Pharmacology Hormones Question And Answers

Hypothalamus And Anterior Pituitary Hormones

 

Question 1.  Enumerate the hormones secreted by the hypothalamus and anterior pituitary. Mention their primary actions and uses.
Answer:

The pituitary gland, under the influence of the hypothalamus, secretes many hormones which either control the secretion of other glands or directly act on the target tissues. These are peptides and act by binding to specific receptors present in the target cells.

The hypothalamic and anterior pituitary hormones are used in the respective deficiency states for replacement and as diagnostic tools to detect their deficiency states. Their analogs are now available and are preferred for use as they are more convenient to use. Posterior pituitary hormones are discussed in.

Read And Learn More: Pharmacology Question And Answers

Hormones secreted by the hypothalamus and anterior pituitary and their chief functions:

Hypothalamic Hormones

Question 2. Short notes:

1. Gonadotrophins
2. GnRH
3. GnRH analogs
4. Name 4 GnRH antagonists. Mention their uses
5. Explain why GnRH antagonists are preferred over GnRH agonists/analogs
   

Answer:

1. Growth hormone-releasing hormone (GH-RH):

Stimulates the anterior pituitary to secrete growth hormone. Sermorelin is an analog of GH-RH used in diagnostic tests of growth hormone deficiency.

Somatostatin:

• Somatostatin is a growth hormone release inhibiting hormone (GH-RIH) present in the hypothalamus, parts of the CNS, pancreas, and in the gastrointestinal tract.
• It inhibits the secretion of GH, TSH, PRL, insulin, glucagon, and gastrointestinal secretions, but it is very short-acting.
• Steatorrhea, diarrhea, nausea, and dyspepsia are due to their effects on the gut.

Octreotide:

• Octreotide is the synthetic analog of somatostatin which is longer-acting, more potent, and useful in acromegaly, some hormone-secreting tumors, carcinoid syndrome, diarrhea associated with diabetes, and bleeding esophageal varices.
• It is given subcutaneously and depot preparations to be injected into the gluteal region every 4 weeks are also available.
• Octreotide has a weak effect on pancreatic beta cells—hence hyperglycemia is not common.
• It can cause nausea, vomiting, abdominal cramps, flatulence, and vitamin B₁₂ deficiency.

Lanreotide:

Lanreotide is another somatostatin analog that is longer-acting than octreotide and is also used in acromegaly, TSH-secreting tumors, and neuroendocrine tumors.

Pegvisomant:

Pegvisomant is a growth hormone receptor antagonist—useful in acromegaly.

2. Thyrotrophin-releasing hormone (TRH):

• Secreted by the hypothalamus stimulates the release of TSH from the anterior pituitary.
• Protirelin is a synthetic analog of TRH used in the diagnosis of thyroid disorders.

3. Corticotrophin-releasing factor (CRF): 

Releases ACTH and β-endorphins from the anterior pituitary. It is used in diagnostic tests for Cushing’s disease.

Hypothalamic hormones, their analogs, and their uses:

Question 3. Write short notes on GnRH/GnRH analogs/GnRH agonists.
Answer:

• Gonadotrophin-releasing hormone (GnRH) and its analogs: GnRH secreted in a pulsatile manner, regulates the secretion of gonadotrophins, i.e. enhances FSH and LH production.
• Gonadorelin is synthetic GnRH. Leuprolide, goserelin, buserelin, nafarelin, histrelin, and triptorelin are synthetic analogs (and agonists) of GnRH which are more potent and longer-acting.
• On the other hand, continuous secretion or exogenous administration of GnRH or its analogs inhibits the secretion of gonadotrophins by the pituitary gland and is used in prostatic cancers, precocious puberty, and endometriosis.

GnRH Analogs Uses :

Pulsatile Administration

1. Infertility:

• Infertility in women: Pulsatile administration of a GnRH agonist may be used in women to induce ovulation. The risk of ovarian hyperstimulation and multiple pregnancies is lesser than with gonadotropins.
• Infertility in men: Hypothalamic hypogonadotropic hypogonadism resulting in infertility responds to pulsatile administration of gonadorelin.

