Hormone: A chemical substance produced in the body that controls and regulates the activity

of certain cells or organs. Many hormones are secreted by special glands is as follows-

1. Pituitary
(a) Anterior
➢ Growth hormone (GH), Prolactin (prl)
➢ Adrenocorticotropic hormone (ACTH)
➢ Thyroid stimulating hormone (TSH)
➢ Gonadotropins-Follicle stimulating hormone (FSH) and Luteinizing hormone (LH)
➢ Interstitial-cell stimulating hormone (ICSH)
(b) Intermediate lobe.
➢ Melanocyte-stimulating hormones (MSHs)

(c) Posterior-
➢ Oxytocin,
➢ Antidiuretic hormone (ADH, Vasopressin).
2. Thyroid
➢ Thyroxine (T .),
➢ Triiodothyronine (T 3),
➢ Calcitonin.
3. Parathyroid
➢ Parathormone (PTH).
4. Pancreas (Islets of Langerhans)
➢ Insulin,
➢ Glucagon.
5. Adrenals
(a) Cortex-
➢ Glucocorticoids (hydrocortisone)
➢ Mineralocorticoids (aldosterone)
➢ Sex steroids ( dehydroepiandrosterone)
(b) Medulla-
➢ Adrenaline,
➢ Noradrenaline
6. Gonads
➢ Androgens (testosterone)
 ➢ Estrogens (estradiol)
➢ Progestins (progesterone)

Hypothalamic and pituitary hormones

The hypothalamus is a region of the brain that controls an immense number of bodily functions. It
is located in the middle of the base of the brain, and encapsulates the ventral portion of the third
ventricle.

The pituitary gland, also known as the hypophysis, is a roundish organ that lies immediately
beneath the hypothalamus, resting in a depression of the base of the skull called the sella turcica
 ("Turkish saddle"). In an adult human or sheep, the pituitary is roughly the size and shape of a
garbonzo bean.

The pituitary gland comprises three different structures arising from two different
embryological precursors. The anterior pituitary and the intermediate lobe are derived from the
endoderm of the buccal cavity, while the posterior pituitary is derived from neural ectoderm. The
main parts of the gland, the anterior and posterior lobes, receive independent neuronal input from
the hypothalamus, with which they have an intimate functional relationship.

THE ANTERIOR PITUITARY GLAND

(ADENOHYPOPHYSIS)
The adenohypophysis secretes a number of hormones crucial for normal physiological function.
Within this tissue are specialised cells such as corticotrophs, lactotrophs (mammotrophs),
somatotrophs, thyrotrophs and gonadotrophs, which secrete hormones that regulate different
endocrine organs of the body (Table 32.1). Interspersed among these are other cell types, including
the folliculostellate cells that exert a nurturing and regulatory influence on the hormonesecreting
endocrine cells. by the release from the hypothalamus of ‘factors’—in effect
local hormones—that reach the pituitary through the bloodstream.1 The blood supply to the
hypothalamus divides to form a meshwork of capillaries, the primary plexus (Fig. 32.1), which
drains into the hypophyseal portal vessels. These pass through the pituitary stalk to feed a
secondary plexus of capillaries in the anterior pituitary. Peptidergic neurons in the hypothalamus
secrete a variety of releasing or inhibitory hormones directly into the capillaries of the primary
capillary plexus
ANTERIOR PITUITARY HORMONES
 GROWTH HORMONE (SOMATOTROPHIN)
Growth hormone is secreted by the somatotroph cells and is the most abundant pituitary hormone. Secretion is
high in the newborn, decreasing at 4 years to an intermediate level, which is then maintained until after puberty,
after which there is a further decline. Several recombinant preparations of growth hormone, or somatropin, are
available for treating growth defects and other developmental problems Regulation of secretion.
Secretion of growth hormone is regulated by the action of hypothalamic GHRF and modulated by somatostatin,
One of the mediators of growth hormone action, insulin-like growth factor (IGF)-1, which is released from the
liver.
has an inhibitory effect on growth hormone secretion by stimulating somatostatin release from the hypothalamus.
Growth hormone release, like other anterior pituitary secretions, is pulsatile, and its plasma concentration may
fluctuate 10- to 100-fold. These surges occur repeatedly during the day and night, and reflect the dynamics of
hypothalamic control. Deep sleep is a potent stimulus to
growth hormone secretion, particularly in children.
Actions
The main effect of growth hormone (and its analogues) is to stimulate normal growth and, in doing this, it affects
many tissues, acting in conjunction with other hormones secreted from the thyroid, the gonads and the adrenal
cortex. It stimulates hepatic production of the IGFs—constimediates many of these anabolic effects, acting on
skeletal muscle and also on the cartilage at the epiphyses of long bones, thus influencing bone growth.
Disorders of production and clinical use
An excessive production of growth hormone in children results in gigantism. An excessive
production in adults, which is usually the result of a benign pituitary tumour, results in acromegaly,
in which there is enlargement mainly of facial structures and of the hands and feet.
PROLACTIN
Prolactin is secreted from the anterior pituitary by lactotroph mammotroph) cells. These are
abundant in the gland and increase in number during pregnancy, probably under the influence of
oestrogen.
Regulation of secretion
Prolactin secretion is under tonic inhibitory control by the hypothalamus the inhibitory mediator
being dopamine (acting on D2 receptors on the lactotrophs). The main stimulus for release is
suckling; in rats, both the smell and the sounds of hungry pups are also effective triggers.
 ✓ Oestrogens increase both prolactin secretion and the proliferation of lactotrophs through
release, from a subset of lactotrophs, of the neuropeptide galanin.

✓ Dopamine antagonists (used mainly as antipsychotic drugs;) are potent stimulants of

prolactin release, whereas agonists such as bromocriptine suppress prolactin release.
Bromocriptine is also used in parkinsonism

ADRENOCORTICOTROPHIC HORMONE

Adrenocorticotrophic hormone (ACTH, corticotrophin) is the anterior pituitary secretion that

controls the synthesis and release of the glucocorticoids of the adrenal cortex. It is a 39-residue
peptide derived from the precursor pro-opiomelanocortin (POMC; ) by sequential proteolytic
processing. Failure of ACTH action because of defects in its receptor or intracellular signalling
pathways can lead to severe glucocorticoid deficiency.

