Chapter -10 -Medicinal chemsitry -2 B.Pharmacy -5 semester

1. Drugs acting on Endocrine system
Human endocrine system, group of ductless glands that regulate body processes by
secreting chemical substances called hormones. Hormones act on near by tissues or
are carried in the blood stream to act on specific target organs and distant tissues.
Diseases of the endocrine system can result from the over secretion or under secretion
of hormones or from the inability of target organs or tissues to respond to hormones
effectively.
List of endocrine glands in the human body :
1. Brain : Pineal gland ; Pituitary gland ; Hypothalamus
2. Thymus glands
3. Pancreas
4. Thyroid glands
5. Adrenal glands
6. Ovaries and testis.

3. Steroid is a class of natural or synthetic organic compounds characterized by a molecular
structure of 17 carbon atoms arranged of four rings.
Steroids are important in biology, chemistry and medicine.
The steroid group includes all the sex hormones, adrenal cortical hormones, bile acids and
sterol of vertebrates.
Among the synthetic steroids of therapeutic value are a large number of different
categories of steroids are frequently distinguished from each other by names that relate
to their biological source. Ex : Phytosterols,
adrenal steroids and bile acids, androgens and cardiotonic steroids
Steroids vary from one another in the nature of the attached groups, the position
of the groups and the configuration of the steroid nucleus.

4. Steroid numbering system, nomenclature and sterochemistry
Gonane : This parent structure, named gonane may
be modified in a practically unlimited number of
ways by removal, replacement or addition of a few
atoms a time.
The steroids nucleus is a three dimensional structure
and atoms or groups are attached to it by spatially
directed bonds. For example, androstane, common
to a number of natural and synthetic steroids exists
in two forms in which the A/B ring fusions called cis
and trans respectively.

5. In the cis isomer, bonds to the methyl group, and to the hydrogen atom, H –atom on
both the sides they are Beta configuration. Where as the trans isomer, The methyl
group projects up and the hydrogen projects down.
Steroid structures are represented as plane projection diagrams such as 4 and 5,
which correspond 2 and 3 respectively.
Stereochemistry of steroids
The stereochemistry of the rings markedly affects biological activity of a given class of
steroids. There are 6 asymmetric carbon atoms 5,8,9,10,13,14 in the nucleus. There
are 64 optically active forms are possible.

6. It consist of two conformations – Chair form and boat form. Chair conformation is
more stable than boat conformation due to less angle strain.
Hence all cyclo hexane rings exist in chair form. H-atom on the β side of the
molecule are denoted as solid lines and the α side is denoted by dotted lines.
Stereoisomerism based on :
1. the way in which the rings are fused together.
2. The way in which configuration of substituent groups, particularly those
at C3 and C17.
A/B Fusion : Fusion of rings A and B may either trans or cis to give 2 isomeric C27
hydrocarbons.
B/C Fusion : Fusion of the rings B and C was trans. The C10 angular methyl group
must be trans to be C9 hydrogen atom.
C/D Fusion : The complete X-ray crystallographic analysis of cholesteryl iodide reveals
that the ring union is trans in the sterols, bile acids and related steroids.

7. 1. Above the plane of the nucleus – β configuration.
2. Below the plane of the nucleus – α configuration.
3. Configuration of substituents is unknown – wavy line.
4. If some carbon atoms are missing in steroid nucleus, the numbering of the
remainder will not change
Nomenclature

9. Gonane
Oestrane
Androstane
Pregnane

10. Cholane
Cholestane
5. If side chain doesnot contain methylene group, this is indicated by the prefix “
Nor “ proceeded by the no : of carbon atom that has disappeared. Ex : 23- nor 5α/β
cholane

11. 23 – nor -5α/β cholane.
If the steroid nucleus doesnot contain angular methyl group, this is indicated by the
prefix “ Nor” proceeded by the number that designating the methyl group, for
example : 10-nor 5 α/β androstane.

