Unit IV

Drugs acting on Endocrine system

INTRODUCTION
The steroids form a group of structurally related compounds, which are widely distributed in animals and
plants. The structures of steroids are based on the 1, 2-cyclopentano phenanthrene skeleton.

Steroids consist of four rings. Perhydrophenanthrene (rings A, B, and C) is a completely saturated

derivative of phenanthrene, while D is a five-membered cyclopentane ring.
The major therapeutic classes of steroids are the following:
• Anti-inflammatory agents: Cortisone
• Sex hormones: Estrogen, progesterone, and testosterone
• Oral contraceptives: Norethisterone
• Cardiac steroids: Digitoxigenin
• Diuretics: Spironolactone
• Antibiotics: Fusidic acid
• Neuromuscular blockers: Pancuronium chloride
• Vitamin D precursor: Ergosterol

STEROID NOMENCLATURE AND STRUCTURE

Steroids consist of four fused rings (A, B, C, and D). Chemically, these hydrocarbons are cyclopentano
per hydro phenenthrenes. They contain a five-membered cyclopentane (D) ring and the three rings of
phenanthrene. A perhydro phenanthrene (ring A, B, and C) is the saturated derivative of phenanthrene.

Gonane: The parent tetracyclic hydrocarbon without methyl groups at C-10 and C-13 and without a side
chain at C-17 is named gonane. E.g. 5 (α or β) gonane (C =17)

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Estrane: The hydrocarbon with a methyl group at C-13 but without a methyl group at C-10 and without a
side chain at C-17 is named as estrange E.g. 5 (α or β) estrane (C =18)

Androstane: The hydrocarbon with methyl groups at C-10 and C-13 but without a side chain at C-17 is
named as androstane (Fig. 5). E.g. 5 (α or β) androstane. (C =19)

Pregnane: The hydrocarbon with methyl groups at C-10 and C-13, with a side chain at C-17 upto C-21
containing is named Pregnane (Fig. 6). It is a parent hydrocarbon for two series of steroids stemming from
5α-pregnane and 5β-pregnane (C=21).

Cholane & Cholestane: The hydrocarbon with methyl groups at C-10 and C-13, with a side chain at C-17
upto Carbon chain 24 is named Cholane and upto Carbon chain 27 named Cholestane.

The polycyclic hydrocarbon, known as 5α-cholestane, is used to illustrate the numbering system for a
steroid.
• The ring juncture or backbone carbons are shown in the structure of 5α-cholestane with a heavy dark line.
• Solid lines denote groups above the plane of the nucleus (β-confi guration) and dotted or broken lines
denote groups below the plane (α-confi guration). If the confi guration of substituent is unknown, its
bond to the nucleus is drawn as a wavy line.
• The configuration of the H at C-5 is always indicated in the name.
• Circles were sometimes used to indicate α-hydrogens and dark dots to indicate β-hydrogens.
• Compounds with 5α-cholestane belong to allo-series, while compounds derived from 5 β-cholestane

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belong to the normal series.

• If the double bond is not between sequentially numbered carbons, in such cases, both carbons are
indicated in the same.
• When a methyl group is missing from the side chain, this is indicated by the prefix ‘nor’ with the number
of carbon atom, which has disappeared.

The symbol Δ is often used to designate a C = C bond in a steroid. If C = C is in between carbons 5 and 4,
the compound is referred to as a Δ4 steriod, and if the C = C bond is between positions 5 and 10, the
compound is designated as Δ 5(10) steroid. Example, Estra-1,3,5 (10) triene-3,17b-diol.

Since 17 β-estradiol contains 18 carbon atoms, it is considered as a derivative of estrane, a basic nucleus.

Stereochemistry: The absolute stereochemistry of the molecule and any substituent is shown with solid (β)
and dashed (α) bonds; a (axial) bond is perpendicular to the plane of the molecule while equatorial bond
(e) is horizontal to the plane of the molecule.

The aliphatic side chain at position is always assumed to be of β-configuration.

The term cis and trans are used occasionally to indicate the backbone stereochemistry between rings.
For example, 5 α-steroids are A/B trans and 5 β-steroids are A/B cis. The terms syn and anti are used
analogously to trans and cis.

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Conformations: There are six asymmetric carbon atoms in the nucleus 5, 8, 9, 10, 13, and 14. Therefore,
there are 26 = 64 optically active forms possible. Cholestane, androstane, and pregnane can exist in two
conformations, that is, chair form and boat form.

