:Fifth edition
`
`LLERGY
`
`Principles & Practice
`
`VOLUME
`
`EDITED BY
`
`ELLIOTT MIDDLETON' JR.' MD
`Professor Emeritus of Medicine and Pediatrics;
`Former Director, Division of Allergy
`and Clinical Immunology
`School of Medicine and Biomedical Sciences
`State University of New York at Buffalo
`Buffalo, New York
`
`ELLIOT F. ELLIS, MD
`Professor Emeritus of Pediatrics
`School of Medicine and Biomedical Sciences
`State University of New York at Buffalo
`Buffalo, New York
`
`JOHN w. YUNGINGER, MD
`Consultant in Pediatrics
`and Internal Medicine (Allergy)
`Mayo Clinic
`Professor of Pediatrics
`Mayo Medical School
`Rochester, Minnesota
`
`CHARLES E. REED, MD
`Professor Emeritus of Medicine
`Mayo Medical School
`Rochester, Minnesota
`
`N. FRANKLIN ADKINSON' JR.' MD
`Professor of Medicine
`The Johns Hopkins Asthma and Allergy Center
`The Hopkins Bayview Medical Campus
`Baltimore, Maryland
`
`WILLIAM W. BussE, MD
`Professor of Medicine
`University of Wiscon in Hospital
`and Clinics
`Head, Allergy and Clinical Immunology
`Department of Medicine
`University of Wisconsin School of Medicine
`Madison, Wisconsin
`
`with over 450 i/lus1rations and 24 color plates
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`:fifth edition
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`

`

`CHAPTER
`
`_
`
`46 Glucoco1·ticosteroids
`
`Their Mechanisms of Action and Use in Allergic Diseases
`
`Robert P. Schleimer
`
`HISTORY
`The glucocorticoid hormones of the adrenal cortex and their synthetic
`analogs (hereafter referred to simply as steroids) represent the single
`most effective class of drugs for the therapy of diseases of inflamma(cid:173)
`tion. The modem history of these important natural hormones began in
`1855 when Addison first desc1ibed a wasting disease after destruction
`of the adrenal gland. 1 The adrenal gland was subsequently shown to be
`essential for life by ablation experiments and restoration with adrenal
`extracts. The importance of the adrenal gland in homeostatic processes
`is partly related to its role in the regulation of glucose metabolism and
`electrolyte levels. Hyperactivity of the adrenal gland was first de(cid:173)
`scribed as a syndrome by Cushing in the I 930s. 2 This was followed by
`a flurry of research that revealed that the main activity found in adrenal
`extracts was attributable to adrenal steroids, including cortisol (hydro(cid:173)
`cortisone, the major glucocorticoid in humans), cortisone, corticoste(cid:173)
`rone, and the major adrenal mineralocorticoid, aldosterone. Within just
`a few years of the elucidation of the stucture of the adrenal steroids,
`cortisone was first used to treat arthritis by Hench et al with such
`remarkable results that their work led to the Nobel Prize within the next
`year and promoted the testing of teroids in virtually all inflammatory
`diseases.3 Because many of the undesired effects of steroid therapy
`tl'ke a substantial amount of time to develop, the impact of these side
`effects was not appreciated until the next few years; this revelation
`somewhat dampened enthusiasm for these "miracle cure" drugs. A
`resurgence of interest in steroids has occurred after the development of
`effective, topically active drugs with dramatically reduced side effects.
`In the last two or three decades, much work has been directed toward an
`understanding of the mechanism of the antiinflammatory action of
`these drugs. This chapter focuses on the general pharmacologic aspects
`of glucocorticoids,4-6 the mechanism of their antiinflammatory actions,
`and their use in the therapy of allergic diseases, with an emphasis on
`asthma.
