Endocrine System Drugs

PHARMACOLOGY NOTES: ENDOCRINE SYSTEM AND RELATED DRUGS
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Anterior pituitary hormones

Anterior pituitary hormones produced by characteristic cells which are characterized by their stainig
properties
somatotropes GH
Acdophils
lactotropes Prolactin
anterior
pitutary cells gonadotropes FSH & LH
Basophils thyrotropes TSH
cortico-
ACTH & MSH
lipotropes
HORMONE Amino Acid Count Mol Wt
GH Single chain: 191 22000
SOMATOSTATIN Single chain: 14 -
PL 199 23000
FSH Chain A: 92 & Chian B: 111 33 kDa
LH Chain A: 92 & Chian B: 121 30 kDa
TSH 210 30000
ACTH 39 4500
GROWTH HORMONE (GH)
Physiological functions
 Growth promotion of all organs (except brain and eye)

 Increased utilization of fat by muscles and lipolysis by adipose tissue
 Decreased glucose utilization by muscles and increased gluconeogenesis, glycogenolysis

 Increased amino acid uptake and Protein synthesis
 Increase calcium uptake and retention
Somatomedins or Insulin-like growth factors (mainly IGF-1, also IGF-2)
 peptides in nature
 extracellular mediators of GH response like growth promoting, nitrogen retaining and certain
metabolic actions of GH
Pathological involvement
GH produced in excess GH produced insufficient
Childrens Gigantism Pitutary Dwarfism
Adult Acromegaly -
Therapeutic uses
Pitutary dwarfism Renal failure
Turners synydrome Catabolic states
Adverse effects of GH and similar preparations
Immune reaction, glucose intolerance and insulin like state, lipodystropy
GH Inhibitors: Somatostatin
 inhibits the secretion of GH, prolactin, and TSH by pituitary; insulin and glucagon by pancreas,
 inhibits almost all gastrointestinal secretions including that of gastrin and HCl.
 Somatostatin constricts splanchnic (thus decreases gi blood flow), hepatic and renal blood vessels.
 During Surgical removal of pituitary adenomas these are preferred, but somatostatin analogues are
being increasingly used.
Disadvantages of somatostatin
 short duration of action (t½ 2–3 min),

 lack of specificity for inhibiting only GH secretion and GH rebound on discontinuation.
 The g.i. action produces steatorrhoea, diarrhoea, hypochlorhydria, dyspepsia and nausea as side
effect
Synthetic analouges of somatostatin
Octreotide Lanreotied Pegvisomant
90 min 10-15 days -
PROLACTIN
Physiological function
 Growth and development of breast during pregnancy.

 induces synthesis of milk proteins and lactose.
 After parturition, prolactin induces milk secretion,
 Continued high level of prolactin during breastfeeding is responsible for
o lactational amenorrhoea,
o inhibition of ovulation and
o infertility for several months postpartum.
 Prolactin suppresses hypothalamo-pituitarygonadal axis by inhibiting GnRH release.
 Prolactin may affect immune response through action on T-lymphocytes.
Regulation of secretion
 Prolactin is under predominant inhibitory control of hypothalamus through PRIH which is dopamine
that acts on pituitary lactotrope D2 receptor.
 Dopaminergic agonists decrease plasma prolactin levels
 dopaminergic antagonists and DA depleter cause increase plasma prolactin levels
 Prolactin levels in blood are low in childhood, increase in girls at puberty and are higher in adult
females than in males. A progressive increase occurs during pregnancy, peaking at term.
 Subsequently, high prolactin secretion is maintained by suckling: it falls if breast feeding is

discontinued.
 Stress, exertion and hypoglycaemia also stimulate prolactin release.
Physio-pathological involvement
Prolactin levels Male Female
Galactorrhea Loss of libido

High (hyperprolactinaemia)
Ammenorrhea Infertility
The causes of hyperprolactinaemia are
 Disorders of hypothalamus > removing the inhibitory control over pituitary

 Antidopaminergic and DA depleting drugs
 Prolactin secreting tumours—these may be microprolactinomas or macroprolactinomas.
Prolactin inhibitors: Bromocriptine, Cabergoline
Actions
Decreases prolactin release from pituitary by activating dopaminergic receptors on lactotrope cells: is a
strong antigalactopoietic.
Uses
 As antigalactopoietic in Hyperprolactinemia due to microprolactinomas causing galactorrhoea,

amenorrhoea and infertility in women;
 Gynaecomastia, impotence and sterility in men.
 Acromegaly due to small pituitary tumours and inoperable cases.
Adverse effects: Hypotension, Behavioral alterations, mental confusion, hallucinations, abnormal

movements, livedo reticularis
Gonadotropins: FSH & LH
Actions
FSH LH
 supports spermatogenesis and  stimulates testosterone secretion by

 trophic influence on seminiferous the interstitial cells
MALE
tubules  ICSH
 testicular atrophy
 It induces preovulatory swelling of the
ripe of graafian follicle and triggers
ovulation
 induces follicular growth, development  luteinization of the ruptured follicle
of ovum and sustains corpus luteum till the next
FEMALE
 secretion of estrogens menstrual cycle.
 Ovarian atrophy  atresia of the remaining follicles.
 Progesterone secretion occurs only
under the influence of LH.
 Gametogenesis promotion
 Conversion of cholesterol to pregnenolone (RDS in steroidal hormones synthesis)
Receptors of gonadotropins
Location of FSH receptors Location of LH receptors
MALE TESTES Seminiferous tubules (sertoli Interstitial (leydigs) cells

cells)
FEMALE OVERIES Granulosa cells Theca cells, Granulosa cells,

luteal cells
Secretion regulation
 Decapeptide Gonadorelin (GnRH) by hypothalamus stimulates release of FSH and LH

 In men, the levels of FSH and LH remain practically constant (LH > FSH) while in menstruating
women they fluctuate cyclically. The Gn secretion increases at puberty and is higher in women than
in men.
 Inhibin—a peptide from ovaries and testes, selectively inhibits FSH release, but not LH release.
 Dopamine inhibits only LH release.
 Testosterone is weaker than estrogens in inhibiting Gn secretion, but has effect on both FSH and LH.
 In females estradiol and progesterone inhibit both FSH and LH secretion mainly through
hypothalamus, but also by direct action on pituitary.
Pathological involvement
 delayed puberty or precocious puberty both in girls and boys.

 Inadequate Gn secretion results in amenorrhoea and infertility in women;
 Inadequate Gn secretion results in oligozoospermia, infertility in men.
 Excess production of Gn in adult women causes polycystic ovaries.
PREPARATION CONTENT SOURCE
Menotropins FSH+LH Urine of menopausal women
Urofollitropins/ Menotropins FSH -
HCG HCG Urine of pregnant women
rFollitropins (Follitropins ɑ , β) FSH Recombinant preparation
rLH (leutropin) LH Recombinant preparation
rHCG (choriogonadotropins) HCG Recombinant preparation
USES
 Amenorrhea & Infertility females

 Hypogonadotropic hypogonadism in males
 Cryptorchidism
 In vitro fertilization
Synthetic gonadorelin (GnRH)
Short acting analogue (4-8 min) metabolized by enzymatic hydrolysis
Uses
 Testing pituitary gonadal axis in males

 Hypogonadism in females
Superactive GnRH agonist : Goserelin, Leuprolide, Nafarelin, Triptorelin,
 longer acting (t½ 2–6 hours) because of high affinity for GnRH receptor and resistance to enzymatic
hydrolysis.
MOA
 Because physiological release of GnRH is in pulses, whereas these agonists act continuously; they
only initially increase Gn secretion.
 After 1–2 weeks they cause desensitization and down regulation of GnRH receptors > inhibition of
FSH and LH secretion > suppression of gonadal function.
 Spermatogenesis or ovulation cease and testosterone or estradiol levels fall to castration levels.
 Recovery occurs within 2 months of stopping treatment.
Uses
precocious puberty, prostatic carcinoma, endometriosis, premenopausal breast cancer, uterine

leiomyoma, polycystic ovarian disease
to assist induced ovulation
They also have potential to be used as contraceptive for both males and females.
TSH : THYROTROPIN
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 into thyroid by increasing Na+: Iodide symporter (NIS).
• 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 T3 and T4.
Synthesis and release of TSH by pituitary is controlled by hypothalamus primarily through TRH, while
somatostatin inhibits TSH secretion.
Dopamine also reduces TSH production induced by TRH.
In majority of cases of myxoedema TSH levels are markedly elevated because of deficient feedback
inhibition.
Graves’ disease is due to an immunoglobulin of the IgG class which attaches to the thyroid cells and
stimulates them in the same way as TSH. Consequently, TSH levels are low.
ADRENOCORTICOTROPIC HORMONE (ACTH, CORTICOTROPIN)
derived from a larger peptide pro-opio melanocortin (MW 30,000) which also gives rise to endorphins,
two lipotropins and two MSHs.
Physiological function
ACTH promotes steroidogenesis in adrenal cortex by stimulating cAMP formation in cortical cells
(through specific cell surface GPCRs) > rapidly increases the availability of cholesterol for conversion to
pregnenolone which is the rate limiting step in the production of gluco, mineralo and weakly androgenic
steroids.
Induction of steroidogenic enzymes occurs after a delay resulting in 2nd phase ACTH action. The stores
of adrenal steroids are very limited and rate of synthesis primarily governs the rate of release.
ACTH also exerts trophic influence on adrenal cortex (again through cAMP): high doses cause
hypertrophy and hyperplasia. Lack of ACTH results in adrenal atrophy.
However, zona glomerulosa is little affected because angiotensin II also exerts trophic influence on this
layer and sustains aldosterone secretion.
Hypothalamus regulates ACTH release from pituitary through corticotropin-releasing hormone (CRH).
The CRH receptor on corticotropes is also a GPCR which increases ACTH synthesis as well as release by
raising cytosolic cAMP.
Secretion of ACTH has a circadian rhythm. Peak plasma levels occur in the early morning, decrease
during day and are lowest at midnight.
Corticosteroids exert inhibitory feedback influence on ACTH production by acting directly on the
pituitary as well as indirectly through hypothalamus.
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THYROID HORMONE & DRUGS

The thyroid gland secretes 3 hormones—
triiodothyronine (T3)
Thyroid hormones produced by thyroid follicles
thyroxine (T4)
produced by interfollicular ‘C’

Calcitonin Ca level regulating hormone
cells
The thyroid hormones are synthesized and stored in the thyroid follicles as part of
thyroglobulin molecule—which is a glycoprotein synthesized by thyroid cells
The synthesis, storage and release of T4 and T3 involves the following processes.
1. Iodide uptake
Thyroid cells have an active transport process Na+: iodide symporter (NIS) to concentrate this
anion; is stimulated by TSH
2. Oxidation and iodination
Iodide carried across the apical membrane by another transporter termed ‘pendrin’
oxidized by thyroid peroxidase enzyme to iodinium (I+) ions or hypoiodous acid (HOI) or
enzyme-linked hypoiodate (E-OI) with the help of H2O2.
These oxidized forms of iodine combine with tyrosil residues of thyroglobulin to form
monoiodotyrosine (MIT) and diiodotyrosine (DIT) these residues are remain attached to the
thyroglobulin chains.
3. Coupling
Pairs of iodinated tyrosil residues couple together to form T3 and T4.
Normally much more T4 than T3 is formed, but during I2 deficiency relatively more MIT is
available and a greater proportion of T3 is formed.
Thus, more active hormone is generated with lesser amount of I2.