THYROID STIMULATING HORMONE (TSH, THYROTROPIN)

✓ It is a 210 amino acid, two chain glycoprotein (22% sugar), MW 30000.

Physiological function TSH stimulates thyroid to synthesize and secrete thyroxine (T4) and
triiodothyronine (T3). Its actions are Induces hyperplasia and hypertrophy of thyroid follicles and
increases blood supply to the gland. Promotes trapping of iodide by thyroid. Promotes
organification of trapped iodine and its incorporation into T3 and T4 by increasing peroxidase
activity.Enhances endocytotic uptake of thyroid colloid by the follicular cells and proteolysis of
thyroglobulin to release more of T 3 and T 4. This action starts within minutes of TSH
administration.
Gonadotropins: Luteinizing and Follicle Stimulating Hormones

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are

called gonadotropins because stimulate the gonads - in males, the testes, and in females, the
ovaries. They are not necessary for life, but are essential for reproduction. These two hormones
are secreted from cells in the anterior pituitary called gonadotrophs. Most gonadotrophs secrete
only LH or FSH, but some appear to secrete both hormones.

LH and FSH are large glycoproteins composed of alpha and beta subunits. The alpha subunit is
identical in all three of these anterior pituitary hormones, while the beta subunit is unique and
endows each hormone with the ability to bind its own receptor.

Physiologic Effects of Gonadotropins

Physiologic effects of the gonadotrophins are known only in the ovaries and testes. Together, then
regulate many aspects of gonadal function in both males and females.

Luteinizing Hormone

In both sexes, LH stimulates secretion of sex steroids from the gonads. In the testes, LH binds to
receptors on Leydig cells, stimulating synthesis and secretion of testosterone. Theca cells in the
ovary respond to LH stimulation by secretion of testosterone, which is converted into estrogen by
adjacent granulosa cells.

In females, ovulation of mature follicles on the ovary is induced by a

large burst of LH secretion known as the preovulatory LH
surge. Residual cells within ovulated follicles proliferate to form corpora
lutea, which secrete the steroid hormones progesterone and estradiol.
Progesterone is necessary for maintenance of pregnancy, and, in most
mammals, LH is required for continued development and function of
corpora lutea. The name luteinizing hormone derives from this effect of
inducing luteinization of ovarian follicles.

Follicle-Stimulating Hormone

As its name implies, FSH stimulates the maturation of ovarian follicles. Administration of FSH to
humans and animals induces "superovulation", or development of more than the usual number of
mature follicles and hence, an increased number of mature gametes.

FSH is also critical for sperm production. It supports the function of Sertoli cells, which in turn
support many aspects of sperm cell maturation.

Control of Gonadotropin Secretion

The principle regulator of LH and FSH secretion is gonadotropin-releasing hormone (GnRH, also
known as LH-releasing hormone). GnRH is a ten amino acid peptide that is synthesized and
secreted from hypothalamic neurons and binds to receptors on gonadotrophs.
As depicted in the figure to the right, GnRH stimultes
secretion of LH, which in turn stimulates gonadal
secretion of the sex steroids testosterone, estrogen and
progesterone. In a classical negative feedback loop, sex
steroids inhibit secretion of GnRH and also appear to
have direct negative effects on gonadotrophs.

This regulatory loop leads to pulsatile secretion of LH

and, to a much lesser extent, FSH. The number of
pulses of GnRH and LH varies from a few per day to
one or more per hour. In females, pulse frequency is
clearly related to stage of the cycle.

Numerous hormones influence GnRH secretion, and

positive and negative control over GnRH and gonadotropin secretion is actually considerably more
complex than depicted in the figure. For example, the gonads secrete at least two additional
hormones - inhibin and activin - which selectively inhibit and activate FSH secretion from the
pituitary.

Disease States

Diminished secretion of LH or FSH can result in failure of gonadal function (hypogonadism). This
condition is typically manifest in males as failure in production of normal numbers of sperm. In
females, cessation of reproductive cycles is commonly observed.

Elevated blood levels of gonadotropins usually reflect lack of steroid negative feedback. Removal
of the gonads from either males or females, as is commonly done to animals, leads to persistent
elevation in LH and FSH. In humans, excessive secretion of FSH and/or LH most commonly the
result of gonadal failure or pituitary tumors. In general, elevated levels of gonadotropins per se
have no biological effect.

Pharmacologic Manipulation of Gonadotropin Secretion

Normal patterns of gonadotropin secretion are absolutely required for reproduction, and interfering
particularly with LH secretion is a widely-used strategy for contraception. Oral contraceptive pills
contain a progestin (progesterone-mimicking compound), usually combined with an estrogen. As
discussed above, progesterone and estrogen inhibit LH secretion, and oral contraceptives are
effective because they inhibit the LH surge that induces ovulation.

Another route to suppressing gonadotropin secretion is to block the GnRH receptor. GnRH
receptor antagonists have potent contraceptive effects in both males and females, but have not been
widely deployed for that purpose.

POSTERIOR PITUITARY GLAND

(NEUROHYPOPHYSIS)

The neurohypophysis consists largely of the terminals of nerve cells that lie in the supraoptic and
paraventricular nuclei of the hypothalamus. Their axons form the hypothalamic–hypophyseal
tract, and the fibres terminate in dilated nerve endings in close association with capillaries
in the posterior pituitary gland (Fig. 32.1). Peptides, synthesized in the hypothalamic nuclei, pass
down these axons into the posterior pituitary, where they are stored and eventually secreted into
the bloodstream. The two main hormones of the posterior pituitary are oxytocin (which contracts
the smooth muscle of the uterus; and ADH (also called vasopressin, Several similar peptides
have been synthesised that vary in their antidiuretic, vasopressor and oxytocic (uterine stimulant)
properties.

Physiologic Effects of Antidiuretic Hormone

Effects on the Kidney

The single most important effect of antidiuretic hormone is to conserve body water by reducing
the loss of water in urine. A diuretic is an agent that increases the rate of urine formation.
Injection of small amounts of antidiuretic hormone into a person or animal results in antidiuresis
or decreased formation of urine, and the hormone was named for this effect.