2. Diagnosis of hypogonadism:

A rise in LH levels following gonadorelin indicates that hypogonadism is of hypogonadotropic etiology (GnRH stimulation testing).

Continuous Administration:

1. Controlled ovulation:

• In vitro fertilization requires induction and timing of ovulation so that multiple mature oocytes are available but the endogenous LH surge can result in premature ovulation.
• This can be suppressed by daily GnRH administration. Subcutaneous leuprolide or nasal application of nafarelin may be used.

2. Endometriosis:

Continuous administration of GnRH agonists reduces estrogen and progesterone levels, alters the cyclical changes in their levels, and reduces the pain of endometriosis.

3. Uterine fibroids:

• A GnRH agonist (leuprolide, goserelin, or nafarelin) administered for 3–6 months reduces the size of the fibroid.
• Used for 3 months prior to hysterectomy, they facilitate easy removal of the uterus and also reduce blood loss.

4. Central precocious puberty:

• GnRH agonists continued daily till 11 years of age stop the development of gonads.
• The development process resumes after stopping the drug.

5. Prostatic cancer:

• Continuous administration of GnRH agonists with an androgen receptor antagonist like flutamide induces pharmacological castration.
• (GnRH agonists cause flare-ups of the disease in the first 2 weeks due to an increase in testosterone levels.
• Hence, an androgen antagonist like flutamide is added).

6. Other cancers: Breast and ovarian cancers also respond.

• Adverse effects: In women, flushing, sweating, and headache—symptoms resemble menopause; allergic reactions, depression, and loss of libido. In men, continuous
• GnRH administration can cause flushing, loss of libido, and gynecomastia.
• Danazol is a synthetic steroid. It inhibits the release of GnRH and thereby inhibits the midcycle surge of FSH and LH.

GnRH Antagonists:

• Cetrorelix, ganirelix, abarelix, and degarelix are synthetic GnRH antagonists. They bind to and block pituitary GnRH receptors—therefore, suppressing the secretion of LH, and FSH and delaying ovulation.
• GnRH antagonists can cause allergic reactions, headaches, and nausea in women. In men, they can cause hot flushes, sweating, decreased libido, and gynecomastia apart from allergic reactions.

GnRH Antagonists Uses:

1. In vitro fertilization: GnRH antagonists prevent LH surge and are used in in vitro fertilization.
2. They are preferred over GnRH agonists because of the following advantages:
   • Less ovarian hyperstimulation.
   • The duration of treatment required is lesser.
   • A lower dose of gonadotrophins is required.
3. Uterine fibroids and endometriosis Cetrorelix is useful.
4. Prostatic cancer: They control the symptoms of advanced prostatic cancer.

Anterior Pituitary Hormones

Question 4. Short note: Growth hormone.
Answer:

Growth hormone (GH):

• Growth hormone ( is a peptide that stimulates the growth of all organs except the brain and eye.
• It increases the uptake of amino acids by the tissues and promotes protein synthesis and positive nitrogen balance.
• It causes lipolysis and reduces glucose uptake by skeletal muscles.
• It brings about linear growth.
• These anabolic actions are mediated by somatomedins or insulin-like growth factors (IGF) produced in the liver. The secretion of growth hormone is regulated by

GHRH and somatostatin (GHIH). GH deficiency in children results in dwarfism, while excessive production results in gigantism in children and acromegaly in adults.

Growth hormone Uses: 

1. GH deficiency: Replacement therapy with GH in deficient children and adults.
2. Other uses: GH has been tried in chronic renal failure and in catabolic states—like severe burns and AIDS. It is abused by athletes to promote growth.

Mecasermin:

• Mecasermin is a recombinant human IGF-1 that is useful in the treatment of severe IGF-1 deficiency that does not respond to GH.
• The common adverse effect is hypoglycemia which should be avoided by carbohydrate meals along with mecasermin.

Corticotrophin:

• Corticotrophin (adrenocorticotrophic hormone, ACTH): Controls the synthesis and release of glucocorticoids, mineralocorticoids, and androgens from the adrenal cortex.
• It is used in the diagnosis of adrenocortical insufficiency.