12. If the ring contraction occur in the steroid nucleus, this is again indicated by the
prefix “ nor” proceeded by a capital letter indicting ring affected. For example : A –
nor 5α/β androstane
A –nor 5α/β androstane
If there is enlargement of ring in the steroid nucleus, indicated by the prefix “
Homo” proceeded by a capital letter indicating ring affected.
Ex : β-homo - 5α/β pregnane

13. If there is a ring fission or breaking occurs, indicated by the prefix “ Seco” proceeded by
a number of position of broken bond.
For example : 2,3 Seco -5α/β – androstane – 2,3 dioic acid
If steroid nucleus contains 3 membered ring, indicated by prefix “ cyclo” –
For example : 3α5α - Cyclocholestane

14. 3α5α cyclocholestane
Metabolism of steroids
Steroids are primarily oxidized by cytochrome P450 oxidase enzymes such as
CYP3A4. These reactions allow the cholesterol to be broken up by other enzymes in
to bile acids.These acids can be eliminated through bile. The steroid hormones,
lacking the side chain of cholesterol and bile acids are hydroxylated at various ring
positions or oxidized at the 17 position. Which is conjugated with sulfate or
glucuronic acid and excreted in the urine.

15. Sex hormones
A hormone is a chemical released in to the blood and transported to affect cells in other
parts of the body. Hormones regulate many things in the body such as growth and
development. Male and female gender development; levels of salts and sugars in the
blood : The amount of fluid in the body : Sex hormone is a chemical substance produced
by a sex gland which has an effect on the sexual features of an organism.
Types of male and female hormones
Estrogen
13-methyl-6,7,8,9,11,12,14,15,16,17-
decahydrocyclopenta[a]phenanthrene-3,17-
diol

16. Estrogen is a female sex hormone , It is responsible for the development and
regulation of the female reproductive system and secondary sex characteristics.
There are three major endogenous estrogens : oestrone, oestradiol and oestriol.
Among these oestrone and oestradiol is more prevalent.
E-1 –OESTRONE
E-2 – ESTRADIOL
E-3 - OESTRIOL
E-4 – ESTETROL – Produced during pregnancy.
MOA :
Estradiol is a naturally occurring hormone circulating endogenously in females. It is
commercially available in several hormone therapy products for managing conditions
associated with reduced estrogen, such as vulvovaginal atrophy and hot flashes. Some
available forms of estradiol include oral tablets, injections, vaginal rings, transdermal
patches, sprays, gels, and creams

17. Estrogen is found in the the breast, uterine, ovarian, skin, prostate, bone, fat, and brain
tissues. The main source of estrogen in adult women during the reproductive period of
life is the ovarian follicle, which secretes 70 to 500 mcg of estradiol each day.
After menopause, however, the majority of endogenous estrogen is produced by
transformation of androstenedione (which is secreted by the adrenal cortex) to estrone in
the peripheral tissues. Both estrone and its sulphate conjugated form, estrone sulphate,
represent the most abundant estrogens found in postmenopausal women.
Estradiol, however, is considerably more potent than estrone and estriol at the estrogen
receptor (ER). Estradiol workings by binding to subtypes of the estrogen receptor:
estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ).
It also exerts potent agonism of G Protein-coupled estrogen receptor (GPER), which is
recognized an important regulator of this drug's rapid effects. Once the estrogen receptor
has bound to its ligand, it enters the nucleus of the target cell, regulating gene
transcription and formation of of messenger RNA.
This mRNA makes contact with ribosomes producing specific proteins that express the
effect of estradiol upon the target cell. Agonism of estrogen receptors increases pro-
estrogenic effects, leading to the relief of vasomotor and urogenital symptoms of a
postmenopausal or low estradiol state

18. SAR :
1. Each oestrogen contains a phenolic A ring with a hydroxyl group at carbon 3 abd
a beta – OH or ketone in position17 of ring D.
2. The phenolic A ring is the principal structural feature responsible for selective,
high affility binding to both receptors.
3. Ring –A and 3-OH, 17β – OH groups is necessary for activity.
4. Activity depends on mode of action subcutaneous - Estradiol ˃˃ Estrone˃
estriol.
5. Removal of 3-OH group, epimerization of 17 β – OH group, introduction of
unsaturation in “ β” ring, expansion of “ D” ring drastically decrease the activity.
6. Compound without steroid nucleus also showed activity.