Antidiuretic hormone stimulates water reabsorbtion by stimulating insertion of "water channels"

or aquaporins into the membranes of kidney tubules. These channels transport solute-free water
through tubular cells and back into blood, leading to a decrease in plasma osmolarity and an
increase osmolarity of urine.

Disease States

The most common disease of man and animals related to antidiuretic hormone is diabetes
insipidus. This condition can arise from either of two situations:

• Hypothalamic ("central") diabetes insipidus results from a deficiency in secretion of

antidiuretic hormone from the posterior pituitary. Causes of this disease include head
trauma, and infections or tumors involving the hypothalamus.

• Nephrogenic diabetes insipidus occurs when the kidney is unable to respond to antidiuretic
hormone. Most commonly, this results from some type of renal disease, but mutations in
the ADH receptor gene or in the gene encoding aquaporin-2 have also been demonstrated
in affected humans.

Oxytocin

Oxytocin in a nine amino acid peptide that is synthesized in hypothalamic

neurons and transported down axons of the posterior pituitary for secretion
into blood. Oxytocin is also secreted within the brain and from a few other
tissues, including the ovaries and testes. Oxytocin differs from antidiuretic
hormone in two of the nine amino acids. Both hormones are packaged into
granules and secreted along with carrier proteins called neurophysins.

Pharmacological Effects of Oxytocin

In years past, oxytocin had the reputation of being an "uncomplicated"

hormone, with only a few well-defined activities related to birth and lactation.
As has been the case with so many hormones, further research has demonstrated many subtle but
profound influences of this little peptide, particularly in regards to its effects in the brain. Oxytocin
has been implicated in setting a number of social behaviors in species ranging from mice to
humans. For example, secretion or administration of oxytocin in humans appears to enhance trust
and cooperation within socially-close groups, while promoting defensive aggression toward
unrelated, competing groups.

Oxytocin has been best studied in females where it clearly mediates three major effects:

1. Stimulation of milk ejection (milk letdown): Milk is initially secreted into small sacs
within the mammary gland called alveoli, from which it must be ejected for consumption
or harvesting. Mammary alveoli are surrounded by smooth muscle (myoepithelial) cells
which are a prominant target cell for oxytocin. Oxytocin stimulates contraction of
myoepithelial cells, causing milk to be ejected into the ducts and cisterns.

2. Stimulation of uterine smooth muscle contraction at birth: At the end of gestation, the
uterus must contract vigorously and for a prolonged period of time in order to deliver the
fetus. During the later stages of gestation, there is an increase in abundance of oxytocin
receptors on uterine smooth muscle cells, which is associated with increased "irritability"
of the uterus (and sometimes the mother as well). Oxytocin is released during labor when
the fetus stimulates the cervix and vagina, and it enhances contraction of uterine smooth
muscle-----------------------------------------------> to facilitate parturition or birth.

In cases where uterine contractions are not sufficient to complete delivery, physicians and
veterinarians sometimes administer oxytocin ("pitocin") to further stimulate uterine
contractions - great care must be exercised in such situations to assure that the fetus can
indeed be delivered and to avoid rupture of the uterus.

3. Establishment of maternal behavior: Successful reproduction in mammals demands that

mothers become attached to and nourish their offspring immediately after birth. It is also
important that non-lactating females do not manifest such nurturing behavior. The same
events that affect the uterus and mammary gland at the time of birth also affect the brain.
During parturition, there is an increase in concentration of oxytocin in cerebrospinal fluid,
and oxytocin acting within the brain plays a major role in establishing maternal behavior.

Evidence for this role of oxytocin come from two types of experiments. First, infusion of
oxytocin into the ventricles of the brain of virgin rats or non-pregnant sheep rapidly induces
maternal behavior. Second, administration into the brain of antibodies that neutralize
oxytocin or of oxytocin antagonists will prevent mother rats from accepting their pups.
Other studies support the contention that this behavioral effect of oxytocin is broadly
applicable among mammals.

While all of the effects described above certainly occur in response to oxytocin, doubt has recently
been cast on its necessity in parturition and maternal behavior. Mice that are unable to secrete
oxytocin due to targeted disruptions of the oxytocin gene will mate, deliver their pups without
apparent difficulty and display normal maternal behavior. However, they do show deficits in milk
ejection and have subtle derangements in social behavior. It may be best to view oxytocin as a
major facilitator of parturition and maternal behavior rather than a necessary component of these
processes.
Both sexes secrete oxytocin - what about its role in males? Males synthesize oxytocin in the same
regions of the hypothalamus as in females, and also within the testes and perhaps other
reproductive tissues. Pulses of oxytocin can be detected during ejaculation. Current evidence
suggests that oxytocin is involved in facilitating sperm transport within the male reproductive
system and perhaps also in the female, due to its presence in seminal fluid. It may also have effects
on some aspects of male sexual behavior.

Control of Oxytocin Secretion

A number of factors can inhibit oxytocin release, among them acute stress. For example, oxytocin
neurons are repressed by catecholamines, which are released from the adrenal gland in response
to many types of stress, including fright. As a practical endocrine tip - don't wear a gorilla costume
into a milking parlor full of cows or set off firecrackers around a mother nursing her baby.

Both the production of oxytocin and response to oxytocin are modulated by circulating levels of
sex steroids. The burst of oxytocin released at birth seems to be triggered in part by cervical and
vaginal stimulation by the fetus, but also because of abruptly declining concentrations of
progesterone. Another well-studied effect of steroid hormones is the marked increase in synthesis
of uterine (myometrial) oxytocin receptors late in gestation, resulting from increasing
concentrations of circulating estrogen.

THYROID HORMONES AND THYROID DRUGS.

The thyroid gland secretes three main hormones: thyroxine (T4), tri-iodothyronine (T3) and
calcitonin. T4 and T3 are critically important for normal growth and development and for
controlling energy metabolism. Calcitonin is involved in the control of plasma [Ca2+] and is used
to treat osteoporosis and other metabolic bone diseases.The term thyroid hormone will be used
here solely to refer to T4 and T3.

