Glucocorticoid

Glucocorticoids can also be injected directly into the arthritic joint, a technique that can be invaluable in the management of acute exacerbations. There is, of course, considerable controversy about whether intra-articular glucocorticoids will produce harmful catabolic effects in joints that are already weakened by arthritic changes. At the very least, the number of injections into an arthritic joint should be limited, and a common rule of thumb is to not exceed more than four injections in one joint within one year.77 

In addition to direct effects on genes regulating inflammation, glucocorticoids also inhibit the transcription factors that initiate synthesis of pro-inflammatory cytokines (e.g., interleukin-1, tumor necrosis factor), enzymes (e.g., COX-2, nitric oxide synthase), and receptor proteins (e.g., natural killer receptors).17,87,89 Glucocorticoids may also exert some of their effects via a membrane-bound receptor that regulates activity of macrophages, eosinophils, T lymphocytes, and several other types of cells involved in the inflammatory response.89 Consequently, glucocorticoids affect many aspects of inflammation, and their powerful anti-inflammatory effects in rheumatoid arthritis result from their ability to blunt various cellular and chemical components of the inflammatory response. 

The side effects of glucocorticoids are numerous (see Chapter 29). These drugs exert a general catabolic effect on all types of supportive tissue (i.e., muscle, tendon, bone). Osteoporosis is a particular a problem in the patient with arthritis because many of these 

SECTION 4 Drugs Used to Treat Pain and Inflammation 

Glucocorticoids reduce plasma leakage through several mechanisms (Williams and Yarwood, 1990). Actions of 

Depletion of endogenous glucocorticoids in experimental animals can increase the amount of plasma leakage produced by allergen challenge and other inflammatory stimuli (Boschetto et al., 1992 Ohrui et al., 1992). This observation may be important clinically, because the responsiveness of airway blood vessels to inflammatory mediators could increase after glucocorticoid treatment is stopped. 

Azathioprine is administered to patients who do not respond to calcineurin inhibitors, sirolimus and glucocorticoids. Daily doses of 3-10 mg/kg of azathioprine are administered 1 or 2 days before renal transplantation or on the day of surgery for prophylactic therapy. Mycophenolate mofetil is increasingly used in place of azathioprine for tissue transplantation since it is less myelotoxic and causes few opportunistic infections. 

Cyclophosphamide disturbs the mechanisms associated with DNA synthesis and cell proliferation by alkylating DNA in proliferating and nonproliferating cells. Its mechanisms of immunosuppressive effects are similar to its antineoplastic actions. Cyclophosphamide affects both B and T cells, but it produces more toxicity to B cells because they recover slowly. It has some unpredictable effects on T-cell-mediated immunity where it actually augments some T-cell-mediated responses however, the overall response is inhibitory. 

Drugs Glucocorticoid Activity Mineralocorticoid Activity - V. v.- Duration 

0 T lysosomal membrane stabOity —phagocytosis ° i capillary permeability 

Synthetic derivatives of cortisol are often used to manage inflammatory conditions or to promote immunosuppression. This chapter discusses the duration of action of several antiinflammatory steroids, their cellular effects and biochemical actions, as well as the many and severe adverse effects. 

Asthma is an inflammatory disease associated with bronchial hyperactivity (BHR), bronchospasm, t mucus secretion, edema, and cellular infiltration. 

Early asthmatic responses (EAR) lasting firom 30 to 60 minutes are associated with bronchospasm from the actions of released histamine and leukotrienes. 

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Several cortisone derivatives with glucocorticoid effects are most active, if they contain fluorine in the 9or-position together with an Il(9-OH group. Both substituents are introduced by the cleavage of a 9,11 -epoxide with hydrogen fluoride. The regio- and stereoselective formation of the -epoxide is achieved by bromohydrination of a 9,11-double bond and subsequent alkali treatment (J. Fried, 1954). 

Cortisol-Cortisone Conversion. Under normal conditions, this equilibrium slightly favors the oxidized compound. Similarly, the conversion of corticosterone to 11-deoxycorticosterone is also mediated by the liP-hydroxysteroid dehydrogenase enzyme system and requites NAD(P) /NAD(P)H. This conversion is especially important both in the protection of the human fetus from excessive glucocorticoid exposure, and in the protection of distal nephron mineral ocorticoid receptors from glucocorticoid exposure (14). The impairment of this conversion is thought to result in hypertension associated with renal insufficiency (15). 

