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MASTERSKILLUNIVERSITY COLLEGE OF HEALTH SCIENCES
THE LEADER
In Nursing & Allied HealthEducation in Malaysia
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Practice and Therapeutics
LecturerK.Anandarajagopal,M.Pharm.,
Adrenocorticoids
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LEARNING OBJECTIVES
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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.
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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
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Steroid Nomenclature
and Structures
rings A &B are trans fused
rings A &B are cis fused
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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
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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.
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Pharmacologic and Pharmacokinetic
Properties for Some Adrenocorticoids
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Pharmacokinetics of Commonly
Used Oral Adrenocorticoids
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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.
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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.
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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.
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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.
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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.
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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.
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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).
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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.
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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.
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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.
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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.
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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.
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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.
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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
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Potency Ranking
for Topical Corticosteroides
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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.
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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 .
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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.
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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
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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.
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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.
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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%.
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Pharmacokinetics
of Inhaled and Intranasal Corticosteroids
S f th SAR f
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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-isopropylidine- dioxy
(acetonide) derivative, which
cannot hydrogen bond,
restores biologic activity.
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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.
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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.
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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.
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