`
`PHARMACOLOGY
`Structure-Activity Relationships
`The structures of hydrocorti one and other related natural and synthetic
`steroids commonly used orally or parenterally are shown in Figure
`46-1. The shaded areas on the structures in Figure 46-1 emphasize
`structural variation from hydrocortisone, the parent molecule, in the
`other natural and synthetic steroids. Hydrocortisone has a four-ring,
`21-carbon structure. Structw·al elements important for antiinflamma(cid:173)
`tory action are numerous. 5
`7 In the A-ring, the 4,5 double bond and the
`·
`3-ketone group are essential for glucocorticoid and antiinflammatory
`activity. The addition of a 1,2 double bond, such as is seen in predniso(cid:173)
`lone, prednisone, methylprednisolone, and dexamethasone (see Figure
`46-1 ), increases the glucocorticoid activity relative to mineralocorti(cid:173)
`coid effects. In the B-ring the addition of a 9a-fluoro group, such as is
`seen in dexamethasone, betamethasone, and triamcinolone, increases
`all biologic activities, both glucocorticoid and mineralocorticoid. Jn
`the C-ring the 1 I-hydroxyl group is essential for antiinflarnmatory and
`glucocorticoid effects but not for mineralocorticoid effects. For ex(cid:173)
`ample, desoxycorticosterone, which lacks the 11-hydroxyl group, has
`mineralocorticoid activity but Jacks glucocorticoid effects. Steroids
`bearing an I I-ketone group (e.g., cortisone, prednisone) must be first
`converted to 11-hydroxy molecules for glucocorticoid activity (see
`
`638
`
`below). In the D-ring, the addition of a 16-methyl group eliminates
`mineralocorticoid activity (as seen in the case of dexamethasone) (see
`Figure 46-1). Removal of the 17a substituent greatly reduces antiin(cid:173)
`flammatory activity (although not completely, as in the example of
`corticosterone). This fact has been exploited by the pharmaceucical
`industry. As illustrated in Figure 46-2, some topical steroid prepara(cid:173)
`tions are l 6a-, l 7a-acetal, or l 7a-, 21 a-ester derivatives (e.g., budes(cid:173)
`onide and beclometbasone dipropionate [BDP]), which are readily
`cleaved after absorption, dramatically reducing systemic effects.8·9
`These glucocorticoids also have high affinity for the glucocorticoid
`receptor, increasing their topical actions. All natural and most active
`synthetic glucocorticoids contain a 21-hydroxyl group. The relative
`potencies and pbarmacologic effects of some common glucocorticoids
`are shown in Table 46-1.
`
`Synthesis
`Adrenal production of hydrocortisone and aldosterone results from a
`single branching pathway in which cholesterol is converted, via a
`pregnenolone intermediate, to progesterone. Progesterone is sequen(cid:173)
`tially hydroxylated at the 17-, 21-, and] ]-positions to form hydrocor(cid:173)
`tisone.4 The regulation of adrenal cortex production of hydrocortisone
`is illustrated in Figure 46-3. Glucocorticoids are primarily produced.in
`the zona fasciculata of the adrenal cortex, as a resull of stimulation with
`adrenocorticotropic hormone (ACTH); in the absence of this trophic
`hormone, this area of the adrenal cortex atrophies. ACTH is a product
`of the basophil cells of the anterior pituitary gland ru1d is released as_a
`result of stimulation by corticotropin-releasing factor (CRF), whic~ is
`released from the hypothalamus. ACTH (and glucocorticoid) secretion
`displays a diurnal rhythm with levels reaching peak values in the early
`morning, declining throughout the day to reach their lowest in the early
`evening. Additional CRF release, and therefore subsequent ACTH
`production and steroid synthesis, can result from environmental stress
`via the input of higher centers to the hypothalamus (see Figure 46-~) or
`from increased cirtulating levels of cytokines such as intedeuk/~~11
`(IL-l), IL-2, IL-6, or tumor necrosis factor (TNF'.cachectm)" 14
`These cytokines can also directly induce adrenal cortisol synthesis.
`Amines such as histamine or serotonin, as well as prostaglandms · uch_
`as prostaglandin E (PGE), have been reported to stimulate rele~e of
`17 Circu-.
`steroids from the adrenal gland both indirectly and directly 14
`•
`lating cortisol regulates its own production by inhibiting secretion ot
`ACTH, as well as by inhibiting the production of cytokines th<:t stimu(cid:173)
`late ACTH release (Figure 46-4).4·5 • 111• 11 • 18 The inhibition ot ACTH
`secretion by acute increases in glucocorticoids is one of th<! mos~
`rapidly occu~-ring steroid effects and requires only nunutes; removal ~f
`steroid readily reverses the effect. However, chrome elev3:tt0ns .
