Steroids and drugs affecting hormonal

systems (2)

Busaban Sirithunyalug

Progestins

The term progestin is used for any natural or man-made substance

that has properties similar to natural progesterone.

There are many types of progestins, and each has a different profile
in terms of progestational, estrogenic, and androgenic activity
and/or effects.

Activation of the progesterone receptor (PR) by progesterone receptor

ligands.

PRE = progesterone
response element

The Female Body

Estrogen
- Development of
secondary sex
characteristics
- Growth of uterus
during puberty
- Initial growth of
endometrium
during menstrual
cycle

Progesterone
- Development of
breasts during
puberty
- Growth of
endometrium
during menstrual
cycle
- Inhibition of
uterine contractions
during pregnancy

Human progesterone receptor:

Isoforms A & B form
AF-3

AF-1

DBD

AF-2

HBD

hPR-B

AF-1

DBD

AF-2

HBD

hPR-A

Differential transcriptional activities

Cell type- and promoter-specific
Often PR-B > PR-A
PR-B mediates the stimulatory activities of progesterone
PR-A repressor of PR-B and ER signaling
Present at unequal levels in breast tumors;
some tissues PR-A predominance as early event
in carcinogenesis

Progestrogen
Progesterone
21 carbon atoms

Only naturally occuring progestrogen

(endogenous)

Half-life 5 minutes when taken orally

(rapid metabolism); unpredictable
absorption
Sedative side effect

Pregn-4-ene-3,20-dione

Produced directly from pregnenolone

& secreted from the corpus lutium (ovary)
(20-30mg/day)
during second half of the menstrual cycle
(also from placenta, testis & adrenal gland)
Responsible for changes associated
with luteal phase of the menstrual cycle.
(normal men secrete about 1-5 mg daily)

Many analogues have medicinal use

mostly menstrual disorders,
contraceptive use (+ estrogen or alone),
though some anticancer application

Menstrual Cycle- hormones

Progesterone is essential for maintaining
pregnancy, suppression of ovulation and for the
survival of embryo.

progesterone 4-5

progesterone

Metabolism of progesterone
O

O
Progesterone

OH

HO

OH

O
OH

5-Pregnanediol, ring A-B cis

Major metabolite

6-Hydroxyprogesterone

20-Hydroxyprogesterone

Metabolism of progesterone
Ring A & D

Note 6-OH

3-keto-4-ene moiety is critical for progestational activity

Numerous efforts have been put to devise progesterones that have higher affinity for
its receptor and also that extend the life of the drug.

Biosynthesis and Metabolism of Estradiol and Progesterone

H3C
CH3

H3C
CH3

CH3

CH3

cholesterol

CH3 OH

CH3

CH3

CH3

HO

HO

HO

CH3 OH

pregnenolone

testosterone

estradiol

H3C
CH3

progesterone

CH3 O

CH3

HO

O
CH3

OH

CH3

CH3

HO

H3C

H3C

CH3

OH

5-metabolite

20/-hydroxy
metabolite

CH3

CH3 OH

CH3

CH3

estrone

OH
HO

O
OH

6a-hydroxy
metabolite

Conjugation to glucuronides, sulfates, etc.

estriol

Progestins (synthetic progestrogens)

Three structural classes
Progesterone derivatives
17-hydroxyprogesterone derivatives
19- norprogesterone derivatives
Testosterone &19- nortestosterone derivatives
Miscellaneous
Some of the synthetic progestins are pro-drugs need to be
metabolized become bioactive compounds

Progestins (synthetic progestrogens)

Medroxyprogesterone acetate
Provera

17-hydroxyprogesterone
IM,PO

12

17- acyl group slows metabolism of the 20-one (ring D) to alcohol

6-methyl enhance activity & prevent metabolic hydroxylation C6 & ring A
100% oral bioavilability, very popular orally effective progestin

Long term injection; causes ovulation to cease by decreasing FSH/LH levels

(contraception with progestin alone)