Thyroid-Stimulating Hormone (Thyrotropin)

Thyroid-stimulating hormone, also known as thyrotropin, is secreted from cells in the anterior
pituitary called thyrotrophs, finds its receptors on epithelial cells in the thyroid gland, and
stimulates that gland to synthesize and release thyroid hormones.
TSH is a glycoprotein hormone composed of two subunits
which are non-covalently bound to one another. The alpha
subunit of TSH is also present in two other pituitary
glycoprotein hormones, follicle-stimulating hormone and
luteinizing hormone, and, in primates, in the placental
hormone chorionic gonadotropin. Each of these hormones also has a unique beta subunit, which
provides receptor specificity. In other words, TSH is composed of alpha subunit bound to the TSH
beta subunit, and TSH associates only with its own receptor. Free alpha and beta subunits have
essentially no biological activity.
The most important controller of TSH
secretion is thyroid-releasing
hormone. Thyroid-releasing hormone
is secreted by hypothalamic neurons
into hypothalamic-hypophyseal portal
blood, finds its receptors on
thyrotrophs in the anterior pituitary
and stimulates secretion of TSH.
One interesting aspect of thyroid-releasing hormone is that it is only three amino acids long. Its
basic sequence is glutamic acid-histidine-proline, although both ends of the peptide are modified.
Secretion of thyroid-releasing hormone, and hence, TSH, is inhibited by high blood levels of
thyroid hormones in a classical negative feedback loop.
Additional information about TSH and its effects and control are presented in the section on
the thyroid gland.

ACTIONS OF THE THYROID HORMONES

EFFECTS ON METABOLISM
✓ The thyroid hormones produce a general increase in the metabolism of carbohydrates, fats
and proteins, and regulate these processes in most tissues, T3 being three to five times more
active than T4 in this respect
✓ Thyroid hormones directly control the activity of some of the enzymes of carbohydrate
metabolism, most effects are brought about in conjunction with other hormones, such as
insulin, glucagon, the glucocorticoids and the catecholamines. There is an increase in
oxygen consumption and heat production, which is manifested as an increase in the
measured basal metabolic rate.
Administration of thyroid hormone results in augmented cardiac rate and output, and increased
tendency to dysrhythmias such as atrial fibrillation.
The thyroid hormones have a critical effect on growth, partly by a direct action on cells, and also
indirectly by influencing growth hormone production and potentiating its effects on its target
tissues.
ABNORMALITIES OF THYROID FUNCTION
thyroid dysfunction is often associated with enlargement of the gland, known as goitre.
HYPERTHYROIDISM (THYROTOXICOSIS)
In thyrotoxicosis, there is excessive activity of the thyroid hormones, resulting in a high metabolic
rate, an increase in skin temperature and sweating, and a marked sensitivity to heat. Nervousness,
tremor, tachycardia, heat sensitivity and increased appetite associated with loss of weight occur.
There are several types of hyperthyroidism, but only two are common: diffuse toxic goitre (also
called Graves’ disease3 or exophthalmic goitre) and toxic nodular goitre.
SIMPLE, NON-TOXIC GOITRE
A dietary deficiency of iodine, if prolonged, causes a rise in plasma TRH and eventually an
increase in the size of the gland. This condition is known as simple or non-toxic goitre. Another
cause is ingestion of goitrogens (e.g. from cassava root).
HYPOTHYROIDISM
A decreased activity of the thyroid results in hypothyroidism, and in severe cases myxoedema.
Once again, this disease is immunological in origin, and the manifestations include low metabolic
rate, slow speech, deep hoarse voice, lethargy, bradycardia, sensitivity to cold and mental
impairment. Patients also develop a characteristic thickening of the skin (caused by the
subcutaneous deposition of glycosaminoglycans), which gives myxoedema its name. Hashimoto’s
thyroiditis, a chronic autoimmune disease in which there is an immune reaction against
thyroglobulin or some other component of thyroid tissue, can lead to hypothyroidism and
myxoedema

CLASSIFICATION
1-Inhibit hormone synthesis (Antithyroid drugs)
Propylthiouracil, Methimazole, Carb
2 Inhibit iodide trapping (Ionic inhibitors)
Thiocyanates (-SCN), Perchlorates (-Cl04),
Nitrates (-N03).
3-Inhibit hormone release
Iodine, Iodides of Na and K, Organic iodide.
4-Destroy thyroid tissue
Radioactive iodine (131I, 12s1, 123J) .

ANTITHYRO I D DRUGS
By convention, only the synthesis inhibitors are called antithyroid drugs, though this term has
also been applied to all thyroid inhibitors. Thiourea derivatives were found to produce goiter
and hypothyroidism in rats in the 1940s. Open chain compounds were found to be toxic.
Subsequently, methyl and propyl thiouracil and thioimidazole derivatives methimazole and
carbimazole were found to be safe and effective.
Antithyroid drugs bind to thyroid peroxidase and prevent oxidation of iodide/iodotyrosyl residues,
thereby;
(i) Inhibit iodination of tyrosine residues in thyroglobulin
(ii) Inhibit coupling of iodotyrosine residues to form T3 and T4.
Action (ii) has been observed at lower concentration of antithyroid drugs than action (i). Thyroid
colloid is depleted over time and blood levels of T3/T4 are reduced. They do not interfere with
trapping of iodide and do not modify the action of T3 and T4 on peripheral tissues or on pituitary.
Goiter is not the result of potentiation of TSH action on thyroid, but is due to increased TSH release
as a consequence of reduction in feedback inhibition.
No goiter occurs if antithyroid drugs are given to hypophysectomised animals or if T4 is given
along with them. Antithyroid drugs do not affect release of T3 and T4-their effects are not apparent
till thyroid is depleted of its hormone content. Propylthiouracil also inhibits peripheral
conversion of T4 to T3 by 01 type of 5'01, but not by 02 type. This may partly contribute to its
effects. Methimazole and carbimazole do not have this action and may even antagonize that of
propylthiouracil.
THIOUREYLENES
The thioureylene group of drugs comprises carbimazole, methimazole and propylthiouracil.
Chemically, they are related to thiourea, and the thiocarbamide (S–C–N) group is essential for
antithyroid activity.
Mechanism of action
Thioureylenes decrease the output of thyroid hormones from the gland, and cause a gradual
reduction in the signs and symptoms of thyrotoxicosis, the basal metabolic rate and pulse rate
returning to normal over a period of 3–4 weeks. Their mode of action is not completely understood,
but there is evidence that they inhibit the iodination of tyrosyl residues in thyroglobulin
It is thought that they inhibit the thyroperoxidase-catalysed oxidation reactions by acting as
substrates for the postulated peroxidase–iodinium complex, thus competitively inhibiting the
interaction with tyrosine. Propylthiouracil has the additional effect of reducing the deiodination of
T4 to T3 in peripheral tissues.
Pharmacokinetics All antithyroid drugs are quickly absorbed orally, widely distributed in the
body, enter milk and cross placenta; are metabolized in liver and excreted in urine primarily as
metabolites.
Important side effects are: g.i. intolerance, rashes and joint pain. Loss or graying of hair, loss
of taste liver damage are infrequent.