`glucocorticoid in the circulation can produce a more long-lastmg 111111-
`bition of ACTH secretion that can result in atrophy of the antenor
`pituitary and can have serious consequences when patients on chronic
`steroid therapy are suddenly withdrawn from treatment. The recov_e~
`of hypothalamic-pituitary-adrenal (HPA) axis function after with
`drawal of glucocorticoid u·eatment has been reviewed. 19· 20 Altl~oug1
`recovery of the HPA axis is rapid (i.e., requires days) after bne~ (1.e.f .
`week or less) treatment with glucocorticoids. treatment lastmg . 01
`more than a few weeks should be assumed to have a long-Iastmg
`.
`""
`. c·
`<lino in duration
`to J?
`suppressive euect on the HPA axis 1.e., correspon
`"·
`somewhat to the dose and duration of treatment and lastmg up
`-
`
`000003
`
`

`

`CHAPTER 46 Glt1eocorticosteroids
`
`639
`
`15
`
`4
`
`6
`Hyd rocorti sone
`
`Cortisone
`
`Beclomethasone dipropionate
`
`Prednisolone
`
`Prednisone
`
`Methylpredn isolone
`
`Dexamethasone
`
`FIGURE 46-1
`
`Chemical structure of some important oral glucocorticoids.
`
`months) after discontinuation of treatment. Recovery of tbe adrenal
`cortex is generally slower than recovery of bypotbalarnic-pituitary
`function. 20
`
`Metabolism and Excretion
`Greater than 90% of circulating cortisol is bound to plasma proteins.4
`There are two plasma protein binding sites of importance for steroids in
`the circulation. Cortisol (and some other steroids) binds to the
`corticosteroid-binding globulin, transcortin, with bigb affinity; this
`binding site bas a relatively low capacity. Relative binding to trans(cid:173)
`cortin of common glucocorticoids is prednisolone = hydrocortisone <::
`methylprednisolone (approximately 3%);:::: dexamethasone (approxi(cid:173)
`mately 0.1 %). 21 Additionally, steroids bind to serum albumin with low
`affinity; tbis is a bigb-capacity reservoir. At low concentrations of
`cortisol or synthetic steroids sucb as prednisone, the binding to
`Iran cortin is quantitatively more important in influencing free steroid
`levels. On the other hand, with high steroid doses, the transcortin(cid:173)
`bindmg site is saturated and the albumin-binding site becomes the
`more influential. Many synthetic glucocorticoids such as dexametha(cid:173)
`so~e exhibit little or no binding to transcortin. Because pharmacologic
`actions, metabolism and excretion of steroids are all related to un(cid:173)
`bound steroid conc~ntrations, the binding of circulating steroids to
`transcortin and albumin can play an important role in modifying glu(cid:173)
`cocorticoid potency, half-life, and duration of action. Thus hepatic
`diseases that result in decreased levels of transcortin and albumin can
`influence steroid efficacy.
`The metabolic fate of hydrocortisone is illustrated in Figure
`46-4.4
`5
`7 Reduction of the 4/5 double bond and 3-ketone groups yields
`·
`•
`~n ina~tive compound that is subsequently conjugated (e.g., by ~e
`1orm~t1on o~ a glucuronide) to pr~duce a highly water-soluble ster01d
`hat is readily excreted (step l m Figure 46-4). Another common
`metabolic reaction (step 2) is hydroxylation at the 2-position in the
`
`Budesonide
`
`F
`
`Flunisolide
`
`-
`
`F
`
`Fluticasone propionate
`
`fH20 H
`=o
`/CH3
`H ,,,,,,o-T"-
`11111110 CH3
`
`Triamcinolone acetonide
`
`FIGURE 46-2
`
`Some commonly u ed topical steroids.