Coupling is an oxidative reaction and is catalysed by the same thyroid peroxidase.
Oxidation of iodide and coupling are both stimulated by TSH
4. Storage and release
Thyroglobulin containing iodinated tyrosil and thyronil residues is transported to the interior
of the follicles and remains stored as thyroid colloid till it is taken back into the cells by
endocytosis and broken down by lysosomal proteases.
The T4 and T3 so released is secreted into circulation while MIT and DIT residues are
deiodinated and the iodide released is reutilized.
5. Peripheral conversion of T4 to T3
Peripheral tissues, especially liver and kidney, convert T4 to T3. About 1/3 of T4 secreted by
thyroid undergoes this change and most of the T3 in plasma is derived from liver.
Target tissues take up T3 from circulation for their metabolic need, except brain and pituitary
which take up T4 and convert it to T3 within their own cells.
Almost equal amounts of 3, 5, 3´ triiodothyronine (normal T3 : active) and 3, 3´, 5´

triiodothyronine (reverse T3 or rT3: inactive) are produced in the periphery.
The T4 to T3 conversion is carried out by the enzyme iodothyronine deiodinase which exists in 3
forms (D1, D2, D3). These forms differ in their organ and cellular localization as well as product
formed.
Whereas type 2 deiodinase (D2) generates T3 and D3 generates rT3, the D1 form generates
both T3 and rT3.
ACTIONS
1. Growth and development
 T4 and T3 are essential for normal growth and development.

 The milestones of development are delayed and practically every organ and tissue of the
body suffers. The greatest sufferer, however, is the nervous system.
2. Intermediary metabolism
Lipid
 enhance lipolysis
 plasma free fatty acid levels are elevated.
 cholesterol metabolism are accelerated, but its conversion to bile acids dominates.
 hypocholesterolemia. LDL levels in blood are reduced.
Carbohydrate
 Carbohydrate metabolism is also stimulated.

 utilization of sugar by tissues is increased (mainly secondary to increased BMR),
 glycogenolysis and gluconeogenesis in liver
 hyperglycaemia occurs
Protein
 protein being used as energy source.

 negative nitrogen balance and tissue wasting.
 Weight loss is a feature of hyperthyroidism
3. Calorigenesis
 T3 and T4 increase BMR by stimulation of cellular metabolism and resetting of the

energystat.
 important for maintaining body temperature
 However, metabolic rate in brain, gonads, uterus, spleen and lymph nodes is not
significantly affected.
4. CVS
 Heart rate, contractility and output are increased

 Atrial fibrillation and other irregularities are common in hyperthyroidism.
5. Nervous system
 Mental retardation is the hallmark of cretinism; sluggishness and other behavioral features
are seen in myxoedema.
 Hyperthyroid individuals are anxious, nervous, excitable, exhibit tremors and hyperreflexia.
6. Skeletal muscle
 Muscles are flabby and weak in myxoedema

 thyrotoxicosis produces increased muscle tone, tremor and weakness due to myopathy
7. GIT
 Propulsive activity of gut is increased by T3/T4.

 Hypothyroid patients are often constipated, while diarrhoea is common in hyperthyroidism.
8. Kidney
T3 and T4 do not cause diuresis in euthyroid individuals, but the rate of urine flow is often
increased when myxoedematous patients are treated with it.
9. Haemopoiesis
 Hypothyroid patients suffer from some degree of anaemia which is restored only by T4
treatment.
 Thus, T4 appears to be facilitatory to erythropoiesis.
10. Reproduction
 Fertility is impaired in hypothyroidism and women suffer from oligomenorrhoea.

 Normal thyroid function is required for maintenance of pregnancy and lactation.
USES
The most important use of thyroid hormone is for replacement therapy in deficiency states:
1. Cretinism
2. Adult hypothyroidism (Myxoedema)
3. Myxoedema coma
4. Nontoxic goiter
5. Thyroid nodule
6. Papillary carcinoma of thyroid
Thyroid inhibitors
ANTITHYROID DRUGS (Thioamides)
Antithyroid drugs bind to the 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.
As a result thyroid colloid is depleted over time and blood levels of T3/T4 are progressively
lowered
Action (ii) has been observed at lower concentration of antithyroid drugs than action (i).
Pharmacokinetics
All are concentrated in thyroid: intrathyroid t½ is longer: effect of a single dose lasts longer than
would be expected from the plasma t½.
Carbimazole acts largely by getting converted to methimazole in the body and is longer acting
than propythiouracil.
Adverse effects
Hypothyroidism and goiter can occur due to overtreatment, but is reversible on stopping the
drug.
Use
Anti-thyroid drugs control thyrotoxicosis in both Graves’ disease and toxic nodular goiter.
IODINE AND IODIDES
it is the fastest acting thyroid inhibitor.
Excess iodide inhibits its own transport into thyroid cells by interfering with expression of NIS
on the cell membrane.
In addition, it attenuates TSH and cAMP induced thyroid stimulation.
Excess iodide rapidly and briefly interferes with iodination of tyrosil and thyronil residues of
thyroglobulin (probably by altering redox potential of thyroid cells) resulting in reduced T3/T4
synthesis (Wolff-Chaikoff effect).
However, within a few days, the gland ‘escapes’ from this effect and hormone synthesis
resumes.
Uses
1. Preoperative preparation for thyroidectomy in Graves’ disease
2. Thyroid storm
3. Prophylaxis of endemic goiter
4. Antiseptic As tincture iodine, povidone iodine
Adverse effects
1. Acute reaction
Manifestations are swelling of lips, eyelids, angioedema of larynx (may be dangerous), fever,
joint pain, petechial haemorrhages, thrombocytopenia, lymphadenopathy.
2. Chronic overdose (iodism)
Inflammation of mucous membranes, salivation, rhinorrhoea, sneezing, lacrimation, swelling of

eyelids, burning sensation in mouth, headache, rashes, g.i. symptoms, etc.
Given to pregnant or nursing mothers, it may be responsible for foetal/infantile goiter and
hypothyroidism.
Thyrotoxicosis may be aggravated in multinodular goiter.
RADIOACTIVE IODINE
127 131
The stable isotope of iodine is I, isotope of medicinal importance is: I: physical half-life 8
days.
The chemical behaviour of 131I is similar to the stable isotope.
131
I emits X-rays as well as β particles. The former are useful in tracer studies, because they
traverse the tissues and can be monitored by a counter, while the latter are utilized for their
destructive effect on thyroid cells.
131I is concentrated by thyroid, incorporated in colloid—emits radiation from within the

follicles.
The β particles penetrate only 0.5–2 mm of tissue.
The thyroid follicular cells are affected from within, undergo pyknosis and necrosis followed by
fibrosis when a sufficiently large dose has been administered, without damage to neighbouring
tissues.
With carefully selected doses, it is possible to achieve partial ablation of thyroid.
Radioactive iodine is administered as sodium salt of 131I dissolved in water and taken orally.
Therapeutic The most common indication is hyperthyroidism due to Graves’ disease or toxic
nodular goiter.
Advantages
1. Treatment is simple, outpatient basis and inexpensive.
2. No surgical risk, scar or injury
3. Once hyperthyroidism is controlled, cure is permanent.
131I is the treatment of choice after 25 years of age and if CHF, angina or any other
contraindication to surgery is present.
Disadvantages
1. Hypothyroidism
2. Long latent period of response.
3. Contraindicated during pregnancy.
4. Not suitable for young patients
β ADRENERGIC BLOCKERS
Propranolol (and other nonselective β blockers) have emerged as an important form of therapy
to rapidly alleviate manifestations of thyrotoxicosis that are due to sympathetic overactivity,
viz. palpitation, tremor, nervousness, severe myopathy, sweating.
They have little effect on thyroid function and the hypermetabolic state.
They are used in hyperthyroidism in the following situations.
(i) While awaiting response to propylthiouracil/ carbimazole or 131I.
(ii) Along with iodide for preoperative preparation before subtotal thyroidectomy.
(iii) Thyroid storm (thyrotoxic crisis): This is an emergency due to decompensated

hyperthyroidism.
CORTICOIDS
Biosynthesis (steroidogenesis)
Adrenal steroidogenesis takes place under the influence of ACTH which
Role of ACTH in steroidogenesis
 Makes more cholesterol available for conversion to pregnenolone

 induces steroidogenic enzymes.
In adrenal cortical cells only minute quantities of the hormones is stored, rate of release is governed by
the rate of biosynthesis.
The circulating corticosteroids levels controls
 ACTH release from pituitary

 CRH release from hypothalamus
Thus provide feedback regulation of the hypothalamo-pituitary- adrenal (HPA) axis
Actions
Corticoids have direct and permissive actions on the basis of way of producing effect
 By direct action- produces effect of own actions
 By permissive action- they do not themselves produce an effect, their presence facilitates other
hormones to exert that action
Corticoids have Mineralocorticoidal and Glucocorticoidal actions on the basis of effect they are
producing
Mineralocorticoid actions
Target cell > action > consequences
 Enhancement of Na+ reabsorption in the distal convoluted tubule in kidney.

