouthwash three times daily over 30 days significantly reduced pain and lesion surface area in a phase II clinical trial with 49 patients. Fluticasone propionate spray four times daily and betamethasone sodium phosphate mouth rinse four times daily were both effective in a 6-week randomized, cross-over study of 48 patients. A comparative study suggested that clobetasol ointment in an adhesive base, plus antimycotics, was as effective as oral prednisone 50 mg daily. Clobetasol propionate 0.05% ointment was superior to fluocinonide 0.05% ointment in a placebo-controlled, comparative study for treatment of atrophic–erosive oral lichen planus.