19. Metabolism of oestrogens

20. Uses : commonly used in the birth control and menopausal hormone therapy
Adverse reactions : Breast tenderness, breast enlargement, head ache, nausea, fluid
retention and edema.
Estradiol
13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol

21. MOA : Estradiol acts primarily as an agonist of the estrogen receptor ( ER) , a nuclear
steroid hormone receptor. There are two types of the estrogen receptor – ER , ER α and
Erβ and estradiol potently binds to and activates both of these receptors. The result of ER
activation is a modulation of gene transcription and expression in ER – expressing cells,
which is the predominant mechanism by which estradiol mediates its biological effects in
the body.
Metabolism : Estradiol is also metabolized via hydroxylation in to catechol estrogens. It is
specifically metabolized by CYP1A2, CYP3A4 and CYP2C9 via 2- hydroxylation in to 2-
hydroxy estradiol. Estradiol is additionally conjugated with an ester in to lipoidal estradiol
forms like estradiol palmitate and estradiol stearate.
Therapeutic uses : Primarily in hormone therapy for menopausal symptoms as well as
transgender hormone replacement therapy.

22. oestriol
13-methyl-6,7,8,9,11,12,14,15,16,17- decahydrocylcopenta phenantherene – 3,16,17 –
triol.
MOA : Estriol is an estrogen, specifically an agonist of the estrogen receptors Erα and
Erβ. It is a far less potent estrogen than is estradiol and as such is a relatively weak
estrogen.

23. Metabolism
Estriol is metabolized via glucuronidation and sulfation.
Therapeutic uses : It is primarily used in the hormone therapy for menopausal
symptoms.
Oestrione
3-hydroxy – 13 –methyl-
7,8,9,11,12,14,15,16 – octahydro –
cyclopenta phenthrene – 17 –one.

24. Estrogens enter the cells of responsive tissues (e.g. female organs, breasts, hypothalamus,
pituitary) where they interact with estrogen receptors. Hormone-bound estrogen
receptors dimerize, translocate to the nucleus of cells and bind to estrogen response
elements (ERE) of genes. Binding to ERE alters the transcription rate of affected genes.
Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-
binding globulin (TBG), and other serum proteins and suppress follicle-stimulating
hormone (FSH) release from the anterior pituitary.
Estrogen receptor alpha
Metabolism : estrone is conjugated in to estrogen
conjugates such as estrone sulfate and estrone
glucuronide by sulfo transferases and glucuronidases
and can also bne hydroxylated by cytochrome P450
enzymes in catechol estrogens such as 2- hydroxy
estrone and 4- hydroxy estrone.
Therapeutic uses : hormone therapy in menopausal
symptoms.
Adverse effects – Bloating, breast tenderness or
swelling, nausea, leg, cramps.

25. Diethyl stilbestrol
4- (4- hydroxy phenyl) hex- 3-en-3yl) Phenol
MOA : Estrogens diffuse in to their target cells and interact with a protein receptor, the
estrogen receptor. Target cells include the female reproductive tract, the mammary
gland, the hypothalamus and the pituitary. The effect of estrogen binding their
receptors increases the hepatic synthesis of sex hormones binding globulin (SHBG),
thyroid binding globulin (TBG) and suppress follicle – stimulating hormone ( FSH) from
the anterior pituitary.

26. Metabolism :
DES is metabolized mainly by glucuronidation and oxidation with the latter
including aromatic hydroxylation of the ethyl side chain and dehydrogenation in
to dienestrol.
Therapeutic uses : Menopausal hormone therapy for the treatment of vaginal
atrophy, hot flashes, gonorrheal vaginitis and breast cancer.
Adverse reactions : DES is associated with high rates of side effects including
nausea, vomiting, abdominal discomfort, headache, and bloating.
Progesterone
17-acetyl-10,13-dimethyl-
1,2,6,7,8,9,11,12,14,15,16,17-
dodecahydro cyclopenta – phenanthren-
3-one.

