MASTERSKILL

UNIVERSITY COLLEGE OF HEALTH SCIENCES

THE LEADER In Nursing & Allied Health Education in Malaysia

PHA3THB/S1

PREMIER

RECOGNISED o TRUSTED

July 2010

Practice and Therapeutics

Adrenocorticoids

Lecturer K.Anandarajagopal,M.Pharm.,
PHA3THB/S2 PREMIER
o

RECOGNISED o TRUSTED

July 2010

LEARNING OBJECTIVES

PHA3THB/S3

PREMIER

RECOGNISED o TRUSTED

July 2010

INTRODUCTION
  The adrenal glands are flattened, caplike structures located above the kidneys. The inner core (medulla) of the gland secretes catecholamines, while the shell (cortex) of the gland synthesizes steroids known as the adrenocorticoids. The adrenocorticoids are divided according mechanism of action into glucocorticoids mineralocorticoids (aldosterone). to their biochemical (hydrocortisone) and

The adrenocorticoids and sex hormones have much in common. All are steroids, and the rules that define their structures, chemistry, and nomenclature are the same. Changes in the geometry of the ring junctures generally result in inactive compounds. The adrenocorticoids and the sex hormones, which include estrogens, progestins, and androgens, are mainly biosynthesized from cholesterol, which, in turn, is synthesized from acetyl-CoA. PHA3THB/S4 PREMIER
o

 

RECOGNISED o TRUSTED

July 2010

 

Despite their similarities in chemical structures and stereochemistry, each class of steroids demonstrates unique and distinctively different biologic activities. Adrenocorticoids are composed of two classes of steroids, glucocorticoids, which regulate carbohydrate, lipid, and protein metabolism and mineralocorticoids, which influence salt balance and water retention. The sex hormones include the female sex hormones, progestins and estrogens, and the male sex hormones, androgens. Minor structural modifications to the steroid nucleus, such as changes in or insertion of functional groups at different positions, cause marked changes in physiologic activity. This topic focuses   the similarities among the steroids and reviews steroid nomenclature, stereochemistry, and the general mechanism of action. adrenocorticoids and discusses the biosynthesis, metabolism, medicinal chemistry, pharmacology and pharmacokinetics of endogenous steroid hormones, synthetic agonists, and synthetic antagonists

 

PHA3THB/S5

PREMIER

RECOGNISED o TRUSTED

July 2010

Steroid Nomenclature and Structures

rings A &B are trans fused

rings A &B are cis fused

PHA3THB/S6

PREMIER

RECOGNISED o TRUSTED

July 2010

 

The stereochemistry of the rings markedly affects the biologic activity of a given class of steroids. Nearly all biologically active hormonal steroids have the cholestane-type backbone, except for the cardiac glycosides, which have a cis-trans-cis ring fusions. The metabolites for many of the hormonal steroids have a 5F configuration making them inactive. In most of the important steroids discussed in this section, a double bond is present between positions 4 and 5 or 5 and 6, and consequently there is no cis or trans relationship between rings A and B. The symbol is often used to designate a carbon-carbon double bond (C=C) in a steroid. If the C=C is between the 4 and 5 position, the compound is referred to as a 4 steroid; if the C=C is between positions 5 and 10, the compound is designated a 5/10 steroid. PHA3THB/S7 PREMIER
o

 

 

RECOGNISED o TRUSTED

July 2010

Cholesterol (cholest-5-en-3F-ol) is a 5 steroid or, more specifically, a 5-sterol because it is an unsaturated alcohol. These biologically active steroids include members of the 5E-pregnane, 5Eandrostane, and 5E-estrane steroid classes. The adrenocorticoids (adrenal cortex hormones) are pregnanes and are exemplified by hydrocortisone (cortisol), which is a 11F, 17E, 21-trihydroxypregn4-ene-3,20-dione 21-acetate. Progesterone (pregn-4-ene-F,20-dione), a female sex hormone synthesized by the corpus luteum, is also a pregnane analogue. The male sex hormones (androgens) are based on the structure of 5-androstane. PHA3THB/S8 PREMIER
o

 

RECOGNISED o TRUSTED

July 2010

    

Testosterone, an important naturally occurring androgen, is named 17Fhydroxy-4-androsten-3-one. The estrogens, which are female sex hormones synthesized by the graafian follicle of the ovaries, are hydroxyl analogues containing an aromatic A ring. Although the A ring does not contain isolated C = C groups, these analogues are named as if the bonds were in the positions shown in 17 -estradiol. Hence, 17 -estradiol, a typical member of this class of drugs, is named estra1,3,5-triene-3,17- -diol. Aliphatic side chains at position 17 are always assumed to be when cholestane or pregnane nomenclature is employed; hence, the notation 17 need not be used when naming these compounds. If a pregnane has a 17 nomenclature. chain, however, this should be indicated in the

 

Finally, the final (e) in the name for the parent steroid hydrocarbon is always dropped when it precedes a vowel, regardless of whether a number appears between the two parts of the word.

