Topical Corticosteroids

Mechanism of Action

The mechanism of action of topical corticosteroids is extensive, involving anti-inflammatory, anti-mitotic, and immunosuppressive properties.[14]

The anti-inflammatory effects of topical corticosteroids include vasoconstriction, inhibition of phospholipase A2 release, and a direct inhibitory action on DNA and inflammatory transcription factors.[14][15] Vasoconstriction of the blood vessels within the upper dermis decreases the number of inflammatory mediators delivered to the region.[14] The anti-inflammatory effect is also attributed to the synthesis of lipocortin, which inhibits phospholipase A2, thereby reducing the production of prostaglandins and leukotrienes.[15] Topical corticosteroids also act directly at the DNA level to increase the expression of anti-inflammatory genes and indirectly inhibit inflammatory transcription factors, such as NF-kB, to decrease the expression of pro-inflammatory genes.[14]

The anti-mitotic effect of topical corticosteroids plays a major role in psoriasis; it is proposed that this decrease in epidermal mitosis is secondary to an increase in lipocortin, an endogenous glucocorticoid-regulated protein. An anti-mitotic effect is also present in the dermis, inhibiting cell proliferation and collagen synthesis.[16][17]

The immunosuppressive effects of topical corticosteroids involve inhibiting humoral factors in the inflammatory response and suppressing all immune cells' maturation, differentiation, and proliferation.[16]

Pharmacokinetics

Absorption: Several factors, including the formulation, the epidermal barrier, and occlusive dressings, influence the percutaneous absorption of topical corticosteroids. Topical corticosteroids can be absorbed through intact skin, with inflammation increasing absorption. The application of occlusive dressings significantly enhances absorption.

Distribution: Corticosteroids bind to plasma proteins to varying extents.

Metabolism: Corticosteroids are primarily metabolized in the liver. The conversion of topical corticosteroids in the skin can be adjusted to enhance their potency. For instance, halogenation, as seen in clobetasol, helps prevent de-esterification, allowing the steroid to remain active for longer.[18]

Elimination: The steroids are excreted mainly by the kidneys, and some metabolites are also eliminated through the bile.

Administration

Available Dosage Forms

Topical corticosteroids are administered topically; however, successful administration depends upon obtaining an accurate diagnosis, choosing the correct drug, selecting the appropriate vehicle and potency, and the frequency of application.[1] The vehicle is the carrier of the drug. The vehicle selection depends on the region affected and the type of lesion present. Various vehicles also hydrate the skin and increase absorption. The vehicle options are listed below.[19] 

• Ointments: Ointments are used for thick hyperkeratotic lesions, as they are the most effective vehicle due to their occlusive nature. However, they should not be applied to hairy areas, which may lead to folliculitis.
• Creams: Creams are less potent than ointment but cosmetically more appealing since they leave no residue; the drying, non-occlusive nature leads to their administration for acute exudative inflammation and dermatitis within the intertriginous areas.[1]
• Lotions: Lotions are less occlusive and greasy and work well in hair-bearing regions.
• Gels: Similar to lotions, gels are less greasy and occlusive, making them suitable for hair-bearing areas. They are particularly beneficial for the scalp as they do not lead to hair matting like other products.
• Foams: Foams are highly effective for steroid delivery to the scalp but are costly.[20]

Strength, Classification, and Administration

The potency of topical corticosteroids refers to the amount of medication required to achieve the desired therapeutic effect. The gold standard for determining potency is the vasoconstrictor assay, which measures vasoconstrictive properties based on cutaneous vasoconstriction.[21] The United States classification consists of 7 classes: class I superpotent and class VII least potent.[22]

Class I are superpotent corticosteroids: clobetasol propionate 0.05% in any vehicle, augmented betamethasone dipropionate 0.05% gel or ointment, diflorasone diacetate 0.05% ointment, fluocinonide 0.1% cream, and halobetasol propionate 0.05% cream or ointment.[1]   

Class II are high-potency corticosteroids: amcinonide 0.1% ointment, augmented betamethasone dipropionate 0.05% cream or lotion, betamethasone dipropionate 0.05% ointment, desoximetasone cream or gel or ointment, diflorasone diacetate 0.05% cream, fluocinonide 0.05% cream or gel or ointment, and halcinonide 0.1% cream or ointment or solution.[1]