27. MOA : Progesterone shares the pharmacological actions of the progestins. Progesterone
binds to the progesterone and estrogen receptors. Their target cells are female
reproductive tract, the mammary gland and hypothalamus and the pituitary.
Progesterone will slow the frequency of release of gonadotropin – releasing hormone
from the hypothalamus and blunt the pre –ovulatory LH surge. Progesterone is
essential for the development of decidual tissue and is necessary to increase
endometrial receptivity for implantation of an embryo. Once the embryo has been
implanted, progesterone acts to maintain pregnancy. Progesterone stimulated the
growth of mammary alveolar tissue and replaces the smooth uterine muscle and
thereby producing the androgenic activity.
SAR :
1. Steroidal nucleus is essential for activity.
2. Substitution at 17 alpha with ethynyl, methyl, ethyl reduce
activity.
3. Ethindrone more active orally than progesterone
4. Removal of methyl group at C-19 is more active –
Ex : Nor ethindrone.
Nor ethindrone.

28. 5. Unsaturation of B or C ring of 19 – Androstane derivatives increase
activity.
6. Acetylation of the 17 –Beta – OH of nor ethindrone long duration of
action.
Metabolism : Progesterone is metabolized primarily by the liver to pregnane diols and
pregnanolones.
Uses : Taking progesterone by mouth and applying progesterone gel in to the vaginal
tract are effective strategies for treating absence of menstrual periods in the menopausal
women.
Adv.reactions : Stomach upset, changes in appetite, weight gain, fluid retention and
swelling, fatigue, drowsiness, insomnia, allergic skin rashes and fever.

29. Nandralone
17-Hydroxy -13 –methyl –
2,6,7,8,9,10,11,12,14,15,16,17 do deca hydro
– 1 H – cyclopenta phenanthren – 3-one.
MOA : Nandrolone is an androgen receptor agonist. It bound to the receptor complexea
and allow it to enter the nucleus and bind directly to specific nucleotide sequence of
the chromosomal DNA.

30. 1. Some of the structural modification that have been introduced in to the
testosterone in an attempt to maximize the anabolic effects and minimize
the androgenic.
2. Structural modifications to the A and B- rings of testosterone that increase
anabolic activity
3. Substitution at C-17 confers oral or depot activity.

31. Metabolism : nandrolone is unusual in that unlike most anabolic steroids. It is a less
effective product known as Dihydronandrolone.
Therapeutic uses : nandrolone esters are used clinically for people in catabolic states
with major burns, cancer and AIDS.
Adverse reactions : Side effects of nandrolone esters include masculinization among
others.
Testosterone
17- hydroxy – 13-methyl –
2,6,7,8,9,10,11,12,14,15,16,17 –
dodecahydro – 1H – cyclopenta
phenanthren – 3-one.

32. MOA :
 The androgen receptor exists in the cytoplasm bound to the heat shock proteins
HSP90, HSP70, and other chaperones. After binding to an androgen, the
androgen receptor dissociates from HSP90 and undergoes a conformational
change to slow the rate of dissociation from the androgen receptor. The
androgen-receptor complex is transported into the nucleus where it binds to
DNA and recruits other transcriptional regulators to form a pre-initiation
complex and eventually induce expression of specific genes.
 Testosterone and its active metabolite dihydrotestosterone (DHT) antagonize the
androgen receptor to develop masculine sex organs including the prostate,
seminal vesicles, penis, and scrotum.
 Antagonism of the androgen receptor is also responsible for the development of
secondary sexual characteristics including facial and body hair, enlargement of
the larynx, thickening of the vocal cords, and changes in muscle and fat
distribution

33. SAR :
1. It lacks the 2- carbon side chain attached to the 17- position and making in to a 19-
carbon steroid ( an androstane).
2. 17- alpha methyl group increase the duration of action and improve biovailability.
3. The esterification of 17- beta – OH group increases duration of action and
bioavailability.
4. The removal of 19 th carbon led to more anabolic selective molecule and less
androgenic activity.
Metabolism :
Testosterone is metabolized to 17 – keto steroids through two different pathways .
The major active metabolites are estradiol and di hydro testosterone.
Enzyme: UDP-
glucuronosyl
transferase 1-10
BioSystem:
HUMAN

34. Enzyme: UDP-glucuronosyltransferase 1-10
BioSystem: HUMAN
Therapeutic uses : For management of acquired hypogonadism, hypogonadism
associated with HIV infection.
Adverse reactions : Acne, swelling, breast enlargement in males.