PHA3THB/S9

PREMIER

RECOGNISED o TRUSTED

July 2010

Mechanism of Action
  In addition to their structural similarities, adrenocorticoids, estrogens, progestins, and androgens share a common mode of action. They are present in the body only in extremely low concentrations (e.g., 0.11.0 nM), where they exert potent physiologic effects on sensitive tissues. They bind with high affinity to intracellular receptors. The steroid hormones act on target cells to regulate gene expression and protein biosynthesis via the formation of steroid-receptor complexes, as outlined in the following figure. The lipophilic steroid hormones are carried in the bloodstream, with the majority of the hormones reversibly bound to serum carrier proteins. The free steroids can diffuse through the cell membrane and enter cells. Those cells sensitive to the particular steroid hormone (referred to as target cells) contain steroid receptors capable of high- affinity binding with the steroid. These receptors are soluble intracellular proteins that can both bind steroid ligand with high affinity and act as transcriptional factors via interaction with specific DNA sites.

PHA3THB/S10

PREMIER

RECOGNISED o TRUSTED

July 2010

Recent investigations on estrogen, progestin, and androgen action indicate that active, unoccupied receptors are also present in the nucleus of the cell. Prior to the binding of the steroid, the steroid receptor is complexed with heat shock proteins (HSP). In the current model, the steroid enters the cell and binds to the steroid receptor in the cytoplasm or nucleus. This binding initiates a conformational change and dissociation of the HSP allowing steroid receptor dimerization and translocation to the nucleus. PHA3THB/S11 PREMIER
o

RECOGNISED o TRUSTED

July 2010

The receptor dimer interacts with particular regions of the cellular DNA, referred to as hormone-responsive elements (HRE), and with various nuclear transcriptional factors. Binding of the nuclear steroid-receptor complex to DNA initiates transcription of the DNA sequence to produce mRNA. Finally, the elevated levels of mRNA lead to an increase in protein synthesis in the endoplasmic reticulum. These proteins include enzymes, receptors, and secreted factors that subsequently result in the steroid hormonal response regulating cell function, growth, differentiation and playing central roles in normal physiological processes as well as in many important diseases. The steroid receptor proteins are part of a larger family of nuclear receptor proteins that also include receptors for vitamin D, thyroid hormones, and retinoids. PHA3THB/S12 PREMIER
o

RECOGNISED o TRUSTED

July 2010

Biosynthesis
There are two steps i. Pregnenolone Formation ii. Pregnenolone to Glucocorticoids and Mineralocorticoids

i. Pregnenolone Formation
 In the adrenal glands cholesterol is converted by enzymatic cleavage of its side chain to pregnenolone, which serves as the biosynthetic precursor of the adrenocorticoids. This biotransformation is performed by a mitochondrial cytochrome P450 enzyme complex. This enzyme complex found in the mitochondrial membrane consists of three proteins-CYP11A1, adrenodoxin, and adrenodoxin reductase. Defects in CYP11A1 lead to a lack of glucocorticoids, feminization and hypertension. Three oxidation steps are involved in the conversion, and three moles of NADPH and molecular oxygen are consumed for each mole of cholesterol converted to pregnenolone. PHA3THB/S13 PREMIER
o

  

RECOGNISED o TRUSTED

July 2010

The first oxidation results in the formation of cholest-5ene-3F, 22R-diol (step a), followed by the second oxidation yielding cholest-5ene-3F,20R,22R-triol (step b). The third oxidation step catalyzes the cleavage of the C20-C22 bond to release pregnenolone and isocaproic aldehyde (step c). Pregnenolone serves as the common precursor in the formation of the adrenocorticoids and other steroid hormones.

PHA3THB/S14

PREMIER

RECOGNISED o TRUSTED

July 2010

ii. Pregnenolone to Glucocorticoids and Mineralocorticoids

  Hydrocortisone and aldosterone are regulated by independent mechanisms. The glucocorticoids are biosynthesized and released under the influence of peptide hormones secreted by the hypothalamus and adenohypophysis (anterior pituitary gland) to activate the adrenal cortex (HPA axis). The peptide hormone in the hypothalamus is corticotropin-releasing factor (CRF). Where as in the adenohypophysis is adrenocorticotropic hormone (ACTH; corticotropin) for glucocorticoid biosynthesis. The only steroid stored in the adrenal gland is cholesterol, found in the form of cholesterol esters stored in lipid droplets. ACTH stimulates the conversion of cholesterol esters to glucocorticoids by initiating a series of biochemical events through its surface receptor. The ACTH receptor protein is coupled to a G protein and to adenyl cyclase. Binding of ACTH to its receptor leads to activation of adenyl cyclase via the G protein. The result is an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. One of the processes influenced by elevated cAMP levels is the activation of cholesterol esterase, which cleaves cholesterol esters and liberates free cholesterol.