 There is an associated increase in K+ and H+ excretion.
Deficiency mineralocorticoid-Aldosterone
- decreased tubular reabsorptive capacity for Na+; Na+ deficient state occurs
- kidney is not able to retain Na+ even in the Na+ deficient state → Na+ is progressively lost: kidneys
absorb water without the attendant Na+ (to maintain e.c.f. volume which nevertheless
decreases) → dilutional hyponatraemia
- because of dilutional hyponatraemia → excess water enters cells as reflex action of body→
cellular hydration: decreased blood volume and raised haematocrit.
- increase in K+ and H+ excretion → Hyperkalaemia and acidosis accompany.
These distortions of fluid and electrolyte balance progress and contribute to the circulatory collapse.
MOA mineralocorticoid-Aldosterone
The action of aldosterone is exerted by gene mediated increased transcription of m-RNA in renal tubular
cells which promotes synthesis of aldosterone-induced proteins-AIP eg: Na+K+ ATPase.
The Na+K+ ATPase of tubular basolateral membrane responsible for generating gradients for movement
of cations in these cells is the major AIP.
Glucocorticoid actions (Glucocorticoids are catabolic)
Carbohydrate metabolism
These all actions results
 promote glycogen deposition in liver by inducing hepatic glycogen synthase in hyperglycaemia +
 promoting gluconeogenesis (amino acids are utilized) resistance to insulin
 inhibit glucose utilization by peripheral tissues.
= diabetes-like state
 increased glucose release from liver
Protein metabolism
 amino acids mobilized into liver → used up in gluconeogenesis, negative nitrogen

as a result excess urea is produced balance
 They also cause protein breakdown from peripheral tissues
 They also increase uric acid excretion
Fat metabolism
 The lipolytic action of glucocorticoids is permissive, by promoting lipolysis due to Glucagon, Growth
hormone, Adr and Thyroxine.
 cAMP induced breakdown of triglycerides is enhanced.
 Fat depots in different areas of the body respond differently—redistribution of body fat occurs.
peripheral adipocytes truncal adipocytes
These adipocytes less sensitive to insulin and more These adipocytes respond mainly to raised
sensitive to corticosteroid insulin levels caused by glucocorticoid
induced hyperglycaemia
Subcutaneous tissue loses fat deposited over face,

neck and shoulder producing ‘moon face’, ‘fish
mouth’ and ‘buffalo hump’
Calcium metabolism
negative
 Glucocorticoids inhibit intestinal absorption and enhance renal excretion of Ca2+. Ca
2+
 Loss of osteoid (decreased formation and increased resorption) indirectly results in loss of Ca2+ balance
Water excretion
 The effect on water excretion is independent of action on Na+ transport; hydrocortisone and other
glucocorticoids, but not aldosterone, maintain normal g.f.r.
 In adrenal insufficiency, the capacity to excrete a water load is markedly reduced—such patients are
prone to water intoxication from i.v. infusions.
 Glucocorticoids also enhance secretory activity of renal tubules.
CVS
They have a Direct action, where
Glucocorticoids restrict capillary permeability, maintain tone of arterioles and myocardial contractility.
They have a Permissive action,
 for the pressor action of Adr and angiotensin

 Thus in development of hypertension—should be used cautiously in hypertensives
Adrenal insufficiency responsible for cardiovascular collapse due to-
low cardiac output, arteriolar dilatation, poor vasoconstrictor response to Adr (repeated doses of Adr
cause destructive changes in blood vessels) and increased permeability of capillaries, hypovolemia (due
to lack of mineralocorticoid)
Skeletal muscles
Optimum level of corticosteroids is needed for normal muscular activity.
Hypocorticism: diminished work capacity and weakness are primarily due to hypodynamic circulation.
Hypercorticism: excess mineralocorticoid action → hypokalaemia → weakness; Excess glucocorticoid

action → muscle wasting and myopathy → weakness.
CNS
 Mild euphoria is quite common with pharmacological doses of glucocorticoids. This is a direct effect
on brain.
 Glucocorticoids also maintain the level of sensory perception and normal level of excitability of
neurones.
Stomach
Secretion of gastric acid and pepsin is increased—may aggravate peptic ulcer.
Lymphoid tissue and blood cells
 enhance the rate of destruction of lymphoid cells (T cells are more sensitive than B cells)
 However, a marked lytic response is shown by malignant lymphatic cells. This is the basis of their use
in lymphomas.
 Glucocorticoids increase the number of RBCs, platelets and neutrophils in circulation.
 They decrease lymphocytes, eosinophils and basophils. This is not due to destruction of the
concerned cells, but due to their sequestration in tissues.
 Blood counts come back to normal after 24 hours.
Inflammatory responses
 Inflammatory response is suppressed. The action is nonspecific and covers all components and
stages of inflammation.
 most important overall mechanism appears to be limitation of recruitment of inflammatory cells at
the local site and production of proinflammatory mediators like PGs, LTs, PAF through indirect
inhibition of phospholipase A2.
Immunological and allergic responses
The clinical effect appears to be due to suppression of recruitment of leukocytes at the site of contact
with antigen and of inflammatory response to the immunological injury.
Glucocorticoids cause greater suppression of CMI in which T cells are primarily involved, e.g. delayed
hypersensitivity and graft rejection. This is the basis of their use in autoimmune diseases and organ
transplantation
PHARMACOKINETICS
All natural and synthetic corticoids, except DOCA are absorbed and are effective by the oral route.
Oral bioavailability of synthetic corticoids is high.
Hydrocortisone is 90% bound to plasma protein, mostly to a specific cortisol-binding globulin (CBG;
transcortin) as well as to albumin. Transcortin concentration is increased during pregnancy and by oral
contraceptives—corticoid levels in blood are increased but hypercorticism does not occur, because free
cortisol levels are normal.
Metabolic Pathways are—
(i) Reduction of 4, 5 double bond and hydroxylation of 3-keto group.

(ii) Reduction of 20-keto to 20-hydroxy form.
(iii) Oxidative cleavage of 20C side chain (only in case of compounds having a 17-hydroxyl
group) to yield 17-ketosteroids.
(iv) These metabolites are further conjugated with glucuronic acid or sulfate and are excreted
in urine.
Uses based on replacement therapy
Acute adrenal insufficiency
It is an emergency situation where low levels of cortisol can cause weakness, fatigue, Low blood
pressure and Loss of consciousness.
DOC- Hydrocortisone or dexamethasone
The amount of fluid infused i.v. is guided by monitoring central venous pressure, because these patients
have reduced capacity to excrete water load.
Short-term i.v. infusion of a vasopressor (dopamine) may be needed.
Chronic adrenal insufficiency (Addison’s disease)
Hydrocortisone given orally is the most commonly used drug along with adequate salt and water
allowance.
Some patients who continue to excrete excess Na+ need additional mineralocorticoid: fludrocortisone is
added.
Congenital adrenal hyperplasia (Adrenogenital syndrome)
It is a familial disorder due to genetic deficiency of steroidogenic enzymes, mostly 21-hydroxylase. As a

result the synthesis of hydrocortisone and aldosterone suffers.
There is compensatory increase in ACTH secretion— adrenals hypertrophy; enzyme deficiency being
only partial in most cases, normal amounts of gluco - and mineralocorticoids are produced along with
excessive amounts of weak androgens → virilization and/or precocious sexual development.
If the deficiency is severe, salt wasting also occurs.
Uses based on pharmacotherapy
1. Arthritides: as adjuvants to NSAIDs, in Rheumatoid arthritis, Osteoarthritis, Rheumatic fever, Gout.

2. Collagen diseases (systemic lupus erythematosus, nephrotic syndrome, glomerulonephritis and
related diseases)
3. Severe allergic reactions (used for short periods in anaphylaxis, angioneurotic edema, urticaria and
serum sickness) However, even i.v. injection of a glucocorticoid takes 1–2 hours to act and is not a
substitute for Adr (which acts immediately) in anaphylactic shock and angioedema of larynx.
4. Autoimmune diseases (Autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura,
active chronic hepatitis) respond to corticoids.
5. Bronchial asthma inhaled glucocorticoid therapy is now recommended in most cases needing
inhaled β2 agonists almost daily. Systemic corticosteroids are used only for: Status asthmaticus,
Actue asthma exacerbation, Severe chronic asthma
6. Other lung diseases: Corticosteroids benefit aspiration pneumonia and pulmonary edema from
drowning. Given during late pregnancy, corticoids accelerate lung maturation and surfactant
production in the foetal lung and prevent respiratory distress syndrome at birth.
7. Infective diseases : lepra reaction, certain forms of bacterial meningitis and Pneumocystis carinii
pneumonia with hypoxia in AIDS patients.
8. Eye diseases: Used in inflammatory ocular diseases, in diseases of the anterior chamber—allergic
conjunctivitis, iritis, iridocyclitis, keratitis
9. Skin diseases: Used in many eczematous skin diseases, Systemic therapy is needed exfoliative
dermatitis, Stevens-Johnson syndrome
10. Intestinal diseases: used in Ulcerative colitis, Crohn’s disease, coeliac disease are inflammatory
bowel diseases with exacerbations and remissions.
11. Cerebral edema or inflammatory conditions: due to tumours, tubercular meningitis, DOC Dexa-or
betamethasone are preferred because they donot have Na+ retaining activity. In Neurocysticercosis:
When albendazole/praziquantel is used to kill cysticerci lodged in the brain, prednisolone given for
2–4 weeks to suppress the reaction to the dying larvae.
12. Malignancies
13. Used chemotherapy of acute lymphatic leukaemia, Hodgkin’s and other lymphomas (because of
their marked lympholytic action in these conditions)
14. Used in hormone responsive breast carcinoma— act probably by causing HPA suppression so as to
reduce production of adrenal androgens which are converted to estrogens in the body
15. Organ transplantation and skin allograft: High dose corticoids are given along with other
immunosuppressants to prevent the rejection reaction.
16. To test pituitary-adrenal axis function Dexamethasone used
17. Thyroid storm and septic shock
Adverse effects
A. Mineralocorticoid
 Sodium and water retention, edema, hypokalaemic alkalosis and a progressive rise in BP. These are
now rare due to availability of highly selective glucocorticoids.
 Gradual rise in BP occurs due to excess glucocorticoid action as well.
B. Glucocorticoid
 Cushing’s habitus
 Fragile skin, purple striae, Cutaneous atrophy localized to the site occurs with topical application as
well.
 Hyperglycaemia, may be glycosuria, precipitation of diabetes.
 Muscular weakness
 Susceptibility to infection
 Delayed healing of wounds and surgical incisions.
 Peptic ulceration
 Osteoporosis
 Posterior subcapsular cataract may develop after several years of use, especially in children.
 Glaucoma
 Growth retardation in children
 Psychiatric disturbances: mild euphoria frequently accompanies high dose steroid treatment.
 Suppression of hypothalamo-pituitary-adrenal (HPA) axis: occurs depending both on dose and
duration of therapy.
Diabetes mellitus (DM)

metabolic disorder characterized by:
Hyperglycaemia _
Glycosuria _
Hyperlipidaemia _
negative nitrogen balance _
ketonaemia _
A widespread pathological change is
thickening of capillary basement membrane lumen narrowing,