`
`.. ----------------------~
`
`000004
`
`

`

`--- . -··- -- -- -·-----~----------------------------.---------::.-_ ___ --·-
`
`. .... --·
`
`-- -
`
`640
`
`SECI'ION D Pharmacology
`
`Sensory input,
`stress
`
`IL-1, TNF {Cachectin)
`
`D
`
`Activated macro(cid:173)
`phages and other
`accessory cells
`
`ACTH
`
`Adrenal cortex
`Zona fasciculata
`
`@ oy
`\
`
`HO~
`
`0~\
`
`0
`
`i
`I
`CD
`. (Y ®J
`j
`HO~ ~~
`
`OH
`
`Schematic of regulation of glucocorticoid production. Filled
`FIGURE 46-3
`arrows indicate inhibitory influences; open arrows indicate stimulation.
`
`FIGURE 46-4
`ticoids.
`
`Some major steps for the metabolic deactivation of glucocor-
`
`Table 46-1 Relative Potencies and Pharmacologic Effects of Common Oral Glucocorticoids
`
`PREPARATION
`
`Hydrocortisone
`Cortisone
`Prednisolone
`Prednisone
`6cx-Methylprednisolone
`Triamcinolone
`Dexamethasone
`Betamethasone
`
`POTENCY RELATIVE
`TO HYDROCORTISONE
`
`RELATIVE TO SODIUM-
`RETAINING POTENCY
`
`APPROXIMATELY EQUIVALENT
`DOSH {MG)
`
`DURATION OF ACT!Ol'\'*
`
`1
`0.8
`4
`4
`5
`5
`25
`25
`
`1
`0.8
`0.8
`0.8
`0.5
`0
`0
`0
`
`20
`25
`5
`5
`4
`4
`0.75
`0.75
`
`Short
`Short
`Intermediate
`Intermediate
`Intermediate
`Intermediate
`Long
`Long
`
`*Short, 8- to 12-bour biologic half-life; intermediate, 12- to 36-hour biologic half-life; long, 36- to 72-hour biologic half life.
`
`A-ring. Conversion of the 11-hydroxyl group to a ketone group by 11~
`hydroxysteroid dehydrogenase yields ·a compound devoid of gluco(cid:173)
`corticoid activity (step 3). However, the 11-ketone and 11-hydroxyl
`steroids are readily interconverted (e.g., see Figure 46-1).2 2 Other
`common metabolic fates are reduction of the 20-ketone group . (step 4)
`and hydroxylation of the 6-carbon in the B-ring, which is associated
`with removal of a fluoride atom in the case of fiunisolide (step 5). In
`the case of cortisol, greater than 98% of the steroid is metabolized
`before being excreted into the urine. Liver mixed-function oxidases
`and glucuronyl transferases (among other conjugating enzymes) are
`important in the metabolism of many steroids. The susceptibility of
`natural and synthetic steroids to the above-mentioned metabolic
`transformations can influence the plasma half-life of the compounds.
`Thus dexamethasone and triamcinolone are much less susceptible to
`rnany of these biotransformations, a fact that contributes to their longer
`half-lives. Further, as a consequence of the need for hepatic metabo(cid:173)
`lism of steroids, liver disease, drugs, or other chemicals that modify
`liver function can affect the biologic half-life of administered steroids.
`Compounds that induce liver mixed-function oxidases such as barbitu(cid:173)
`rates, diphenylhydantoin, and ephedrine, or many agents of occupa(cid:173)
`tional exposure can shorten the biologic half-life of steroids by increas(cid:173)
`ing the rate of their metabolism.23-25 On the other hand, compounds
`
`that interfere wioth liver mixed-function oxidases, such as troleandomy(cid:173)
`cin (TAO; see below), prolong the plasma half-life and metab?lic
`action of administered methylpre.dnisolone.26·27 TAO, whic~ has lim(cid:173)
`ited usefulness because of hepatotoxicity, enhances the anti~sthmauc
`activity of methylprednisolone but not prednisolone, suggesting that.it
`has little intrinsic antiasthmatic effects.27 •28 The effect of TAO JD
`"sparing" the metabolic destruction of methylprednisolone probably
`explains its efficacy in the combination therapy.