Class III are medium- to high-potency corticosteroids: amcinonide 0.1% cream, betamethasone dipropionate 0.05% cream, fluticasone propionate 0.005% ointment, and triamcinolone acetonide 0.5% cream or ointment.[1]

Class IV and V are medium-potency corticosteroids: betamethasone valerate 0.1% cream or lotion or foam, desoximetasone 0.05% cream, fluocinolone acetonide 0.025% cream or ointment, fluticasone propionate 0.05% cream, hydrocortisone butyrate 0.1% ointment, hydrocortisone probutate 0.1% cream, hydrocortisone valerate 0.2% cream or ointment, mometasone furoate 0.1% cream or lotion or ointment, triamcinolone acetonide 0.025% cream or lotion or ointment, and triamcinolone acetonide 0.1% cream or lotion or ointment.[1]

Class VI are low-potency corticosteroids: alclometasone dipropionate 0.05% cream or ointment, desonide 0.05% in any vehicle, fluocinolone 0.01% cream, and hydrocortisone butyrate 0.1% cream.[1]

Class VII are least-potent corticosteroids: hydrocortisone 1% and 2.5% cream lotion or ointment.[1]

Corticosteroids are better absorbed and more permeable in regions of the thin epidermis, such as the eyelid, than thicker regions of the epidermis, such as the sole. The penetration difference between them varies by 300-fold.[23] The penetration increases 2- to 10-fold in diseased states, such as inflammation and desquamation.[1][24] High-potency steroids are used for the palms and soles due to the thick stratum corneum and in non-facial/non-intertriginous areas for severe dermatoses, such as psoriasis and severe atopic and contact dermatitis.[1] Medium- to high-potency steroids are useful for regions of thin epidermis and areas of occlusion, such as the eyelid and axilla, respectively.[20] Low-to-medium strength preparations should be used for large surface areas to decrease the risk of systemic absorption.[1]

The amount of steroid used plays a significant part in the efficacy of treatment but also in avoiding adverse effects from overuse. One fingertip unit (FTU) is equal to 0.5 grams. The suggested dose of FTU is dependent upon the body region being treated. Topical corticosteroids are recommended for once to twice daily use.[25] A study regarding topical corticosteroid use for atopic dermatitis demonstrated no beneficial evidence for applying topical corticosteroids more than once daily. Applying it more often only increased adverse effects.[26]

Dosage

According to the AAFP (American Academy of Family Physicians) guidelines on the quantity of ointment based on fingertip units (FTUs), the following information is provided for one application and the weight required for twice-daily dosing over 30 days.[27]

Fingertip units needed for one application:

• Face and neck: 2.5 FTUs
• Front of the trunk: 7 FTUs
• Back of trunk: 7 FTUs
• One arm: 3 FTUs
• One hand (front and back): 1 FTU

Weight required for twice-daily dosing for 30 Days:

• Face and neck: 75 g
• Front of the trunk: 210 g
• Back of the trunk: 210 g
• One arm: 90 g
• One hand (front and back): 30 g

Specific Patient Populations

Pregnancy considerations: A systemic review suggests that maternal use of topical corticosteroids, regardless of potency, is not associated with significant adverse pregnancy outcomes. However, there could be a potential link between cumulative doses of potent corticosteroids and low birth weight; additional research is required.[28]

Breastfeeding considerations: Extensive use of potent corticosteroids may cause systemic effects in the mother, but short-term application is unlikely to pose a risk to the breastfed infant. To minimize potential risk, the least potent corticosteroid should be applied to the smallest skin area, ensuring the infant's skin does not directly contact treated areas. Lower potency corticosteroids should be used on the nipple or areola, and only water-miscible creams or gels should be applied to the breast. Any topical corticosteroid should be thoroughly wiped off before nursing.[29][30]

Pediatric patients: Very potent topical corticosteroids should not be used in children without specialist dermatological advice. For mild eczema, start with mild corticosteroids and use high-potency steroids for flare-ups. Proactive treatment with mild corticosteroids twice a week can help prevent flare-ups.[31] Pediatric patients may be more vulnerable to HPA axis suppression and Cushing syndrome caused by topical corticosteroids due to their higher skin surface area relative to body weight than adults.