CARBIMAZOLE
Carbimazole is used to treat hyperthyroidism. The patient is usually rendered euthyroid within
four to six weeks, and the dose is then reduced. Treatment is maintained for one to two years and
the drug is then gradually withdrawn. If relapse occurs, the dose is raised until clinical
improvement is restored. If dosage adjustment proves difficult, smoother control may be obtained
by giving a replacement dose of thyroxine together with a blocking dose of carbimazole.
Mechanism of action
The action of carbimazole is via its active metabolite methimazole, which is a substrate-inhibitor
of peroxidase and is itself iodinated and degraded within the thyroid, diverting oxidized iodine
away from thyroglobulin and decreasing thyroid hormone biosynthesis. Methimazole is
concentrated by cells with a peroxidase system (salivary gland, neutrophils and
macrophage/monocytes, in addition to thyroid follicular cells). It has an immunosuppressive action
within the thyroid.
Adverse effects
Carbimazole is usually well tolerated, although pruritus and rashes are fairly common. These
usually respond to switching to propylthiouracil (see below). Neutropenia is a rare but potentially
fatal adverse effect.
➢ GPAT
β-ADRENOCEPTOR ANTAGONISTS Beta-blockers improve symptoms of hyperthyroidism,
including anxiety, tachycardia and tremor. They inhibit the conversion of T4 to T3 in the tissues.
They are useful:

Parathormone
Parathyroid hormone (PTH), also called parathormone or parathyrin, is a hormone secreted by
the parathyroid glands that is important in bone remodeling, which is an ongoing process in
which bone tissue is alternately resorbed and rebuilt over time. It essentially increases blood
calcium levels. The bones act as a (metaphorical) "bank of calcium" (GPAT)from which the
body can make "withdrawals"(GPAT) as needed to keep the amount of calcium in the blood at
appropriate levels despite the ever-present challenges of metabolism, stress,
and nutritional variations. PTH is "a key that unlocks the bank vault" (GPAT) to remove the
calcium. In consequence, PTH is vital to health, and health problems that yield too little or too
much PTH (such as hypoparathyroidism, hyperparathyroidism, or paraneoplastic syndromes) can
wreak havoc in the form of bone disease, hypocalcaemia, and hypercalcaemia.
PTH is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino
acids, which is a prohormone; effective hormone-receptor interaction requires solely the 34-N-
terminal amino acids. While PTH acts to increase the concentration of ionic calcium (Ca2+) in
the blood, calcitonin, a hormone produced by the parafollicular cells (C cells) of the thyroid gland,
acts to decrease ionic calcium concentration.
Regulation of serum calcium
Parathyroid hormone regulates serum calcium through its effects on bone, kidney, and the
intestine.
In bone, PTH enhances the release of calcium from the large reservoir contained in the
bones. Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly
stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather,
PTH binds to osteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to
increase their expression of RANKL (Receptor activator of nuclear factor kappa-B ligand) and
inhibits their secretion of Osteoprotegerin (OPG). Free OPG competitively binds to RANKL as a
decoy receptor, preventing RANKL from interacting with RANK, a receptor for RANKL. The
binding of RANKL to RANK (facilitated by the decreased amount of OPG available for binding
the excess RANKL) stimulates these osteoclast precursors to fuse, forming new osteoclasts, which
ultimately enhances bone resorption.