`Local metabolism of endogenous cortisol at tissue sites has re(cid:173)
`cently been found to regulate steroid action. For example. 11 P- hydro~~
`ysteroid dehydrogenase (11~ HSD [step 3, Figure ~6-4]) "protec~~
`mineralocorticoid receptors in the kidney from cortisol and proba Y
`"d
`· the
`dampens the antiinflarnrnatory effects of endogenous stero1 _s m .
`skin and lungs29-32 by quantitative conversion of hydrocortis?ne_ in
`those tissues to cortisone, which has no intrinsic receptor-binding
`activity. Inhibition of this enzyme by a compound found in liconce,
`glycyrrhetinic acid, produces mineralocorticoid effects in the ]udne~
`(by allowing hydrocortisone access to mineralocorticoid re~eRtors) an_
`antiinflarnrnatory effects in the skin. The possibility that snrular co:
`pounds will have efficacy in the lungs has been raised.31 Local m~~a 0~
`lism occurs with sorne inhaled glucocorticoids. Beclomethasone 1groh
`pionate is converted to beclomethasone 17 a propionate (BMP), w ic
`
`000005
`
`

`

`is a high-affinity, active glucocorticoid. Recent studies using the in(cid:173)
`haled glucocorticoid budesonide in rat and human lung indicate a
`prolonged retention of the glucocorticoid resulting from a reversible
`fatty acid conjugation forming highly lipid-soluble compounds. Tt has
`been suggested that this leads to a slow release of active budesonide
`upon deesterification of the fatty acid conjugated drug.33-35 Formation
`of fatty acid-esterified budesonide has been proposed to prolong the
`local activity of this compound in the airways by providing a depot of
`active drug.
`
`Administration and Absorption
`Both natural and synthetic steroids are lipophilic compounds that are
`readily absorbed after oral, subcutaneous, intravenous, or topical ad(cid:173)
`ministration. Phosphate or hemisuccinate esters of glucocorticoids are
`commonly used intravenously because of their improved water solubil(cid:173)
`ity. After topical application to the skin, significant quantities of steroid
`can remain locally for prolonged periods. Similarly, depot preparations
`of steroids are available in which a subcutaneous injection releases
`steroid into the circulation for prolonged periods of time.4 Steroids are
`commonly used orally for the treatment of chronic asthma.36·37 How(cid:173)
`ever, the use of topical steroids for the treatment of asthma, allergic
`rhinitis, and dermatologic conditions is rapidly increasing because of
`reduced incidence of side effects.37 Parenteral steroid administration is
`sometimes used for the treatment of severe exacerbations of asthma or
`anaphylaxis.38 In patients who have intact liver metabolic function,
`prednisone is often used because it is less expensive than prednisolone.
`One study suggests that methylprednisolone may penetrate the lungs
`better than prednisolone.38 A recent study comparing the use of oral
`prednisone and intravenous methylprednisolone in severe exacerba(cid:173)
`tions of asthma indicated no additional benefit of intravenous glucocor(cid:173)
`ticoid and substantial cost savings by using the oral glucocorticoid
`prepa.ration.39
`A subset of asthmatic subjects who are "resistant" to the antiasth(cid:173)
`matic actions of steroids has been described.40-44 Leukocytes from
`these patients have been shown to be resistant to steroid
`in vitro
`despite having apparently normal steroid receptor numbers. It is pos(cid:173)
`sible that this resistance is the result of in ufficiencies in receptor
`affinity for the steroid, binding to the glucocorticoid response element
`(ORE), interaction of the steroid-receptor complex with transcription
`factors, or po ttranscriptional events (see below).44
`Factors Influencing Local and Systemic Activity
`of Presently Available Inhaled Glucocorticoids
`Many of the important factors that influence the ability of an inhaled
`Steroid to have specificity for actions in the lung are summarized
`!fl Figure 46-5. Values for these tables are derived from several
`sources.45-47 For compounds with a low oral bioavailability, the
`majority of the dose that ends up in the systemic circulation is absorbed
`from the lungs. The volume of distribution gives some insight into
`tissue binding. These data and some direcl evidence sugge t that
`fluticasone propionate and budesorude bind well to lung tissue.