PHA3THB/S15

PREMIER

RECOGNISED o TRUSTED

July 2010

Free cholesterol is then converted within mitochondria to pregnenolone via the side-chain cleavage reaction described earlier in Fig. Pregnenolone is converted to adrenocorticoids by a series of enzymatic oxidations and double bond isomerizafion. The next several enzymatic steps in the biosynthesis of glucocorticoids occur in the endoplasmic reticulum of the adrenal cortex cell. Approximately 15-20 mg of hydrocortisone is synthesized daily. The pathway for the formation of the potent mineralocorticoid molecule, aldosterone, is similar to that for hydrocortisone and uses several of the same enzymes.

 

PHA3THB/S16

PREMIER

RECOGNISED o TRUSTED

July 2010

Metabolism
 Hydrocortisone and cortisone are biochemically inter- convertible by the enzyme 11F-hydroxysteroid dehydrogenase, with the reaction equilibrium towards hydrocortisone. Hydrocortisone is metabolized by the liver following administration by any route with a half-life of about 1-.5 hours. Hydrocortisone is mainly excreted in the urine as inactive O-glucuronide conjugates and minor O- sulfate conjugates of urocortisol, 5Fdihydrocortisol, and urocortisone

 

PHA3THB/S17

PREMIER

RECOGNISED o TRUSTED

July 2010

Development of Adrenocorticoid Drugs

Systemic Corticosteroids Overview
 The clinically available adrenocorticoids may be administered by intravenous injection, oral tablets or solutions, topical formulations, intraarticular administration, and by oral or nasal inhalation . The route of administration depends on the disease being treated and the physicochemical, pharmacologic, and pharmacokinetic properties of the drug. Only a handful of corticosteroids are used clinically by the oral route, including hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone. These corticosteroids are often described as short-acting, intermediate acting or long acting according to their biologic half-life and duration of action. They are well- absorbed, undergo little first pass metabolism in the liver, and demonstrate oral bioavailability (F) of 70-80%, except for triamcinolone. PHA3THB/S18 PREMIER RECOGNISED o TRUSTED July 2010

Pharmacologic and Pharmacokinetic Properties for Some Adrenocorticoids

PHA3THB/S19

PREMIER

RECOGNISED o TRUSTED

July 2010

Pharmacokinetics of Commonly Used Oral Adrenocorticoids

PHA3THB/S20

PREMIER

RECOGNISED o TRUSTED

July 2010

Systemic corticosteroids
 The degree of systemic side effects is dosedependent, related to the half-life of the drug, frequency administration, time of day when administered, and route of administration; i.e., higher the plasma corticosteroid concentration and longer the half-life, the greater will be the systemic side effects. Regardless of the route of administration, all of the synthetic adrenocorticoids are excreted from the body in a manner similar to the endogenous adrenocorticoids (i.e., they are metabolized in the liver and excreted into the urine primarily as glucuronide conjugates, but also as sulphate conjugates). PHA3THB/S21 PREMIER
o

RECOGNISED o TRUSTED

July 2010

Cortisone, Hydrocortisone and Their Derivatives

 Cortisone is administered orally or IM injection as its 21- acetate (cortisone acetate). Cortisone acetate or hydrocortisone are usually the corticosteroid of choice for replacement therapy in patients with adrenocortical insufficiency, because these drugs have both glucocorticoid and mineralocorticoid properties. Following oral administration cortisone acetate and hydrocortisone acetate are completely and rapidly deacetylated by first pass metabolism. The pharmacokinetic for hydrocortisone acetate is indistinguishable from that of orally administered hydrocortisone. Oral hydrocortisone is completely absorbed with a bioavailability >95% and a half-life of 12 hours. Cortisone acetate is slowly absorbed from IM injection sites over a period of 24-48 hours, and is reserved for patients who are unable to take the drug orally.

 

PHA3THB/S22

PREMIER

RECOGNISED o TRUSTED

July 2010

The acetate ester derivative demonstrates increased stability and has a longer duration of action when administered by IM injection. Thus, smaller doses can be used. Similarly, hydrocortisone may be dispensed as its 21-acetate (hydrocortisone acetate), which is superior to cortisone acetate when injected intra-articularly. Systemic absorption of hydrocortisone acetate from intra-articular injection sites is usually complete within 24-48 hours.

