Unit V

Drugs acting on endocrine system

• The endocrine system helps to maintain internal homeostasis
through the use of endogenous chemicals known as
hormones. A hormone is typically regarded as a chemical
messenger that is released into the bloodstream to exert an
effect on target cells located some distance from the
hormonal release site. The endocrine system is a series of
glands that produce hormones which regulate respiration,
metabolism, growth and development, tissue function, sexual
function, reproduction etc.
• Endocrine glands are ductless glands of the endocrine
system that secrete their products, hormones, directly
into the blood. The major glands of the endocrine
system include the pineal gland, pituitary gland,
pancreas, ovaries, testes, thyroid gland, parathyroid
gland, hypothalamus and adrenal glands
• Introduction to steroids

Steroids are the class of naturally occurring organic

compounds with four rings arranged in a specific
molecular configuration. Steroids exhibit two principal
biological functions such as important components of
cell membranes which alter membrane fluidity and as
signaling molecules.
• Classification of Steroids

Anabolic Steroids: Interact with androgen receptor and enhance

muscle mass and male sex hormones.
Glucocorticoids: Regulate metabolism and immune function and
anti-inflammatory activity.

Mineralocorticoids: Maintain blood volume and renal excretion

Progestins: Development of female sex organs
Phytosteroids: Plant steroids
Ergosteroids: Steroids of the fungi and vitamin D
• Nomenclature of steroids

Beginning in the 1950s, nomenclature rules for steroids were

being developed, and the most recent IUPACIUB Joint

Commission rules for systematic steroid nomenclature were

published in 1989. The steroid core structure is composed of

seventeen carbon atoms (C17), bonded in four "fused" rings.

Three six-member cyclohexane rings (rings A, B and C in the first

illustration) and one five-member cyclopentane ring (the D

ring). Steroids vary by the functional groups attached to this four

ring core and by the oxidation state of the rings.

Almost all steroids are named as derivatives of any one of the following basic
steroidal ring.
• Solid line indicates groups above the plane of the nucleus (β-configuration)
and dotted line denote groups below the plane (α- configuration).
• The configuration of the hydrogen (-H) at C-5 position is always indicate in the
name.
• Compounds with 5-α cholestane belong to the ‘allo series’ while compounds
derived from the 5-βcholestane belongs to the ‘normal series’.
• The symbol Δ (delta) is used to indicate C=C bond in steroids.
Drugs for erectile dysfunction
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
 Mechanism of action

Sildenafil acts by blocking phosphodiesterase-5 (PDE5), an enzyme that

promotes breakdown of cyclic guanosine monophosphate (cGMP), which

regulates blood flow in the penis.

Metabolism Sildenafil is broken down in the liver by hepatic metabolism using

cytochrome p450 enzymes, mainly CYP450 3A4 (major route), but also by

CYP2C9 (minor route) hepatic isoenzymes

 Adverse effect

Dizziness, headache, flushing, or stomach upset may occur. Vision

changes such as increased sensitivity to light, blurred vision, or

trouble telling blue and green colors apart may also occur.

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[8.7.0.0³,⁸.0¹¹,¹⁶] heptadeca-1(10),11,13,15-
tetraene-4,7-dione.
 Mechanism of action

• It is a phosphodiesterase-5 (PDE5) inhibitor. It works by increasing blood flow

to the penis to help a man get and keep an erection. Metabolism Tadalafil is

predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol

metabolite undergoes extensive methylation and glucuronidation to form the

methylcatechol and methylcatechol glucuronide conjugate, respectively.

• Adverse effect: Headache, stomach upset, back pain,
muscle pain, stuffy nose, flushing, or dizziness may occur.
• 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)
 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
Or meloxifene 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, sold under the

brand name Plan B, 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
• Mechanism of action

Mifepristone is an anti-progestin that blocks the action

of progesterone, a hormone necessary to maintain a
pregnancy. By blocking the action of progesterone,
mifepristone alters the endometrium (the uterine
lining), induces bleeding, and causes the uterine lining
to shed
 Metabolism
• Metabolism of mifepristone is primarily via pathways involving N-

demethylation and terminal hydroxylation of the 17-propynyl chain.

• Adverse effect: Nausea, vomiting, diarrhea, weakness, or dizziness

may occur. Bleeding and cramping are expected during this treatment.

