Professional Documents
Culture Documents
Endocrine System Drugs
Endocrine System Drugs
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PHARMACOLOGY NOTES: ENDOCRINE SYSTEM AND RELATED DRUGS
somatotropes GH
Acdophils
lactotropes Prolactin
anterior
pitutary cells gonadotropes FSH & LH
cortico-
ACTH & MSH
lipotropes
PL 199 23000
ACTH 39 4500
Physiological functions
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peptides in nature
extracellular mediators of GH response like growth promoting, nitrogen retaining and certain
metabolic actions of GH
Pathological involvement
Adult Acromegaly -
Therapeutic uses
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.
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Disadvantages of somatostatin
PROLACTIN
Physiological function
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.
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Physio-pathological involvement
Actions
Decreases prolactin release from pituitary by activating dopaminergic receptors on lactotrope cells: is a
strong antigalactopoietic.
Uses
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Actions
FSH LH
Gametogenesis promotion
Conversion of cholesterol to pregnenolone (RDS in steroidal hormones synthesis)
Receptors of gonadotropins
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Secretion regulation
Pathological involvement
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USES
Uses
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
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They also have potential to be used as contraceptive for both males and females.
TSH : THYROTROPIN
• 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
Regulation of secretion
Synthesis and release of TSH by pituitary is controlled by hypothalamus primarily through TRH, while
somatostatin inhibits TSH secretion.
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.
derived from a larger peptide pro-opio melanocortin (MW 30,000) which also gives rise to endorphins,
two lipotropins and two MSHs.
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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.
Regulation of 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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triiodothyronine (T3)
Thyroid hormones produced by thyroid follicles
thyroxine (T4)
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
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
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.
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.
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
2. Intermediary metabolism
Lipid
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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
Protein
3. Calorigenesis
4. CVS
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
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7. GIT
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
USES
The most important use of thyroid hormone is for replacement therapy in deficiency states:
1. Cretinism
3. Myxoedema coma
4. Nontoxic goiter
5. Thyroid nodule
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Thyroid inhibitors
Antithyroid drugs bind to the thyroid peroxidase and prevent oxidation of iodide/ iodotyrosyl
residues, thereby;
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.
Excess iodide inhibits its own transport into thyroid cells by interfering with expression of NIS
on the cell membrane.
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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
2. Thyroid storm
Adverse effects
1. Acute reaction
Manifestations are swelling of lips, eyelids, angioedema of larynx (may be dangerous), fever,
joint pain, petechial haemorrhages, thrombocytopenia, lymphadenopathy.
Given to pregnant or nursing mothers, it may be responsible for foetal/infantile goiter and
hypothyroidism.
RADIOACTIVE IODINE
127 131
The stable isotope of iodine is I, isotope of medicinal importance is: I: physical half-life 8
days.
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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.
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.
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
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
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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.
(ii) Along with iodide for preoperative preparation before subtotal thyroidectomy.
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CORTICOIDS
Biosynthesis (steroidogenesis)
In adrenal cortical cells only minute quantities of the hormones is stored, rate of release is governed by
the rate of biosynthesis.
Actions
Corticoids have direct and permissive actions on the basis of way of producing effect
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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
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.
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
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Protein metabolism
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.
These adipocytes less sensitive to insulin and more These adipocytes respond mainly to raised
sensitive to corticosteroid insulin levels caused by glucocorticoid
induced hyperglycaemia
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
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Glucocorticoids restrict capillary permeability, maintain tone of arterioles and myocardial contractility.
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
Hypocorticism: diminished work capacity and weakness are primarily due to hypodynamic circulation.
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
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
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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.
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.
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.
It is an emergency situation where low levels of cortisol can cause weakness, fatigue, Low blood
pressure and Loss of consciousness.
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The amount of fluid infused i.v. is guided by monitoring central venous pressure, because these patients
have reduced capacity to excrete water load.
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.
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.
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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
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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.
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Hyperglycaemia _
Glycosuria _
Hyperlipidaemia _
negative nitrogen balance _
ketonaemia _
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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.
Under basal condition ~1U insulin is secreted per hour by human pancreas.
Secretion of insulin from β cells is regulated by chemical, hormonal and neural mechanisms.
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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.
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Hormonal
A number of hormones, e.g. growth hormone, corticosteroids, thyroxine modify insulin release
in response to glucose.
Neural
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:
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1. Insulin facilitates glucose transport across cell membrane; skeletal muscle and fat cells are
highly sensitive.
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.
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.
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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.
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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.
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ultralente - large particles is crystalline and practically insoluble in water & long-acting.
Lente insulin - Their 7:3 ratio mixture is called ‘Lente insulin’ and is intermediate-acting.
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)
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.
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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.
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to control meal-time glycaemia, for which a rapid acting insulin or an oral hypoglycaemic is used concurrently.
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REACTIONS TO INSULIN
1. Hypoglycaemia
This is the most frequent and potentially the most serious reaction.
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
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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.
Fall in blood glucose level by 10% per hour can be considered adequate response.
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.
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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
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.
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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
3. Hypersensitivity
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Repaglinide
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
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
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Exenatide
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.
Sitagliptin
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.
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:
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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.
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.
MOA
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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
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
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Miglitol
Amylin analogue
Amylin, ‘islet amyloid polypeptide’ (IAP), is produced by pancreatic β cells & acts in the brain
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.
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Androsterone
Regulation of secretion
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
Growth of genitals, Growth of hair, Thickening of skin and increased activity of sebaceous
glands, Behavioral changes, intrauterine development of the male phenotype.
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2. Testes
Estradiol produced from testosterone, and not testosterone itself, is responsible for
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.
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).
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Males Females
Acne Acne
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
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.
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USES
1. Testicular failure
Testosterone therapy has been shown to improve weakness and muscle wasting in AIDS
patients with low testosterone levels.
ANABOLIC STEROIDS
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
Danazol
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Uses are:
Side effects
Cyproterone acetate
Flutamide
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
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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
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.
1. Androgens
Androgens used if Hypogonadism is cause of ED. In such cases testosterone therapy is given.
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.
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4. Prostaglandin E1
Alprostadil (PGE1) injected directly into the corpus cavernosum using a fine needle produces
erection lasting 1–2 hours to permit intercourse.
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Estradiol is the major estrogen secreted by the ovary. It is synthesized in the graafian follicle,
corpus luteum and placenta from cholesterol.
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.
Regulation of secretion
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
ACTIONS
1. Sex organs
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3. Metabolic effects
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.
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.
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Mechanism of action
ERα predominates in uterus, vagina, breast, bone, hypothalamus and blood vessels
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)
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Vasomotor disturbances
Urogenital atrophy
Osteoporosis
Dermatological changes
Psychological/Cognitive disturbances
Increased risk of cardiovascular diseases
Benifites of HRT
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
Adverse effects
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Fulvestrant
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
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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
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
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
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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
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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
2. Breast
3. CNS
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
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concurrently for HRT or in contraceptives. Such effect not found in Micronized oral
progesterone formulation
5. Pituitary
PHARMACOKINETICS
ADVERSE EFFECTS
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
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ANTIPROGESTIN
Uses
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
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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
• 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.
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.
MALE CONTRACEPTIVE
1. Antiandrogens.
3. Androgens.
4. Superactive Gn RH analogues.
5. Cytotoxic drugs.
6. Gossypol.
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