Hydrocortisone activation

Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 335, 1060-1063. Teng, C., Ko, F., Wang, J., Lin, C., Wu, T., Chen, C., and Huang, T.F. 1991. Antihaemostatic and antithrombotic effect of some antiplatelet agents isolated from Chinese herbs. J. Pharm. Pharmacol. 43, 667-669. 

Sobering investigators uncovered a second significant breakthrough in microbial biotechnology of steroid production. They discovered that Corynebacterium simplex converted hydrocortisone (cortisol) (29) to prednisolone via a 1,2-dehydrogenation reaction. This A -3-ketosteroid is a highly active antiinflammatory commercial product (162). 

One of the first indications that the antiinflammatory potency of the corticoids could be increased was the observation that incorporation of a 9a-fluoro group in hydrocortisone resulted in a tenfold increase in activity. Treatment of hydrocortisone acetate (170a) with phosphorus oxychloride in pyridine yields the corresponding olefin, 172. This, on being subjected to the reaction sequence depicted in the transformation of 104 to 108 (addition of HOBr, closure to the epoxide and ring opening with HF),... 

Whole microbial cells as well as microbially derived enzymes have played a significant role in the production of novel antibiotics. The potential of microorganisms as chemical catalysts, however, was first fully realized in the synthesis of industrially important steroids. These reactions have assumed increasing importance following the discovery that certain steroids such as hydrocortisone have anti-inflammatory activity, whilst derivatives of the steroidal sex hormones are nsefiil as oral contraceptive agents. More recently, chiral inversion of non-steroidal anti-inflammatory dmgs (NS AIDs) has been demonstrated. 

An important problem in emulsified organic-aqueous systems is that of scale-up, which is concerned with the realization of stable emulsions and the separation of phases after the reaction. The use of biphasic membrane systems that contain the enzyme and keep the two phases separated is likely to solve this problem. In the case of 5-naproxen an ee of 92% has been demonstrated without any decay in activity over a period of two weeks of continuous operation. A number of examples of biocatalytic membrane reactors have been provided by Giorno and Drioli (2000) and include the conversion of fumaric acid to L-aspartic acid, L-aspartic acid to L-alanine, and cortexolone to hydrocortisone and prednisolone. 

Monitor for adverse reactions from mineralocorticoid administration (e.g., hypertension, hypokalemia, fluid retention) and decrease the dose if these occur. Remember that hydrocortisone also possesses mineralocorticoid activity. 

Non-prescription and herbal products with glucocorticoid activity (e.g., non-prescription anti-itch products with hydrocortisone, herbal products with magnolia bark or those claiming to contain adrenal cortex extracts or other by-products)... 

Clearly the physicochemical properties of a drug are a decisive factor in its overall activity. Where possible, molecular structures should be optimized to obtain best clinical performance. Rarely does an oral drug have physicochemical features suitable for topical or transdermal therapy, and it can take a great deal of systematic research to identify where the best balance of activity and permeability lies. Experience with corticosteroids suggests that as much as a 100-fold improvement in clinical activity may be attainable through molecular design, for today s most potent topical corticosteroids are more active than hydrocortisone by a factor at least this large. 

Hydrocortisone (M S) l Adenylate cyclase activity Bovine cornea [20]... 

The cellular mechanism of action of hydrocortisone, a glucocorticoid, is also related to proteins but not by the enhancement of cAMP production. Hydrocortisone is transported by simple diffusion across the membrane of the cell into the cytoplasm and binds to a specific receptor The steroid-receptor complex is activated and enters the nucleus, where it regulates transcription of specific gene sequences into ribonucleic acid (RNA). Eventually, messenger RNA (mRNA) is translated to form specific proteins in the cytoplasm that are involved in the steroid-induced cellular response. 

Because most adrenal crises occur because of glucocorticoid dose reductions or lack of stress-related dose adjustments, patients receiving corticosteroid-replacement therapy should add 5 to 10 mg hydrocortisone (or equivalent) to their normal daily regimen shortly before strenuous activities such as exercise. During times of severe physical stress (e.g., febrile illnesses, after accidents), patients should be instructed to double their daily dose until recovery. 