• 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
 Mechanism of action

• It binds to the progesterone and estrogen

receptors within the female reproductive tract
and the mammary gland.
• Metabolism: The metabolism of Norgestrel can
be increased when combined with Estradiol
dienanthate
Adverse effect:

Nausea, vomiting, stomach cramping/bloating, dizziness, headache,

tiredness, breast tenderness, decrease in breast size, acne, oily scalp,
hair loss, weight gain, and vaginal infections may occur.

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 17αethynyl-18-methylestr-4-en-17β-ol-3-
one
• Mechanism of action: It prevents fertilization by inhibiting the

ovulation and thickening of cervical mucus.

• Metabolism: Levonorgestrel is metabolized in the liver, via

reduction, hydroxylation, and conjugation (specifically

glucuronidation and sulfation). Oxidation occurs primarily at the

C2α and C16β positions, while reduction occurs in the A ring.

Adverse effect: Nausea, vomiting, abdominal pain, tiredness,

dizziness, changes in vaginal bleeding, breast tenderness, diarrhea,

or headache may occur.

• Uses: Levonorgestrel is used to prevent pregnancy after

unprotected sexual intercourse

• 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
 Mechanism of action

Cortisone acetate binds to the cytosolic glucocorticoid

receptor. After binding the receptor the newly formed
receptor-ligand complex translocates itself into the cell
nucleus, where it binds to many glucocorticoid response
elements (GRE) in the promoter region of the target
genes
 Metabolism

Corticosteroids are metabolized through enzymatic

transformations that diminish their physiologic activity
and increase water solubility to enhance their urinary
excretion. The majority of serum cortisol is reduced to
dihydrocortisol and then to tetrahydrocortisol, which is
then conjugated to glucuronic acid.
• Adverse effect: Fluid retention, causing swelling
in lower legs. Problems with mood swings,
memory and behavior and other psychological
effects, such as confusion or delirium.
• Uses: Cortisone is used as an anti-inflammatory
medication
 Mechanism of action

Hydrocortisone binds to the glucocorticoid receptor leading to downstream effects such

as inhibition of phospholipase A2, NF-kappa-B, other inflammatory transcription factors,

and the promotion of antiinflammatory genes.

Metabolism: It is metabolized in the liver to inactive glucuronide and sulfate metabolites.

Adverse effect: Nausea, heartburn, headache, dizziness, menstrual period changes,

trouble sleeping, increased sweating, or acne may occur.

Uses: Hydrocortisone topical is used to treat redness, swelling, itching, and discomfort of

various skin conditions

• Prednisolone Prednisolone is a glucocorticoid.
Chemically, it is 11,17-Dihydroxy-17-(2-hydroxyacetyl)-
10,13-dimethyl6,7,8,9,10,11,12,13,14,15,16,17-
dodecahydrocyclopenta[a] phenanthren-3-one. It is a
medication used to treat certain types of allergies,
inflammatory conditions, autoimmune disorders, and
cancers
 Metabolism

It is metabolized in liver to active metabolite prednisolone, which is then

metabolized to inactive glucuronide and sulfate metabolites.

Adverse effect: Nausea, heartburn, headache, dizziness, menstrual period

changes, trouble sleeping, increased sweating, or acne may occur.

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
• Structure-activity relationship (SAR) Study Presence of
keto (C=O) group and double bond between C4 and C5 is
essential for both gluco and mineralo corticoid activities.
• Presence of double bond between C1 and C2 is essential
for glucocorticoid activity.
• Presence of 11β-hydroxy is essential for glucocorticoid
activity
 Mechanism of action
Betamethasone binds to specific intracellular
glucocorticoid receptors and subsequently binds to
DNA to modify gene expression. The synthesis of
certain anti-inflammatory proteins is induced while the
synthesis of certain inflammatory mediators is inhibited.
Metabolism: It is metabolized in the liver to inactive
glucuronide and sulfate metabolites.
• Adverse effect: Common side effects of
betamethasone include abdominal bloating,
abdominal fat deposits, abnormal hair growth.
• Uses: Betamethasone is used topically to treat itching,
redness, dryness, crusting, scaling, inflammation, and
discomfort of various skin conditions, including
psoriasis and eczema.
 Mechanism of action

• It inhibits phospholipase A2, which decreases the

formation of arachidonic acid derivatives.
• It inhibits NF-Kappa B and other inflammatory
transcription factors.
• It promotes anti-inflammatory genes like interleukin-10.
 Metabolism

• Dexamethasone is 6-hydroxylated by CYP3A4 to 6α-

and 6β-hydroxydexamethasone.
• Dexamethasone is reversibly metabolized to 11-
dehydrodexamethasone by corticosteroid 11-
betadehydrogenase isozyme-2 and can also be
converted back to dexamethasone by Corticosteroid 11-
beta-dehydrogenase isozyme 1.
• Adverse effect: The following side effects are common for patients taking

dexamethasone. Increased appetite.