Clinical Significance-
➢ Hyperparathyroidism, the presence of excessive amounts of parathyroid hormone in the
blood, occurs in two very distinct sets of circumstances. Primary hyperparathyroidism is
due to autonomous, abnormal hypersecretion of PTH from the parathyroid gland,
while secondary hyperparathyroidism is an appropriately high PTH level seen as a
physiological response to hypocalcaemia. A low level of PTH in the blood is known
as hypoparathyroidism and is most commonly due to damage to or removal of parathyroid
glands during thyroid surgery.
Calcitonin and Vitamin D
Plasma calcium is sensed by a calcium-sensitive receptor (CaSR) in parathyroid and renal tubular
cells, and maintainedwithin a narrow physiological range by parathyroid hormone (PTH), vitamin
D and calcitonin. The plasma calcium concentration is the major factor controlling PTH secretion
and a reduction in calcium concentration stimulates PTH release. PTH raises plasma calcium and
lowers phosphate concentration. It acts on kidney and bone. PTH causes phosphaturia and
increases renal tubular reabsorption of calcium, which in association
with mobilization of calcium from bone, increases the plasma calcium concentration. Effects of
PTH on bone include stimulation of osteoclast activity, formation of new osteoclasts from
progenitor cells and transient depression of osteoblast activity. PTH also plays a role in the
regulation of vitamin D metabolism, indirectly increasing gut absorption of calcium by stimulating
production of the active metabolite 1,25- dihydroxycholecalciferol.
➢ Several important metabolic diseases affect the bones, notably hyperparathyroidism,
osteomalacia and rickets,
➢ Paget’s disease and osteoporosis. Some of these diseases (e.g. osteomalacia) are
associated with normal or low plasma calcium concentrations, some (e.g.
hyperparathyroidism) are associated with hypercalcaemia and some (e.g. osteoporosis)
are associated with normal plasma calcium concentrations. Post-menopausal
osteoporosis is the most common of these disorders; iatrogenic glucocorticoid or thyroid
hormone excess are important contributory causes.
The term ‘vitamin D’ covers several related compounds that share the ability to prevent or cure
rickets. These include ergocalciferol (vitamin D2), cholecalciferol (vitamin D3), α-calcidol (1-α-
hydroxycholecalciferol) and calcitriol (1,25-DHCC). The metabolic pathway of vitamin D is
summarized in Figure 39.1. Vitamin D3 is synthesized in skin in response to ultraviolet light
or absorbed in the upper small intestine. It is fat soluble, so bile is necessary for its absorption.
Renal 1-α-hydroxylase is activated by PTH and inhibited by phosphate, which thus influence the
amount of active 1,25-DHCC produced. 1,25-DHCC is, in effect, a hormone synthesized in the
kidney. It augments intestinal calcium absorption, mobilizes calcium from bone and stimulates
calcium reabsorption in the kidney (a minor effect). Storage of vitamin D occurs in the body, so a
single large dose may be effective for several weeks.
Uses
Dietary deficiency of vitamin D occurs where there is poverty and poor diet, accentuated by lack
of sunlight. Asian communities living in northern regions of the UK are at risk (chapatis and
other unleavened breads also reduce the absorption of vitamin D), as are elderly people living
alone. Pregnant and lactating women have increased requirements. Several vitamin D preparations
are available, with different potencies and uses.
1. Calcium and ergocalciferol tablets provide a physiological dose of vitamin D. They are used in
the prophylaxis of rickets and osteomalacia. The small dose of calcium is unnecessary, but a
preparation of vitamin D alone is not available.
2. Calciferol tablets provide a pharmacological dose of vitamin D and are used for treatment of
hypoparathyroidism and in cases of vitamin D-resistant rickets due to intestinal malabsorption or
chronic liver disease.
3. α-Calcidol rapidly undergoes hydroxylation to 1,25- DHCC. It is used in: • renal rickets, together
with a phosphate-binding agent; hypoparathyroidism and (paradoxically) secondary
hyperparathyroidism; • vitamin D-resistant rickets;• nutritional and malabsorptive rickets can be
treated with small doses of α-calcidol instead of conventional vitamin D.
4. Calcitriol (1,25-DHCC) is also available for the treatment of vitamin D-resistant rickets and is
the treatment of choice for pseudohypoparathyroidism (an uncommon metabolic disorder where
low plasma calcium is caused by resistance to the biochemical action of PTH).
Adverse effects
Hypercalcaemia, which can accelerate renal dysfunction, is the main problem. Regular plasma
calcium and creatinine measurements (weekly initially) are essential.
Key points(GPAT)
Vitamin D and calcium metabolism
• Plasma calcium concentrations are tightly controlled by the balance of hypocalcaemic effects of
calcitonin and hypercalcaemic effects of PTH and vitamin D and Ca2_ intake.
• Vitamin D is available in a number of forms, many of which are derived from each other by
sequential metabolism in the skin, liver and kidney, and each of which has specific indications.
• The most potent and rapid-acting orally available vitamin D preparations are 1,25
dihydroxycholecalciferol, and 1-α-hydroxycholecalciferol. They are used in renal rickets or
vitamin D-resistant rickets.
• When patients are hypocalcaemic, calcium can be supplemented orally as calcium carbonate with
or without various preparations of vitamin D. If urgent calcium replacement is required, a 10%
solution of calcium lactate or gluconate (the former yielding more calcium) may be administered
intravenously.
• Patients who are receiving vitamin D plus calcium should have periodic checks of their serum
Ca2_ and creatinine concentrations, as the major adverse effect is hypercalcaemia
CALCITONIN
This is a 32-amino-acid polypeptide hormone secreted by thyroid parafollicular C-cells. Secretion
is determined mainly by the plasma Ca2_ concentration.
Uses
Synthetic or recombinant salmon calcitonin (salcatonin) is used to lower the plasma calcium
concentration in hypercalcaemia, especially from malignancy, and in the treatment of pain and
some of the neurological complications (e.g. deafness due to VIII nerve compression) of severe
Paget’s disease and for post-menopausal osteoporosis (together with calcium and vitamin D
supplements, if diet is inadequate). Calcitonin is given by subcutaneous or intramuscular injection,
or as a nasal spray. Plasma calcium, phosphate, alkaline phosphatase and if possible urine
hydroxyproline excretion are monitored.
Mechanism of action
The main action of calcitonin is on bone; it inhibits bone resorption by binding to a specific
receptor on osteoclasts inhibiting their action. In the kidney, it decreases the reabsorption of both
Ca2_ and phosphate in the proximal tubules.
Adverse effects
Adverse effects include the following:
1. pain at the injection site;
2. nausea and diarrhoea;
3. flushing.

Case history
A 52-year-old woman has had epilepsy since childhood, treated with phenytoin 300 mg/day and
her fits have been well controlled. Since the loss of her job and the death of her husband she
has become an alcoholic. At the age of 54 years, she is seen by her local GP because of weakness
in her legs, difficulty in climbing stairs and getting out of her chair. She has no sensory
symptoms in her limbs and no sphincter problems. Neurological examination of her legs is
normal apart from signs of thigh and hip muscle weakness and slight wasting. Clinical
investigations reveal that haemoglobin, white blood and platelets are normal, but her
erythrocyte sedimentation rate is 30 mm per hour, her blood glucose level is 5.4 mM, sodium is
136 mM, K is 4.6 mM, urea is 10mM and creatinine is 80 μ M. Liver function tests are all
normal, except for an elevated alkaline phosphatase of 600 IU/L, and bilirubin is normal. A
chest x-ray is normal. Further biochemical investigation reveals a plasma calcium
concentration of 1.8mM and a phosphate concentration of 0.6mM.
Question What is the likely cause of her metabolic disturbance and leg weakness, and how
would you treat it ?
Answer
This patient has hypocalcaemia with hypophosphataemia and a raised alkaline phosphatase, but
no evidence of renal dysfunction. This is the clinical picture of a patient with osteomalacia.
The aetiology is secondary to her chronic phenytoin therapy. The mechanism of these effects is
complex and relates to several actions of the drug. Phenytoin is a potent inducer of hepatic drug
metabolizing enzyme systems, including the enzymes involved in vitamin D metabolism,
specifically metabolism of calciferol to 25_-hydroxycholecalciferol by the liver, and its further
metabolism to inactive products. It also impairs the absorption of vitamin D from the gut.
Treatment of this form of drug-induced osteomalacia consists of giving the patient oral Ca2_
supplements together with low-dose 1-α-hydroxy vitamin D (0.5 μg per day), and continuing the
phenytoin if necessary.