35. Drugs used in gentile dysfunction
Sildenafil
5-(2-ethoxy -5 ( 4-methyl piperazin -1yl –sulfonyl)Phenyl) -1- methyl – 3- propyl – 1,6
dihydro -7H – Pyrazolo ( 4,3 –d) pyrimidine – 7-one.

36. MOA :
Sildenafil inhibits the cGMP – specific phospho diesterase type 5 which is responsible
for the degradation of cGMP in the corpus cavernosum which is on the male
gentiles.It increases the gentile blood flow resulting in a relaxation of smooth muscle.
This response is mediated by the release of Nitric oxide (NO) from nerve cells and
endothelial cells which stimulates the synthesis of cGMP in smooth muscle cells. The
inhibition of phosphodiesterase type -5 by sildenafil increases the gentile function by
increasing the cGMP.
Metabolism
Sildenafil appears to be completely metabolized in the liver by 16 metabolism. The
metabolism is mediated mainly by cytochrome P450 microsomal isoenzymes 3A4
and 2C9, The major circulating metabolite, N – demethylated metabolite has PDE
selectively similar to the parent drug. The N- demethylated metabolite is
metabolized to an N- dealkylated and N,N – De ethylated metabolite.

37. Human Phospho diesterase
Enzyme: Cytochrome P450
1A2
BioSystem: HUMAN
EAWAG_RULE_BT0425_PATT
ERN1

38. N-Hydroxylation
of primary
arylamine
N-Hydroxylation of
primary arylamine
N-Dealkylation of N-
acylurea
1-Naphthoxy
Photorearrangement_C2
N-Hydroxylation of
primary arylamine

39. N-Dealkylation of N-
acylurea
1-Naphthoxy
Photorearrangement
_C2
Hydrolysis of oxime
N-Glucuronidation of
hydroxylamine

40. Therapeutic Uses : Treatment of gentile dys function. It is the standard treatment for the
dysfunction including for men with diabetes mellitus.
Adverse reactions : Head ache, flushing, indigestion, nasal congestion and impaired
vision.
Tadalafil
6- (1,3 – benzodioxol – 5yl) -2-methyl -
hexa hydro pyrazolo – pyrido – Indole
-1.4 dione.

41. Metabolism
Hydrolysis of cyclic tertiary carboxamide
Hydrolysis of cyclic tertiary
carboxamide

42. Therapeutic uses : Tadalafil is used to treat male gentile function problems.
Adverse Reactions : Headache, stomach discomfort or pain.
Oral Contraceptives
They are also called as Birth control pills, which are safe, reliable option for
preventing unwanted pregnancy. Most oral contraceptives contain a combination
of 2 types of hormones an estrogen and progestin with different combinations.
Some pills contain only progestin named as “ Minipill”
1.Estrogen and progestin prevent eggs from being released from the ovaries.
2.Progestin causes thining of the endometrium which prevents implantation of a
fertilized egg.
3. Progestin thickness the mucus in the cervix, preventing sperm from reaching the eggs.

