GLUCOCORTICOIDS

2014

GLUCOCORTICOIDS are members of the corticosteroid family, with actions similar to the steroid hormones secreted by the adrenal cortex. There are two main types of corticosteroids: glucocorticoids and MINERALOCORTICOIDS. Glucocorticoids that are important physiologically include hydrocortisone (cortisol), corticosterone and cortisone. These are essential for utilization of carbohydrate, fat and protein in the body, and in the normal response to stress. Naturally occurring and synthetic glucocorticoids have a powerful antiinflammatory effect. In contrast, the mineralocorticoids (e.g. aldosterone) are necessary for the regulation of the salt and water balance of the body. Corticosteroids can be used in hormone replacement therapy. For instance, the glucocorticoid hydrocortisone and the mineralocorticoid fludrocortisone can be given to patients for replacement therapy where there is a deficiency, or in Addison’s disease, or following adrenalectomy or hypopituitarism. The glucocorticoids are potent antiinflammatory and antiallergic agents, frequently used to treat inflammatory and/or allergic reactions of the skin, airways and elsewhere. Absorption of a high dose of corticosteroid over a period of time may also cause undesirable systemic side-effects. They are relatively safe when given by local application (skin-creams), inhalation into the lungs in the prophylactic treatment of asthma, or by local injection (e.g. into the region of tendinitis, or sometimes intrathecally). Systemic use is normally kept for short-term use, or emergencies such as anaphylactic shock.

Glucocorticoid effects involve interaction between the steroids and intracellular receptors that belong to the nuclear receptor superfamily. The effect is mediated via an interaction with DNA and modified gene transcription. Nuclear receptors for glucocorticoids are widely distributed and after activation undergo a conformational change which exposes DNA-binding domains. The steroid receptor complex then binds to DNA, and either induces (initiates transcription) or represses (prevents transcription) of particular genes. Some of the effects of glucocorticoids on gene transcription are mediated by interaction of the steroid-receptor complex with a transcription factor activator protein termed AP-1. In turn, AP-1 is involved in the induction of several genes, e.g. inducible cyclooxygenase (COX-2) and for IL-2. The results of these changes in gene transcription are multiple. In particular, glucocorticoids decrease prostanoid production (by inhibition of COX-2), and possibly by inhibiting transcription of the gene for phospholipase A2, and also inhibition of the antiinflammatory mediator lipocortin-1.

Glucocorticoids have a very wide application as antiinflammatory agents in therapeutics. The route by which they are administered depends largely on their relative freedom from dangerous side-effects. Many are used by topical application, but some are intrinsically more powerful than others and may only be used when weaker corticosteroids have failed. Different salts may be used for certain purposes.

Some examples of current uses follow. Betamethasone is used for many purposes, including the treatment of cerebral oedema and congenital adrenal hyperplasia. Cortisone has both glucocorticoid and mineralocorticoid properties (in approximately equal measures), and can be used orally to correct hormonal deficiency, e.g. following adrenalectomy. It is converted in the body to hydrocortisone, and is now rarely used. Dexamethasone is used for many purposes, ranging from the suppression of inflammatory and allergic disorders, in shock, diagnosis of Cushing’s disease, congenital adrenal hyperplasia, cerebral oedema and in the treatment of rheumatic disease. Hydrocortisone has both glucocorticoid and mineralocorticoid properties (in approximately equal measures). and can be used orally to correct hormonal deficiency, e.g. following adrenalectomy. More commonly, it is used to treat inflammation, including arthritis, adrenocortical insufficiency, shock, inflammatory bowel disease, haemorrhoids and hypersensitivity reactions. Administration is in a number of forms (hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate) and by many routes. Methylprednisolone is used to treat allergic reactions, cerebral oedema, shock, rheumatic disease and inflammatory skin disorders, such as eczema and psoriasis. Administration (as methylprednisolone, methylprednisolone acetate or methylprednisolone sodium succinate) is oral in the form of tablets, as a topical cream or by injection. Prednisolone is used for the treatment of a number of rheumatic and allergic conditions (particularly those affecting the joints or the lungs), collagen disorders, for ulcerative colitis, inflammatory bowel disease, Crohn’s disease, haemorrhoids and as an immunosuppressant in myasthenia gravis. It may also be used for systemic corticosteroid therapy. Administration (as prednisolone, prednisolone acetate and prednisolone sodium phosphate) is oral, as suppositories or by injection. Prednisone is converted in the body into prednisolone, and is used orally for a variety of inflammatory and allergic disorders. See also dermatological agents.