➢ GPAT
Bisphosphonates resemble pyrophosphate structurally, except that the two phosphorus atoms are
linked by carbon rather than by oxygen. The P-C-P backbone structure renders such compounds
very stable – no enzyme is known that degrades them.
Uses
Alendronic acid or risedronate (by mouth) are first-choice bisphosphonates for the prevention
and treatment of osteoporosis; etidronate is an alternative if these are not tolerated.
Bisphosphonates are also used to treat Paget’s disease of bone, in the treatment of hypercalcaemia
of malignancy (e.g. pamidronate i.v.) and to reduce skeletal complications in breast cancer
metastatic to bone and multiple myeloma (e.g. clodronate p.o. or i.v.). They are effective for
glucocorticoidassociated and post-menopausal osteoporosis. In Paget’s disease, risedronate is
given for two months and this can be repeated after at least two months off treatment. Etidronate
is started at low dosage up to six months when many patients achieve remission; a further course
may be given following relapse. Use for longer than six months at a time does not prolong
remission. High doses should be used only if lower doses fail or if rapid control of disease is
needed. Serum alkaline phosphatase, phosphate and if possible urinary hydroxyproline are
monitored during treatment of Paget’s disease.
Mechanism of action
Bisphosphonates modify the crystal growth of calcium hydroxyapatite by chemical adsorption to
the crystal surface, reducing bone remodelling and turnover by osteoclasts.
Adverse effects
Renal impairment is a caution or contraindication for all bisphosphonates. Oesophagitis and
ulceration can be severe. This is minimized by taking alendronic acid or risedronate when sitting
upright or standing, on an empty stomach before breakfast, and remaining standing for half an
hour before eating. Other adverse effects include the gamut of gastrointestinal symptoms.
Etidronate increases the risk of fracture in patients with Paget’s disease.
Diabetes mellitus (OM) It is a metabolic disorder characterized by hyperglycaemia, glycosuria,
hyperlipaemia, negative nitrogen balance and sometimes ketonaemia. A widespread pathological
change is thickening of capil lary basement membrane, increase in vessel wall matrix and cellular
proliferation resulting in vascular complications like lumen narrowing, early atherosclerosis,
sclerosis of glomerular capillaries, retinopathy, neuropathy and peripheral vascular insufficiency.
Type I Insulin-dependent diabetes mellitus (IDDM)- juvenile onset diabetes mellitus:
There is β cell destruction in pancreatic islets majority of cases are autoimmune antibodies that
destroy β cells.
➢ sorbitol (a reduced product of glucose) in tissues are believed to be causative in the
pathological changes of diabetes. The concentration of glycosylated haemoglobin (HbA1c)
is taken as an index of protein glycosylated.
Type-II Noninsulin-dependent diabetes mellitus,(NIDDM)- maturity onset diabetes mellitus
there is no loss or moderate reduction in β cell, insulin in circulation is low, normal or even high
no anti- β cell antibody is demonstrable.

Pathophysiology
• Diabetes Mellitus
• Type I diabetes (Insulin-dependent)
o Due to lack of insulin production
o Juvenile diabetes mellitus
• Type II diabetes (non insulin-dependent
o Due to decrease sensitivity of tissue to insulin (insulin resistance)
o Adult-onset diabetes

Type I diabetes
• Damage of B cells
o Viral infection, autoimmune disorder, genetic predisposition
o Appears at a young age
o Very rapidly
• High glucose concentration
o Loss of glucose in urine
o Osmotic diuresis (dehydration)
o Polyurea
• Structural changes in tissue
o Malfunction of blood vessels
o Risk of heart attack, stroke, kidney disease, retinopathy and
blindness, ischemia and gangrene of limbs
o Also neurological problems
• Switch to use of fats
o Causes metabolic acidosis
o Diabetic coma... death

Type II diabetes
 • Accounts for 80-90% of cases
• Manifest at mature age (adult onset diabetes)
• Increased plasma insulin
• Many metabolic abnormalities
o Except ketosis
• Patients usually obese
o Can be managed through diet

Insulin
Insulin was discovered in 1921 by Banting and Best who demonstrated the hypoglycaemic
action of an extract of pancreas prepared after degeneration of the exocrine part due to ligation of
pancreatic duct. It was first obtained in pure crystalline form in 1926 and the chemical structure
was fully worked out in 1956 by Sanger. Insulin is a two chain polypeptide having 51 amino acids
and MW about 6000. The A-chain has 21 while B-chain has 30 amino acids. There are minor
differences between human, pork and beef insulins.
Thus, pork insulin is more homologous to human insulin than is beef insulin. The A and B chains
are held together by two disulfide bonds. Insulin is synthesized in the β cells of pancreatic islets
as a single chain peptide Preproinsulin (110 AA) from which 24 AAs are first removed to produce
Proinsulin (Fig. 19.1). The connecting or 'C' peptide (35 AA) is split off by proteolysis in Golgi
apparatus; both insulin and C peptide are stored in granules within the cell. The C peptide is
secreted in the blood along with insulin.

