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PREMIER o RECOGNISED o TRUSTEDPREMIER o RECOGNISED o TRUSTED July 2010PHA3THB/S1

MASTERSKILLUNIVERSITY COLLEGE OF HEALTH SCIENCES

THE LEADER

In Nursing & Allied HealthEducation in Malaysia




Practice and Therapeutics

LecturerK.Anandarajagopal,M.Pharm.,

Adrenocorticoids




LEARNING OBJECTIVES




INTRODUCTION

The adrenal glands are flattened, caplike structures located above thekidneys.

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 to their biochemical

mechanism of action into glucocorticoids (hydrocortisone) and

mineralocorticoids (aldosterone).

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.




Despite their similarities in chemical structures and stereochemistry, each classof 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




Steroid Nomenclature

and Structures

rings A &B are trans fused

rings A &B are cis fused




The stereochemistry of the rings markedly affects the biologic activity of agiven 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 5 F configurationmaking 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.




Cholesterol (cholest-5-en-3 F-ol) is a

5

steroidor, more specifically, a 5-sterol because it is

an unsaturated alcohol.

These biologically active steroids include members of the 5E-pregnane, 5E-

androstane, and 5E-estrane steroid classes.

The adrenocorticoids (adrenal cortexhormones) are pregnanes and are

exemplified by hydrocortisone (cortisol),

which is a 11 F, 17E, 21-trihydroxypregn-

4-ene-3,20-dione 21-acetate.

Progesterone (pregn-4-ene- F,20-dione), a

female sex hormone synthesized by thecorpus luteum, is also a pregnane

analogue.

The male sex hormones (androgens) are

based on the structure of 5-androstane.




Testosterone, an important naturally occurring androgen, is named 17 F-hydroxy-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 estra-

1,3,5-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 chain, however, this should be indicated in thenomenclature.

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.




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., 0.1-

1.0 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, asoutlined 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 targetcells) 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.




Recent investigations onestrogen, progestin, and

androgen action indicate

that active, unoccupied

receptors are also present in

the nucleus of the cell.

Prior to the binding of thesteroid, the steroid receptor

is complexed with heat

shock proteins (HSP).

In the current model, the

steroid enters the cell andbinds 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.




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 normalphysiological 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.




Biosynthesis

There are two stepsi. Pregnenolone Formation

ii. Pregnenolone to Glucocorticoids and Mineralocorticoids

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 andhypertension.

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.

i. Pregnenolone Formation




The first oxidation results inthe formation of cholest-5-

ene-3 F, 22R-diol (step a),

followed by the second

oxidation yielding cholest-5-

ene-3 F,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 thecommon precursor in the

formation of the

adrenocorticoids and other

steroid hormones.




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. Theresult 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.




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 doublebond 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.




Metabolism

Hydrocortisone and cortisone are biochemically inter- convertible by theenzyme 11 F-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-glucuronideconjugates and minor O- sulfate conjugates of urocortisol, 5 F-

dihydrocortisol, and urocortisone




Development

of Adrenocorticoid Drugs

Systemic Corticosteroids Overview The clinically available adrenocorticoids may be administered by

intravenous injection, oral tablets or solutions, topical formulations, intra-

articular 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.




Pharmacologic and Pharmacokinetic

Properties for Some Adrenocorticoids




Pharmacokinetics of Commonly

Used Oral Adrenocorticoids




Systemic corticosteroids

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).

The degree of systemicside effects is dose-

dependent, 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.




Cortisone, Hydrocortisone

and Their Derivatives

Cortisone is administered orally or IM injection as its 21- acetate (cortisoneacetate). 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 drugorally.




The acetate ester derivative demonstrates increased stability and has alonger 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 injectionsites is usually complete within 24-48 hours.




Other ester derivatives that are availableinclude hydrocortisone cypionate [21-( F-

cyclopentylpropionate) ester],

hydrocortisone butyrate (17E-butyrate

ester), hydrocortisone buteprate (l7E-

butyrate, 21-propionate esters),

hydrocortisone valerate (17E-valerateester), 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 thegastrointestinal 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 anti-

inflammatory steroids.




The phosphate ester is completely and rapidly metabolized byphosphatases, 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 hydrocortisonevalerate 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 psychosisare exaggerated manifestations of the normal metabolic functions of the

hormones.




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-fluoro-substituent, 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 Addison¶s disease.




Prednisone, Predinisolone

and its Derivatives

Investigators observed that the1-dehydro derivatives of cortisone and

hydrocortisone, namely prednisone and

prednisolone, are more potent anti-

rheumatic 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 morepotent 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).




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.




Methylprednisolone

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 17 F-ketol

group to C21- COOH and C20-COOH, and 6 F-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 levelsfor methylprednisolone is attained in about 30-60 minutes following its IV

administration and 15% of its IV dose is recovered unchanged in the urine.

O

OH

H

HH

OH

O

H3C

Studies with methylcorticoids revealed 2E

-methyl

derivatives to be inactive, whereas the 2E-methyl-9E-

fluoro analogues had potent mineralocorticoid activity.