`Although inhaled steroids have a range of affinities for the glucocor(cid:173)
`tico1d receptor, all inhaled steroids have a high affinity compared with
`most oral glucocorticoids. The plasma half-life for the steroids varies
`over a substantial range as well, from less than 2 hours for budesonide,
`fiunisolide,.and triamcinolone acetonide to over 5 hours for BDP/BMP
`and fluticasone propionate.
`When steroids are inhaled using a typical metered-dose inhaler
`(MDI), over half of the drug is deposited in the mouth and pharynx and
`subsequently wallowed. A small proportion, perhaps 10% to 20%, is
`delivered to the lungs. Addition of a spacer device and/or mouth rinsing
`can increase the proportion of drug that is delivered to the lungs and
`reuuce local side effects, uch as dysphonia and thrnsh. Because such
`a lar~e proportion of drug is swallowed, it is in1portant that inhaled
`>tero1ds have a low oral bioavailability (see Figure 46-5).
`
`'10LECULAR BIOLOGY
`~: ~~tion of steroid ho~·mones requires the steps del~nea.ted in Figt.ire
`d6.6. Free hormone (i.e., that not bound to album111 or transcort111)
`c:~fuses across the .plasma membrane and becomes associated with a
`ss-spec1fic steroid receptor (e.g .. for glucocort1co1ds vs. sex ste-
`
`CHAPTER 46 Glttcocorticosteroids
`
`641
`
`roids). After the association of steroid with the receptor, a molecular
`transformation of the steroid-receptor complex takes place, involving
`dissociation of heat shock proteins, phosphorylation of the receptor,
`dimerization of receptors, and translocation into the nucleus where it
`binds to a specific GRE in the chromatin. This binding is mediated
`through elongated zinc-associated structural elements termed zinc fin(cid:173)
`gers specific for the GRE. Glucocorticoid-receptor complexes then
`dissociate from this binding site, glucoc01ticoid receptors a.re recycled
`to the cytoplasm, and reassociation with heat shock proteins occurs
`before glucocorticoid binding can again take place. Present models of
`how steroids modify gene transcription are shown in Figure 46-7. In
`the case of steroid induction of transcription, binding of the steroid(cid:173)
`receptor complex to the GRE leads to catalysis by ribonucleic acid
`(RNA) polymerase, and the new transcripts undergo posttranscrip(cid:173)
`tional processing and are transported to the cytoplasm where they are
`translated and new proteins are formed (Figure 46-7, A). After post(cid:173)
`translational processing, the new proteins a.re either released from the
`cell (in cases of proteins designed for export) or exert intracellular
`activity.
`The suppressive effects of glucocorticoids are believed to be the
`most important in mediating their antiinfla.mmatory actions.49 The
`molecular mechanisms by which glucocorticoids influence gene ex(cid:173)
`pression are summarized in Figure 46-7, Band C. Suppression of the
`expression of inflammatory genes can occur through several mecha(cid:173)
`nisms.49 These include direct target gene repression, in which case
`binding of the GR to a "negative" GRE in the promoter of a target gene
`can suppress expression of the gene (see Figure 46-7, B). GR can also
`exert gene repression by indirect mechanisms. GR is able to bind to
`numerous activating transcription factors, including AP-1, CREB,
`OCT-l, NF-IL-6, and others. Binding to these transcription factors
`inrerferes with their ability to activate inflammatory gene expression
`by preventing their interactions with promoter sites to which they bind
`(see Figure 46-7, C, top). This interaction can be bidirectional. Thus
`high levels of transcription factors can theoretically suppress glur.:ocor(cid:173)
`ticoid action by neutralizing receptors (a potential mechanism of g!u(cid:173)
`cocorticoid resistance). Glucocorticoids can also repress gene expres(cid:173)
`sion by inducing inhibitors of transcription factors. A good example is
`hc.B, a protein that prevents NF-KB from entering the nucleus and
`activating inflammatory genes50·51 (Figure 46-7 C, middle). Whether
`GR ~ctivates IKB via a GRE is not firmly established. Another mecha(cid:173)
`nism of indirect target gene repression hinges on the fact that most
`genes of inflammation have AU-rich elements. These a.re 3' RNA
`sequences that target the messenger RNA (mRNA) for rapid degrada(cid:173)
`tion. Glucocorticoids have been shown to destabilize AURE-contain(cid:173)
`ing mRNAs by an as-yet-undefined mechanism52 (see Figure 46-7, C,
`bottom). The relative importance of the above mechanisms in gluco(cid:173)
`corticoid action is likely to vary depending on the cell type. cytokine
`produced, and cell activation stimulus.