Thyroid-stimulating hormone (TSH, thyrotrophin):

• Stimulates the production and secretion of thyroid hormones and thus regulates thyroid function.
• Recombinant TSH is used to test thyroid function and to increase the uptake of radioactive iodine in thyroid carcinoma.

Gonadotrophins

• Follicle-stimulating hormone (FSH) and luteinizing hormone (LH): Produced by the anterior pituitary, regulate gonadal function.
• They stimulate follicular development in women and also stimulate ovarian steroidogenesis (estrogen and progesterone synthesis). In men, they promote spermatogenesis.
• Recombinant forms of FSH available are follitropin a and follitropin b; recombinant LH is lutropin a.

Uses of anterior pituitary hormones:

Gonadotrophins Uses:

Gonadotrophins (FSH-LH) or menotropins are used in

1.  Infertility in women:
   • For ovulation and then conception: A definite pattern of FSH and LH release is required in women for ovulation. In women having anovulation, gonadotrophins are used to induce ovulation as alternatives to clomiphene citrate but gonadotrophins are more expensive.
   • Controlled ovarian hyperstimulation: For assisted reproduction, FSH and LH, if required, are given from the 3rd day for 7–12 days. Once the follicle has developed, HCG is given to support follicular maturation and then ovulation. Disadvantages are—multiple pregnancies and ovarian hyperstimulation syndrome (OHSS).
   • For in vitro fertilization: To time the ovulation.
2. Infertility in men: Infertility associated with low sperm count in hypogonadal men due to hypothalami pituitary cause is treated with FSH and LH.
3. Gonadotrophin: Gonadotrophin deficiency in men for replacement.
4. Undescended testes: Surgery is the preferred option now. Earlier, in order to stimulate the descent of the testes, LH was given to stimulate the production of androgens.
5. Delayed puberty: HCG may be tried as an alternative to testosterone to stimulate testosterone synthesis in boys with delayed puberty.

Gonadotrophins Adverse effects:

• Include OHSS with polycystic ovary, abdominal pain, bleeding in the ovaries, and shock.
• They can also cause allergic reactions.

Question 5. Write short notes on prolactin.
Or
Explain why bromocriptine is used in acromegaly. Mention the uses of bromocriptine.
Answer:

Prolactin:

• This peptide hormone promotes the growth and development of the breast during pregnancy. It stimulates milk production along with other hormones like estrogens and progestins.
• Deficiency results in lactation failure, while excess prolactin results in galactorrhea.
• Prolactin also inhibits GnRH release resulting in lactational amenorrhea in the postpartum period.

Regulation of secretion:

• Suckling stimulates the release of prolactin-releasing factors from the hypothalamus.
• Estrogens and dopamine antagonists also stimulate prolactin release. Prolactin is not used clinically. Dopamine inhibits prolactin secretion.

Dopamine agonists like bromocriptine, cabergoline, pergolide, and Quinagolide inhibit prolactin release from the pituitary by acting directly on the dopamine receptors.

Bromocriptine:

An ergot derivative is a dopamine agonist. It reduces the secretion of prolactin by activating the DA receptors in the pituitary. In patients with acromegaly, it reduces GH release. Stimulation of dopamine receptors in CTZ leads to nausea and vomiting.

Prolactin Uses:

• To suppress lactation:  Bromocriptine and other dopamine agonists stimulate the dopamine receptors in the pituitary to inhibit the release of prolactin. Bromocriptine is used to suppress lactation and breast engorgement after delivery (like in stillbirth) and following abortion.
• In galactorrhea: In galactorrhea due to excess prolactin, bromocriptine or cabergoline may be used.
• Prolactin-secreting: Prolactin-secreting tumors or prolactinomas may respond.
• Acromegaly: In normal subjects, dopamine agonists stimulate the release of growth hormone by the pituitary but in patients with acromegaly, they suppress growth hormone release by a paradoxical effect.
• Bromocriptine: Bromocriptine is, therefore, used in acromegaly but the response is seen only in a few patients. Bromocriptine also helps to reduce prolactin release. Octreotide, pituitary surgery, and radiation therapy may be needed in acromegaly.
• Parkinsonism: Bromocriptine is used as an adjunct and also to treat the on-off phenomenon

Thyroid Hormones

Question 6. Explain the synthesis, actions, and uses of thyroid hormones.
Answer:

Thyroxine (tetraiodothyronine, T₄) and triiodothyronine (T₃) are the hormones secreted by the thyroid gland. T₄ is the less active precursor of T₃. The other hormone, calcitonin is secreted by the parafollicular cells.