• Irritability.

• Difficulty sleeping (insomnia).

• Swelling in your ankles and feet (fluid retention) Heartburn.

• Muscle weakness.

• Impaired wound healing.

• Increased blood sugar levels.

• Uses: It relieves inflammation (swelling, heat, redness, and pain) and is

used to treat certain forms of arthritis

Thyroid and antithyroid drugs
 THYROID HORMONES

•Thyroid gland produces thyroid hormones. These hormones are

essential for life and have many effects on body metabolism, growth,

and development. Thyroid hormones are derivatives of the amino acid

tyrosine bound covalently to iodine. The two principal thyroid

hormones are: Thyroxine (also known as T4 or L-3,5,3',5'-

tetraiodothyronine) Triiodotyronine (T3 or L-3,5,3'-triiodothyronine).

• The thyroid hormones are basically two tyrosines
linked together with the critical addition of iodine at
three or four positions on the aromatic rings. The
number and position of the iodines is important.
Several other iodinated molecules are generated that
have little or no biological activity; so called "reverse
T3" (3,3’,5’-T3) is such an example.
Thyroid hormones are poorly soluble in water, and

more than 99% of the T3 and T4 circulating in blood is bound to

carrier proteins.

The principle carrier of thyroid hormones is thyroxine-binding

globulin, a glycoprotein synthesized in the liver.

Two other carriers of import are transthyrein and albumin.

Carrier proteins allow maintenance of a stable pool of thyroid

hormones from which the active, free hormones are released for
uptake by target cells.
 BIOSYNTHESIS OF THYROID HORMONES

• Thyroid hormones are biosynthesized in the body

through various steps, which can be covered under the
following headings-
• (i) Iodine Metabolism:-Iodine enters the body in the
form of iodate or iodide in the water we drink or food
we eat; the iodate is converted to iodide in the stomach.
The thyroid gland traps and concentrates iodide and
uses it in the synthesis and storage of thyroid hormones
• (ii) Thyroglobulin and its Iodination:- Under TSH action,

amino acids are transported into thyroid follicular cells

and they are incorporated into the synthesis of a

glycoprotein, thyroglobulin, which serves as a matrix in

which thyroid hormones are formed. Thyroglobulin is

synthesized on the rough endoplasmic reticulum (RER)

• (iii) Thyroglobulin: Reabsorption and T3/T4 Secretion from the Cell Upon

proper stimulation by TSH, droplets of iodinated thyroglobulin return to

the follicular cell by pinocytosis. The droplets fuse with lysosomes,

forming an endosome. Proteases from the lysosomes breakdown peptide

bonds between the iodinated residues and thyroglobulin molecules to

yield T3 and T4 and MIT and DIT. Free T3 and T4 cross the cell membrane

and are discharged into the capillaries. MIT and DIT are liberated into the

cytoplasm, the iodines are removed by a deiodinase, and they and the

tyrosines are reused

 TRANSPORTATION OF T3/T4

Thyroid hormones secreted into the blood are quickly bound to plasma

carrier proteins. T3 and T4 have high binding affinity for their carrier

proteins as indicated by the fact that 99.96% of T4 is bound and only 0.04%

is free, and 99.6% T3 is bound and only 0.4% is free. This indicates that

thyroid hormones are stored in the lumen of the thyroid follicle and that

there is a reservoir of bound hormone in the plasma. Thyroid hormones that

are bound extend their half-life to days rather than minutes in the free form
• Thyroid hormones increase the metabolic turnover of several hormones,

ie, in a hyperthyroid individual, the half-life of cortisol is shortened from

100 minutes to 50 minutes; in hypothyroidism the half-life increases 150

minutes. TRH is one of the neurohormones that stimulates prolactin (PRL)

synthesis. In about half of the hypothyroid patients, PRL levels increase

because T3/T4 negative feedback hormones are deficient and TRH

increases. When these patients receive thyroid hormone treatment, the

PRL levels returned to normal. Finally, ovulation may be inhibited and

infertility is common in some hypothyroid and hyperthyroid patients. This

is corrected when the women are again euthyroid

LIOTHYRONINE SODIUM:

It is the L-isomer of triiodothyronine (T3), a form of thyroid hormone used to

treat hypothyroidism and myxedema coma.