PHA3THB/S23

PREMIER

RECOGNISED o TRUSTED

July 2010

Other ester derivatives that are available include hydrocortisone cypionate [21-(Fcyclopentylpropionate) ester], hydrocortisone butyrate (17E-butyrate ester), hydrocortisone buteprate (l7Ebutyrate, 21-propionate esters), hydrocortisone valerate (17E-valerate ester), hydrocortisone sodium succinate (21-sodium succinate ester), and hydrocortisone sodium phosphate (the 21-sodium phosphate ester). The water-insoluble hydrocortisone cypionate is used orally in doses expressed in terms of hydrocortisone for slower absorption from the gastrointestinal tract (GI). The extremely water-soluble 21-sodium succinate and 21-sodium phosphate esters are used for intravenous or intramuscular injection (IV or IM) in the management of emergency conditions that can be treated with antiinflammatory steroids. PHA3THB/S24 PREMIER
o

RECOGNISED o TRUSTED

July 2010

The phosphate ester is completely and rapidly metabolized by phosphatases, with a half-life of less than 5 minutes. Peak hydrocortisone levels are reached in about 10 minutes. The sodium succinate ester is slowly and incompletely hydrolysed and peak hydrocortisone levels attained in 30-45 minutes. The usual intramuscular dosage ranges from 100-500 mg daily. Hydrocortisone butyrate, hydrocortisone buteprate, and hydrocortisone valerate are used topically. When these drugs are used in doses necessary to suppress symptoms of rheumatoid arthritis, they also affect other metabolic processes. Side effects such as excessive sodium retention and potassium excretion, negative nitrogen balance, increased gastric acidity, edema, and psychosis are exaggerated manifestations of the normal metabolic functions of the hormones.

  

PHA3THB/S25

PREMIER

RECOGNISED o TRUSTED

July 2010

Fludrocortisone
     A 9E-bromo analogue that had one-third the glucocorticoid activity of cortisone acetate was prepared in these investigations. Other halogens were introduced into the 9E-position, and it was soon observed that glucocorticoid activity is inversely proportional to the size of the halogen at C-9. The 9E-fluoro analogue (fludrocortisone) is approximately 11 times more potent than cortisone acetate. Fludrocortisone is orally administered as its 21-acetate derivative. Although glucocorticoid activity is increased 11- fold by insertion of the 9E-fluorosubstituent, mineralocorticoid activity is increased 300-800 times. Because of its intense sodium-retaining activity, fludrocortisone is contraindicated in all conditions except those which require a high degree of mineralocorticoid activity because it leads to edema. Fludrocortisone acetate is used orally for the treatmewnt of Addisons disease.

PHA3THB/S26

PREMIER

RECOGNISED o TRUSTED

July 2010

Prednisone, Predinisolone and its Derivatives

 Investigators observed that the 1-dehydro derivatives of cortisone and hydrocortisone, namely prednisone and prednisolone, are more potent antirheumatic and anti-allergenic agents than hydrocortisone and produced fewer undesirable side effects.  These compounds are known as 1-corticoids because they contain an additional double bond between positions.  Both prednisone and prednisolone were found to have adrenocortical activity.  Prednisone and prednisolone were found to be three or four times more potent than cortisone or hydrocortisone.  The increased potency reflects the effect in the change in geometry for ring A caused by the introduction of the additional C1=C2 function on glucocorticoid receptor affinity and altered pharmacokinetics (primarily metabolism). PHA3THB/S27 PREMIER
o

RECOGNISED o TRUSTED

July 2010

The order of glucocorticoid receptor affinity is dexamethasone (10X) > triamcinolone (5X) > methylprednisolone (4X) > prednisolone (2X) > hydrocortisone (1X). For all practical purposes, prednisone and prednisolone are equally potent and may be used interchangeably. When prednisone or prednisolone is used in the treatment of rheumatoid arthritis, smaller doses are required than for hydrocortisone; the usual dose is 5 mg two to four times a day. PHA3THB/S28 PREMIER
o

 

RECOGNISED o TRUSTED

July 2010

Methylprednisolone
H

OH OH H O
H3C

 Studies with methylcorticoids revealed 2E-methyl derivatives to be inactive, whereas the 2E-methyl-9Efluoro analogues had potent mineralocorticoid activity.
    

Methylprednisolone (6E-methyl analogue of prednisolone) is extensively metabolized with about 10% recovered unchanged in urine. The metabolic pathways include reduction of C20 ketone, oxidation of 17F-ketol group to C21- COOH and C20-COOH, and 6F-hydroxylation. These compounds potentiated glucocorticoid activity with negligible salt retention for short term therapy. Methyiprednisolone is administered intravenously as its water-soluble sodium salt of the 21-succinate ester. The succinate ester is slowly and incompletely hydrolysed; peak plasma levels for methylprednisolone is attained in about 30-60 minutes following its IV administration and 15% of its IV dose is recovered unchanged in the urine.

PHA3THB/S29

PREMIER

RECOGNISED o TRUSTED

July 2010

Triamcinolone
O

HO H F H

OH OH OH

research involved synthesis and examination of compounds containing both a 9E-fluoro group and a double bond between C1 and C2. Triamcinolone has structural features of 1-corticoid & 9E-fluoro corticoid.