Triamcinolone

O

OH

H

HF

OH

O

OH

OH

1-corticoid research involved synthesis and examination of compoundscontaining both a 9E-fluoro group and a double bond between C1 and C2.

Triamcinolone has structural features of 1-corticoid & 9E-fluoro 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 6 F-hydroxy metabolite.




DexamethasoneO

OH

H

HF

OH

O

CH3

OH

These studies led to the development of dexamethasone (9-fluoro-16E-methyl analogue).

A 16 F-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 6 F-hydroxy metabolite being recovered in

urine.




Betamethasone

O

OH

H

HF

OH

O

CH3

OH

Shortly after the introduction of dexamethasone, betamethasone, whichdiffers 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.




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 absorbedafter 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 determinedusing 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.




Once absorbed

through the skin,

topical

corticosteroids are

handled through

metabolic

pathways similar

to the systemically

administered

corticosteroids.

They are

metabolized,

primarily in theliver, and are then

excreted into the

urine or in the bile.

Topical corticosteroids




Potency Ranking

for Topical Corticosteroides




Triamcinolone to be used topically is generally dispensed as it¶s 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 of

triamcinolone and is about 8 times more active than prednisolone.

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 dipropionatederivative in inhalation aerosol therapy for

asthma and rhinitis (see section for

inhaled and intranasal glucocorticoids)

but not for treatment of steroid-

responsive dermatoses.




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 anti-

inflammatory agents depending upon concentration and vehicle used .




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 17-

propionate, 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.




Thus, substitution of a chlorine (or a fluorine) atom for the 21-hydroxyl

group on the glucocorticoids greatly enhances topical anti- inflammatoryactivity.

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 groupderivative.

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 .

Amcinonide¶s potency is greatly enhanced by the more lipophilic

cyclopentanone ketal and 21-acetate.amcinonide




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 tissueprovide 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 half-

life 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.




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 systemiccirculation 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.




Several of the topicalcorticosteroids such as

mometasone furoate,

beclomethasone dipropionate,

tnamcinolone acetonide and

flunisolide, were reintroduced as

inhalation and intranasal dosageforms 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 bio-transformed in the liver into

inactive metabolites.

Mometasone furoate and fluticasone propionate are very potent anti-

inflammatory steroids with an oral bioavailability of less than 1%.




Pharmacokinetics

of Inhaled and Intranasal Corticosteroids

S f th SAR f




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 areassociated with inhibition of the inflammatory process, or

mineralocorticoid.

In fact, most naturally occurring and semi-synthetic analogues exhibit both

of these actions.

The 17 F-ketol (-COCH2OH) side chain and the 4

-3-ketone functions arefound 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.




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. Ithas been suggested that association of these steroids with receptors

involves F-surfaces of rings C and D and the 17 F-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.




Many functional groups, such as l7E-OH, 17E-CH3

, 16E-CH3

and 16 F-CH3

,

16E-CH3O and l6E-OH substituents, abolish or reverse this activity in 11-

desoxycorticosterone 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 16 F-methylation enhances glucocorticoid activity,

anti-inflammatory action is increased disproportionately to glycogenic

action in both series.




In humans, eosinopenic and hyperglycemic potencies are essentially the

same. There is a close correlation in efficacy ratios derived from these testsand 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.




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.

1- corticoids have a much longer half-life in the blood than hydrocortisone;

ring A is resistant to metabolism to its 5 F- metabolite.

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




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 11 F-OH analogues), 6, and 16increases 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 1,2-

dihydro derivative, are 11-desoxysteroids and are biologically active, the

11 F-OH group of hydrocortisone is essential for the drug-receptor

interaction.




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- F-

OH) 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 duein part to increased hydrophilicity.

The 9E-F group increases glucocorticoid activity and nearly prevents

metabolic oxidation of the 11 F-OH group to a ketone. Redox metabolism of

4-steroids is mainly restricted to the 4-3-ketone, 6 and 16 positions and

the 17 F-ketol side chain whereas for the 1-corticoids it is only the 6 and 16positions and 17 F-ketol side chain.

The 9E-F group may increase activity by an inductive effect, which

increases the acidic dissociation constant of the 11 F- OH group and thereby

increases the ability of the drug to hydrogen bond to the glucocorticoid

receptor.




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,17E-isopropylidinedioxy

(acetonide) derivative, which

cannot hydrogen bond,

restores biologic activity.




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 sodium-

retaining 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.




A double bond between positions 1 and 2 (1-corticoids) also reduces thesodium retention activity of the parent drug. This functional group,

however, contributes to the parent drug only about one-fifth the sodium-

excreting 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 sodiumretention.

Other substituents reported to inhibit sodium retention include 16E-CH3

and 16 F-CH3, 16E-CH3O, and 6E-Cl functions.




A 1 7E-OH group, present in naturally occurring and semi-syntheticanalogues, 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 anti-

inflammatory 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 at 21 enhances or retains

mineralocorticoid receptor affinity.



PREMIER RECOGNISED TRUSTEDPREMIER RECOGNISED TRUSTED J l 2010PHA3THB/S55

adrenocorticoids edited

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