Synthesis, storage, and secretion:

The thyroid hormones are synthesized and stored in the thyroid follicles. The principal source of iodine is diet.

The main 4 steps involved in the synthesis of thyroid hormones are as follows:

• Uptake of plasma iodide by thyroid cells by an active transport process with the help of sodium iodide symporter.
• Oxidation of iodide to I⁺ (iodonium ions) by a thyroperoxidase enzyme with the help of hydrogen peroxide.
• Iodination: These bind to tyrosine residues of thyroglobulin (Tg) to form monoiodotyrosine (MIT) and diiodotyrosine (DIT).
• Coupling: Pairs of MIT and DIT are coupled to form T₃ (MIT + DIT) and T₄ (DIT+DIT) catalyzed by the same peroxidase enzyme.

1. Storage: Thyroglobulin (Tg) containing iodinated tyrosine residues is stored in the follicles.

2. Release: The hormones T₄ and T₃ are released into the circulation.

3. Regulation: The thyroid secretion is regulated by TSH secreted by the anterior pituitary and

TRH from the hypothalamus. Normally about 70–90 mg of T₄  and 15–30 mg of T3 are secreted daily. In the peripheral tissues, most of the secreted T₄ is converted to T₃ which is the active hormone.

Thyroid hormones Actions: Thyroid hormones influence many body functions.

• Thyroid hormones are essential for normal growth, development, function, and maintenance of all body tissues. Congenital deficiency results in cretinism.
• They increase basal metabolic rate (BMR), body temperature rises (calorigenesis), increase carbohydrate metabolism with increased utilization of sugars by the tissues, glycogenolysis, and gluconeogenesis. Therefore, in hyperthyroidism, hyperglycemia is seen.
• Protein metabolism: Thyroid hormones are catabolic and proteins are used to generate energy. In hyperthyroidism, there is negative nitrogen balance, tissue wasting, and weight loss. Stimulate lipolysis by potentiating the effect of lipolytic hormones. They facilitate erythropoiesis.
• Thyroid hormones are essential for normal functioning of the CNS (mental retardation is seen in cretinism), skeletal muscles (muscle weakness in myxoedema), cardiovascular system, reproductive system, and gastrointestinal system (hypothyroid patients are constipated while hyperthyroid have diarrhea).

Thyroid hormones Mechanism of action:

• Thyroid hormones act on thyroid receptors which are nuclear receptors like the steroid receptors.
• T₃ enters into the cells, binds to the receptor, and the T₃ receptor complex moves to the nucleus where it binds to DNA, activates gene transcription, and regulates protein synthesis

Thyroid hormones Preparations:

T₄ is preferred to T₃ for therapeutic use except in emergencies because:

• Though T₃ is fast-acting it has the risk of precipitating angina, arrhythmias, or cardiac failure.
• T₄ is longer acting (used OD) and also gets slowly converted to T₃ thus providing both T₃ and T₄.
• T₄ is stable.
• Lower cost

Comparison between T₃ And T₄ :  

Thyroid hormones Use:

1. Replacement therapy:

• Cretinism may be sporadic or endemic:  Congenital absence of thyroid or defective thyroid hormone synthesis causes sporadic cretinism. Early detection and treatment produce good results with normal physical and mental development. Levothyroxine 25 mcg/day is started and gradually increased. Replacement should be continued lifelong.
• Hypothyroidism in adults:  Treatment started with levothyroxine 50 mg daily and increased gradually every 2–3 weeks, depending on the plasma TSH levels up to a maintenance dose of 100–200 mg/day. Larger doses are required in pregnancy.
• Myxoedema coma: A medical emergency may be precipitated by infection, trauma, inaction .uate treatment, or exposure to cold. Clinical features include hypothermia, bradycardia, hypotension, hypoglycemia, hypoventilation, lactic acidosis, and coma.
• Treatment: IV thyroxine 300–500 mg or liothyronine 100 mg thrice daily given with prophylactic corticosteroids to avoid adrenal insufficiency. Gradual warming, prophylactic antibiotics, ventilatory support, and correction of fluid and electrolyte balance are all important.
• Myxoedema with coronary artery disease: If myxoedema is rapidly corrected in patients with coronary artery disease, the sudden increase in myocardial workload could result in angina, arrhythmias, or even myocardial infarction.