`There are several consequences of these molecular mechanisms of
`steroid action:
`I. The responsiveness of a given cell type to glucocort,i.£_oids is
`determined in part by the number of glucocorticoid receptors in
`that particular cell type.53 Thus there are cases in which a given
`target cell type has reduced steroid receptor number and so
`displays reduced steroid responsiveness. This can also result
`from impaired access of the receptor to the GRE because of the
`presence of other deoxyribonucleic acid (DNA)-binding moi(cid:173)
`eties or a steroid receptor with a weak steroid or GRE-binding
`domain.
`2. Steroid receptor antagonists have been developed that bind to
`the receptor but do not allow either translocation or productive
`interaction with the GRE, preventing the action of glucocorti(cid:173)
`coids. These compounds are useful in vivo in antagonizing
`·55
`undesired steroid actions. 54
`3. The requirement of transcription and translational events for
`steroid action is often responsible for a significant time delay
`between exposure of a given cell type or tissue to teroid and the
`eventual steroid effect.
`4. In the case of indirect repression (see Figure 46-7, C, top),
`overproduction of a transcriptional activator (e.g., AP-1) could
`antagonize steroid actions by binding GC receptors.
`5. The requirement for transcription and translation in many ste(cid:173)
`roid responses can render steroid actions sensitive to inhibitors
`of either transcription or protein synthesis.
`
`000006
`
`

`

`642
`
`SECTION D Pharmacology
`
`Factors influencing local and systemic activity of presently available inhaled glucocorticoids
`
`0
`
`1. Delivery device/delivery method
`• Presence of a spacer and mouth rinsing can reduce the oral
`deposition of inhaled dose by up to 90%.
`
`.
`2. Oral bioavailibility
`• Drug absorbed in the stomach and intestine is immediately
`transported to the liver by the hepatic portal system.
`• ICS are all efficiently metabolized by the liver during this first
`pass. A small percentage survives this hepatic transit intact:
`
`Oral Bioavailability of Inhaled Glucocorticoids
`
`BDP
`
`-
`
`BUD
`
`6-11%
`
`FLUN
`
`21%
`
`FP
`
`<1%
`
`TM
`
`10%
`
`3. Volume of distribution (Vo)
`• The Yo for ICS is determined in part by binding to lung
`and other tissues.
`• ICS vary in their tissue binding.
`• Tissue binding is related to water solubility and other
`characteristics:
`
`BDP/BMP
`
`BUD
`
`FLUN
`
`Yo (L/Kg)
`
`NA
`
`2.7-4.3
`
`H20 sol (µ.g/ml)
`
`0.1/10
`
`14
`
`1.8
`
`100
`
`FP
`
`3.7
`
`TM
`
`1.4-2.1
`
`0.04
`
`40
`
`4. Plasma clearance/terminal half life
`• Persistence of plasma levels (t1 ; 2 or half life) of ICS
`reflects the balance between metabolism and flux from
`tissue binding sites into the circulation.
`• Systemic side effects relate to receptor binding affinity,
`plasma concentration, and maintenance of elevated plasma
`levels:
`·
`
`BDP/BMP
`
`BUD
`
`FLUN
`
`FP
`
`TM
`
`GR binding*
`
`0.4/13.5
`
`9.4
`
`Clearance (L/min)
`
`t1 /2 (terminal)
`
`NA
`
`1~
`
`.9-1.5
`
`1.5-2.8
`
`1.8
`
`1.0
`
`1.6
`
`18-22
`
`2.3-3.6
`
`0.9
`
`0.8-1.2
`
`3.1-14
`
`1.5
`
`* Relative to dexamethasone.