Leads to atherosclerosis, sclerosis of
increase in vessel wall matrix and vascular glomerular capillaries,
complications retinopathy, neuropathy
increase in vascular cellular proliferation
Enhanced nonenzymatic glycosylation of tissue proteins (such as glycosylated haemoglobin
HbA1c) due to persistent exposure to high glucose concentrations
accumulation of sorbitol (a reduced product of glucose) in tissues are believed to be
causative in the pathological changes of diabetes.
Index of protein glycosylation
concentration of glycosylated haemoglobin (HbA1c) in blood

it reflects the state of glycaemia over the preceding 2–3 months
Types of diabetes mellitus
Type I Insulin-dependent diabetes mellitus (IDDM)/juvenile onset diabetes mellitus:
There is β cell destruction in pancreatic islets; majority of cases are
autoimmune (type 1A) - β cell antibody is found

idiopathic (type 1B) - no β cell antibody is found
circulating insulin levels are low or very low
patients are more prone to ketosis
low degree of genetic predisposition
Type II Noninsulin-dependent diabetes mellitus (NIDDM)/maturity onset diabetes mellitus
There no loss or moderate reduction in β cell

insulin in circulation is low, normal or even high
no β cell antibody is found
high degree of genetic predisposition;
late onset (past middle age)
Over 90% cases of diabetes are type 2 DM
Causes of Type II DM may be:
impaired insulin secretion due to

Abnormality in gluco-receptor of β cells, respond at higher glucose concentration
relative β cell deficiency
Reduced sensitivity of peripheral tissues to insulin: ‘down regulation’ of insulin receptors.
Excess of hyperglycaemic hormones (glucagon, etc.)/obesity: cause relative insulin
deficiency— the β cells lag behind.
INSULIN
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
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.
Assay
Insulin is bioassayed by measuring blood sugar depression in rabbits (1 U reduces blood glucose
of a fasting rabbit to 45 mg/dl) or by its potency to induce hypoglycaemic convulsions in mice.
1 mg of the International Standard of insulin = 28 units.
Plasma insulin can be measured by radioimmunoassay or enzyme immunoassay.
Regulation of insulin secretion
Under basal condition ~1U 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 β cells (by
a glucose transporter GLUT1) and its phosphorylation by glucokinase.
Glucose entry and metabolism leads to activation of the glucosensor which indirectly
inhibits the ATP-sensitive K+ channel (K+ ATP) resulting in partial depolarization of the β
cells.
ly rectifying ATP-sensitive K+ channel (KATP) in the membrane of pancreatic β cells.
This increases intracellular Ca2+ availability (due to increased influx, decreased efflux and
release from intracellular stores) → exocytotic release of insulin storing granules.
Glucose and insulin release
glucose is the principal regulator and synthesis stimulator of insulin

Glucose induces a brief pulse of insulin output within 2 min (first phase) followed by a
delayed but more sustained second phase of insulin release.
Glucose and other nutrients are more effective in invoking insulin release when given orally
than i.v.
They generate chemical signals ‘incretins’ from the gut which act on β cells in the pancreas
to cause anticipatory release of insulin. The incretins involved are glucagon-like peptide-1
(GLP- 1), glucose-dependent insulinotropic polypeptide (GIP), vasoactive intestinal peptide
(VIP), pancreozymin-cholecystokinin
Hormonal
A number of hormones, e.g. growth hormone, corticosteroids, thyroxine modify insulin release
in response to glucose.
Neural
Adrenergic α2 receptor Adrenergic β2 receptor Cholinergic—muscarinic

activation stimulation activation
decreases insulin release increases insulin release (less insulin release

(predominant) prominent)
The primary central site of regulation of insulin secretion is in the hypothalamus: stimulation of
ventrolateral nuclei evokes insulin release, whereas stimulation of ventromedial nuclei has the
opposite effect.
ACTIONS OF INSULIN The overall effects of insulin are to dispose meal derived glucose, amino
acids, fatty acids and favour storage of fuel. It is a major anabolic hormone: promotes synthesis
of gylcogen, lipids and protein. The actions of insulin and the results of its deficiency can be
summarized as:
1. Insulin facilitates glucose transport across cell membrane; skeletal muscle and fat cells are
highly sensitive.
Regulating dynamic equilibrium of GLUT1 & GLUT 4, synthesis of GLUT4 is upregulated by

insulin.
2. intracellularly glucose is utilization by its 1phosphorylation and 2increased glycogen

synthesis and 3decreased glycogenolysis
1
Phosphorylation of glucose to form glucose- 6-phosphate,promoted by insulin through
increased glucokinase production.
2
glycogen synthesis from glucose in liver, muscle and fat by stimulating the enzyme
glycogen synthase.
3
Insulin also inhibits glycogen degrading enzyme phosphorylase → decreased
glycogenolysis in liver.
3. Insulin inhibits gluconeogenesis (from protein, FFA and glycerol) in liver by gene mediated
decreased synthesis of phosphoenol pyruvate carboxykinase.
In insulin deficiency, proteins and amino acids are funneled from peripheral tissues to liver
where these substances are converted to carbohydrate and urea.
Thus, in diabetes there is underutilization and over production of glucose → hyperglycaemia →

glycosuria.
4. Insulin inhibits lipolysis in adipose tissue and favours triglyceride synthesis.
In diabetes increased lipolysis due to unchecked action of lipolytic hormones (glucagon, Adr,
thyroxine) → increased FFA and glycerol in blood → taken up by liver to produce acetyl-CoA.
Normally acetyl-CoA is resynthesized to fatty acids and triglycerides, but this process is reduced
in diabetics and acetyl CoA is diverted to produce ketone bodies (acetone, acetoacetate, β-
hydroxy-butyrate).
The ketone bodies are released in blood—partly used up by muscle and heart as energy source,
but when their capacity is exceeded, ketonaemia and ketonuria result.
5. Insulin enhances synthesis of vascular endothelial lipoprotein lipase and thus increases
clearance of VLDL and chylomicrons.
6. Insulin facilitates Amino Acids entry and their synthesis into proteins, as well as inhibits
protein breakdown in muscle and most other cells.
Insulin deficiency leads to protein breakdown → AAs are released in blood → taken up by liver
and converted to pyruvate, glucose and urea. The excess urea produced is excreted in urine
resulting in negative nitrogen balance.
Thus, catabolism takes the upper hand over anabolism in the diabetic state.
Mechanism of action
Insulin acts on specific receptors located on the cell membrane of practically every cell, but
their density depends on the cell type: liver and fat cells are very rich.
The insulin receptor is a receptor tyrosine kinase (RTK) which is heterotetrameric glycoprotein
consisting of 2 extracellular α and 2 transmembrane β subunits linked together by disulfide
bonds. It is oriented across the cell membrane as a heterodimer
The α subunits carry insulin binding sites, while the β subunits have tyrosine protein kinase
activity.
Fate of insulin
Insulin is distributed only extracellularly. It is a peptide; gets degraded in the g.i.t. if given orally.
Injected insulin or that released from pancreas is metabolized primarily in liver and to a smaller
extent in kidney and muscles. During biotransformation the disulfide bonds are reduced—A
and B chains are separated. These are further broken down to the constituent amino acids. The
plasma t½ is 5–9 min.
Preparations of insulin
Highly purified insulin preparations In the 1970s improved purification techniques like gel
filtration and ion-exchange chromatography were applied to produce ‘single peak’ and
‘monocomponent (MC)’ insulins which contain <10 ppm proinsulin. The MC insulins are more
stable and cause less insulin resistance or injection site lipodystrophy. The immunogenicity of
pork MC insulin is similar to that of recombinant human insulin.
Types of insulin preparations
1. Regular (soluble) insulin

buffered neutral pH solution of unmodified insulin
stabilized by a small amount of zinc.
Self-aggregation to form hexamers around zinc ions
After s.c. injection, insulin monomers are released gradually by dilution, so that
absorption occurs slowly.
The slow onset of action is not applicable to i.v. injection, because insulin hexamer
dissociates rapidly to produce prompt action.
longacting ‘modified’ or ‘retard’ preparations of insulin developed. Recently,
rapidly acting as well as peakless and long-acting insulin analogues have become
available.
2. Lente insulin (Insulin-zinc suspension):
Two types of insulin-zinc suspensions have been produced.
ultralente - large particles is crystalline and practically insoluble in water & long-acting.
semilente - smaller particles and is amorphous & shortacting.
Lente insulin - Their 7:3 ratio mixture is called ‘Lente insulin’ and is intermediate-acting.
3. Isophane (Neutral Protamine Hagedorn or NPH) insulin:
Protamine is added in a quantity just sufficient to complex all insulin molecules; neither of the
two is present in free form and pH is neutral.
On s.c. injection, the complex dissociates slowly to yield an intermediate duration of action.
It is mostly combined with regular insulin (70:30 or 50:50) and injected s.c. twice daily before
breakfast and before dinner (splitmixed regimen)
1. Highly purified (MC) pork regular insulin
2. Highly purified (MC) pork lente insulin
3. Highly purified (MC) pork isophane (NPH) insulin
4. Mixture of highly purified pork regular insulin (30%) and isophane insulin (70%)
Human insulins In the 1980s, the human insulins (having the same amino acid sequence as
human insulin) were produced by recombinant DNA technology in Escherichia coli—‘proinsulin
recombinant bacterial’ (prb) and in yeast— ‘precursor yeast recombinant’ (pyr), or by
‘enzymatic modification of porcine insulin’ (emp).
In the USA pork and beef insulins are no longer manufactured, but they are still available in
U.K., India and some European countries. In Britain now > 90% diabetics who use insulin are
taking human insulins or insulin analogues.
In India also human insulins and analogues are commonly used, except for considerations of
cost.
Human insulin is more water soluble as well as hydrophobic than porcine or bovine insulin.
It has a slightly more rapid s.c. absorption, earlier and more defined peak and slightly shorter
duration of action. Human insulin is also modified similarly to produce isophane (NPH) and
lente preparations. Lente human insulin is no longer prepared in the USA.
The allegation that human insulin produces more hypoglycaemic unawareness has not been
substantiated. However, after prolonged treatment, irrespective of the type of insulin, many
diabetics develop relative hypoglycaemic unawareness/change in hypoglycaemic symptoms,
because of autonomic neuropathy, changes in perception/attitude and other factors.
Clinical superiority of human insulin over pork MC insulin has not been demonstrated. Though
new patients may be started on human insulins, the only indication for transfer from purified
pork to human insulin is allergy to pork insulin. It is unwise to transfer stabilized patients from
one to another species insulin without good reason.
Insulin analogues
Using recombinant DNA technology, analogues of insulin have been produced with
modified pharmacokinetics on s.c. injection, but similar pharmacodynamic effects.
Greater stability and consistency are the other advantages.
Insulin Chemical changes Pharmacokinetics Pharmacodynamics