43. 11- (4-dimethyl amino) phenyl) -17 – Hydroxy -13 –methyl -17- prop-1-ynyl -
1,2,6,7,8,11,12,14,15,16 –deca hydro cyclopenta (a) Phenanthren – 3-one.
MOA : The anti progestational activity of mifepristone results from competitive
interaction with progesterone ate progesterone – receptor sites. Based on studies
with various oral doses in several anaimal species, the compound inhibits the activity
of endogenous or exogenous progesterone.
Mifepristone

44. Metabolism of Mifepristone
16-Hydroxylation of
sterol
2-Hydroxylation of sterol
4-Hydroxylation of sterol
N-Dealkylation of mixed
tertiary amine

45. Therapeutic uses :
Mifepristone followed by a prostaglandin analog which is used for medical abortion.
Adverse reactions :
Nausea, vomiting, dry mouth, tiredness, dizziness, headache, muscle pain
Norgestril
13-ethyl-17-ethynyl-17-hydroxy –
1,2,6,7,8,9,10,11,12,14,15,16 – dodeca
hydro cyclopenta (a) Phenathren – 3-one.

46. Norgestrel (and more specifically the active stereoisomer levonorgestrel) binds to the
progesterone and estrogen receptors within the female reproductive tract, the mammary
gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins like
levonorgestrel will slow the frequency of release of gonadotropin releasing hormone
(GnRH) from the hypothalamus and blunt the pre-ovulatory LH (luteinizing hormone)
surge. Loss of the LH surge inhibits ovulation and thereby prevents pregnancy.
Human Progesterone
Therapeutic uses : Norgesterol is used in combination with ethinyl oestradiol
for birth control process.

47. Levonorgesterol
13-ethyl -17 ethynyl -17 –hydroxy -1,2,6,7,8,9,10,11,12,14,15,16- dodecahydro
cyclopenta phenathren – 3-one.
MOA : Binds to the progesterone and estrogen receptors. Target cells include
the female reproductive tract, the mammary gland, the hypothalamus and the
pituitary.
Uses : Levonorgestrel is a hormonal medication which is used in a number of birth
control methods.
ADVERSE EFFECTS – NAUSEA, BREAST TENDERNESS, HEADACHES.

48. Corticosteroids
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of
vertebrates as well as the synthetic analogues of these hormones. Two main classes of
corticosteroids, glucocorticoids and mineralocorticoids are involved in a wide range of
physiological processes including stress response, immune response and regulation of
inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels and
behavior.
Cortisone
17- hydroxy – 17- (2-hydroxy acetyl) – 10,13- dimethyl – 1,2,6,7,8,9,12,14,15,16 –
decahydrocylcopenta phenathrene -3,11 –dione.

49. MOA :
Cortisone suppresses the immune system, thus reducing inflammation and
attendant pain and swelling at the site of injury.
Uses : Cortisone, a glucortocoid and adrenaline are the main hormones
released by the body as a reaction to stress. They elevate blood pressure and
prepare the body for a fight or flight response.
Adverse reactions : Asthma, hyperglycemic, insulin resistance, diabetes
mellitus, osteroporosis, anxiety, depression, amenorrhoea, catracts, cushing
syndrome.
Hydrocortisone
11,17,21 trihydroxy pregn-4ene -3,20 dione

50. MOA : Hydrocortisone binds to the cytosolic glucocorticoid receptor. After binding, it
form receptor – ligand complex translocates itself in to the cell nucleus, where it binds
to many glucocorticoid response elements. The anti inflammatory actions of
corticosteroids are thought to involve lipoproteins, phospholipase A2 inhibitory
proteins.
Meatbolism : Primarily hepatic CYP3A4
Uses : Adrenocortical insufficieny, adrenogenital syndrome, high blood calcium,
Rheumatoid arthritis.
Adverse reactions : Mood changes, increased risk of infection and swelling.
Prednisolone
11,17,21 –Trihydroxypregna-1,4
diene-3,20 dione.

51. MOA : Glucocorticoids such as prednisolone can inhibit leukocyte infiltration at the site of
inflammation. It interfere with mediators of inflammatory response and supress humoral
immune responses. The anti – inflammatory actions of glucocorticoids are through to
involve Phospholipase A2 inhibitory proteins, lipocortins which control the biosynthesis of
potent mediators of inflammation such as prostaglandins and leukotrienes.
Metabolism : Excreted in the urine as either free of gluco conjugate
Thera peutic uses : Asthma, Uveitis, pyoderma gangrenosum, rheumatoid arthritis, crohns
disease, Bells palsy, systemic lupus.
Adverse reactions : Increased appetite, weight gain, nausea and malaise.
Betamethasone
9- fluoro -11,17 –dihydroxy-17 – (
2- hydroxy acetyl) – 10,13,16 –
trimethyl –
6,7,8,9,10,11,12,13,14,15,16,17 –
dodeca hydro – 3H – cyclopenta
phenathren – 3-one.