(receptors)
GnRH LH surge

Progesterone derivatives

25 times as potent as
ethisterone

Extra double bond at C-6

Orally active

Cyproterone acetate

Typical Progesterone Agonists

O
CH3

CH3
OCO(CH2)4CH3

CH3

Derivatize ring D
O

17-hydroxy progesterone
caproate

17-hydroxyprogesterones

im, provide contraception for 3 months

Derivatize rings B & D

O
CH3

CH3

CH3

OCOCH3

CH3

CH3

CH3

OCOCH3

CH3

O
CH3

Medroxyprogesterone acetate

Megestrol CH3
acetate

The substituents that have been found useful are 6 methyl, 6-Me, 6-ene and 6-chloro

CH3

O
Cl

Chlormadinone
acetate

CH3
OCOCH3

SAR

15

Progesterone-derived progestins and classification.

pregnanes

norpregnanes

17-hydroxyprogesterone derived

19- norprogesterone derived

Gestonorone

Unusual Progesterone Agonists

CH3 OH

Testosterone Derivatives

CH3 OH

CH

CCH3

CH3

CH3
O

CH3

Dimethisterone

Ethisterone

19-Nor-testosterone Derivatives
CH3 OH

CH3 OH

CH

H3C

HO N

Norethisterone

Norethindrone

Same compound

Norgestimate

OH
CH

CH

CH

H3C

OCOCH3

Norgestrel

Testosterone & nortestosterone

derivatives

Two important
discoveries

17-alkynyl
testosterone had
greater
progestational than
androgenic activity
19-norprogesterone
still maintain
progestational
activity

17-alkynyl blocks
metabolic or bacterial
oxidation to
corresponding 17-ones
(ring D)

OH

OH
CH3

O
Testosterone (28)

17-Methyltestosterone (29)

OH

OH
CH2CH3

O
17-Ethyltestosterone (30)

androgenic

18

activity

CH

O
Ethisterone (31)

androgenic & progestrogenic

activity

CH3 OH
CH3
O

Testosterone derivatives
2-carbon acetylenic side chain

17-ethynyltestosterone

19

17-ethinyl group completely alters

the structural profile of the molecule
testosterone derivative looses its anabolic activity
lipid solubility & prevent oxidation (blocked metabolism
by liver enzymes)
hence these derivatives are oral active

Test

20

Nortestosterone derivatives ; estrane &

gonane subdivided

19-nor group increases the affinity of the molecule to progesterone

receptor and hence the 19-nor testosterone derivatives are more
active
Estrane family
(Primolut N)

Cycloprogynova

Gonane family

21

Norethisterone 19-nor-17-ethinyltestosterone
Nor = C10 CH3
progestational ethisterone 5-10
and slight estrogenic activity but less
androgenic
Orally active first generation progestin for
treatment of amenorrhoea, endometriosis

Norgestrel is a racemic mixture

Ethyl gr. at C13
Active form = levo-norgestrel

19-nortestosterone derivatives
Levonorgestrel (Microgynon )
(Norgestrel, marvelon )
Nordette

22

Norgestimate

Gonane family

Levo-form is active enantiomer

C13 ethyl group C13 methyl group
High progestational and androgenic
activity with strong antiestrogen
effects
Second gen.
May be used for prevention of pregnancy
(emergency contraceptive)
Levonorgestrel 0.75 mg (postinor )

19-nortestosterone, 3-oxime pro-drug

Be metabolized to 17-deacetylnorgestimate
(norgestrel 3- oxime) & norgestrel which provide
the progestational action
Orally active & used with an estrogen in oral
contraceptive products
Minimal androgenic action (third gen. progestin)

has high progestational activity while

showing slight estrogenic effects

23

Classification of Progestins (19-nor-Testosterone)

The estrane family (typically, first generation progestins) consist of norethindrone and other
progestins that metabolize to norethindrone. These include norethindrone acetate and
ethynodiol diacetate .
The gonane family: This classification is further subdivided into two groups:
Second generation progestins, which have varying degrees of androgenic
and estrogenic activities. These include levonorgestrel and norgestrel.
Newer gonanes, or third generation progestins; these are reported to have the
least androgenic effects and include desogestrel and norgestimate.
Drospirenone, the last progestin, is also the newest (4th) generation. Drospirenone is a unique
progestin as it differs from the others because it is derived from 17-spirolactone, not from the
19-nortestosterone derivatives.
Typically the third (and fourth) generation progestins tend to be highly selective and possess
minimal androgenic properties. These include norgestimate, desogestrel, and drospirenone.