1-corticoid

 The 9E-fluoro group increases the anti-inflammatory potency, but it also markedly increases the mineralocorticoid potency. This is undesirable if the drug is to be used internally for the treatment of rheumatoid arthritis.  By inserting a l6E-hydroxy group into 9E-fluoroprednisolone resulted in triamcinolone with glucocorticoid activity equivalent to prednisolone but with decreased mineralocorticoid activity.  In fact, l6E-hydroxy analogues of natural corticoids retain glucocorticoid activity and have a considerably reduced mineralocorticoid activity.  The lower than expected oral anti-inflammatory potency for triamcinolone has been attributed to its low oral bioavailability due in part to increased hydrophilicity from the 16E-hydroxyl group and first pass metabolism primarily to its 6F-hydroxy metabolite.

PHA3THB/S30

PREMIER

RECOGNISED o TRUSTED

July 2010

O HO OH OH H F O H
CH 3

Dexamethasone
    

These studies led to the development of dexamethasone (9-fluoro-16Emethyl analogue). A 16F-methyl group increases the stability of the steroid to metabolism in human plasma in vitro. Unlike 16E-hydroxy1ation, a methyl group increases the anti-inflammatory activity by increasing lipophilicity and consequently receptor affinity. Like the 16E-hydroxyl group, the methyl group appears to reduce markedly the salt-retaining properties of the corticosteroid. The activity of dexamethasone, as measured by glycogen deposition, is 20 times greater than that of hydrocortisone. Clinical data indicate that dexamethasone has 5-7 times the anti- rheumatic potency of prednisolone. It is roughly 30 times more potent than hydrocortisone. Routes of metabolism for dexamethasone are similar to those for prednisolone with its primary 6F-hydroxy metabolite being recovered in urine. PHA3THB/S31 PREMIER
o

 

RECOGNISED o TRUSTED

July 2010

Betamethasone
O

HO H F H

OH OH
CH3

Shortly after the introduction of dexamethasone, betamethasone, which differs from dexamethasone only in configuration of the 16-methyl, was made available for the treatment of rheumatic diseases and dermatologic disorders. This analogue, which contains a 16 -methyl group, is as effective as dexamethasone or slightly more active . Although this drug has been reported to be less toxic than other corticosteroids, some clinical investigators suggest it is best used for short-term therapy. Toxic side effects, such as increased appetite, weight gain and facial mooning, occur with prolonged use. Generally, a 0.5-mg tablet of betamethasone is equivalent to a 5.0-mg tablet of prednisolone.

 

 

PHA3THB/S32

PREMIER

RECOGNISED o TRUSTED

July 2010

Topical Glucocorticoids
  Topically applied glucocorticoids are also capable of being systemically absorbed, although to a much smaller extent. The extent of absorption of topical adrenocorticoids is determined by several factors, including the type of cream or ointment, the condition of the skin to which it is being applied, and the use of occlusive dressings. Previous studies with halobetasol propionate showed that about 6% of the drug was systemically absorbed after topical application. Although this is a small fraction of the dose, the very high potency of halobetasol propionate contributed to its ability to cause mild adrenal suppression in some patients. The relative potency of the topical glucocorticoids is commonly determined using topical vasoconstriction assays, and is dependent on the intrinsic activity of the drug, its concentration in the formulation, and the vehicle in which it is applied.

PHA3THB/S33

PREMIER

RECOGNISED o TRUSTED

July 2010

 Once absorbed through the skin, topical corticosteroids are handled through metabolic pathways similar to the systemically administered corticosteroids.  They are metabolized, primarily in the liver, and are then excreted into the urine or in the bile.
Topical corticosteroids

PHA3THB/S34

PREMIER

RECOGNISED o TRUSTED

July 2010

Potency Ranking for Topical Corticosteroides

PHA3THB/S35

PREMIER

RECOGNISED o TRUSTED

July 2010

Triamcinolone to be used topically is generally dispensed as its more potent and lipophilic acetonide, a 16E,17E- methylenedioxy cyclic ketal or isopropylidene derivative. It is effective in the treatment of psoriasis and other corticoid-sensitive dermatologic conditions. Topically, triamcinolone acetonide is a more potent derivative triamcinolone and is about 8 times more active than prednisolone. of

    

Newer synthetic glucocorticoids have incorporated chlorine atoms onto the steroid molecule as fluorine substitutes. Beclomethasone, a 9E-chloro analogue of betamethasone, is a potent glucocorticoid with about 1/2 the potency of its fluoro analogue. It is used topically as its dipropionate derivative in inhalation aerosol therapy for asthma and rhinitis (see section for inhaled and intranasal glucocorticoids) but not for treatment of steroidresponsive dermatoses. PHA3THB/S36 PREMIER
o