52. MOA : Betamethasone is a glucocorticoid receptor agonist. This leads to changes in
genetic espression once this complex binds with GRE. The anti inflammatory actions
of the corticosteroids are thought to involve lip[ocortins, phospholipase A2
inhibitory actions through inhibition of arachidonic acid, conntrol the biosynthesis of
prostaglandins and leukotrienes. Betamethasone binds to plasma transcortin and it
becomes active when it is not bound to transcortin.

53. Therapeutic uses : It is used for a number of diseases including rheumatic disorders
such as rheumatoid arthritis and systemic lupus erythematosus, skin diseases such as
dermatitis and psoriasis, allergic conditions such as asthma and angiodema.
Adv.report : Muscle weakness, severe allergic reactions, psychosis.
Dexamethasone
Dexamethasone is a glucocorticoid available in various modes of administration that is
used for the treatment of various inflammatory conditions, including bronchial asthma,
as well as endocrine and rheumatic disorders.

54. The short term effects of corticosteroids are decreased vasodilation and permeability of
capillaries, as well as decreased leukocyte migration to sites of inflammation.
Corticosteroids binding to the glucocorticoid receptor mediates changes in gene
expression that lead to multiple downstream effects over hours to days.
Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit
phospholipase A2, which decreases the formation of arachidonic acid derivatives; they
inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-
inflammatory genes like interleukin-10.3
Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are
immunosuppressive.3 High doses of glucocorticoids for an extended period bind to the
mineralocorticoid receptor, raising sodium levels and decreasing potassium levels.

55. Biotransformation of the Dexamethasone
2-Hydroxylation of
sterol
4-Hydroxylation
of sterol
Epoxidation of alkene
Oxidation of
primary alcohol
to aldehyde

56. Uses : Rheumatic problems, severe allergies, asthma, COPD, Croup, brain swelling, along
with antibiotics in tuberculosis.
Thyroid and Antithyroid drugs
Thyroid gland produces thyroid hormones. These hormones are essential for the
body metabolism, growth and development. Thyroid hormones are derivatives of
the amino acid tyrosine bound covalently to iodine.
The two principal thyroid hormones are T3 and T4.
Thyroid hormones have two major physiological effects – They increase protein
synthesis in every body tissue and increase oxygen consumption dependent upon
Na+/K+ ATP ase. Certain types of thyroid tumors appear to be more prevalent in
certain age groups.
Thyroid problems have a strong genetic component and may skip generations.
Hypothyroidism in Adults :

57. Hypothyroidism is a common condition where the thyroid doesn’t create and release
enough thyroid hormone into your bloodstream. This makes your metabolism slow down.
Also called underactive thyroid, hypothyroidism can make you feel tired, gain weight and be
unable to tolerate cold temperatures. The main treatment for hypothyroidism is hormone
replacement therapy.
Thyroiditis
Thyroiditis is the inflammation of thyroid gland can be divided in to categories of auto
immune ( long –term inflammatory disease ; Grave’s disease, Hashimoto’s disease),
Riedel’s and miscellanous. More common in women than in men.
Hyperthyroidism
Hyperthyroidism is a metabolic imbalance that results from thyroid hormone over
production.
Grave’s disease
Toxic goiter is a cause of 80% of hyperthyroidism. Highest incidence between ages of
30 and 40.

58. Antithyroid drugs :
Anti –thyroid drugs are compounds that interfere with the body’s production of
thyroid hormone, thereby reducing symptoms of hyperthyroidism. ATDs were
discovered accidentally in the mid – 1940 when thiocyanate compounds used for
heart disease were found to cause hypothyroidism.
L-Thyroxine
2-Amino-3 (4- (4-hydroxy-3,5-diiodophenoxy) -3,5 –
diiodophenyl) Propanoic acid.