Liothyronine is the most potent form of thyroid hormone. As such, it acts on the

body to increase the basal metabolic rate, affect protein synthesis and increase

the body's sensitivity to catecholamines (such as adrenaline).

The thyroid hormones are essential to proper development and differentiation of

all cells of the human body. These hormones also regulate protein, fat, and

carbohydrate metabolism, affecting how human cells use energetic compounds.

In comparison to levothyroxine (T4), liothyronine has a faster onset of action as

well as a shorter biological half-life, which may be due to less plasma protein

binding to thyroxine-binding globulin and transthyretin .

• Side effects: Liothyronine may cause a number of side effects,
mostly similar to symptoms of hyperthyroidism, which
include: Weight loss, tremor, headache, upset stomach,
vomiting, diarrhea, stomach cramps, nervousness, irritability,
insomnia excessive sweating, increased appetite, fever,
changes in menstrual cycle, sensitivity to heat, temporary hair
loss, particularly in children during the first month of therapy
• 1. The ether oxygen can be replaced isosterically by sulphur or methylene which

also provide an angle of 120. This change does not qualitatively impair the activity.

• 2. A phenolic hydroxyl group at 4’ position is important for hydrogen bonding to

transport proteins. It can, however, be replaced by isosteric groups like NH2 or by

a group that can generate a hydroxyl group after metabolism (OCH3 or OCOCH3).

But such a change results in reduced hormonal activity.

• 3. The 3’-position ortho to the hydroxyl and away from the other aromatic ring

must be substituted by a lipophilic group. This can be a halogen (preferably

Iodine) or any alkyl group approximately of the same size as Iodine such as an

isopropyl group.
• 4. The 3’-monosubstituted compounds are more active than the 3’,5’-disubstituted

molecules. Triiodothyronine is four times more potent than thyroxine, while 3’-

isopropyl-3,5-diiodothyronine has seven times the activity.

• 5. The iodine atoms at 3 and 5 positions can be replaced by non-polar groups

(such as methyl), as long as they keep the aromatic rings perpendicular to each

other.

• 6. The amino acid side chain can be varied, but should be para to the aromatic

ring.
 Thyroid hormone receptors and mechanism of action

Receptors for thyroid hormones are intracellular DNA-binding proteins that

function as hormone-responsive transcription factors and Thyroid hormones

enter cells through membrane transporter proteins.

Once inside the nucleus, the hormone binds its receptor, and the hormone-

receptor complex interacts with specific sequences of DNA in the promoters

of responsive genes.

The effect of the hormone-receptor complex binding to DNA is to modulate

gene expression, either by stimulating or by inhibiting transcription of

specific genes.
 Physiologic effects of thyroid hormones
• Thyroid hormones have profound effects on development,
growth and metabolism etc.
• Thyroid hormones stimulate diverse metabolic activities like
to an increase in basal metabolic rate.
• Increased thyroid hormone levels stimulate fat mobilization,
leading to increased concentrations of fatty acids in plasma.
They also enhance oxidation of fatty acids in many tissues.
• Thyroid hormones also stimulate carbohydrate metabolism,
including enhancement of insulin-dependent entry of
glucose into cells and increased gluconeogenesis and
glycogenolysis to generate free glucose.
Thyroid hormones are necessary for normal growth in children and as

evidenced by the growth-retardation observed in thyroid deficiency. Normal

levels of thyroid hormone are essential to the development of the fetal and

neonatal brain.

Thyroid hormones increases heart rate, cardiac contractility and cardiac output.

They also promote vasodilation, which leads to enhanced blood flow to many

organs.

Normal reproductive behavior and physiology is dependent on having

essentially normal levels of thyroid hormone.

Hypothyroidism in particular is commonly associated with infertility.

• Disease is associated with both inadequate production and
overproduction of thyroid hormones: A. Hypothyroidism is
the result due to thyroid hormone deficiency. It take place
due to
• 1. Iodine deficiency: Inadequate iodine intake and thyroid
hormones unable to synthesized.
• 2. Primary thyroid disease: Inflammatory diseases of the
thyroid that destroy parts of the gland are clearly an
important cause of hypothyroidism.
Common symptoms of hypothyroidism arising after early
childhood include lethargy, fatigue, cold-intolerance, weakness,
hair loss and reproductive failure. If these signs are severe, the
clinical condition is called myxedema.
• In the case of iodide deficiency, the thyroid becomes inordinantly large and

is called a goiter (Simple goiter). A goitre (struma), also called a

bronchocele, is a swelling in the neck (just below the Adam's apple or

larynx) due to an enlarged thyroid gland.

