Glucocorticoids For Asthma And Allergic Rhinitis

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Beclomethasone Dipropionate. Beclomethasone dipropionate (Beclovent, Beconase, Vanceril, Vancenase)

(BDP) is rapidly converted in the lungs to beclomethasone 17-monopropionate (17-BMP), the metabolite that provides the bulk of the anti-inflammatory activity. The monopropi-onate also has higher affinity for the GR than either the dipropionate or beclomethasone. The portion of BDP that is swallowed is rapidly hydrolyzed to 17-BMP, 21-BMP (which arises by a transesterification reaction from 17-BMP), and beclomethasone itself.154 Beclomethasone has much less GC activity than the monopropionate.155

Budesonide. Budesonide (Pulmicort Turbohaler, Rhinocort) is extensively metabolized in the liver, with 85% to 95% of the orally absorbed drug metabolized by the firstpass effect. The major metabolites are 6^-hydroxybudes-onide and 16a-hydroxyprednisolone, both with less than 1% of the activity of the parent compound. Metabolism involves the CYP3A4 enzyme, so coadministration of budesonide with a known CYP3A4 inhibitor should be monitored carefully.

Ciclesonide. Ciclesonide (Omnaris) is a prodrug that requires hydrolysis of the isobutyrate ester at C21 to form the active corticosteroid (des-ciclesonide). It has minimal oral bioavailability due to extensive metabolism, mainly by CYP3A4. The metabolites of ciclesonide have not been fully characterized.

Flunisolide. The portion of a flunisolide (AeroBid, Nasarel) dose that is swallowed is rapidly converted to the 6^-hydroxy metabolite after first-pass metabolism in the liver. The 6^-hydroxy metabolite is approximately as active as hydrocortisone itself, but the small amount produced usually has limited systemic effects. Water-soluble conjugates are inactive.

Fluticasone Propionate. The main metabolite of flu-ticasone propionate (Flovent, Flonase) found in circulation in humans is the 17^-carboxylate derivative. As expected, a charged carboxylate in place of the normal acetol functionality at C17 greatly reduces affinity for the GR (2,000fold less than the parent), and this metabolite is essentially inactive. The metabolite is formed via the CYP3A4 system, so care should be taken if fluticasone propionate is coadministered with a CYP3A4 inhibitor such as keto-conazole or ritonavir. Clinically induced Cushing syndrome has been observed when inhaled fluticasone propi-onate was administered concurrently with ritonavir.156 Fluticasone is also available in an inhaled formulation in combination with the long-acting ^2-agonist salmeterol (Advair Diskus).

Mometasone Furoate. Mometasone furoate (Asmanex, Nasonex) undergoes extensive metabolism to multiple metabolites. No major metabolites are detectable in human plasma after oral administration, but the 6^-hydroxy metabolite is detectable by use of human liver microsomes. This metabolite is formed via the CYP3A4 pathway.

Triamcinolone Acetonide. The three main metabolites of triamcinolone acetonide (Azmacort, Nasacort) are 6jS-hydroxy triamcinolone acetonide, 21-carboxy triamcinolone acetonide, and 6^-hydroxy-21-carboxy triamcinolone ace-tonide. All are much less active than the parent compound. The 6^-hydroxyl group and the 21-carboxy group are both structural features that greatly reduce GC action. The increased water solubility of these metabolites also facilitates more rapid excretion.

Eplerenone (Inspra) Figure 25.32 • Aldosterone receptor antagonists.

A11 otet ra h y d rod eoxy co rt i coste ro n e (3a,21-Dihydroxy-5a-pregnan-20-one)

Figure 25.33 • Neurosteroid examples.

A11 otet ra h y d rod eoxy co rt i coste ro n e (3a,21-Dihydroxy-5a-pregnan-20-one)

Figure 25.33 • Neurosteroid examples.

Mineralocorticoid Receptor Antagonists (Aldosterone Antagonists)

Antagonism of the MR can have profound effects on the renin-angiotensin system, thus having significant cardiac effects. Structurally, these compounds have an A-ring enone, essential for recognition by the receptor, but the la-substituent and the D-ring spirolactone provide structural elements that lead to antagonism (Fig. 25.32).

Spironolactone, USP. Spironolactone, la-(acetylthio)-1la-hydroxy-3-oxopregn-4-ene-3-one-21-carboxylic acid y-lactone (Aldactone) is an aldosterone antagonist of great medical importance because of its diuretic activity. Spironolactone is discussed in Chapter 18.

Eplerenone, USP. Eplerenone, 9,11a-epoxy-1la-hy-droxy-3-oxopregn-4-ene-la,21-dicarboxylic acid, y-lactone, methyl ester (Inspra), is a newer aldosterone antagonist that is used for the treatment of hypertension.


Although the main effects of the steroid hormones described in this chapter have been focused on sexual development, maintenance of sexual organ function, and inflammatory processes, steroids also play important roles in the brain. Two terms have been developed to describe the specific steroids that act on the nervous system, neurosteroids and neuroactive steroids. Neurosteroids are synthesized in the brain, either from cholesterol or from other steroid hormones, and have their specific actions in the nervous system. Neuroactive steroids are synthesized in other steroido-genic tissues, but have their actions in the brain after transport from the site of synthesis. Many of the neuros-teroids are the same as steroid hormones acting peripherally, but some have unique roles in the brain. Neurosteroids include pregnenolone, progesterone, and DHEA, as well as their sulfate esters. Metabolites of progesterone and 11-de-oxycorticosterone, allopregnanolone and allotetrahy-drodeoxycorticosterone (allotetrahydroDOC; Fig. 25.33), respectively, represent neurosteroids with specific central actions.

In addition to the action of neurosteroids/neuroactive steroids via traditional steroid receptors (progesterone, estradiol), many neurosteroids act at different sites, especially the neurosteroids with a 3a-hydroxyl (Fig. 25.33). Allopregnanolone and allotetrahydroDOC are positive modulators of GABAa receptors, while pregnenolone sulfate and DHEA sulfate are negative modulators of the GABAA receptors. DHEA sulfate and pregnenolone sulfate also have actions at NMDA receptors and sigma type 1 receptors, while progesterone interacts with kainite, glycine, 5HT3, and nicotinic acetylcholine receptors. Although much of the neurosteroid research has been conducted in animal models, the clinical significance of neurosteroids is an area of growing interest.79 Neurosteroids have been hypothesized to have neuroprotective effects, anxiolytic effects, and may play roles in modulating seizures. The actions of steroids in the brain will undoubtedly be the focus of much more research in the years to come.


1 would like to thank Debra Peters for assistance with the illustration of several figures. I would also like to express my appreciation to the authors of various review articles on the steroids and the authors of previous versions of this text. Without the dedication and hard work of these individuals, the assembly of this chapter would have been a much more challenging task.

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