analogue
Insulin lispro reversing proline and  dissociate rapidly  better control of meal-
lysine at the carboxy s.c. on injection time glycaemia
terminus B 28 and B 29  quick and more  lower incidence of late
positions defined peak post-prandial
 shorter duration of hypoglycaemia
action  slightly greater
reduction in HbA1c
Insulin aspart proline at B 28 of This change reduces  closely mimics the
human insulin is the tendency for self- physiological insulin
replaced by aspartic aggregation release pattern after a
acid meal
Insulin lysine replacing rapidly acting insulin  better control of meal-
glulisine asparagine at B 23 and analogue time glycaemia
glutamic acid replacing continuous  lower incidence of late
lysine at B 29 subcutaneous insulin post-prandial
infusion (CSII) hypoglycaemia
Insulin biosynthetic insulin has soluble at pH4 of the  smooth ‘peakless’
glargine 2 additional arginine formulation, effect
residues at the carboxy precipitates at neutral  once daily injection
terminus of B chain pH.  Fasting and
and glycine replaces Because of acidic pH, it interdigestive blood
asparagine at A 21 cannot be mixed with glucose levels are
any other insulin effectively lowered
preparation; must be irrespective of time
injected separately.  Lower incidence of
A depot is created night-time
from which monomeric hypoglycaemic
insulin dissociates episodes compared to
slowly to enter the isophane insulin
circulation  does not control meal-
time glycaemia
Insulin Myristoyl (a fatty acid) it binds to albumin  Fasting and

detemir radical is attached to after s.c. injection from interdigestive blood
the amino group of which the free form glucose levels
lysine at B29 of insulin becomes available controlled
chain slowly  does not control meal-
twice daily dosing may time glycaemia
be needed
to control meal-time glycaemia, for which a rapid acting insulin or an oral hypoglycaemic is used concurrently.
REACTIONS TO INSULIN
1. Hypoglycaemia
This is the most frequent and potentially the most serious reaction.
The symptoms can be divided into
counter-regulatory sympathetic stimulation neuroglucopenic symptoms
behavioural changes, visual disturbances,

sweating, anxiety, palpitation, tremor hunger, fatigue, weakness, muscular
incoordination
Occur early Occurs late
Treatment Glucagon, Glucose must be given orally or i.v. (for severe cases)—reverses the
symptoms rapidly.
2. Local reactions Swelling, erythema and stinging, Lipodystrophy of the subcutaneous fat.
3. Allergy (Urticaria, angioedema and anaphylaxis) due to contaminating proteins, and is very
rare with human/highly purified insulins.
4. Edema short-lived dependent edema (due to Na+ retention) when insulin therapy is started.
USES OF INSULIN
Diabetes mellitus
The purpose of therapy in diabetes mellitus is to restore metabolism to normal, avoid

symptoms due to hyperglycaemia and glucosuria, prevent short-term complications (infection,
ketoacidosis, etc.) and long-term sequelae (cardiovascular, retinal, neurological, renal, etc.)
Insulin is must for type 1DM cases, as well as for post pancreatectomy diabetes and
gestational diabetes.
Many type 2 cases can be controlled by diet, reduction in body weight and appropriate exercise
supplemented, if required, by oral hypoglycaemics.
When instituted, insulin therapy has to be tailored according to the requirement and
convenience of each patient.
Diabetic ketoacidosis (Diabetic coma)
Ketoacidosis of different grades generally occurs in insulin dependent diabetics. It is infrequent

in type 2 DM. The most common precipitating cause is infection; others are trauma, stroke,
pancreatitis, stressful conditions and inadequate doses of insulin.
1. Insulin Regular insulin is used to rapidly correct the metabolic abnormalities.
Fall in blood glucose level by 10% per hour can be considered adequate response.
2. Intravenous fluids It is vital to correct dehydration.
After the blood sugar has reached 300 mg/dl, 5% glucose in ½N saline is the most appropriate
fluid because blood glucose falls before ketones are fully cleared from the circulation. Also
glucose is needed to restore the depleted hepatic glycogen.
3. KCl
Though upto 400 mEq of K+ may be lost in urine during ketoacidosis, serum K+ is usually normal
due to exchange with intracellular stores. When insulin therapy is instituted ketosis subsides
and K+ is driven back intracellularly— dangerous hypokalemia can occur.
After 4 hours it is appropriate to add 10–20 mEq/hr KCl to the i.v. fluid. Further rate of infusion
is guided by serum K+ measurements and ECG.
4. Sodium bicarbonate
It is not routinely needed.
Acidosis subsides as ketosis is controlled.
However, if arterial blood pH is < 7.1, acidosis is not corrected spontaneously or

hyperventilation is exhausting, 50 mEq of sod. bicarbonate is added to the i.v. fluid.
Bicarbonate infusion is continued slowly till blood pH rises above 7.2.
5. Phosphate When serum PO4 is in the lownormal range, 5–10 m mol/hr of sod./pot.
phosphate infusion is advocated. However, routine use of PO4 in all cases is still controversial.
6. Antibiotics and other supportive measures and treatment of precipitating cause must be
instituted simultaneously.
Hyperosmolar (nonketotic hyperglycaemic) coma This usually occurs in elderly type 2 patients.
Its cause is obscure, but appears to be precipitated by the same factors as ketoacidosis,
especially those resulting in dehydration.
Oral hypoglycemic
Sulfonylureas (KATP Channel blockers)
MOA
Sulfonylureas provoke rate & release of insulin from pancreas, at any glucose concentration,
even at low-glucose concentration risking production of severe and unpredictable
hypoglycaemia.
In type 2 DM the kinetics of insulin release in response to glucose or meals is delayed and
subdued.
The SUs primarily augment the 2nd phase insulin secretion with little effect on the 1st phase.
That they do not cause hypoglycaemia in pancreatectomised animals and in type 1 diabetics
(presence of at least 30% functional β cells is essential for their action), confirms their
indirect action through pancreas.
Hepatic degradation of insulin is also slowed.
Extrapancreatic action : With down regulation of sulfonylurea receptors (SUR1) on β cells,
they sensitize the target tissues (especially liver) to the action of insulin.
Adverse effects
1. Hypoglycaemia
 more common in elderly, liver and kidney disease patients

 Tolbutamide carries lowest risk due to its low potency and short duration of action.
2. Nonspecific side effects
 weight gain upto 1–3 kg, as a consequence insulinaemic action.

 Nausea, vomiting, flatulence, diarrhoea or constipation
3. Hypersensitivity
Rashes, photosensitivity, purpura, transient leukopenia, rarely agranulocytosis.
Meglitinide / D-phenylalanine analogues (KATP Channel blockers)
Repaglinide
normalise mealtime glucose excursions.

quick and short lasting insulinemic action.
It is administered before each major meal to control postprandial hyperglycaemia; the dose
should be omitted if a meal is missed.
Because of short lasting action it may have a lower risk of serious hypoglycaemia.
Side effects are mild headache, dyspepsia, arthralgia and weight gain.
Nateglinide
D-phenylalanine derivative which principally stimulates the 1st phase insulin secretion
faster onset and shorter lasting hypoglycaemia than repaglinide.
Ingested 10 min before meal, it limits postprandial hyperglycaemia in type 2 diabetics
without producing late phase hypoglycaemia.
There is little effect on fasting blood glucose level
Side effects dizziness, nausea, flu like symptoms and joint pain.
Uses of Meglitinide
1. Type 2 DM Patients with pronounced post prandial hyperglyceamia

2. To supplement metformin/long-acting insulin.
Glucagon-like peptide-1 (GLP-1) receptor agonists
GLP-1 is an important incretin released from the gut in response to ingested glucose.
By GLP-1 action on pancreatic β cells, it causes insulin release only at high glucose
concentration, promote β cell health as well.
inhibits glucagon release from α cells
slows gastric emptying and suppresses appetite

Failure of incretins has been implicated in the pathogenesis of β cell dysfunction of type 2
DM, particularly progression of the disease.
GLP-1 based therapy appears to be the most effective measure for preserving β cell
function in type 2 DM.
not suitable for clinical use because of rapid degradation by the enzyme dipeptidyl
peptidase-4 (DPP-4)
Exenatide
It is a synthetic DPP-4 resistant peptidal analogue which activates GLP-1 receptors.

Being a peptide, it is inactive orally. Given by s.c.
Benefits noted are lowering of postprandial as well as fasting lood glucose, HbA1c and body
weight.
The most important side effect is nausea and vomiting occurring in ~ 50% recipients, but
tolerance develops later
Liraglutide
tight binding to plasma proteins extends t½ to > 12 hours and duration of action to > 24
hours.
Nausea and diarrhoea are the frequent side effects
Use of liraglutide
o improved glycaemic control in type 2 diabetics.
o as an antiobesity drug even for nondiabetics.
Dipeptidyl peptidase-4 (DPP-4) inhibitor
Sitagliptin
competitive and selective DPP-4 inhibitor

potentiates the action of GLP-1 and GIP
boosts post prandial insulin release
decreases glucagon secretion and

lowers meal-time as well as fasting blood glucose in type 2 diabetics.
It is body weight neutral and carries low risk of hypoglycaemia unless combined with SUs or
insulin.
The HbA1c lowering caused by sitagliptin is equivalent to that with metformin.
t½ averaging 12 hours, dose reduction is needed in renal impairment, but not in liver
disease.
side effects are nausea, loose stools, headache, rashes, allergic reactions and edema.
Nasopharyngitis and cough
Vildagliptin
enzyme covalently. The complex dissociates very slowly resulting in persistent DPP-4
inhibition even after the free drug has been cleared from circulation. This explains the
longer duration of action (12–24 hours) despite short plasma t½ (2–4 hours).
Dose reduction is needed in moderately severe liver and kidney disease.
No significant drug interactions have been reported.
Vildagliptin is less selective than sitagliptin for DPP-4; causes some inhibition of DPP-8, DPP-
9 as well
Saxagliptin
it binds covalently with DPP-4 and acts for 24 hours despite a plasma t½ of 2–4 hours.
It is metabolized by CYP3A4 and generates an active metabolite that has a t½ of 3–7 hours.
Biguanide (AMPK activator)
METFORMIN
Mechanism of action
Biguanides do not cause insulin release, but presence of insulin is essential for their action.
activation of AMP dependent protein kinase (AMPK), consequences are:
o Suppresses hepatic gluconeogenesis and glucose output from liver. This is the major
action responsible for lowering of blood glucose in diabetics.
o Enhances insulin-mediated glucose uptake and disposal in skeletal muscle and fat.
Insulin resistance exhibited by type-2 diabetics is thus overcome. This translates
into—
 Promotion of glycogen storage in skeletal muscle
 reduced lipogenesis in adipose tissue
 enhanced fatty acid oxidation
Interferes with mitochondrial respiratory chain and promotes peripheral glucose utilization
through anaerobic glycolysis.
Pharmacokinetics It accumulates in renal failure and increases the risk of lactic acidosis.
Adverse effects Lactic acidosis & Vit B12 deficiency
Uses DOC for all type 2 DM patients
Advantages of metformin are:
nonhypoglycaemic
weight loss promoting
has potential to prevent macrovascular as well as microvascular complications of diabetes
no acceleration of β cell exhaustion/ failure in type 2 DM
antihyperglycaemic efficacy (HbA1c reduction by 0.8–1.2%) equivalent to other oral drugs.
can be combined with any other oral or injectable antidiabetic, if one drug is not adequate.
Thiazolidinedione (PPARγ agonist) _ Pioglitazone
MOA
selective agonists for the nuclear peroxisome proliferator-activated receptor γ (PPAR γ)