Hydrocortisone given parenterally is the corticosteroid of choice because of its combined glucocorticoid and mineralocorticoid activity. The starting dose is 100 mg IV by rapid infusion, followed by a continuous infusion or intermittent bolus of 100 to 200 mg every 24 hours. IV administration is continued for 24 to 48 hours. If the patient is stable at that time, oral hydrocortisone can be started at a dose of 50 mg every 8 hours for another 48 hours. A hydrocortisone taper is then initiated until the dosage is 30 to 50 mg/day in divided doses. 

Adrenalectomy causes a decrease of G-6-PDH activity in liver homogenates of rats. This can be restored to normal levels by administration of cortisone or corticosterone while hydrocortisone and progesterone dosages resulted in a partial restoration of activity (W17). 

Benzoic acids substituted with a basic side chain also are also of interest as pro-moieties whose physicochemical properties and rates of enzymatic hydrolysis can readily be modulated. A number of drugs have been converted to prodrugs with this type of pro-moiety, e.g., hydrocortisone, prednisolone, acyclovir, chloramphenicol, and paracetamol [148] [149], These prodrugs appear well suited as parenteral formulations, being water-soluble, stable in slightly acidic solution, and readily hydrolyzed enzymatically. As examples, we consider here the hydrolysis in human plasma of a number of (aminomethyl)ben-zoates of metronidazole (8.109-8.115, Sect. 8.5.5.1, Table 8.9) [138], These prodrugs are very rapidly activated, which may be beneficial for parenteral administration. However, this type of pro-moiety may be cleaved too rapidly after oral administration to be of interest for poorly absorbed drugs. 

Triamcinolone is a corticosteroid that is more potent than hydrocortisone and has a longer duration of action. Triamcinolone has only slight mineralocorticoid activity, whereas hydrocortisone has high mineralocorticoid activity and therefore triamcinolone is unsuitable for disease suppression on a long-term basis. Triamcinolone is available as injection, dental paste, nasal spray and as cream or ointment preparations. Hydrocortisone is available as cream, tablets and injections. 

In the case of the prescription relating to Daktacort (Q91-94), for candidates not familiar with its use, it is important to identify the active ingredients. Daktacort is listed in the BNF under hydrocortisone but its main use is as an antifungal agent. 

The natural glucocorticoid is hydrocortisone (cortisol). Semi-synthetic 9a-bromohydrocortisone 21-acetate was found to be less active as an anti-inflammatory agent than hydrocortisone 21-acetate by a factor of three, and 9a-iodohydrocortisone 21-acetate was also less active by a factor of 10. However, 9a-fluorohydrocortisone 21-acetate (fludrocortisone acetate) was discovered to be about 11 times more active than hydrocortisone acetate. Although the bromination sequence shown is equally applicable to chlorine and iodine compounds, fluorine must be introduced indirectly by the P-epoxide formed by base treatment of the 9a-bromo-lip-hydroxy analogue. 

Figure 6.40 Multiple peak trapping on a SPE cartridge (a) single trap and (b) four times trapping. 1 pg of hydrocortisone per injection, 2 mm Cis HD SPE cartridge, 600 MHz, 3-mm z-gradient LC-SEl probe with an active volume of 60 pi, 1024 transients.

The adrenal glands secrete over 50 different steroids, the most important of which are aldosterone and hydrocortisone. Aldosterone causes salt retention in the body. It is not commercially available. Hydrocortisone is useful for its anti-inflammatory and antiallergic activity. Cortisone and its derivatives have similar activity and it is reduced in vivo to hydrocortisone. The two substances are used to treat rheumatoid arthritis. The 11-P-hydroxyl of hydrocortisone is believed to be of major importance in binding to the receptors of enzymes. Anti-inflammatory activity is significantly Increased by various substituents 6a-fluoro, 9a-fluoro, 21-hydroxy, 2a-methyl, 9a-chloro, and a double bond at C-1. 

Fluorination at Cja-position increases the mineralocorticoid activity of both Cji-hydroxy (hydrocortisone) and C -deoxy (deoxycorticosterone) compounds. 

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