Medical Pharmacology Topics   

Preliminary Outline

Corticosteroids   Glucocorticoids      Endogenous          Cortisol      Synthetic          Prednisone          Prednisolone          Methylprednisolone          Triamcinolone          Paramethasone          Betamethasone          Dexamethasone   Mineralocorticoids      Endogenous          Aldosterone      Synthetic          Fludrocortisone          Corticosterone

Glucocorticoids

Glucocorticoid replacement therapy is used to treat congenital adrenal hyperplasia and adrenal insufficiency (primary and secondary). Both glucocorticoids and mineralocorticoids must be replaced in primary insufficiency, but usually only glucocorticoids have to be replaced in secondary insufficiency.

The main pharmacological application of glucocorticoid is their suppression of inflammation and immune response. They inhibit phospholipase activity through lipocortins, resulting in decreased prostaglandins, leukotrines and platelet-activation factor. They also inhibit secretions and effects of proinflammatory and trophic cytokines (TNF, IL-1, etc.) through various mechanisms, including up-regulation of IkB to inhibit NFkB. Corticosteroids also induce programmed cell death in lymphocytes and other immune cells.

Corticoid steroids mechanism of action is through alteration of gene expression. They bind to cytosolic receptors and are taken into the nucleus, where they bind to steroid responsive elements to stop transcription of  pro-opiomelanocortin, cytokines, collagenase, stromelysin and adhesion molecules. On the other hand, they induce encoding of lipocortin and IkB.

Cortical steroid analogs are more useful if they are specific to either glucocorticoid or mineralocorticoid activity. For example, cortisol (or hydrocortisone ?) is not very useful clinically because it has equal glucocorticoid and mineralocorticoid activity. Some synthetic corticosteroids with mostly glucocorticoid activity are prednisone, prednisolone methylprednisolone and triamcinolone. These agents have about 4-5 times the glucocorticoid activity of cortisol. Other agents like paramethasone, betamethasone and dexamethasone, have 10-25 times the glucocorticoid activity of cortisol and have no mineralocorticoid activity. Therefore, the endogenous level of cortisol (about 15 mg/day) is equivalent to about 3 mg/day of prednisone and less than 1 mg/day of dexamethasone. Corticosterone and fludrocortisone have mostly mineralocorticoid activity.

Some indications for glucocorticoid therapy are:

• allergic disorders
• hematological disorders (anemias, malignancies)
• hepatic inflammation
• rheumatoid arthritis
• respiratory disorders (asthma)
• ocular disorders
• renal disease
• cerebral edema
• collagen disorders (lupus)
• dermatologic disease
• GI disease
• neuromuscular disorders (multiple sclerosis, myasthenia gravis)
• septic shock
• rheumatic carditis

Glucocorticoids are very lipophilic, well absorbed from the GI track and easily cross most biomembranes. Most are highly protein bound, to cortisol-binding globulin (COB) and albumin (3-30% free in plasma). They are metabolized mostly by the liver, with a lesser degree of extrahepatic metabolism.

Dangers of pharmacotherapy with systemic glucocorticoids include Cushing's syndrome, increased susceptibility to infection, suppression of the diagnostic signs of inflammation, and withdrawal problems ("rebound" phenomenon: impaired responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis leading to adrenal insufficiency). Specific potential adverse reactions include:

• edema
• hypokalemia
• aggravation of diabetes
• negative nitrogen balance
• myopathy
• osteoporosis and/or osteonecrosis
• cutaneous eruption (fluorinate derivatives)
• CNS effects ("steroid psychosis")
• suppression of growth (irreversible)

Several conditions should be considered for a rational steroid therapy:

• Accurate diagnosis
• Failure of alternative therapy
• Use minimum dosage necessary to achieve realistic therapeutic goals
• Access the risk of adverse effects (dose X duration of treatment X health of patient)
• Local administration if possible
• Use steroid-sparing agents (azathioprine, cyclophosphamide)
• Alternative day therapy, if practical, to avoid HPA axis "rebound"
• Avoid abrupt withdrawal

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