• Cretinism is a condition due to untreated congenital deficiency of thyroid

hormones (hypothyroidism) during fetal life or early infancy. The brain

and skeleton fail to develop properly, resulting in mental retardation and

dwarfism B. Hyperthyroidism. It is associated with an over production of

thyroid hormone.
 SYNTHESIS OF L-THYROXINE

• Thyroxine Sodium: Levothyroxine occurs as light yellow to buff-coloured

powder or fine, slightly coloured crystalline powder. It is stored in tightly-

closed, light-resistant containers. It is readily absorbed from the

gastrointestinal tract. It is eliminated slowly from the body and has a

halflife of 6 to 7 days.

• Use: It is primarily indicated for the treatment of hypothyroidism.

Treatment is usually long term as it is replacing thyroid hormone the body

is not producing. The dosage is usually adjusted according to response and

blood test results.

 Anti-thyroid Drugs

Anti-thyroid drugs (ATDs) 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’s

when thiocyanate compounds used for heart disease were found to cause

hypothyroidism. This led to the development of a number of compounds

specifically tailored to reduce thyroid hormone production.

CLASSIFICATION OF ANTITHYROID DRUGS

1. Thiourylene Derivatives

a. Thiouracils: Methylthiouracil, Propylthiouracil, etc.

b. Imidazoles: Methimazole, Carbimazole, Centimizone, etc.

2. Ion Inhibitors

3. Radioactive Iodine
• Propylthiouracil (PTU)
• Use: PTU is used to manage hyperthyroidism associated with
Grave's disease. It is also used before inactivating the thyroid
gland with radioactive iodine therapy. PTU may also be used
when it is not advisable to remove the thyroid gland.
• Dose: The initial adult dose of PTU is 300 mg/day. The drug
should be taken every eight hours.
• Occasionally adult doses may exceed 300 mg/day if
moderate or severe hyperthyroidism is present.
• A common, long-term adult dose after initial treatment is
100-150 mg/day. Children's initial and continuing doses vary.
• Drug Interaction: PTU may increase the effect of oral blood thinners, for

example warfarin (Coumadin).

• Therefore, warfarin dose changes and monitoring for the effects of

warfarin on blood clotting are necessary.

• Contraindications: There is evidence that PTU may cause harm to the

foetus during pregnancy. If

• hyperthyroidism becomes more severe during pregnancy, however, PTU

may be considered useful under.

• Side effects: PTU is generally well-tolerated with side effects
occurring in 1 of every 100 patients. The

• most common side effects are related to the skin and include
rash, itching, hives, abnormal hair loss, and

• skin pigmentation. Other common side effects are swelling,

nausea, vomiting, heartburn, loss of taste, joint or muscle
aches, numbness and headache.
• IMIDAZOLE DERIVATIVES The imidazole derivatives are also
used as antithyroid drugs. They include methimazole and
carbimazole. An antithyroid drug centimizone was discovered
at Central Drug Research Institute, Lucknow. These drugs bind
to thyroid peroxidase and prevent oxidation of
iodine/iodotyrosyl residues, thereby Inhibit iodination of
tyrosine residues in thyroglobulin and also Inhibit coupling of
iodotyrosine residues to form T3 and T4.
• Dose: The initial adult dose of methimazole is 15 mg/day for mild

hyperthyroidism, 30-40 mg/day for moderately severe

hyperthyroidism and 60 mg/day for severe hyperthyroidism. The drug

is usually taken every eight hours but may be taken once daily under

physician supervision. A common, long-term, adult dose after initial

treatment is 5-30 mg/day. Children's initial and continuing doses vary.

• Drug Interaction: There are no known drug interactions with

methimazole.
• Contraindications: Methimazole may cause harm to the foetus

during pregnancy. It may also harm the foetus during nursing,

and is therefore contraindicated.

• Side effects: Methimazole is generally well-tolerated with side

effects occurring in 3 out of every 100 patients. The most

common side effects are related to the skin and include rash,

itching, hives, abnormal hair loss, and skin pigmentation. Other

common side effects are swelling, nausea, vomiting, heartburn,

loss of taste, joint or muscle aches, numbness and headache.