19-Nortestosterone Derivatives
1st Generation: Binds AR
AR related ADEs (weight gain, acne)
Norethindrone

2nd Generation, lower affinity for AR

due to 13-ethyl
Norelgestromin
Decreased
AR activity

Norethynodrel
*isomer of
norethindrone

Gestodene
Increased oral
activity
Norgestimate

Ethynodiol diacetate
*esters removed in
stomach
Norgestrel
L>R for activity
Plan B

Desogestrel
Chiral center

Third generation progestins

(tend to have fewer male-like side effects)
Desogestrel Oilezz

Gestodene Meliane
Gonane family

Pro-drug : be oxidized to 3-one

(3-keto-desogestrel)
minimal androgenic activity
It shows less negative impact on
metabolism, weight gain, acne, and
other side effects typical of older
progestins.

26

The compound shown below, called progestene, was synthesized and

compared to progesterone in terms of its receptor binding and biological
activity.

OH
C CH

27

progestene

a. Use your knowledge of SAR in progesterone derivatives

to briefly discuss the modifications made to progesterone
to create progestene. (6 pts.)
addition of ethynyl group (provides oral
availability)
removal of 19-methyl group (provides PR
binding)
modification of 18-methyl group to ethyl
(appears to accentuate binding to PR)
removal of pregnane side chain and replacement
with 17-hydroxyl (probably provides AR
binding)

What is the IUPAC name for compound 1 shown

below? (4 pts.)

HO

HO

CH2OH
O
OH

compound 1

3, 11, 17, 21-tetrahydroxy-5-pregn-20-one

Grading: +1 for correct order and in 3, 11, 17, 21; +1 for
tetrahydroxy; +1 for 5(regardless of where it was in the name);
+1 for pregn-20-one.
28

Tibolone
(Livial)

29

Chemical IUPAC Name is

(7alfa,17beta)-17-ethynyl-17-hydroxy7-methylestr-5(10)en-3-one

Estrogenic, progestagenic &

androgenic activity

estrogenic effects on the vagina, on

bone and on the thermoregulatory
centres in the brain (hot flushes)

used mainly for hormone

replacement therapy in postmenopausal women not for
contraception
19-nortestosterone
Non-estrogen steroid
matabolite 3
estrogenic, androgenic
progestogenic properties

estrogenic androgenic
climacteric symptom
menstrual bleeding
HRT

Estranes: have some androgenic activity

as well as estrogenic/anti-estrogenic
actions. Rapidly absorbed
Gonanes: More potent than estranes and
less androgenic activity and are now used
in the 3rd generation combination oral
contraceptives
31

Testosterone-derived progestins and classification

lynestrenol

Miscellaneous synthetic progestins

Drospirenone
Yasmin

Spironolactone

spirolactone

Drospirenone is a unique progestin as it differs from the others because it is

derived from 17-spirolactone, not from the 19-nortestosterone derivatives.

analog to spironolactone (mineralocorticoid receptor antagonist) with 2 cyclopropyl

groups
Antimineralocorticoid activity as well as progestational activity
Antiandrogenic effects (fourth gen.)
less water retention

33

-Monophasic combinations, contain the same amount of drug in each tablet ( 3

mg of drosperinone and 30 mg of ethinyl estradiol )

 progesterone diosgenin
OAc
H

CH3

acetylation

Ac2O

H
HO

CrO3

AcO
Diosgenin

CH3

Oxidative clevage

AcO
O
C O
O

AcO
C O
H

Acid hydrolysis

HOAc

C O

1) H2/Pd
2) OHO

34

Progesterone

3) Al(OCH(CH3)2)3

AcO
16-Dehydropregnenolone acetate

Oral Contraceptive Agents

Combination of estrogens & progestins

Continuous progestin therapy without concomitant administration
of estrogen e.g. minipills
All combination birth control pills contain estrogen (typically ethinyl
estradiol) and a progestin.

35

Monophasic, biphasic & triphasic combination tablet

In contrast to estrogen, there are many types of progestin found in

various oral contraceptive brands.
The older progestin types are usually referred to as first- and
second-generation while the newer ones are called thirdgeneration (and fourth)

How does birth control work?