A.- ng deduction. This is an irreversible reaction which is a foremost determinant of the secretion rate of cortisol (double bonds and C-3 carbonyl). Catalyzed predominantiy by cortisone P-reductase and 3a-hydroxysteroid dehydrogenases, SP sterols result, although 5a sterols are more prevalent in the case of other glucocorticoids. Urocortisol and urocortisone result from the metabohsm of cortisol and cortisone, respectively. Compounds can be complexed to glucuronic acid at this point. 

Glucuronidation. Complexation of the steroid to glucuronic acid, most predominantiy via the C-3 hydroxyl, leads to a considerable portion of the excreted metabohtes of ah. glucocorticoids. In infants, sulfurylation (formation of a sulfate ester) is also predominant (16). 

Other eactions. Most of the metabohtes of cortisol are neutral (alcohol or glucuronide complex) compounds. However, oxidation at C-21 to C-21 carboxyhc acids (17) accounts for some of the identifiable metabohtes of glucocorticoids (18). 

Transactivation. Protein synthesis is initiated or inhibited by the action of the activated GR on DNA. The use of glucocorticoids leads to antiinflammatory effects by first controlling gene expression, which subsequentiy leads to the synthesis and/or suppression of inflammation regulatory proteins. 

Glucocorticoids have been shown to inhibit gene transcription of other proteins involved in the inflammatory process, including the key inflammation mediators called cytokines (IL-1, IL3—6, IL8, GM-CSF, TNFa) (10,58,63—65). Steroids have been also shown to suppress the formation of cytokine receptors (10) dexamethasone, in particular, downregulates gene transcription of angiotensin II type 2 receptors (66). 

Mineralocorticoids foUow a mechanistic route similar to that of glucocorticoids, though differing in the proteins expressed. The activated MR-DNA complex promotes the expression of aldosterone-induced proteins (AIPs), which then act to increase conductance of the luminal membrane and concurrently increase pump activity of the basolateral membrane. These actions result from a number of AlP-influenced cellular characteristics,... 

Methylated Glucocorticoids. The preparation of 2a-methyl-9a- uorocortisol has been reported (76). This compound shows enhanced glucocorticoid activity and greatiy enhanced mineralocorticoid activity, so much that it surpasses aldosterone (19) ia sodium-retaining and potassium-excreting potency. Attention was then turned to the preparation of 6-methylated corticoids... 

Steroid Hormones and Neurosteroids. Steroids (qv) can affect neuroendocrine function, stress responses, and behavioral sexual dimorphism (78,79) (see Steroids). Mineralocorticoid, glucocorticoid, androgen, estrogen, and progesterone receptors are localized in the brain and spinal cord. In addition to genomic actions, the neurosteroid can act more acutely to modulate the actions of other receptors or ion channels (80). Pregnenolone [145-13-17, ( ) dehydroepiandosterone [53-43-0] C H2 02 (319) are excitatory neurosteroids found in rat brain, independent of adrenal... 

These steioids aie capable of preventing or suppressing the development of the sweUing, redness, local heat, and tenderness which characterize inflammation. They inhibit not only the acute symptoms of the inflammatory process, such as edema, fibrin deposition, and capillary dilatation, but also the chronic manifestations. There is evidence that glucocorticoids induce the synthesis of a protein that inhibits phosphoHpase A 2 (60), diminishing the release of arachidonic acid from phosphoHpids (Fig. 2), thereby reducing chemotaxis and inflammation. 

Unfortunately steroids merely suppress the inflammation while the underlying cause of the disease remains. Another serious concern about steroids is that of toxicity. The abmpt withdrawal of glucocorticoid steroids results in acute adrenal insufficiency. Long term use may induce osteoporosis, peptidic ulcers, the retention of fluid, or an increased susceptibiUty to infections. Because of these problems, steroids are rarely the first line of treatment for any inflammatory condition, and their use in rheumatoid arthritis begins after more conservative therapies have failed. 

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