Side effects, corticoids

Hydrocortisone and Prednisolone. Following the discovery of the antiinflammatory actions of cortisone (1) and cortisol (2), there was a need not only to develop highly efficient routes to the corticoids, but to discover novel stmctures with fewer side effects than those of the corticoids, eg, sodium and water retention, reduced carbohydrate tolerance (steroid diabetes), osteoporosis, and depressed host defense. 

One of the side effects of adrenocorticotropic hormone (ACTH) and corticoid therapy in humans is the development or reactivation of gastroduodenal ulcers. Daily subcutaneous administration of cortisol or A -cortisol to rats for 4 days results in the regular development of gastric ulcers (38). This procedure has been adapted to testing antiulcer activity (39). There are certain differences between steroid ulcers and "natural" ulcers in localization, rate of development, and severity (40). 

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 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. 

One year after the introduction of fludrocortisone, the A-corticoids were brought forth into clinical medicine. Investigators at Sobering observed that the 1-dehydro derivatives of cortisone and hydrocortisone—namely, prednisone and prednisolone—are more potent antirheumatic and antiallergenic agents than the parent compounds and produced fewer undesirable side effects. These compounds are known as A -corticoids, because they contain an additional double bond between positions 1 and 2 (Fig. 33.10). 

Triamcinolone to be used topically is generally dispensed as its more potent and lipophilic acetonide, a 16a,17a-methylenedioxy cyclic ketal or isopropylidene derivative (Fig. 33.14) (see Inhaled and Intranasal Glucocorticoids). It is effective in the treatment of psoriasis and other corticoid-sensitive dermatologic conditions. Topically, triamcinolone acetonide is a more potent derivative of triamcinolone and is approximately eight times more active than prednisolone. The side effects of the drug, however, have occurred with sufficient frequency ... 

When these drugs are administered in doses that have similar antirheumatic strengths, the general incidence of adverse reactions with prednisone and prednisolone is about the same as that with hydrocortisone. The compounds differ, however, in their tendencies to induce individual side effects. The incidence and degree of salt and water retention and blood pressure elevation are less with the A -corticoids. Conversely, these analogues are more likely to promote digestive complaints, peptic ulcer, vasomotor symptoms, and cutaneous ecchymosis. 

Although these analogues have unwanted side effects, most clinical investigators prefer the A -corticoids to... 

This property has led to its widespread use. The considerably poorer therapeutic index of triamcinolone (as measured in dc s) does not seem to have become a problem in human medicine, although the pattern of side effects varies somewhat from that usually observed with other synthetic corticoids. 

Superpotent formulations include clobetasol propionate, optimized betamethasone diproprionate, and difluorosone. These corticoids are grouped together since they are unique in being a class of compounds that are not only superpotent, but must be used with caution they have the potential for significant topical and systemic side effects far in excess of other currently utilized formulations. 

When in the late 1940 s the remarkable therapeutic effects of the glucocorticoids cortisone and hydrocortisone were discovered, new raw materials had to be developed to produce these complicated molecules, and new synthetic methods devised to convert either a 20-ketopregnane or 21-acetoxy-20-ketopregnane to the dihydroxyacetone side-chain characteristic of these corticoids. This latter challenge produced some extremely useful new organic chemical reactions, many of which have wider application outside of steroids. 

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