1. Interrupts endogenous
cycle of estrogen and
progesterone.
2. Continuous dosing leads to
feedback inhibition of gonadatropins
(LH, FSH)
3. No LH surge for ovulation
4. Prevent ovulation, and follicule
maturation so fertilization and
pregnancy cannot be physiologically
supported

Progesterones: increase thickness of cervical

mucus to physically prevent sperm from swimming
upstream

Competitive progesterone receptor

antagonists : 11-substituted steroids
Mifepristone (RU 486)
Invented as cortisone antagonist

37

19-Norsteroid strongly bind PR and inhibit

the activity of progesterone

Has luteolytic effect and is effective as

postcoital contraceptive

Abortion pill (terminate early pregnancy =

abortifacient) (pregnancy depend on
progesterone activity)
Orally active prostaglandin

Adverse effects : prolong bleeding

Adrenal Cortex Hormones

Catabolic steroid

38

Adrenal Cortex Hormones

39

Release from adrenal cortex

glucocorticoids, mineralocorticoids and androgens (little
physiological significant)
Adrenocorticoids (corticosteroids)
Glucocorticoids : regulate carbohydrate, protein and lipid
metabolism, inflammatory process (interfere with
prostaglandin synthesis), immune suppressive action :
cortisol
Mineralocorticoids : influence salt balance and water
retention (retention of Na/Cl; excretion of K) : aldosterone
Plasma cortisol concentration is 100- fold higher than
aldosterone

Steroids of adrenal cortex

(ACTH)
desmolase

40

(Angiotensin II & III)

desmolase

(ACTH)
desmolase

Negative feedback system

41

Adrenal Cortex & Steroidogenic pathways

Aminoglutetimide block this step cortisol
(cholesterol to pregnenolone by inhibiting the enzyme P450scc)

Stress hormone = cortisol

42

Biosynthesis of
hydrocortisone and
aldosterone

No glucocorticoid
activity

acetal is a molecule with two

single bonded oxygens attached
to the same carbon atom.

43

Acetal formation

Unique to zonaglomerulosa
no 17-alpha-hydroxylase
activity but an 18hydroxylase activity

Hyperfunction & Hypofunction of the

adrenal cortex

Hyperfunction :
Aldosteronism : hypertension ; surgical , spironolactone

Hypercortisolism = Cushing syndrome : buffalo hump, moon

face, osteoporosis : surgical, radiation, aminoglutetimide,
ketoconazole

Hypofunction : Addisons disease ; cortisol, fludrocortisone,

dexamethasone
: Cortisone acetate or hydrocortisone usually is the corticosteroid
of choice for replacement therypy (gluco- & mieralocorticoid
properties)

46

Cortisol deficiency

47

48

49

Glucocorticoids
Cortisone

Cortisol (hydrocortisone)
Stress hormone, elevates blood pressure
Numerous effects on the immune system

Replacement
therapy

(17-hydroxy-11-dehydrocorticosterone)
inactive metabolite of cortisol by enzyme
11-hydroxysteroid dehydrogenase (11-HSD)

Corticosterone
Weak potency (0.5)
Converted to aldosterone
(by aldosterone synthase)

50

HO
O

OH

HO
HO

OH

cortisol

11--hydroxy steroid dehydrogenase

11- HSD
O

Cortisone

Hydrocortisone

Structural modifications of the hydrocortisone molecule by halogenation,

methylation, acetylation, esterification, and/or double bond introduction
have led to topical corticosteroid preparations with variable antiinflammatory potency, glucocorticoid vs mineralocorticoid activity, and
adverse effects.
51

Structure-Activity Relationship
(SAR)
1. Required for activity: ketone at 3 position;
4=5 double bond
2. Small modifications in the basic corticosteroid
structure alter:
a.
b.
c.
d.
e.

carbohydrate-potency
sodium-retaining potency
anti-inflammatory potency
drug half-life
transcortin binding
9 Fluoride
( potency)

52

16-CH3-methyl group
(antiinflammatory)
(sodium retention)

Corticosteroid metabolism (liver)

a. reduction of double bond at 4=5 position to yield inactive
metabolite
b. conjugation of inactive metabolite
c. excretion
Liver disease affects steroid metabolism.
prednisone--------> prednisolone
(inactive)
(active)

