Topical corticoids

Skin manifestations of accompanying atopic eczema require a parallel local anti-inflammatory therapy, specifically with topic corticoids, anti-itching preparations and various fatty ointments. In the future, tacrolimus and pime-crolimus preparations might play a special role because they are able to substitute the application of corticoids [18]. 

The introduction of a 16a-hydroxy group into 6a,9-difluoro-prednisolone led to a compound (fluocinolone) with the anticipated favorable biological spectrum, namely high anti-inflammatory activity (35-fold that of hydrocortisone, seven-fold that of triamcinolone) and - in contrast to the C-16 unsubstituted compound - no retention of sodium. The corresponding 16,17-acetonide (fluocinolone acetonide) exhibited 100-fold the anti-inflammatory activity of hydrocortisone, with no sodium retention. In clinical trials, 6a,9-difluoro-16a-hydroxyprednisolone was found to be a potent suppressor of inflammatory conditions such as rheumatoid arthritis, as well as allergic conditions such as asthma, whilst its acetonide proved to be highly effective as topical corticoid. 

The vasoconstrictive property of corticoids may contribute to their anti-inflammatory effects. The mechanisms by which topical corticoids cause vasoconstriction remains unclear but is thought to be related to their inhibition of natural vasodilators, histamine, bradykinins, and prostaglandins [2, 46]. Some have suggested that corticosteroids potentiate norepinephrine [34], while others suggest that corticoids cause the release of norepinephrine [81]. Corticoids are thought to also have a direct effect on vascular endothelial cells. 

The rate of absorption is influenced by the status of the skin, chemical structure of the steroid and such other factors as formulation and formulation vehicle. Topical corticoids applied to diseased skin will be absorbed to some degree into the systemic circulation. When administration is chronic or when large areas of skin are involved, the absorption may be sufficient to cause systemic effects including cushinoid changes and adrenocortical suppression. 

Topical corticoids are minimally absorbed from healthy skin. On the forearm, approximately 1% of the applied dose of hydrocortisone penetrates [21, 59]. Other corticoids for which data exist are not necessarily absorbed to a greater degree than hydrocortisone [23], suggesting that they may owe their increased efficacy to their potency rather than enhanced penetration. To put this in perspective, only 1% of corticoids applied to healthy skin is therapeutically active, with approximately 99% being wasted either by being rubbed off, washed off, or exfoliating with the stratum corneum. 

Table 2. A partial list of topical corticoids available in the United States, ranked according to their potencies...

The potency of topical corticoids can be further enhanced by enhancing percutaneous absorption. One such way of optimizing absorption is by altering the formulation vehicle. It is now very clear, however, that some vehicles enhance the penetration and biologic activity of therapeutic agents [82]. It is important for vehicles to be free of the three S s, namely, sting, stench, and stain. Ointment bases tend to give better activity to the corticoid than do cream or lotion vehicles [82]. 

Certain factors increase the penetration and therefore the tendency to suppression - application to large surface areas, occlusion, inflamed skin and higher concentrations. Of concern in children is growth retardation associated with excessive and prolonged use of topical corticoids [9, 68, 89, 93]. A summary of adverse effects caused by corticoids is in Table 3. 

Regional differences in response are partially based mainly on the differences in penetration of skin in various areas. Thus, areas with increased permeability, such as the scrotum, eyelids, ears, scalp, and face respond far better to topical corticoids than such areas as the dorsa of the hands, extensor surfaces of knees and elbows, and the palms and soles [63]. 

Previously, patients applied topical corticoids three to four times daily. Studies on the percutaneous absorption of hydrocortisone failed to reveal a significant increase in absorption applied on a repetitive basis compared with a single dose [49]. Clinical trials of various corticoids suggest that less-frequent applications are equally effective [25]. In view of the relatively slow process of corticoid absorption, a phenomenon referred to as the reservoir effect [91], there may not be any advantage in frequent applications. 