`
`v
`
`FIGURE 46-5
`
`Factors influencing local and systemic activity of presently available inhaled glucocorticoids.
`
`6. The half-life of steroid-receptor complexes and the proportion
`of steroid receptors that are bound by drug are determined by
`affinity of a given steroid for the receptors. The more potent,
`longer-lasting steroids (e.g., the 6a- and 9a-ftu01inated steroids,
`such as most inhaled steroids) have greater affinity for the
`steroid receptor.
`
`METABOLIC EFFECTS
`Glucocorticoids regulate carbohydrate, lipid, and protein metabolism;
`water and electrolyte homeostasis; and the functions of mosl major
`organ systems, including the lung, the kidney, the cardiovascular sys(cid:173)
`5 The variety of glucocorticoid actions
`tem, and the nervous system.4
`•
`on these systems is diverse and beyond the scope of this review. The
`glucocorticoid namesake effect, regulation of glucose metabolism,
`includes stimulation of glucose formation, reduction of the peripheral
`usage of glucose, and promotion of glucose storage in the form of
`glycogen. These actions of glucocorticoids maintain glucose levels
`
`dunng periods of starvation-an action that may protect cerebral cen(cid:173)
`ters, which are restricted to glucose for metabolic energy. Glucocorti(cid:173)
`coids stimulate the gluconeogenic fotmalion of glucose from ~mino
`acids derived from muscle and bone, one consequence of which 15
`muscle wasting and osteoporosis during prolonged steroid usage_. Glu(cid:173)
`cocorticoids facilitate release of fatty acids from neutral hp1ds m
`adipose tissue with chronic use and produce rearrangements of body fal
`localization. Several clinically used glucocorticoids (such as hydrocm(cid:173)
`tisone and prednisolone) have mi.neralocorticoid properties. produ~u~)
`salt retention by timulating reabsorption of sodium at the renal dista
`tubules.
`EFFECTS OF GLUCOCORTICOIDS ON THE
`PRODUCTION OF INFLAMMATORY CELLS
`The oral or intravenous administration of glucocorticoids (e.g .. 50 mg
`of prednisone) causes marked changes in circulating leukocyte n~r
`bers. Most striking of these changes is a fall in the numberofbasop 1 ~.
`
`000007
`
`

`

`CHAPTER 46 Glucocorticosteroids
`
`643
`
`Cytoplasm
`
`Nucleus
`
`G
`
`. •
`T
`ransco rtrn
`
`l . Free GC enters
`the cell
`
`56 p-
`
`I 3. Hsp disassociate I
`
`FIGURE 46-6 Molecular basis of glucocorticoid action. For explanation, see text.
`
`5. GR complex
`enters the
`nucleus
`
`eosinophils, and monocytes to approximately 20% of the normal circu(cid:173)
`lating quantity of each of these cell types.56-58 Recirculating lympho(cid:173)
`cyte numbers also fall but not as dramatically. The nonrecirculating
`lymphocytes, that is, those that remain in the circulation and generally
`do not enter the lymph, are only modestly depressed by steroid admin(cid:173)
`istration.59 A greater fall in the number of T cells than B cells causes a
`relative enrichment of B cells. 59·60 Among T cells, steroids cause a fall
`in helper/inducer (CD4) but not cytotoxic/suppressor (CD8) cell num(cid:173)
`bers.61 ·62 Null and natural killer (NK) cell numbers are not influenced
`by acute steroid administration. 63
`Changes in leukocyte number occur within 4 to 6 hours and abate
`by 24 to 48 hours after a single steroid dose. In contradistinction
`to the effects of steroids in reducing basophil, eosinophil, and
`monocyte numbers, steroid administration elevates the number of
`~eutrophils in the circulation. 64·65 The increase in neutrophils that
`follows administration of steroid probably results from combined
`effects of a decreased egress of these cells from the blood, increased
`survival, a decrease in the size of the marginated granulocyte pool,
`and an increase in production of neutrophils by the bone man·ow. 64-66
`The increased production of neutrophils by the bone man-ow may
`be one of the more important effects because steroid treatment in
`patients with impaired marrow function causes little increase in
`circulating neutrophil levels.67 However, th