53

reduction

Cis- fonfiguration of ring A/B

54

Urocortisol = 3- hydroxy-5tetrahydrocortisol = major

inactive metabolite

(5 pregnane geometry in bile acids)

Solubility
O
HO

CH2OH
HO

OH

OH

H
H

CH2OCOCH3

H
H

O
Hydrocortisone acetate

Hydrocortisone

Orally active

O
HO

C21 acetate

CH2OPO 3Na2
OH

H
H

C21 sodium phosphate ester

, iv

O
Hydrocortisone sodium phosphate

55

Synthetic glucocorticoids

Synthetic glucocorticoids
Prednisone

Oxidation of ring A : second double bond

Pro-drug : be converted to prednisolone
: 5 times as potent as hydrocortisone
11-OH maintains good topical antiinflammatory activity
1-ene of prednisone increases antiInflammatory & decreases salt retention
Duration of action : 3 times as long as
that of hydrocortisone
Orally active

57

Cortisol (hydrocortisone)

Prednisolone & 6 - methyl prednisolone

Treatment as anti-inflammatory
and auto-immune conditions (rhumatoid
arthritis)
Orally and acetate ester for im &
Sodium phosphate for iv
-methyl at C6 slightly increase glucocorticoid
and reduce mineralocorticoid

Synthetic glucocorticoids : 16-methyl group

2. Betamethasone

1. Dexamethasone

alpha

9-fluoro ?

C16-methyl group hindered rapid metabolic

reduction of carbonyl function at C20: longer
duration of action
Also increased glucocorticoid and reduces
mineralocorticoid activity
9-fluoro-11 ,17,21-trihydroxy
-16-methylpregna-1,4-diene-3,20-dione
C16-methyl group increase glucocorticoid
and reduces mineralocorticoid activity
Immune suppressive drug
Potency 4-5 times of prednisolone
Orally active

beta

Differs from dexamethasone only in

configuration of 16-methyl gr.
9- fluoro increases both glucocorticiod
& mineralocorticoid activities
Modurate potent ,topical cream
Ester: dipropionate (diprosone)
Valerate (betnovate)

Topical Corticosteroids : Skin absorption VS lipid solubility

betnovate

diprosone

Medium potency
High potency
Betamethasone dipropionate
Very high potency
9 fluoro, 21-chloro-corticoid (analog of
betamethasone 17-propionate)
C21-chloro substituent promotes high glucocorticoid
activity when given by the topical route

59

Clobetasol
(Dermovate)

Isolation from urine of a boy with an adrenal tumor

16-hydroxy analog reduced mineralocorticoid activity

COCH2OH
OH
OH

HO
H
F
O
Triamcinolone

H
F

Topical steroid

O
Triamcinolone Acetonide

16-hydroxy into 9 fluoroprednisolone

16-hydroxy decreases salt retention &
increase glucocorticoid potency but low oral
bioavaiability
Cyclic ketal : condesation with acetone
enhance lipophilicity to provide more
potent topical derivative (skin penetrating
power)
Triamcinolone acetonide is about 8 times
more potent than prednisolone

60

COCH2OH
O
O

HO

Fluocinonide , acetate of
fluocinolone ; high-potency

SAR for glucocorticoids and

mineralocorticoids activities

All trans steroid skeleton is required for anti-inflammatory activity

All natural & most synthetic analogs have a hydroxyl group at C17 & C21
Presence of D4-3keto, 11-OH, 17 ketol= -COCH2OH needed for antiinflammatory activity
Planarity of A ring without losing 19-CH3 group for anti-inflammatory
activity
Substitution of 9-, 16 -methyl favor anti-inflammatory activity in most
cases
F>Cl>Br>I for anti-inflammatory activity (nature & position determine
potency/toxicity) ; C6, C9, C21
Numerous mono-, di-, and tri-halogenated topical corticosteroids available

D4-3keto = Carbonyl gr. at C3, double bond between C4&5

61

Respiratory corticosteroids
Beclometasone dipropionate (BDP)
Beconase, Beclovent

Pro-drug of 17-monopropionate
(17-BMP) which is more active than BDP

62

Fluticasone propionate
Flonase

Budesonide
Pulmicort

Highly potent nonhalogenated

Respiratory corticosteroids : inhaled as

microcrystalls
More lipophillic than oral &
systemic steroids

22 R has higher affinity to GR than 22 S epimer

Butyl acetal chain

Budesonide
Pulmicort, rhinocort
Provided as the mixture
of two epimer

21- chlorocorticoid
Both are very potent anti-inflammatory
Steroids with oral bioavailability of less than 1 %