Chair confirmation is more stable than boat confirmation due to less angle strain, and hence, all
cyclohexane rings in the steriod nucleus exist in the chair confirmation.
Metabolism of steroids
Steroids are primarily oxidized by cytochrome P450 oxidase enzymes, such as CYP3A4. These reactions
introduce oxygen into the steroid ring, allowing the cholesterol to be broken up by other enzymes into bile
acids. These acids can then be eliminated by secretion from the liver in bile. The liver catalyses extensive
phase 1 and phase 2 metabolisms of steroids, thereby regulating their activity and clearance. Hepatic phase
1 metabolism of steroids includes the following types of reactions: (1) 5α/β reduction of the 4-double
bond followed by 3 α/β -reduction of the 3-ketone; (2) oxidations by a large set of hepatic P450 enzymes;
(3) HSD reactions of 11b- and 17b-hydroxyls if available and of hydroxyls introduced by P450s

Classification
The adrenal cortex synthesizes two classes of steroids. They are as follows:
Glucocorticoids: These steroids regulate the carbohydrates, proteins, and the fat metabolism and are
involved in the operation of the processes that enable the body to resist infections and stress.
Example—hydrocortisone and cortisone.
Mineralocorticoids: These steroids mainly influence salt and water balance (and hence, the control of
blood volume and blood pressure) by maintaining proper electrolyte balance.
Example—aldosterone, 11-deoxycorticosterone.

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Sex hormones:
Testosterone (Nuvir, Andriol, Testoviron)
Testosterone is the primary male sex hormone and anabolic steroid. In male humans, testosterone plays a
key role in the development of male reproductive tissues such as testes and prostate, as well as promoting
secondary sexual characteristics such as increased muscle and bone mass, and the growth of body hair. Its
IUPAC name is 17β-Hydroxyandrost-4-en-3-one

Properties and uses: It is a creamy white crystalline powder, insoluble in water, and soluble in alcohol. It
may be used for treatment of breast carcinoma in postmenopausal women.

Structure activity relationship

 It must contain the andostane skeleton for its biological activity.
 Introduction of double bond at C1 position increases the anabolic activity. Example:
methandrostenolone is more active than methyl testosterone.
 Replacement of carbon atom at C2 position by oxygen (e.g. oxandrolone) gives the oral anabolic
activity.
 Presence of Oxygen at C3 and C17 are not essential for the androgenic activity.
 Presence of hydroxy group at C17 position has no androgenic or anabolic activity.

Nandralone
Nandrolone is also known as 19-nortestosterone. It is an androgen and anabolic steroid (AAS) and is used
in the form of esters such as nandrolone decanoate and nandrolone phenylpropionate . Its IUPAC name is
19-norandrost-4-en-17β-ol-3-one

Uses
Nandrolone esters are used in the treatment of anemias, cachexia (wasting syndrome), osteoporosis, breast
cancer.

Progesterones
Progesterones belong to a group of steroid hormones called the progestogens. Its IUPAC name is
(8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta-
[a] phenanthren-3-one

Uses
Progesterone is used in combination with estrogens mainly in hormone therapy for menopausal symptoms
and low sex hormone levels in women. It is also used in women to support pregnancy and fertility and to
treat gynecological disorders.
Structure activity relationship
 Steroidal skeleton is essential for activity.
 Saturation of ring-A decreases the activity.

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 Removal of the keto function removes androgenic activity.

 Substitution at 17α with ethynyl, methyl, ethyl group reduce the activity.

Oestriol
Estriol is the major estrogen involved in pregnancy and is produced naturally by the placenta and [Link]
IUPAC name is 8R,9S,13S,14S,16R,17R)-13-methyl- 6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta
[a]phenanthrene-3,16,17-triol

Uses
Estriol is used in menopausal hormone therapy to treat menopausal symptoms, such as hot flashes,
vulvovaginal atrophy, and dyspareunia.

Structure activity relationship

 Aromatic ring with –OH at C-3 is essential for activity.
 Steroidal structure is essential for activity.
 Unsaturation of ring-B decreases the activity

Oestradiol
Estradiol or oestradiol is an estrogen steroid hormone and the major female sex hormone. It is also used to
treat low estrogen levels in women with ovarian failure. Its IUPAC name is (8R,9S,13S,14S,17S)-13-
Methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]-phenanthrene-3,17-diol

Uses
Estradiol is used to treat menopause symptoms, and to prevent osteoporosis (bone loss) in menopausal
women. Estradiol is also used to treat low estrogen levels in women with ovarian failure. It is also indicated
to treat certain types of breast cancer and prostate cancer.

Structure activity relationship

 Aromatic ring with –OH at C3 is essential for activity.
 Steroidal structure is essential for activity.
 Unsaturation of ring-B decreases the activity
 Methylation of –OH at C3 make the compound orally active (e.g. Mesterolone).
 Insertion of –OH group at C6, C7 and C11 position reduces estrogenic activity.