RECOGNISED o TRUSTED

July 2010

The topical anti-inflammatory potency for beclomethasone dipropionate is about 5000 times greater than hydrocortisone; 500 times greater than betamethasone, or dexamethasone; and about 5 times greater than fluocinolone acetonide or triamcinolone acetonide, as measured by vasoconstrictor assay. Additional mono and difluorinated analogues for topical application include fluorometholone (6E-methyl-9E-fluoro) (ophthalmic use), flurandrenolide (6E-fluoro, 16E,17E-acetonide), fluocinolone acetonide (6E,9E- difluoro-16 E,17E-acetonide) and fluocinonide (21-acetate ester of fluocinolone acetonide). These compounds are classified as high to medium potent antiinflammatory agents depending upon concentration and vehicle used .

PHA3THB/S37

PREMIER

RECOGNISED o TRUSTED

July 2010

 

The acetonides (ketals) derivatives at the 16,17-position enhance lipophilicity to provide potent topical anti-inflammatory agents. Clobetasol propionate, halcinonide, halobetasol propionate, and mometasone furoate are examples of 21-chloro- corticoids, where the 21-chloro group replaces the 21-hydroxyl group. Clobetasol propionate, the 21-chloro analogue of betamethasone 17propionate, is about eight times more active as topical anti-inflammatory agent than betamethasone 17E-valerate, the standard of comparison for topical vasoconstrictor/anti-inflammatory activity. Mometasone furoate, a 9E, 21- dichloro derivative is also about eight times more active than betamethasone 17E- valerate as a topical anti-inflammatory agent.

PHA3THB/S38

PREMIER

RECOGNISED o TRUSTED

July 2010

Thus, substitution of a chlorine (or a fluorine) atom for the 21-hydroxyl group on the glucocorticoids greatly enhances topical anti- inflammatory activity. Clobetasol propionate and halobetasol propionate are high potency topical corticosteroid . Fluticasone propionate is similar to the 21-chloro steroids, except that it has a 1 7E-fluoromethylcarbothioate group instead of the 17-ketol group derivative. Several non-fluorinated analogues of triamcinolone acetonide suggesting that halogens are not always necessary for topical activity. These non-fluorinated cyclic ketals include desonide and amcinonide . Amcinonides potency is greatly enhanced by the more lipophilic cyclopentanone ketal and 21-acetate.
amcinonide

 

 

PHA3THB/S39

PREMIER

RECOGNISED o TRUSTED

July 2010

Inhaled and Intranasal Glucocorticoids

Overview  It is generally accepted that the anti-inflammatory effect of glucocorticosteroids cannot be separated from their adverse effects at the receptor level. Therefore, pulmonary and nasal pharmacokinetics become important determinants for the potential of an inhaled or nasally applied corticosteroid to cause systemic effects, because the lung and nasal tissue provide an enormous surface area from which drug absorption can occur into the systemic circulation. The main areas of concern with regard to drug-induced systemic effects include change in bone mineral density and growth retardation in children, cataracts and glaucoma. The degree of systemic side effects is dose-dependent, related to the halflife of the drug, frequency of administration, time of day when administered, and route of administration; i.e., the higher the plasma corticosteroid concentration and longer the half- life, the greater will be the systemic side effects. PHA3THB/S40 PREMIER
o

RECOGNISED o TRUSTED

July 2010

Thus, the search is to develop inhaled/intranasal corticosteroids with the following desirable pharmacokinetic qualities: they would exhibit fast systemic clearance following gastrointestinal absorption (high degree of first pass intestinal/ hepatic metabolism); a short half-life; lack of active metabolites; and high affinity for the corticosteroid receptor. These qualities determine the proportion of the drug that reaches the target cells as well as the fraction of the dose that reaches the systemic circulation to produce side effects. Modification of the pharmacokinetics through structural alterations has provided several new steroids with a better glucocorticoid receptor affinity and therapeutic index and lower bioavailability than the older drugs. The new inhaled/intranasal glucocorticosteroids like mometasone furoate, budesonide and fluticasone propionate are more lipophilic than those used in oral and systemic therapy and have greater affinity for glucocorticoid receptor than dexamethasone as a consequence of their greater lipophilicity. PHA3THB/S41 PREMIER RECOGNISED o TRUSTED July 2010

Several of the topical corticosteroids such as mometasone furoate, beclomethasone dipropionate, tnamcinolone acetonide and flunisolide, were reintroduced as inhalation and intranasal dosage forms for treatment of respiratory diseases, e.g., asthma or rhinitis. Inhaled budesonide and flunisolide are readily absorbed from the airway mucosa into the blood and are rapidly biotransformed in the liver into inactive metabolites. Mometasone furoate and fluticasone propionate are very potent antiinflammatory steroids with an oral bioavailability of less than 1%. PHA3THB/S42 PREMIER
o