Regulation of insulin secretion

Under basal condition ˜ lU insulin is secreted per hour by human pancreas. Much larger quantity
is secreted after every meal. Secretion of insulin from β cells is regulated by chemical, hormonal
and neural mechanisms. Chemical The β cells have a glucose sensing mechanism dependent on
entry of glucose into cells (through the aegis of a glucose transporter (GLUT2) and its
phosphorylation by glucokinase. Glucose entry and activation of the glucoceptor.
indirectly inhibits the ATP-sensitive K+ channel resulting in partial depolarization of the β cells.
This increases intracellular Ca2+ availability (due to increased influx, decreased efflux and release
from intracellular stores)---- > exocytotic release of insulin storing granules. Other nutrients that
can evoke insulin release are--amino acids, fatty acids and ketone bodies, but glucose is the
principal regulator and it stimulates synthesis of insulin as well. Glucose induces a brief pulse of
insulin output within 2 min (first phase) followed by adelayed but more sustained second phase of
insulin release.
Hormonal A number of hormones, e.g. growth hormone, corticosteroids, thyroxine modify insulin
release in response to glucose. PGE has been shown to inhibit insulin release. More important are
the intra-islet paracrine interactions between the hormones produced by different types of islet
cells. The beta cells constitute the core of the islets and are the most abundant cell type. The a
cells, comprising 25% of the islet cell mass, surround the core and secrete glucagon. The 0 cells
(5-10%) elaborating somatostatin are interspersed between the a cells. There are some PP (or F)
cells (pancreatic polypeptide containing) also.
• Somatostatin inhibits release of both insulin and glucagon.
• Glucagon evokes release of insulin as well as somatostatin.
• Insulin inhibits glucagon secretion.
The three hormones released from closely situated cells influence each other's secretion and
regulation.
The main factor controlling the synthesis and secretion of insulin is the blood glucose
concentration Beta cells respond both to the absolute glucose concentration and to the rate of
change of blood glucose. Other physiological stimuli to insulin release include amino acids
(particularly arginine and leucine), fatty acids, the parasympathetic nervous system and incretins
(see below). The main incretins are GLP-1 and GIP. Pharmacologically, sulfonylurea drugs (see
below) act by releasing insulin. There is a steady basal release of insulin and also a response to an
increase in blood glucose. This response has two phases: an initial rapid phase reflecting release
of stored hormone, and a slower, delayed phase reflecting continued release of stored hormone
and new synthesis The response is abnormal in diabetes mellitus, as discussed later.

ATP-sensitive potassium channels (KATP; Ch. 4) determine the resting membrane potential in B
cells. Glucose enters B cells via a membrane transporter called Glut-2, and its subsequent
metabolism via glucokinase (the ratelimiting enzyme that acts as the ‘glucose sensor’ linking
insulin secretion to extracellular glucose) and glycolysis increases intracellular ATP. This blocks
KATP channels, causing membrane depolarisation and opening of voltage dependent calcium
channels, leading to Ca2+ influx. The resulting increase in cytoplasmic Ca2+ triggers insulin
secretion,
GPAT
Insulin release is inhibited by the sympathetic nervous system Adrenaline (epinephrine) increases
blood glucose by inhibiting insulin release (via α2 adrenoceptors) and by promoting
glycogenolysis via β2- adrenoceptors in striated muscle and liver.

Role of insulin
• Lowers the circulatory concentrations of glucose, fatty acids and
amino acids
• Enhances storage of these in large molecules
• Glycogen
• Triglycerides
• Proteins
Effect of insulin on carbohydrates

• Muscle absorption of glucose

o Conversion of glucose to glycogen for storage
• Liver uptake of glucose
o Conversion of glucose to glycogen for short storage
• Inhibition of gluconeogenesis in the liver

Effects of insulin on fat metabolism

• After the deposit of glycogen is full (6% liver weight) it promotes the
synthesis of fat in the liver
• Exported to circulation as VLDL
o Uptake by adipose tissue
o Stored as fat
• Inhibit hormone-sensitive lipase (no FFA release from adipocytes)
• Promotes glucose uptake in adipocytes
o Synthesis of glycerol and FFA

Effect of insulin on protein metabolism

• Promotes protein synthesis and storage

o Increases uptake of amino acids
o Increases translation of mRNA
▪ Turns on ribosomal assembly
o Inhibits catabolism
o In liver reduces gluconeogenesis (amino acid sparing)

Effects of glucagon on glucose metabolism

• Promotes glycogenolysis
o Through a complex enzymatic cascade
• Increases gluconeogenesis in the liver
o Promotes amino acid uptake
o Converts them to glucose
 ORAL HYPOGL YCAEMIC DRUGS
These drugs lower blood glucose levels and are effective orally. The chief draw back of insulin
is-it must be given by injection. Orally active drugs have always been searched.
The early sulfonamides tested in 1 940s produced hypoglycaemia as side effect. Taking this lead,
the first clinically acceptable sulfonylurea tolbutamide was introduced in 1957. Others followed
soon after. In the 1 970s many so called 'second generation' sulfonylureas have been developed
which are 20-100 times more potent.
Clinically useful biguanide phenformin was developed parallel to sulfonylureas in 1957.
Recently 3 newer classes of drugs, viz. a glucosidase inhibitors, meglitinide analogues and
thiazolidinediones have been inducted.

SUL FONYLUREAS
First generation
▪ Tolbutamide
▪ Chlorpropamide
▪ Second generation
▪ Glibenclamide
▪ (Glyburide)
▪ Glipizide
▪ Gliclazide
▪ Glimepiride
BIGUANI D E S
▪ Metforrnin
MEGLITINIDE I PHENYL ALANINE ANALOGUES
▪ Repaglinide
 ▪ Nateglinide
THIAZO L I D I N E D I O N E S
▪ Rosigli tazone
▪ Pioglitazone
α-GLUCOSIDASE INHIBITORS
▪ Acarbose
▪ Miglitol
➢ New agent Inhibitors of dipeptidyl peptidase 4, also DPP-4 inhibitors or gliptins, are a
class of oral hypoglycemics that block DPP-4 (DPP-IV). They can be used to
treat diabetes mellitus type 2.
The first agent of the class — sitagliptin — was approved by the FDA in 2006
Glucagon increases blood glucose levels, and DPP-4 inhibitors reduce glucagon and blood
glucose levels. The mechanism of DPP-4 inhibitors is to increase incretin levels (GLP-
1 and GIP),

➢ Dapagliflozin (Forxiga) in the EU and Russia) is a drug of the gliflozin class, used to
treat type 2 diabetes. It was developed by Bristol-Myers Squibb in partnership
with AstraZeneca.
➢ Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2) which
are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this
transporter mechanism causes blood glucose to be eliminated through the urine. In clinical
trials, dapagliflozin lowered HbA1c by 0.6 versus placebo percentage points when added to
metformin
MOA
BIGUANIDE MOA

MOA OF THIAZOLIDINEDIONES
▪ Rosigli tazone
▪ Pioglitazone