Acute tolerance (tachyphylaxis) to vasoconstriction and antimitotic effects of and suppression of epidermal DNA synthesis by topical corticoids have been demonstrated [15, 16]. This suggests that the resistance clinically observed after prolonged use might be prevented by less intensive therapy, such as daily application with short resting periods between treatment courses [5, 67]. Another study examining corticoid tachyphylaxis used fluocinolone acetonide under occlusion to the forearm and induced wheal and flare to histamine with the prick technique [80]. By the eighth day, the wheal was nonexistent, adding now a third tachyphylaxis phenomena. 

Although most physicians employ topical corticoids in irritant dermatitis, the two controlled studies in experimental irritant dermatitis to SLS show either no, or a negative [88] or a minimal effect [73]. 

A 55-year-old male patient with chronic hepatitis B was started on TDF. One month after starting treatment he developed odynophagia and a painful tongue. Tenofovir was continued but topical corticoid therapy was added for symptom control. 

Bacitracin given parenteraHy is sufftciendy nephrotoxic that it is rarely used in human medicine for other than topical indications (80). Thus safe and effective use, especially as the zinc salt, is limited almost completely to ointments, sprays, and solutions for skin and ophthalmic use in concentrations of 250 to 1000 units per milliliter. Bacitracin is only rarely skin sensitizing. As in the case of polymyxin, bacitracin is usually combined with other antibiotics to enlarge its spectmm of activity, or with corticoids or analgesics to reUeve pain or itching. 

Antibiotics can be administered either systemic or topical as monotherapy or part of a corticoid-steroid combination. Antibacterial therapy leads not only to reduction of bacterial colonization, but also in many cases to improvement of AE, even when not actively infected 83,84... 

Pure vitamin A has an activity of. 1.5 million tU/g. Moder-ntc-to-ma.ssive doses of vitamin A have been u.sed in pregnancy. lactation, acne, termination of colds, removal of persistent follicular hyperkeratosis of the arms, persistent and abnormal warts, com.s, and callases, and. similar condition.s. Phosphatides or the tocopherols enhance the absorption of vitamin A. Vitamin A applied topically appears to reverse the impairment of wound healing by corticoid.s. 

A number of the potent anti-inflammatory steroids have proven very useful for treating topical manifestation of allergies such as rashes, rhinitis and asthma. Even topical application of the drugs carry the possibility that some would be absorbed and find its way into the circulation, where it could cause the typical corticoid side-effects. Several compounds in both this and other unrelated therapeutic areas include functional groups that will be destroyed by serum enzymes, thus inactivating that portion of the topically applied compound that may have entered the circulation. 

The safety of topical formulations of some of the older corticoids has led to their approval for sale over the counter. Hydrocortisone acetate (4-4) formulated as a salve can, for example, be bought without prescription in drugstores, supermarkets and any other store that sells such products. Indications printed on a typical label start with the phrase For temporary relief of itching associated with minor inflammation and rashes due to. .. and then continue with a long list of possible causes of that syndrome. 

The potent corticoid triamcinolone (desacetyl-29-5) is also available in a range of formulations for the treatment of both allergy and inflammation. A triamcinolone salve, for example, is indicated for topical treatment of rashes and the like (unlike cortisone, this requires a physician s prescription). Treatment of asthma comprises an important indication for the dmg. This use invokes the fact that the lungs originate embryologically from the same cell layer as skin. Triamcinolone is formulated as an inhalable powder for this purpose. Insuflation of the drug consequently constitutes topical administration... 

The very small amount of steroid that reaches the bloodstream from a topically administered drug can at least in theory cause some of the typical corticoid side-effects. This has occasioned research on corticoids that contain weak links that will lead to deactivation of the steroid by serum enzymes. The drug fluticasone (32-6) acts as a typical anti-inflammatory and antiallergic corticoid even though the side chain on ring D consists of a thioamide instead of a 2-hydroxyacetyl function. That thioamide provides the weak link that causes the drug to be destroyed by serum enzymes. As a result, fluticasone powder is used extensively in inhalers for treating asthma. 

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