63

(Nasonex )

Budesonide esterification

Ester formation at C21-OH

Behave like intra cellular depot drug

excess
surplus budesonide also forms esters with long-chain fatty acids, resulting in the formation of a
depot of budesonide esters within the cell.
These conjugates are inactive, but as the concentration of free budesonide in the cell decreases,
free budesonide is released from them under the influence of lipase.

64

65

Glucocorticoids used to treat asthma and allergic

rhinitis (some are also used topically)

66

Aldosterone
Biosynthesis

Pure mineralocorticoid
67

Mineralocorticoids
Aldosterone

Produced from progesterone in

zona glomerulosa of adrenal cortex,
lack of hydroxylation at C17 with aldehyde
formation at C18
Raises blood pressure and fluid volume,
Incresaes Na+ uptake (bind MR)

68

Fludrocortisone

9-fluoro analog of cortisol

Synthetic mineralocorticoid
Treatment of adrenal insufficiency
(addison disease)
9-fluoro increased both
Glucocorticoid (11) & mineralocorticoid (300)

Role of 11 - hydroxysteroid dehydrogenase (11 HSD)

69

MR bind cortisol & aldosterone with equal affinity, and plasma cortisol levels are 1000-fold
higher than aldosterone
Whats to keep cortisol from saturating the MR?
11 - hydroxysteroid dehydrogenase is present in aldosterone target cells.
11 hydroxysteroid dehydrogenase metabolizes cortisol to the form that doesnt bind MR
(cortisone)
Genetic defects or chemical inhibition of this enzyme (licorice-glycyrrhizinic acid) lead to a
pseudo-hyperaldosteronism (severe hypertension) : due to cortisol saturation of MR net
effect similar to aldosterone excess ; licorice intoxication

11 -HSD

liver isozyme

kidney isozyme

11-beta-hydroxysteroid dehydrogenase (11-beta HSD )

This enzyme "protects" the cell from cortisol and

allows aldosterone to act appropriately.

72

73

Licorice Intoxication
The basis of this effect is that licorice contains glycyrrhizinic
acid, a molecule that inhibits 11-beta-hydroxysteroid
dehydrogenase, the enzyme that normally inactivates cortisol
(to cortisone, which has only a very weak affinity for the
mineralocorticoid receptor) in mineralcorticoid target cells.
Cortisol has the same affinity as aldosterone for the
mineralocorticoid receptor, but is present is several thousandfold excess over aldosterone.
If cortisol is not inactivated, the net effect is similar to
aldosterone excess.

Structure-activity relationships
GR

Drug

75

MR

Relative
antiinflammatory
potency

Relative Na+ retaining potency

Duration of
action
(half-life)

Cortisol
(hydrocortisone)

S(8-12h)

Prednisone

0.8

I(12-36h)

Fludrocortisone
(9-fluorocortisol)

10

125

S(8-12h)

Dexamethasone

25

0-2

L(36-72h)

Aldosterone antagonist
Spironolactone

Eplerenone

Thioester promote binding

to inactive conformation of
receptor

17-lactone drug
Potassium sparing diuretic
Anti-androgen effect (can cause gynecomastia)
Hormone therapy for male-tofemale transsexual people
active metabolite

76

Reduced cardiovascular risk

myocardial infarction

77

 (Points to ponder)
General structure of steroid hormones?
How are carbon numbered?
How are rings oriented with respect to each other?
How are steroids named? What is - and - orientation?
How is cholesterol biosynthesized? What is the key step in the biosynthesis

a
78

exemestrane

Exam

79

80

81

83

84

aldosterone

11- deoxycorticosterone
85

danazol

heterocyclic ring at ring A enhances the

anabolic activity

e
86

Fluticasone propionate

O
1.

CH2O
O

HO

O
(CH2)3CH3
6.

OH

O
OH

HO

O
OH
2.

OH

C C CH3

7.

HO

3.