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Oestrione
Oestrione is the major endogenous estrogens. It acts as both a precursor and metabolite of estradiol. Its
IUPAC name is(8R,9S,13S,14S)-3-hydroxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]-
phenanthren-17-one

Uses
Estrone has been available as an injected estrogen for medical use in hormone therapy for menopausal
symptoms.

Structure activity relationship

 Aromatic ring with –OH at C3 is essential for activity.

 Steroidal structure is essential for activity.
 Unsaturation of ring-B decreases the activity
 Insertion of –OH group at C6, C7 and C11 position reduces the estrogenic activity.

Diethyl stilbestrol
Diethylstilbestrol is also known as stilbestrol or stilboestrol . It is a synthetic, nonsteroidal estrogen
medication.

Uses: Diethylstilbestrol is only used in the treatment of prostate cancer and less commonly breast cancer. It
is also used in the treatment of prostate cancer in men.

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Drugs for erectile dysfunction

Erectile dysfunction (ED) is the inability to get or keep an erection firm enough to have sexual intercourse.
It is sometimes referred as impotence. Many men experience it during the time of stress. Patients suffering
from erectile dysfunction should first be evaluated for any underlying physical and psychological
conditions.

Sildenafil
Sildenafil is sold under the brand name Viagra. This medication is most effective when taken on an empty
stomach one hour before sex. It is taken by mouth or injection into a vein. Its IUPAC name is 5-[2-ethoxy-
5- (4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-
One

Uses: Sildenafil is used to treat male sexual function problems (impotence or erectile dysfunction-ED).

Tadalafil
Tadalafil is an orally administered drug used to treat male sexual function problems (impotence or erectile
dysfunction-ED). Tadalafil is sold under the brand name Cialis. It is a pyrazinopyridoindole derivative. Its
IUPAC name is (2R,8R)-2-(2H-1,3-benzodioxol-5-yl)-6-methyl-3,6,17-triazatetracyclo[[Link]³,⁸.0¹¹,¹⁶]
heptadeca-1(10),11,13,15-tetraene-4,7-dione

Uses: It is used to treat erection problems (erectile dysfunction) and symptoms of an enlarged prostate
(benign prostate enlargement). It's also sometimes used to treat pulmonary hypertension (high blood
pressure in the blood vessels that supply the lungs).

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Oral contraceptives
Oral contraceptives (OCPs) are also known as birth control pills. These are medications taken by mouth for
the purpose of birth control. There are various types of female oral contraceptive pill. Example: combined
oral contraceptive pill contains estrogen and a progestin, progestogen-only pill and Ormeloxifene is a
selective estrogen receptor modulator which offers the benefit of only having to be taken once a week.
Sometimes, emergency contraception pills are taken at the time of intercourse, or within a few days
afterwards. Example: Levonorgestrel, Ulipristal acetate, Mifepristone and misoprostol, when used in
combination, are more than 95% effective during the first 50 days of pregnancy.

Mifepristone
Mifepristone is a synthetic steroid and also known as RU-486. It is a medication mainly used in
combination with misoprostol to bring about an abortion during pregnancy. Its IUPAC name is 11β--17α-
(1-propynyl)estra-4,9-dien-17β-ol-3-one

Uses: Mifepristone is used in combination with misoprostol (Cytotec) to end an early pregnancy

Norgestril
Norgestrel is a form of progestin hormone that prevents pregnancy. Chemically, it is also known as rac-13-
ethyl-17α-ethynyl-19-nortestosterone or rac-13-ethyl-17α-ethynylestr-4-en-17β-ol-3-one

Uses: It is a hormone that prevents pregnancy by making vaginal fluid thicker to help prevent sperm from
reaching an egg (fertilization), and changing the lining of the uterus (womb) to prevent attachment of a
fertilized egg.

Levonorgestrol
Levonorgestrel (LNG) is a synthetic estrane steroid and a derivative of testosterone. It is used in
contraception and hormone therapy. Chemically, it is 17α-ethynyl-18-methyl-19-nortestosterone or as 17α-
ethynyl-18-methylestr-4-en-17β-ol-3-one

Uses: Levonorgestrel is used to prevent pregnancy after unprotected sexual intercourse.

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Corticosteroids
Corticosteroids are the class of steroid hormones (C21). These are produced in the adrenal cortex. These are
the class of drugs that lower the inflammation in the body. They also reduce the activity of immune system.