which is expressed mainly in fat cells, but also in muscle and some other cells. Thus, fatty
tissue is a major site of their action.
Activation of genes regulating fatty acid metabolism and lipogenesis in adipose tissue
contributes to the insulin sensitizing action. Lipolysis and plasma fatty acid levels are
reduced. Adipocyte turnover and differentiation is accelerated by glitazones.
lowers serum triglyceride level and raises HDL level without much change in LDL level.
Glitazones tend to reverse insulin resistance by enhancing GLUT4 expression and
translocation. Entry of glucose into muscle and fat is improved.
Hepatic gluconeogenesis is also suppressed.
Improved glycaemic control results in lowering of circulating HbA1C and insulin levels in
type 2 DM patients.
adverse effects:
plasma volume expansion, edema, weight gain, headache, myalgia and mild anaemia.
Contraindications
CHF may be precipitated or worsened. Monitoring of liver function is advised. It is

contraindicated in liver disease and in CHF.
Failure of oral contraception may occur during pioglitazone therapy.
Uses
Pioglitazone is indicated in type 2 DM, but not in type 1 DM. It reduces blood glucose and
HbA1c (by 0.5–1.2%) without increasing circulating insulin.
About 25% patients may not respond (nonresponders), probably due to low baseline insulin
levels. It should be stopped if HbA1c reduction is < 0.5% at 6 months.
α Glucosidase inhibitors
Acarbose , Voglibose
Interference with digestion and absorption of carbohydrates by reversibly inhibition of α-

glucosidases
GLP-1 release is promoted
Postprandial glycaemia is reduced without significant increase in insulin levels.
Regular use lowers HbA1c modestly (by 0.4–0.8%), but change in body weight and lipid
levels is minimal.
Acarbose is a mild antihyperglycaemic and not a hypoglycaemic.
Flatulence, abdominal discomfort and loose stool are produced in about 50% patients due
to fermentation of unabsorbed carbohydrates.
Miglitol
it is a stronger inhibitor of sucrase. Potency for other α-glucosidases is equivalent to

acarbose.
Amylin analogue
Amylin, ‘islet amyloid polypeptide’ (IAP), is produced by pancreatic β cells & acts in the brain
to reduce glucagon secretion from α cells,

delay gastric emptying,
retard glucose absorption and promote satiety.
Pramlintide
before meal attenuates postprandial glycaemia and exerts a centrally mediated anorectic
action.
The duration of action is 2–3 hours.
It has been used as an adjuvant to meal time insulin injection to suppress the glycaemic
peak in both type 1 and type 2 diabetics.
Reduction in body weight is an additional benefit.
Androgens & Related drugs

Natural androgens
Testosterone is secreted by the interstitial (Leydig) cells of the testes
Testes________> testosterone__________ 5α-reductase ___________> dihydrotestosterone
Adrenal cortex _____________> dehydroepiandrosterone and androstenedione
In women ovary produces small quantity of testosterone
Androsterone
It is a metabolite of testosterone which is excreted in urine. It has 1/10 the activity of

testosterone. In male, large quantity of equilin is produced which has 1/5 estrogenic potency of
estradiol
Testosterone is secreted by the interstitial (Leydig) cells of the testes under the influence
of LH.
high concentration of testosterone
o inhibits LH secretion from pituitary _ feedback mechanism
o causes atrophy of interstitial cells (diminish in size and may be accompanied by loss
of function)
FSH is mainly responsible for promotion of spermatogenesis in seminiferous tubular
(Sertoli) cells.
Inhibin, (a protein) produced by Sertoli cells, inhibits FSH secretion from pituitary _
feedback mechanism
Estrogens are more potent inhibitors of Gn secretion even in males, small amount of
estradiol produced by testes as well as that resulting from conversion of testosterone to
estradiol in liver and fat plays a role in feedback inhibition.
ACTIONS
1. Sex organs and secondary sex characters (Androgenic)
Growth of genitals, Growth of hair, Thickening of skin and increased activity of sebaceous
glands, Behavioral changes, intrauterine development of the male phenotype.
2. Testes
High concentration of testosterone is attained locally in the seminiferous tubules by diffusion

from the neighbouring Leydig cells causes spermatogenesis and maturation of spermatozoa.
3. Skeleton and skeletal muscles (Anabolic)
There is rapid bone growth, both in thickness as well as in length.
Estradiol produced from testosterone, and not testosterone itself, is responsible for
fusion of epiphyses in boys (as well as in girls)

bone mineralization.
Testosterone also promotes muscle building, especially if aided by exercise. There is accretion
of nitrogen, minerals (Na, K, Ca, P, S) and water—body weight increases rapidly, more
protoplasm is built.
Appetite is improved and a sense of well being prevails.
4. Erythropoiesis
Testosterone accelerates erythropoiesis by
o increasing erythropoietin production and
o increasing haeme synthesis.
Men have higher hematocrit than women.
PHARMACOKINETICS
after i.m. injection slowly absorbed esters of testosterone—are hydrolysed to the active
free form.
The major metabolic products of testosterone are androsterone and etiocholanolone
which are excreted in urine, mostly as conjugates with glucuronic acid and sulfate.
Small quantities of estradiol are also produced from testosterone by aromatization of A
ring in extraglandular tissues (liver, fat, hypothalamus).
SIDE EFFECTS with Testosterone
Males Females
Virilization, excess body hair menstrual irregularities in women
Acne Acne
painful erections in males -
Oligozoospermia, Gynaecomastia -
Precocious puberty (if given in young age) Precocious puberty (if given in young age)
early closure of epiphysis (if given in young early closure of epiphysis (if given in young
age) age)
Salt retention and edema (elderly) Salt retention and edema (elderly)
Lowering of HDL and rise in LDL levels Lowering of HDL and rise in LDL levels
Cholestatic jaundice: occurs with methyltestosterone and other 17-alkyl substituted

derivatives (fluoxymesterone and some anabolic steroids like oxymetholone, stanozolol) in
a dose dependent manner, but not with parenterally used esters of testosterone. For this
reason, the latter are preferred. However, jaundice is reversible on discontinuation.
Hepatic carcinoma
Gynaecomastia: may occur, especially in children and in patients with liver disease. This is
due to peripheral conversion of testosterone to estrogens. Dihydrotestosterone does not
cause gynaecomastia because it is not converted to estradiol.
Lowering of HDL and rise in LDL levels, especially with 17α-alkylated analogues.
Androgens are contraindicated in
carcinoma of prostate and male breast, liver and kidney disease and
during pregnancy (masculinization of female foetus).
They should not be given to men aged >65 years
to those with coronary artery disease or CHF.
USES
1. Testicular failure
2. Hypopituitarism- associated Hypogonadism
3. AIDS related muscle wasting
Testosterone therapy has been shown to improve weakness and muscle wasting in AIDS
patients with low testosterone levels.
ANABOLIC STEROIDS
The anabolic : androgenic ratio of testosterone is considered as 1; The anabolic selectivity of

these steroids is modest with ratios between 1 to 3 in the rat model, and probably still lower in
man.
The anabolic : androgenic activity ratio is determined by injecting the drug in castrated rats
and measuring the increase in weight of levator ani muscles to that of ventral prostate.
Side effects
The 17-alkyl substituted compounds oxymetholone, stanozolol, can produce jaundice and
worsen lipid profile.
Uses
1. Catabolic states
2. Osteoporosis
3. Suboptimal growth in boys
4. Hypoplastic, haemolytic and malignancy associated anaemia
IMPEDED ANDROGENS / ANTIANDROGENS
Danazol
weak androgenic, anabolic and progestational activities.

it binds to the AR and induces some androgen-specific mRNA production
the most prominent action is suppression of Gn secretion from pituitary in both men and
women → inhibition of testicular/ovarian function.
In addition, it suppresses gonadal function directly by inhibiting steroidogenic enzymes.

In women endometrial atrophy occurs over few a weeks and amenorrhoea may supervene.
Uses are:
Endometriosis, dysmenorrhea, Menorrhagia, Fibrocystic breast disease (chronic cystic

mastitis)
Hereditary angioneurotic edema
Side effects
Complete amenorrhoea, Androgenic side effects

hot flashes in women
night sweats, muscle cramps, g.i. upset
elivation of hepatic enzymes
Cyproterone acetate
AR antagonist is chemically related to progesterone.