8.

HO

CH2O
O
OH

HO
OH
N
4.

OH
9.

CH3

N
Cl
O
5.

N
CH2OH
O

OH

O
10.

O
O

__1__ a) topical, high potency glucocorticoid with no

mineralocorticoid activity
_10__ b) progestational agent usually given by i.m. injection
__4__ c) aromatase inhibitor
__8__ d) orally active corticosteroid with moderate
mineralocorticoid and glucocorticoid activity
__9__ e) orally active androgen with anabolic and
progestational activity
__7__ f) equine estrogen
__6__ g) selective estrogen response modifier
__5__ h) inactive cortisol metabolite
__3__ i) reactive estrogen metabolite
_none j) orally active androgen with no anabolic activity

C 2H 5O
CH 2

CH 2

COOH

CH 3 O

CH

NH

CH

Enalapril

O
C

O
CH 2 OH

CH 2 OH

OH

HO

CH 2 OH
OH

HO

CH 3

F
O

O
1

CH 3

AF is a 64-year-old retired schoolteacher who has been battling

debilitating rheumatoid arthritis (RA) for several years. Unfortunately,
she has been nonresponsive to several different nonsteroidal antiinflammatory drug s (NSAIDs), including the cyclooxygenase 2 (COX-2)
selective ones. She is now in the clinic for reevaluation, and a decision
is made to initiate corticosteroid therapy. AF is an insulin-dependent
diabetic and takes enalapril for high blood pressure.

Case study

1. Identify the therapeutic problem(s) for which the

pharmacist's intervention may benefit the patient.
2. Identify and prioritize the patient-specific factors that must
be considered to achieve the desired therapeutic outcomes.
3. Conduct a thorough and mechanistically oriented structure
activity analysis of all therapeutic alternatives provided in the
case.
4. Evaluate the SAR findings against the patient-specific
factors and desired therapeutic outcomes and make a
therapeutic decision.
5. Counsel your patient.

1. Identify the therapeutic problem(s) for which the pharmacist's

intervention may benefit the patient.
AF has rheumatoid arthritis which did not respond well to NSAIDs
and which now must be treated with alternative therapy. The
component of corticosteroid action useful in the treatment RA is the
gluco component. Because AF is hypertensive and diabetic, the
effect of therapy on blood pressure and blood sugar levels must be
evaluated and dealt with appropriately. If any gastric bleeding is
suspected, corticosteroid therapy cannot be initiated owing to the
inhibitory effect of glucocorticoids on the healing process.
2. Identify and prioritize the patient-specific factors that must be
considered to achieve the desired therapeutic outcomes.
AF is a diabetic stabilized on insulin.
AF has elevated blood pressure that is currently controlled
with prodrug angiotensin-converting enzyme (ACE) inhibitor therapy.
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5. Counsel your patient.

AF's insulin therapy should be carefully titrated as she starts corticosteroid therapy, and
checked regularly until she is stabilized on all medications. Although methylprednisolone
has a negligible effect on sodium and water retention at standard doses, AF should be
sure she monitors her blood pressure on a very regular basis to ensure that no mineralo
action of this selective agent is sneaking through. Age-related renal insufficiency should
be considered when designing her dosage regimen, and the lowest possible effective
dose employed. Regular bone scans should be done to monitor the effect of
glucocorticoid therapy on her bone density. Proper diet and appropriate exercise to
promote bone health will be more important than ever.
If AF experiences GI distress or other signs of gastric bleeding, she should
report this immediately to her physician. The prophylactic use of antacids should be
implemented cautiously as she initiates this new therapy.
Glucocorticoids are sometimes administered on an every-other-day basis (by
which twice the daily dose is given on alternative days). It is claimed that side effects are
minimized by this dosage regimen, but the effect on AF's blood sugar levels and blood
pressure would have to be evaluated before the larger dose was given. Another factor of
importance in selecting the optimal regimen is her compliance status. Some people are
more compliant with a daily regimen because they tie drug administration to an activity
of daily living (e.g., breakfast or brushing teeth) and can become inadvertently
nonadherent if they need to remember whether "today" is the day they take or skip their
dose. Adherence to an established regimen will be critical for AF because her insulin
dose will be set based on the expected effect of regular corticosteroid use.

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