Corticosteroids

The adrenal glands secrete many hormones. The adrenal medulla (inner portion of gland) are the source of the body’s stress hormones [e.g. epinephrine (adrenaline) and norepinephrine (noradrenaline)]. The adrenal cortex (outer region of adrenal glands) secretes several types of hormones known collectively as corticosteroids.

There are two main types of corticosteroids: mineralcorticoids and glucocorticoids (drugs all have both mineralcorticoid and glucocorticoid activity)

• Mineralcorticoids (e.g. aldersterone) maintain salt and fluid balance in body
• Glucocorticoids [e.g. hydrocortisone (cortisol)] affect metabolism and inflammation

	Prednisone and Prednisolone are the most often used glucocorticoids due to their high glucocorticoid activity. Prednisone is transformed by the liver into prednisolone; this allows prednisone and prednisolone to be used interchangeably as medications. Hydrocortisone (cortisol) has much more mineralcorticoid activity than prednisone and is not suitable for long-term use internally. Applied extensively externally as cream or lotion for skin rashes & itches.
	Dexamethasone has very high glucocorticoid activity and low mineralcorticoid activity—thus can be used in high doses—e.g. treat nerve swelling after neurotrama or neurosurgery

Mechanism of Action: Glucocorticosteroids exert their anti-inflammatory effects through a number of mechanisms. Studies have shown that glucocorticoids can suppress the production of proteins involved in inflammation; they can also activate lipocortin enzymes. The lipocortins inhibit the phospholipsase A2 enzyme from catalyzing the release of arachidonic acid from phospholipid membranes to initiate the inflammatory process. Since this phospolipase-catalyzed production of arachidonic acid is “upstream” of the COX-2 catalyzed conversion of arachidonic acid to prostaglandins and thromboxanes, cordicosteroids have a broader effect than nonsteroidal anti-inflammatory drugs (NSAIDs). They prevent the formation of leukotrienes by inhibiting the production of arachidonic acid. Studies have revealed that the adding arachidonic acid removes the anti-inflammatory activity of glucocorticoids, but does not affect the activity of NSAIDs.

Side Effects: All glucocorticoid medications that treat inflammation also affect metabolism and may have unfavorable side effects such as:

· Increased blood glucose levels (possibly leading to diabetes)

· Suppressed calcium adsorption (possibly leading to osteoporosis)

· Swelling and skin changes

· Decreased immunity and psychological changes

Molecular Mechanism of Action

Glucocorticoids are steroid hormones that, due to their lipophilic properties, can readily pass through cell membranes. These steroid hormones then bind to intracellular or intranuclear glucocorticoid receptors; these receptor molecules are “zinc-finger” proteins that have a binding site for specific steroids, resulting in the formation of hormone-receptor complex. This complex forms a dimer, migrates into the nucleus (if not already there), and binds to a small sequence of DNA bases located in the promoter region of a specific gene. The binding of the steroid-receptor complex with DNA is the mechanism through which genes are turned on (or off).

The zinc finger portions of the steroid protein receptors are the receptor regions that noncovalently bind to DNA. Steroid receptor zinc fingers consist of a Zn⁺² ion complexed with four cysteine amino acid residues (a “C₄” zinc finger). This zinc complex binding creates a kink in the protein chain forming a 30-35 amino acid “finger” having an alpha helix portion and two beta sequences. Noncovalent receptor binding occurs by the fit of the zinc finger—particularly its alpha helix--into a DNA major groove.

Transcription is the process occurring within the nucleus that results in the production of a messenger RNA molecule from a specific sequence of DNA (a gene) that codes for a specific protein. Once transcription has occurred, messenger RNA, containing the sequence information from the gene, travels to the cytoplasm and provides the amino acid sequence information necessary to make the specific protein (translation).

The transcription process is influenced by transcription factors . Studies indicated that the glucocorticoid-receptor complex bound to DNA interacts with two specific transcription factors, NF-kappa B and AP-1, that assist in the transcription of inflammatory genes. It is believed that the complex interaction with these two transcription factors lowers the production of the COX-2 enzyme, resulting in lower subsequent production of downstream inflammatory prostaglandins. There is also evidence the presence of the steroid-receptor complex alters the structure of COX-2 messenger RNA.