In contrast to flutamide which increases LH release by blocking feedback inhibition,
cyproterone inhibits LH release by its progestational activity.
Lowering of serum testosterone (consequent to LH inhibition) supplements the direct
antiandrogenic action of cyproterone.
Its clinical indications are— precocious puberty in boys, inappropriate sexual behaviour in
men, acne and hirsutism in women (usually in combination with an estrogen).
Flutamide
Its active metabolite 2-hydroxyflutamide competitively blocks androgen action on accessory

sex organs as well as on pituitary.
Thus, it increases LH secretion by blocking feedback inhibition.
Plasma testosterone levels increase in males which partially overcome the direct
antiandrogenic action. This limits utility of monotherapy with antiandrogens in carcinoma
prostate. They are now used only when
in conjunction with a GnRH agonist (to suppress LH and testosterone secretion) or

after castration to block the residual action of adrenal androgens as combined
androgen blockade (CAB) therapy of metastatic carcinoma prostate.
Reports of liver damage have restricted its use.
Bicalutamide
This more potent and longer acting (t½ 6 days) congener of flutamide is suitable as a
component of CAB therapy.
Side effects are hot flashes, chills, edema and loose stools
Elevation of hepatic transaminase above twice normal is a signal for stopping the drug.
5 α-REDUCTASE INHIBITOR
Finasteride
A relatively selective & competitive inhibitor of 5 α-reductase type 2 isoenzyme which

predominates in male urogenital tract.
Circulating and prostatic DHT concentration are lowered
Treatment with finasteride has resulted in decreased prostate size and increased peak
urinary flow rate in ~50% patients with symptomatic benign hypertrophy of prostate (BHP).
Finasteride has also been found effective in male pattern baldness, though hair follicles
have primarily type 1 enzyme.
Finasteride is effective orally, extensively metabolized in liver—metabolites are excreted in
urine and faeces; plasma t½ 4–8 hours (elderly 6–15 hours).
It is well tolerated by most patients; side effects are decreased libido, impotence and
decreased volume of ejaculate (each in 3–4% patients).
Dutasteride
inhibits both type 1 and type 2 5α-reductase and reduces DHT levels.
It is metabolized by CYP3A4 and is very long-acting (t½ is ~ 9 weeks).
used in BHP and can benefit male pattern baldness.
DRUGS FOR ERECTILE DYSFUNCTION
1. Androgens
Androgens used if Hypogonadism is cause of ED. In such cases testosterone therapy is given.
2. Phosphodiesterase-5 (PDE-5) inhibitors
the first line therapy for ED.
Inhibition of PDE-5, the cGMP degrading isoenzyme in cavernosal and vascular smooth muscle,
results in accumulation of cGMP and marked potentiation of NO action.
3. Papaverine/Phentolamine induced penile erection (PIPE) therapy
4. Prostaglandin E1
Alprostadil (PGE1) injected directly into the corpus cavernosum using a fine needle produces
erection lasting 1–2 hours to permit intercourse.
Estrogens, Progestins and Contraceptives

Natural estrogens
Estradiol is the major estrogen secreted by the ovary. It is synthesized in the graafian follicle,
corpus luteum and placenta from cholesterol.
Estradiol is rapidly oxidized in liver to estrone which is hydroxylated to form estriol.
All three are active and circulate in blood, but estradiol is the most potent estrogen.
In male, large quantity of equilin is produced which has 1/5 estrogenic potency of estradiol.
Synthetic estrogens
inactive orally and have a short duration of action due to rapid metabolism in liver.
Females Males
menstruating women varies from 10–100 μg derived primarily by extraglandular
depending on the phase of the cycle aromatization of adrenal androgens
During pregnancy, placenta secretes large
quantities of estrogens reaches 30mg/day max
postmenopausal women, daily production of
estrogen has been estimated as 2–10 μg
derived primarily by extraglandular
aromatization of adrenal androgens
Estrogens exercise feedback inhibition of FSH (also of LH at higher concentrations) by direct

action on pituitary as well as through hypothalamus.
ACTIONS
1. Sex organs
pubertal changes & Secondary sex characters

proliferation of endometrium in the preovulatory phase
In the absence of progesterone (anovulatory cycles) withdrawal of estrogens alone
produces menstruation.
Deficiency of estrogens is responsible for atrophic changes in the female reproductive tract
that occur after menopause.
3. Metabolic effects
Estrogens are anabolic, similar to but weaker than testosterone.

Continued action of estrogen promotes fusion of epiphyses both in girls and boys.
It promotes positive calcium balance
4. Bone Formation and resorption
Estrogen is important in maintaining bone mass primarily by retarding bone resorption.

o Osteoclast pit formation is inhibited
o there is increased expression of bone matrix proteins such as osteonectin,
osteocalcin, collagen and alkaline phosphatase.
The major action of estrogens is to reduce maturation and activity of osteoclasts by modifying
regulatory cytokine signals from osteoblasts
Estrogens enhance elaboration of OPG (osteoprotegerin) from osteoblasts which binds RANKL
and prevents activation of osteoclast-precursors from fusing and maturing into osteoclasts.
The direct action on osteoclasts is to accelerate their apoptosis.
5. carbohydrate & Lipid metabolism
higher doses of estrogens impair glucose tolerance.

Normal blood sugar is not affected but diabetes may be precipitated or its control vitiated.
However, amounts used for HRT and low dose contraception do not affect carbohydrate
metabolism.
HDL : LDL ratio improved
7. Miscellaneous
blood coagulability is increased due to induction of synthesis of clotting factors (factors II,
VII, IX and X).
Fibrinolytic activity in plasma also tends to increase due to lowering of plasminogen-
activator inhibitor-1 (PAI-1).
Estrogens induce nitric oxide synthase and PGI2 production in vascular endothelium. The
increased availability of NO and PGI2 could promote vasodilatation.
They increase lithogenicity of bile by increasing cholesterol secretion and reducing bile salt
secretion.
Mechanism of action
Two distinct ERs designated Erα and ERβ
ERα predominates in uterus, vagina, breast, bone, hypothalamus and blood vessels
ERβ predominates in prostate gland of males and ovaries in females.
Estradiol binds to both ERα and ERβ with equal affinity, but certain ligands have differing
affinities.
ADVERSE EFFECTS
Most of the adverse effects of estrogens are described with HRT and with oral contraceptives
(see p. 325). In addition, dose dependent adverse effects noted when use is made for other
indications are—
Female Male
Fusion of epiphyses and reduction of adult Fusion of epiphyses and reduction of adult
stature stature
Suppression of libido, gynaecomastia and
feminization
In postmenopausal women, estrogens can
increase the risk of irregular bleeding and
endometrial carcinoma, breast cancer, Benign
hepatomas
genital abnormalities in offspring genital abnormalities in offspring
USES
Senile vaginitis
Delayed puberty in girls
Dysmenorrhoea
Acne
Dysfunctional uterine bleeding
Carcinoma prostate
Hormone replacement therapy (HRT)
Hormone replacement therapy (HRT)
Due to cessation of ovarian function at menopause women suffer a number of physical,

psychological and emotional consequences. Medical problems related to menopause are:
Vasomotor disturbances
Urogenital atrophy
Osteoporosis
Dermatological changes
Psychological/Cognitive disturbances
Increased risk of cardiovascular diseases
Benifites of HRT
Menopausal symptoms and atropic changes are arrested

Prevention ofosteoporosis and fracture
Improved cardiac activity and lipid profile
Tibolone It is a 19-norsteroid developed specifically to be used for HRT. It is converted into 3

metabolites which exert estrogenic, progestational and weak androgenic actions in specific
tissues.
ANTIESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)
ANTIESTROGENS
Clomiphene citrate
It binds to both ERα and ERβ and acts as a pure estrogen antagonist in all human tissues
It induces Gn secretion in women by blocking estrogenic feedback inhibition of pituitary.
The amount of LH/FSH released at each secretory pulse is increased.
the ovaries enlarge and ovulation occurs if the ovaries are responsive to Gn.
uses
To aid in vitro fertilization

Oligozoospermia
Adverse effects
Polycystic ovaries, hot flushes, Risk of ovarian tumour may be increased.

The chief use of clomiphene is for infertility due to failure of ovulation
Fulvestrant
‘selective estrogen receptor down-regulators’ (SERDs) or ‘pure estrogen antagonists’

MOA: it inhibits ER dimerization so that ER interaction with DNA is prevented and receptor
degradation is enhanced. The ER is thus down regulated resulting in more complete
suppression of ER responsive gene function.
USES: for the treatment of metastatic ER positive breast cancer in postmenopausal women
which has stopped responding to tamoxifen.
Selective estrogen receptor modulators (SERMs)
Tamoxifen citrate, Toremifene
acts as potent estrogen antagonist in breast carcinoma cells, blood vessels and at some
peripheral sites, but as partial agonist in uterus, bone, liver and pituitary.
Inhibition of human male breast cancer cells and hot flushes reflect antiestrogenic action,
while the weak estrogen agonistic action manifests as stimulation of endometrial
proliferation, lowering of Gn and prolactin levels in postmenopausal women as well as
improvement in their bone density.
A decrease in total and LDL cholesterol without any change in HDL and triglyceride level
reflects estrogenic action.
With its use following
o risk of endometrial carcinoma
o risk of deep vein thrombosis
Used in breast carcinoma, human male breast cancer, Male infertility
Side effects: Hot flushes, , vaginal bleeding, vaginal discharge, menstrual irregularities
Raloxifene
This SERM has a different pattern of action than tamoxifen.

It is an estrogen partial agonist in bone and cardiovascular system, but an antagonist in
endometrium and breast.
It has high affinity for both Erα and ERβ, and has a distinct DNA target the ‘raloxifene
response element’ (RRE).
raloxifene prevents bone loss in postmenopausal women; bone mineral density (BMD)
In postmenopausal women raloxifene reduces LDL cholesterol, probably by upregulating
hepatic LDL receptors. In contrast to estrogen HRT there is no increase in HDL and
triglyceride levels.
reduces the risk of breast cancer by 65%, though the protection was confined to ER-positive
breast cancer.
Raloxifene does not stimulate endometrial proliferation and there is no increase in the risk
of endometrial carcinoma.
Side effects increase in risk of deep vein thrombosis and pulmonary embolism.
Use
second line drug for prevention and treatment of osteoporosis
AROMATASE INHIBITORS
Aromatization of ‘A’ ring of testosterone and androstenedione is the final and key step in the
production of estrogens (estradiol/estrone) in the body.
In addition to the circulating hormone, locally produced estrogens appear to play an important
role in the development of breast cancer.
Letrozole
It is an orally active nonsteroidal (type 2) compound that reversibly inhibits aromatization

all over the body, including that within the breast cancer cells, resulting in nearly total
estrogen deprivation.
Proliferation of estrogen dependent breast carcinoma cells is suppressed to a greater extent
than with tamoxifen.
Randomized clinical trials have established its utility in:
o Early breast cancer: Letrozole is a first line drug for adjuvant therapy after
mastectomy in ER+ive postmenopausal women.
o Advanced breast cancer: Current guidelines recommend letrozole as first line
therapy
Anastrozole
nonsteroidal and reversible (Type 2) AI, more potent, accumulates in the body to produce
peak effect after 7–10 days.
Uses:
o early as well as advanced breast carcinoma in postmenopausal women
o adjuvant therapy in early ER+ive breast cancer
o palliation of advanced cases in postmenopausal women
Side effect: shot flushes, vaginal dryness & bleeding, Arthralgia and acceleration of
osteoporosis
Exemestane:
This steroidal and irreversible (Type 1) inhibitor of aromatase acts like a suicide substrate by
covalent binding to the enzyme.
As a result >90% suppression of estradiol production is obtained. However, it has weak
androgenic activity similar to androstenedione.
Early breast cancer, advanced breast cancer
PROGESTINS
Natural progestin
It is secreted by the corpus luteum (10–20 mg/day) in the later half of menstrual cycle under
the influence of LH.
Its production declines a few days before the next menstrual flow.
If the ovum gets fertilized and implants—the blastocyst immediately starts producing chorionic
gonadotropin which is absorbed into maternal circulation and sustains the corpus luteum in
early pregnancy.
Placenta starts secreting lots of estrogens and progesterone from 2nd trimester till term.
Synthetic progestins
Progesterone derivatives (21 C) or 19-nortestosterone
These are either progesterone derivatives (21 C) or 19-nortestosterone derivatives, also

called ‘estranes’ (18 C).
The progesterone derivatives are almost pure progestins, have weaker antiovulatory
action
used primarily as adjuvants to estrogens for HRT in postmenopausal women, threatened
abortion, endometriosis, etc. for selective progestational effect.
additional weak estrogenic, androgenic, anabolic and potent antiovulatory action: are
used primarily in combined contraceptive pills.
13-ethyl substitution ‘gonanes’
Estranes with a 13-ethyl substitution are called ‘gonanes’,