Older patients: The dose of topical steroids should be cautious due to increased skin fragility and higher body surface area-to-weight ratio.[20]

Adverse Effects

The adverse effects of topical corticosteroids can be divided into local and systemic effects. Local adverse effects occur with prolonged treatment and are based on the topical steroid potency, vehicle, and application site. The most common local effects include atrophy, striae, rosacea, perioral dermatitis, acne, and purpura.[17]

Skin atrophy is the most common adverse effect due to topical corticosteroids' anti-mitotic effect.[17] Topical steroid causes the skin to undergo 3 phases: pre-atrophy, atrophy, and tachyphylaxis. Atrophy occurs when there is a persistent use in the same region. This leads to epidermal thinning and increased resorption within the dermis ground substance. The loss of connective tissue leads to erythema, telangiectasias, and purpura. Atrophy presents as a burning sensation; the vasoconstrictive effect of the topical corticosteroid relieves the burn.[15] Areas most at risk for atrophy are intertriginous due to thinner skin and increased occlusion. Atrophy is reversible with cessation of steroid use; however, it may take months for the skin to appear normal again.[17]

Tachyphylaxis results from the skin developing tolerance to the topical corticosteroid, which ultimately is a loss of vasoconstriction at the level of the capillaries. The capillaries regain their capacity for vasoconstriction after 4 days. For this reason, pulse therapy is recommended, and the topical corticosteroid should be discontinued for 4 days if it has lost effectiveness.[25]

Striae develop due to injury to the dermis and mechanical stress. Inflammation and edema of the dermis result in collagen deposition in the region of the mechanical stress. Striae appear histologically as scars and are permanent.[17]

Topical corticosteroid usage can result in acne formation due to the degradation of the follicular epithelium and an increase in the concentration of free fatty acids on the skin surface. This fosters an environment for bacteria growth, ultimately leading to comedogenesis.[17]

Steroid rosacea can occur when steroids are prescribed initially for erythema with or without pustules. If a low-dose topical corticosteroid is prescribed, it can lead to good results until the lesions reappear and higher potency steroid use is continuously needed.[17]

Perioral dermatitis occurs due to prolonged use of potent corticosteroids on the face and presents as follicular pustules and papules on an erythematous base surrounding the perioral region but sparing the vermillion border.[17]

Less common local adverse effects include hypertrichosis, pigment alteration, and delayed wound healing. Systemic adverse effects are less likely due to low percutaneous absorption. However, they can develop with the prolonged use of high-potency steroids on thin epidermal regions. The systemic adverse effects include glaucoma, hypothalamic-pituitary axis suppression, Cushing syndrome, hypertension, and hyperglycemia.[17]

Drug-Drug Interactions

Topical corticosteroids can interact with various medications. For instance, certain corticosteroids like hydrocortisone, fluocinolone, and mometasone may require careful consideration when combined with other drugs, including live vaccines, insulin, methotrexate, and diuretics. Some corticosteroids, such as beclomethasone and clobetasol, should be used cautiously with ketoconazole and rifampicin. However, the severity of these interactions is low, and most topical steroids are safe when used according to the product labeling.[32]

Contraindications

Topical corticosteroids are contraindicated for bacterial infections as their anti-inflammatory and vasoconstrictive effect will mask the infection, ultimately delaying diagnosis and treatment. Topical steroids should also be avoided in impetigo, furuncles and carbuncles, cellulitis, erysipelas, lymphangitis, and erythrasma. Relative contraindications include candida and dermatophytes.[33] The immunosuppressive effects may result in persistent fungal infections that can be identified as tinea incognito, which is significant for increased spread and inflammation with pustule formation.[20]

Warning and Precautions

• Misuse and withdrawal: Topical corticosteroid withdrawal is a poorly characterized condition arising from chronic misuse of topical steroids, particularly among those using them for cosmetic purposes. Symptoms include erythema, itchiness, and burning, with secondary lesions like scales commonly observed. This is an infrequent phenomenon; patient education is still necessary.[34]