RECOGNISED o TRUSTED

July 2010

Pharmacokinetics of Inhaled and Intranasal Corticosteroids

PHA3THB/S43

PREMIER

RECOGNISED o TRUSTED

July 2010

Summary of the SAR for Glucocorticoids and Mineralocorticoid Activity

 The structure in Figure depicts the ring conformation and absolute configuration for hydrocortisone and prednisolone. The all trans (B/C and C/D) backbone that is necessary for activity is very evident. As previously pointed out, the adrenocorticoids are generally classified as either glucocorticoids, which affect intermediary metabolism and are associated with inhibition of the inflammatory process, or mineralocorticoid. In fact, most naturally occurring and semi-synthetic analogues exhibit both of these actions. The 17F-ketol (-COCH2OH) side chain and the 4-3-ketone functions are found in clinically used adrenocorticoids, and these groups do contribute to the potency of the agents. Modifications of these groups may result in derivatives that retain biologic activity. PHA3THB/S44 PREMIER
o

 

RECOGNISED o TRUSTED

July 2010

For example, replacement of the 21-OH group with fluorine increases glucocorticoid and sodium-retaining activities, whereas, substitution with chlorine or bromine abolishes activity. Some compounds that do not contain the ketone system have appreciable activity. It has been suggested that this group makes only a minor contribution to the specificity of action of these drugs or to the steroid-receptor association constant. Based on structure-activity studies, the C and D rings, involving positions 11, 12, 13, 16, 17, 18, 20, and 21, are more important for receptor binding than the A and B rings. Generally, insertion of bulky substituents on the F-side of the molecule abolishes glycogenic activity, while insertion on the of E-side does not. It has been suggested that association of these steroids with receptors involves F-surfaces of rings C and D and the 17F-ketol side chain. It is possible, however, that association with the E-surface of rings A, C, and D, as well as with the ketol side chain, is essential for sodium-retaining activity. PHA3THB/S45 PREMIER
o

RECOGNISED o TRUSTED

July 2010

Many functional groups, such as l7E-OH, 17E-CH3, 16E-CH3 and 16F-CH3, 16E-CH3O and l6E-OH substituents, abolish or reverse this activity in 11desoxycorticosterone and 11-oxygenated steroids. Although some steroids cause sodium retention, many have glucocorticoid and either sodium-retaining or sodium- excreting action. Difficulties in correlating the structures of adrenocorticoids with biologic action are compounded because of differences in assay methods, species variation, and the mode of drug administration. The 9E-F analogue, fludrocortisone acetate, is more active than the 9E-Cl analogue in terms of sodium retention in the dog; the reverse is true in rat. While 16E-methylation or 16F-methylation enhances glucocorticoid activity, anti-inflammatory action is increased disproportionately to glycogenic action in both series.

 

 

PHA3THB/S46

PREMIER

RECOGNISED o TRUSTED

July 2010

 In humans, eosinopenic and hyperglycemic potencies are essentially the same. There is a close correlation in efficacy ratios derived from these tests and anti-rheumatic potency .  Because the eosinopenic-hyperglycemic activity and anti-rheumatic potency show excellent agreement, it has been suggested that these assays afford advantages in the preliminary estimation of anti- inflammatory potency. PHA3THB/S47 PREMIER
o

RECOGNISED o TRUSTED

July 2010

 Several compounds have been studied in animals and used to derive structure-activity relationships.  For example, insertion of a double bond between positions 1 and 2 in hydrocortisone increases glucocorticoid activity.  corticoids have a much longer half-life in the blood than hydrocortisone; ring A is resistant to metabolism to its 5F- metabolite.
1-

 But it is oxidatively metabolized at other positions especially the 6F position and the 17F-ketol.

PHA3THB/S48

PREMIER

RECOGNISED o TRUSTED

July 2010

If, however, a double bond is inserted between positions 9 and 11 (no oxygen function at 11), a decrease in glucocorticoid activity is observed. Except for cortisone, which results in an analogue with decreased glucocorticoid activity when a double bond is inserted between position 6 and 7, such modification of other glucocorticoids generally produces no change in activity. Insertion of E-CH3 groups at positions 2 (in 11F-OH analogues), 6, and 16 increases glucocorticoid activity in animals. Again, insertion of a 2E-CH3 group into the glucocorticoid almost completely prevents reduction of the 4-3-ketone system in vivo and in vitro, however, l6E/F- methyl blocks hydroxylation enhancing potency. Substitution at positions 4E, 7E, 9E, 11E, and 21 decreases activity. Although some analogues, such as 1 6E, 1 7E-acetonides and the 1,2dihydro derivative, are 11-desoxysteroids and are biologically active, the 11F-OH group of hydrocortisone is essential for the drug-receptor interaction. PHA3THB/S49 PREMIER
o