Gonanes are more potent (especially the levoisomers, e.g. levonorgestrel)
strong antiovulatory action with little or no androgenic property.
Desogestrel and norgestimate are prodrugs. Therefore, they do not antagonise the
beneficial action of estrogens on lipid profile and are preferable in women with
hyperandrogenemia.
High antiovulatory potency allows reduction of ethinylestradiol dose when these are
combined in oral contraceptives.
ACTIONS
The main function of progesterone is preparation of the uterus for nidation and maintenance of
pregnancy. The latter is due to prevention of endometrial shedding, decreased uterine motility
and inhibition of immunological rejection of the foetus: progesterone depresses T-cell function
and cell-mediated immunity (CMI).
1. Uterus
preparation of the uterus for nidation and maintenance of pregnancy
By secretory changes in the estrogen primed endometrium.

When pregnancy occurs it brings about decidual changes in endometrium.
2. Breast
Progesterone causes proliferation of acini in the mammary glands. Cyclic epithelial

proliferation and turnover occurs during luteal phase
Continuous exposure to progesterone during pregnancy halts mitotic activity and
stabilizes mammary cells.
Acting in concert with estrogens, it prepares breast for lactation.
3. CNS
High circulating concentration of progesterone (during pregnancy) appears to have a

sedative effect & affect mood.
A slight (0.5 °C) rise in body temperature by resetting the hypothalamic thermostat and
increasing heat production is induced. This is responsible for the higher body
temperature seen during the luteal phase.
4. Metabolism
Prolonged use of oral contraceptives impairs glucose tolerance in some women. This has been
ascribed to the progestational component.
Progestins, especially those with androgenic activity (19-nortestosterone derivatives) raise LDL
and lower HDL cholesterol levels. This may reduce the beneficial effect of estrogen used
concurrently for HRT or in contraceptives. Such effect not found in Micronized oral
progesterone formulation
5. Pituitary
Progesterone is a weak negative feedback inhibitor of Gn secretion from pituitary.

Administration of progestin during follicular phase inhibits the preovulatory LH secretion
and prevents ovulation. This effect is synergestic with estrogen.
The gonanes are potent suppressor of GnRH and thus potent antiovulatory drugs.
PHARMACOKINETICS
Progesterone, inactive orally due to high first-pass effect

Even after an i.m. in oily solution dose it is rapidly cleared from plasma, has a short t½
(ntural 5–7 min & synthetic 8-24 hrs).
major metabolic product is pregnanediol which is excreted in urine as glucuronide and
sulfate conjugates.
ADVERSE EFFECTS
Breast engorgement, increase in the risk of breast cancer

rise in body temperature, and mood swings may occur
Irregular bleeding or amenorrhoea
lower plasma HDL levels (only with 19-nortestosterone derivatives), Blood sugar may rise
and diabetes may be precipitated
Given in early pregnancy, progestins can cause congenital abnormalities.
USES
contraceptive
Hormone replacement therapy (HRT) A progesterone derivative lacking androgenic
activity is preferred.
Dysfunctional uterine bleeding associated with anovular cycles.
Endometriosis due to presence of endometrium at ectopic sites.
Premenstrual syndrome/tension (‘premenstrual dysphoric disorder’)
Threatened/habitual abortion
Endometrial carcinoma
ANTIPROGESTIN
Mifepristone It is a 19-norsteroid with potent anti-progestational and significant

antiglucocorticoid, antiandrogenic activity. Progestational activity in absence of progestin.
In follicular phase, its antiprogestin action suppresses midcycle Gn surge from pituitary →
slowing of follicular development and delay/failure of ovulation.
In luteal phase, it prevents secretory changes by blocking progesterone action on the
endometrium. Later in the cycle, it blocks progesterone support to the endometrium
Mifepristone also sensitizes the myometrium to PGs and induces menstruation.
If implantation has occurred, it blocks decidualization, so that conceptus is dislodged, HCG
production falls, secondary luteolysis occurs–All these effects lead to abortion.
In the absence of progesterone (during anovulatory cycles or after menopause) it exerts
weak progestational activity—induces predecidual changes.
Mifepristone is a partial agonist and competitive antagonist at both A and B forms of PR.
Therefore, it is now regarded as ‘progesterone receptor modulator’ rather than ‘pure
antagonist.’ The weak agonistic action is not manifest in the presence of progesterone.
Uses
Termination of pregnancy of up to 7 weeks:

Cervical ripening
Postcoital contraceptive
Once-a-month contraceptive
Induction of labour
Cushing’s syndrome
HORMONAL CONTRACEPTIVES
FEMALE CONTRACEPTION
TYPES OF METHODS
Oral
1. Combined pill
It contains an estrogen and a progestin in fixed dose for all the days of a treatment cycle
(monophasic).
2. Phased pill
The estrogen dose is kept constant (or varied slightly between 30–40 μg), while the amount of
progestin is low in the first phase and progressively higher in the second and third phases.
recommended for women < 35 years & for women with no withdrawal bleeding or
breakthrough bleeding
3. Progestin-only pill (Minipill)
A low-dose progestin-only pill is an alternative for women in whom an estrogen is

contraindicated.
4. Emergency (postcoital) pill
• Levonorgestrel 0.75 mg two doses 12 hours apart, or 1.5 mg single dose taken as soon as
possible, but before 72 hours of unprotected intercourse.
• Ulipristal 30 mg single dose as soon as possible, but within 120 hours of intercourse.
• Mifepristone 600 mg single dose taken within 72 hours of intercourse.
Injectable
(a) Depot medroxyprogesterone acetate (DMPA) 150 mg at 3-month intervals. After i.m.
injection peak blood levels are reached in 3 weeks and decline with a t½ of ~ 50 days.
(b) Norethindrone (Norethisterone) enanthate (NEE) 200 mg at 2-month intervals. NORISTERAT

200 mg in 1 ml vial for deep i.m. injection during first 5 days of menstrual cycle.
MALE CONTRACEPTIVE
Drugs and approaches tried are—
1. Antiandrogens.
2. Estrogens and progestins.
3. Androgens.
4. Superactive Gn RH analogues.
5. Cytotoxic drugs.
6. Gossypol.

Endocrine System Drugs

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Endocrine System Drugs

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PHARMACOLOGY NOTES: ENDOCRINE SYSTEM AND RELATED DRUGS

Anterior pituitary hormones

Basophils thyrotropes TSH

HORMONE Amino Acid Count Mol Wt

GH Single chain: 191 22000

SOMATOSTATIN Single chain: 14 -

FSH Chain A: 92 & Chian B: 111 33 kDa

LH Chain A: 92 & Chian B: 121 30 kDa

TSH 210 30000

GROWTH HORMONE (GH)

 Growth promotion of all organs (except brain and eye)

 Decreased glucose utilization by muscles and increased gluconeogenesis, glycogenolysis

Somatomedins or Insulin-like growth factors (mainly IGF-1, also IGF-2)

GH produced in excess GH produced insufficient

Childrens Gigantism Pitutary Dwarfism

Pitutary dwarfism Renal failure

Turners synydrome Catabolic states

Adverse effects of GH and similar preparations

Immune reaction, glucose intolerance and insulin like state, lipodystropy

 short duration of action (t½ 2–3 min),

Synthetic analouges of somatostatin

Octreotide Lanreotied Pegvisomant

90 min 10-15 days -

 Growth and development of breast during pregnancy.

 Subsequently, high prolactin secretion is maintained by suckling: it falls if breast feeding is

Prolactin levels Male Female

Galactorrhea Loss of libido

The causes of hyperprolactinaemia are

 Disorders of hypothalamus > removing the inhibitory control over pituitary

Prolactin inhibitors: Bromocriptine, Cabergoline

 As antigalactopoietic in Hyperprolactinemia due to microprolactinomas causing galactorrhoea,

Adverse effects: Hypotension, Behavioral alterations, mental confusion, hallucinations, abnormal

Gonadotropins: FSH & LH

 supports spermatogenesis and  stimulates testosterone secretion by

Location of FSH receptors Location of LH receptors

MALE TESTES Seminiferous tubules (sertoli Interstitial (leydigs) cells

FEMALE OVERIES Granulosa cells Theca cells, Granulosa cells,

 Decapeptide Gonadorelin (GnRH) by hypothalamus stimulates release of FSH and LH

 delayed puberty or precocious puberty both in girls and boys.

PREPARATION CONTENT SOURCE

Menotropins FSH+LH Urine of menopausal women

Urofollitropins/ Menotropins FSH -

HCG HCG Urine of pregnant women

rFollitropins (Follitropins ɑ , β) FSH Recombinant preparation

rLH (leutropin) LH Recombinant preparation

rHCG (choriogonadotropins) HCG Recombinant preparation

 Amenorrhea & Infertility females

Synthetic gonadorelin (GnRH)

Short acting analogue (4-8 min) metabolized by enzymatic hydrolysis

 Testing pituitary gonadal axis in males

Superactive GnRH agonist : Goserelin, Leuprolide, Nafarelin, Triptorelin,

precocious puberty, prostatic carcinoma, endometriosis, premenopausal breast cancer, uterine

to assist induced ovulation

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.

to release more of T3 and T4.

Dopamine also reduces TSH production induced by TRH.

ADRENOCORTICOTROPIC HORMONE (ACTH, CORTICOTROPIN)

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