Cortisone
Cortisone is corticosteroid hormone (glucocorticoid) of pregnane type. It is released by the adrenal gland.
ItsIUPAC Name is (8S,9S,10R,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-
1,2,6,7,8,9,12,14,15,16-decahydro-cyclopenta[a]phenanthrene-3,11-dione

Uses: Cortisone is used as an anti-inflammatory medication

Hydrocortisone
Hydrocortisone is a class of corticosteroids. It is used topically to treat redness, swelling, itching, and
discomfort of various skin conditions. Chemically, it is 11β,17α,21-Trihydroxypregn-4-ene-3,20-dione

Uses: Hydrocortisone topical is used to treat redness, swelling, itching, and discomfort of various skin
conditions.

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Prednisolone
Prednisolone is a glucocorticoid. Chemically, it is 11,17-Dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-
6,7,8,9,10,11,12,13,14,15,16,17-dodecahydrocyclopenta[a] phenanthren-3-one (Fig. 31). It is a medication
used to treat certain types of allergies, inflammatory conditions, autoimmune disorders, and cancers.

Uses
Prednisolone is used to treat allergies, blood disorders, skin diseases, infections, certain cancers.
It is also used to prevent organ rejection after a transplant.
It helps to reduce inflammation

Betamethasone
Betamethasone is in a class of corticosteroids (Fig. 32). It is a steroid medication. It is used for a number of
diseases such as rheumatoid arthritis, systemic lupus erythematosus and skin diseases like dermatitis.

Uses: Betamethasone is used topically to treat itching, redness, dryness, crusting, scaling, inflammation,
and discomfort of various skin conditions, including psoriasis and eczema.

Structure activity relationship

 Aromatic ring with –OH at C3 is essential for activity.
 Steroidal structure is essential for activity.
 Unsaturation of ring-B decreases the activity
 Insertion of –OH group at C6, C7 and C11 position reduces the estrogenic activity.
 Presence of 11β-hydroxy is essential for glucocorticoid activity.

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Dexamethasone
Dexamethasone is a type of corticosteroid medication. It is used in the treatment of rheumatic problems,
skin diseases, allergies, asthma, chronic obstructive lung disease etc. Its IUPAC Name is
(1R,2R,3aS,3bS,9aS,9bR,10S,11aS)-9b-fluoro-1,10-dihydroxy-1-(2-hydroxyacetyl)-2,9a,11a-trimethyl-
1H,2H,3H,3aH,3bH,4H,5H,7H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-7-one

Uses: It relieves inflammation (swelling, heat, redness, and pain) and is used to treat certain forms of
arthritis.

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Thyroid and antithyroid drugs

The thyroid is a butterfly-shaped gland that sits low on the front of the neck. Thyroid has two side lobes,
connected by a bridge (isthmus) in the middle.
The thyroid gland consists of 2 types of cells.
Follicular cells: These are more abundant, and the major secretory cells. They secrete Thyroid
hormone.
Parafollicular cells or C-cells: These are fewer in number & interspersed. They secrete Calcitonin

There are two types of thyroid hormones produced and released by the thyroid gland namely
triiodothyronine (T3) and thyroxine (T4) There are presences of 3 and 4 atoms of iodine in T3 and T4
respectively. The deficiency of iodine leads to decreased production of T3 and T4 that enlarges the thyroid
tissue and will cause the disease known as simple goitre. Both T3 and T4 are used to treat thyroid hormone
deficiency (hypothyroidism).

L-Thyroxine
Levothyroxine is also known as L-thyroxine. Levothyroxine is a synthetic form of thyroxine (T4).

It is manufactured form of the thyroid hormone thyroxine. It is used to treat thyroid hormone deficiency
including the severe form known as myxedema coma. It is also used to treat and prevent certain types of
thyroid tumors.

Uses: Levothyroxine is used to treat an underactive thyroid (hypothyroidism).

L-Thyronine
Thyronine is a deiodinated form of thyroxine. Its IUPAC Name is (2S)-2-amino-3-[4-(4-
hydroxyphenoxy)phenyl]propanoic acid

Uses: It is to treat thyroid hormone deficiency (hypothyroidism).

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Propylthiouracil

Propylthiouracil is a medication used to treat hyperthyroidism. This includes hyperthyroidism due to

Graves' disease and toxic multinodular goiter.
Uses: Propylthiouracil is used to treat overactive thyroid (hyperthyroidism). It works by stopping the
thyroid gland from making too much thyroid hormone.

Methimazole
Methimazole is a thionamide antithyroid agent that inhibits the synthesis of thyroid hormones. It was first
introduced as an antithyroid agent in 1949 and is now commonly used in the management of
hyperthyroidism.

Uses: Methimazole is used to treat hyperthyroidism (overactive thyroid). It is also used before thyroid
surgery or radioactive iodine treatment.

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