59. Levothyroxine is a synthetically prepared levo-isomer of the thyroid hormone thyroxine (T4,
a tetra-iodinated tyrosine derivative) that acts as a replacement in deficiency syndromes
such as hypothyroidism. T4 is the major hormone secreted from the thyroid gland and is
chemically identical to the naturally secreted T4: it increases metabolic rate, decreases
thyroid-stimulating hormone (TSH) production from the anterior lobe of the pituitary gland,
and, in peripheral tissues, is converted to T3. Thyroxine is released from its precursor protein
thyroglobulin through proteolysis and secreted into the blood where is it then peripherally
deiodinated to form triiodothyronine (T3) which exerts a broad spectrum of stimulatory
effects on cell metabolism. T4 and T3 have a relative potency of ~1:4.
SAR :
1. The ether oxygen can be replaced iso sterically by sulphur or methylene which
also provide an angle of 120̊ C.
2. A phenolic hydroxyl group at 4’ position is important for hydrogen bonding to
transport proteins.
3. The 3’ – position ortho to the hydroxyl and away from the other aromatic ring
must be substituted by a lipophilic group.
4. The iodine atoms at 3 and 5 positions can be replaced by non –polar groups.
5. The amino acid side chain can be varied, but should be para to the aromatic
ring.

60. Metabolism
The primary pathway of thyroid hormone metabolism is through sequential
deiodination. The liver is the main site of T4 deiodination and along with kidneys
are responsible for about 80% of circulating T3.
Therapeutic uses :
Levo thyroxine is used to treat hypothyroidism.
Adv.Reactions :
Abdominal pain, nausea, anxious ness, confusion, agitation and
insomnia.

61. L- Thyroinine
2- amino -3 (4 (4- hydroxy phenoxy) phenyl) propanoic acid.
Propyl thiouracil
6-propyl-2-sulfanylpyrimidin-4-one.

62. MOA:
Propylthiouracil binds to thyroid peroxidase and thereby inhibits the conversion of
iodide to iodine. Thyroid peroxidase normally converts iodide to iodine (via hydrogen
peroxide as a cofactor) and also catalyzes the incorporation of the resulting iodide
molecule onto both the 3 and/or 5 positions of the phenol rings of tyrosines found in
thyroglobulin. Thyroglobulin is degraded to produce thyroxine (T4) and tri-iodothyronine
(T3), which are the main hormones produced by the thyroid gland. Therefore
propylthiouracil effectively inhibits the production of new thyroid hormones.
Thyroid peroxidase

63. Metabolism Hydroxylation of
antepenultimate
aliphatic secondary
carbon
Hydroxylation of
penultimate
aliphatic secondary
carbon
Hydroxylation of
terminal methyl
AndFromCyProduct
Terminal
desaturation

64. Uses : Propyl thiouracil is a medication used to treat hyperthyroidism
Adverse effects : Itchiness, hairlosing, swelling, vomiting, musclepains, numbness
and headache.
Methimazole
Methyl-3H-Imidazole – 2-thione
Methimazole's primary mechanism of action appears to be interference in an early step
in thyroid hormone synthesis involving thyroid peroxidase (TPO), however the exact
method through which methimazole inhibits this step is unclear. TPO, along with
hydrogen peroxide, normally catalyzes the conversion of iodide to iodine and then
further catalyzes the incorporation of this iodine onto the 3 and/or 5 positions of the
phenol rings of tyrosine residues in thyroglobulin. These thyroglobulin molecules then
degrade within thyroid follicular cells to form either thyroxine (T4) or tri-iodothyronine
(T3), which are the main hormones produced by the thyroid gland.

65. Metabolism
Isoflavanone C-ring fission
Isoflavanone C-ring fission
Primarily Hepatic

66. Therapeutic uses :
Hyperthyroidism such as in Grave’s disease, a condition that occurs when the thyroid gland
begins to produce an excess of thyroid hormone.
***************Completed************