 

 

RECOGNISED o TRUSTED

July 2010

 

Cortisone, which contains an 11-keto function, is reduced in vivo to hydrocortisone. The drug 2E-methylhydrocortisone exhibits high glucocorticoid activity. This is probably because of steric hindrance to reduction (i.e., C=O to C-FOH) by the methyl group, thus rendering the analogue inactive. Insertion of E-OH groups into most other positions (1, 6, 7, 9, 14, and 16) or reduction of the 20-ketone, however, decreases glucocorticoid activity due in part to increased hydrophilicity. The 9E-F group increases glucocorticoid activity and nearly prevents metabolic oxidation of the 11F-OH group to a ketone. Redox metabolism of 4-steroids is mainly restricted to the 4-3-ketone, 6 and 16 positions and the 17F-ketol side chain whereas for the 1-corticoids it is only the 6 and 16 positions and 17F-ketol side chain. The 9E-F group may increase activity by an inductive effect, which increases the acidic dissociation constant of the 11F- OH group and thereby increases the ability of the drug to hydrogen bond to the glucocorticoid receptor. PHA3THB/S50 PREMIER
o

RECOGNISED o TRUSTED

July 2010

 

A 6E-F group also increases glucocorticoid activity, but it has less effect than the 9E-F function on sodium retention. Insertion of 2E-, 11E- (no OH group at 11), or 21-F groups decreases glucocorticoid activity. Of particular interest is a 12E-F group. When this function is inserted into corticosterone, which has no 17E-OH group, it potentiates activity to the same extent as a 9E-F group. Insertion of a 12E-F group into a 16E, 1 7E-dihydroxy steroid, however, renders the compound inactive. A 9E-F group potentiates activity in such analogues. It has been proposed that hydrogen bonding between the l2E-F and l7E-OH groups renders the analogue inactive. Conversion to the 16E,17Eisopropylidinedioxy (acetonide) derivative, which cannot hydrogen bond, restores biologic activity. PHA3THB/S51 PREMIER
o

 

RECOGNISED o TRUSTED

July 2010

The mineralocorticoid activity of the adrenocorticoids is another action of major significance. Many toxic side effects, making it necessary to withdraw steroid therapy in rheumatoid patients, are a result of this action. Highly active naturally occurring mineralocorticoids have no OH function in positions 11 and 17. In fact, OH groups in any position reduce the sodiumretaining activity of the adrenocorticoid. Generally, 9E-F, 9E-Cl, and 9E-Br substitution causes increased retention of urinary sodium with an order of activity in which F > Cl > Br, but species differences do exist. For these reasons, such compounds are not used internally in the treatment of diseases such as rheumatoid arthritis. Insertion of a l6E-OH group into the molecule affects the sodium retention activity so markedly that it not only negates the effect of the 9E-F atom, but also causes sodium excretion.

 

PHA3THB/S52

PREMIER

RECOGNISED o TRUSTED

July 2010

A double bond between positions 1 and 2 ( 1-corticoids) also reduces the sodium retention activity of the parent drug. This functional group, however, contributes to the parent drug only about one-fifth the sodiumexcreting tendency of a 16E-OH group. 12E-F, 2E-CH3, and 9E-Cl substitution contribute equally to sodium retention. A 21-OH group, found in all these drugs, contributes to this action to the same degree. Because 21-OH groups also contribute to glucocorticoid activity, it is easy to understand why it is difficult to develop compounds with only one major action. A 2E-CH3 group is about three times and a 21-F substituent two times as effective as unsaturation between positions 1 and 2 in reducing sodium retention. Other substituents reported to inhibit sodium retention include 16E-CH3 and 16F-CH3, 16E-CH3O, and 6E-Cl functions. PHA3THB/S53 PREMIER
o

RECOGNISED o TRUSTED

July 2010

A 1 7E-OH group, present in naturally occurring and semi-synthetic analogues, reduces sodium retention to about the same extent as does unsaturation between positions 1 and 2. Conversion of the 17E-hydroxy to either a 1 7E-ester or an ether as with l6E,17E-isopropylidinedioxy (acetonide), greatly enhances the antiinflammatory potency and glucocorticoid receptor affinity (Table 5). However, as evidenced with beclomethasone dipropionate, etherifying the 21-hydroxy group reduces activity and receptor affinity. On the other hand, 21-halogens or 21-halomethylene groups greatly increase topical anti-inflammatory activity with no change or a decrease in mineralocorticoid activity. Perhaps, a hydrogen bonding group mineralocorticoid receptor affinity. at 21 enhances or retains

 

PHA3THB/S54

PREMIER

RECOGNISED o TRUSTED

July 2010

PHA3THB/S55

PREMIER

RECOGNISED o TRUSTED

July 2010