• Endocrine adverse effects: Topical corticosteroids, especially those of higher potency, can suppress the HPA axis due to systemic absorption. Patients using these steroids may need periodic evaluations for adrenal suppression. Factors like prolonged use, large application areas, and use on altered skin barriers increase the risk. If adrenal insufficiency occurs, systemic corticosteroids may be required, but HPA axis function usually recovers once the topical steroid is discontinued. Additionally, systemic absorption can lead to conditions like Cushing syndrome, hyperglycemia, and unmasking of diabetes. Using multiple corticosteroid-containing products may elevate the risk of systemic exposure. Pediatric patients are particularly vulnerable to systemic toxicity from topical corticosteroids.

• Local adverse reactions: Local reactions are common with prolonged use, occlusion, or higher-potency steroids. These can include skin thinning, striae, telangiectasias, itching, acneiform eruptions, folliculitis, hypertrichosis, perioral dermatitis, hypopigmentation, secondary infections, and miliaria.

• Allergic contact dermatitis: Allergic contact dermatitis due to corticosteroids is typically diagnosed when a patient's condition fails to improve. Patch testing can confirm the diagnosis. If irritation occurs, discontinuing the corticosteroid and starting appropriate therapy is recommended.

• Concomitant skin infections: If skin infections develop or are present during treatment, topical corticosteroids should be stopped until the disease is adequately treated with antifungal or antibacterial agents.

Monitoring

Patients need to be monitored carefully, as unsupervised use of these medications can result in local and systemic adverse effects. The duration of treatment should not be greater than 2 to 4 weeks, regardless of potency. High-potency steroids should not be administered for longer than 2 weeks and should then be tapered to avoid adverse effects.[1][25] Guidelines to prevent adverse effects include the use of lower-potency steroids, morning-only applications, alternate-day treatment, and decreasing the extent of occlusion.[35]

Toxicity

Signs and Symptoms of Overdose

Systemic absorption of topical corticosteroids can suppress the HPA axis, hyperglycemia, glucosuria, and Cushing syndrome (eg, central obesity, moon face, skin changes). Pediatric patients are particularly vulnerable due to their higher skin surface area relative to body weight, leading to greater absorption and an increased risk of systemic toxicity. Prolonged use, application over large areas, and occlusive dressings further elevate absorption and the risk of adverse effects.

Management of Overdose

Patients using potent corticosteroids on large areas should be monitored for HPA axis suppression using tests like urinary-free cortisol and ACTH stimulation. If suppression occurs, reduce the drug frequency or switch to a less potent steroid. Discontinuation typically leads to prompt recovery of HPA axis function, but steroid withdrawal can occur, necessitating supplemental systemic corticosteroids.[36] In cases of irritation, discontinue the steroid and treat the irritation.

Enhancing Healthcare Team Outcomes

Topical corticosteroids are one of the most commonly prescribed drugs in dermatology due to the rapid effect of relieving unwanted signs and symptoms. However, if they are not adequately prescribed or patients are not given adequate instructions, topical corticosteroid abuse can occur, resulting in adverse effects.[37] Ideally, dermatologists, nurses, general practitioners, and pharmacists should work together to enforce the way topical corticosteroids are applied. Realistically, expert advice is quickly forgotten, and the product label remains the only direction. A label stating "apply thinly or use sparingly" promotes anxiety that the product may be dangerous, resulting in poor adherence and treatment. To resolve this matter, the fingertip unit (FTU) was designed to make it easier for practitioners to explain to patients how much medication should be applied to different body regions. Taking the time to explain the FTU system can help patients feel confident using an adequate amount of steroids. Recommendations have been made that labels state to "apply enough to cover the affected area" and include an image of the fingertip unit and a chart demonstrating how many fingertip units should be applied to each body region so patients receive appropriate treatment. Patients should also be advised not to exceed the prescribed treatment and to discontinue use under medical supervision. Pharmacists are the last line of healthcare that the patient sees before using the medication, and they play an essential role in enforcing the correct usage and ensuring the patient understands the interprofessional team's treatment plan.[38] An interprofessional team approach and communication among clinicians, pharmacists, and nurses are crucial to decreasing potential adverse effects and improving patient outcomes related to topical corticosteroid therapy.