2. Nontoxic goiter: Endemic or sporadic goiter. Administration of T₄ suppresses TSH production and the goiter regresses (though the extent varies). Iodine deficiency should be corrected.

3. Thyroid carcinoma: A postoperatively higher dose of T₄ induces TSH suppression which in turn reduces the risk of tumor cell proliferation.

4. Miscellaneous: Thyroxine is tried in refractory anemias, infertility, and nonhealing ulcers.

Hyperthyroidism And Antithyroid Drugs

Question 6. Classify/name antithyroid drugs. Describe briefly their uses. Add a note on the treatment of thyroid storm.
Answer:

Hyperthyroidism is due to an excess of circulating thyroid hormones and could be due to various causes. Graves’ disease, an autoimmune disorder, is the most common cause. It is characterized by hyperthyroidism, diffuse goiter, and IgG antibodies that activate TSH receptors. Antithyroid drugs may act by interfering with the synthesis, release, or actions of thyroid hormones.

Antithyroid drugs:

1. Inhibit hormone synthesis
   • Thioureylenes: Propylthiouracil, methimazole, carbimazole
2. Inhibit hormone release
   • Iodine, iodides, iodinated radiocontrast media.
3. Ionic inhibitors
   • Thiocyanate, perchlorate.
4. Destroy thyroid tissue
   • Radioactive iodine
5. Others: Lithium, cholestyramine

Thioureylenes/Thionamides:

Thioureylenes Actions:

Thioureylenes reduce the synthesis of thyroid hormones by inhibiting the iodination of tyrosine residues and the coupling of iodotyrosine residues.

• They bring about these effects by inhibiting the peroxidase enzyme. Propylthiouracil also inhibits peripheral conversion of T₄ to T₃.
• T₃ and T₄ levels gradually fall. Large doses may stimulate the release of TSH resulting in thyroid enlargement.
• Over 3 – 4 weeks of treatment, the signs and symptoms of hyperthyroidism subside (see Compare and contrast of propylthiouracil and methimazole).

Propylthiouracil and methimazole:

Thioureylenes Pharmacokinetics:

• Thioureylenes are effective orally and well absorbed; about 75% propylthiouracil is firmly bound to plasma proteins hence very little crosses the placenta and a negligible fraction reaches the milk; but carbimazole and methimazole cross the placenta and are secreted in the milk.
• Thioureylenes are concentrated in the thyroid and, therefore, their effects persist even when plasma levels fall (their plasma t½ is short). They are metabolized in the liver.

Thioureylenes Adverse effects:

• Allergic reactions like skin rashes, urticaria, dermatitis
• Hepatitis, cholestatic jaundice, and headaches can occur
• Agranulocytosis is a rare but serious adverse effect and is reversible on stopping the antithyroid drug but the patient should be monitored with frequent WBC counts.
• Thioureylenes can also cause arthralgia, myalgia, lymphadenopathy, and rarely, psychosis.

Question 7. Write briefly the uses of antithyroid drugs/propylthiouracil. What is a thyroid storm? How is it treated?
Answer:

Thyroid Storm Uses:

1. Graves’ disease: Graves’ disease or diffuse toxic goiter needs long-term (1–15 years) treatment with antithyroid drugs. Thyroid hormone levels return to normal in about 12 weeks but treatment should be continued. Smaller maintenance doses are then sufficient. Radioactive iodine therapy is now considered the definitive therapy in most patients with Graves’ disease.
2. Toxic nodular goiter: Used when surgery cannot be done as in the elderly.
3. Preoperatively: Hyperthyroid patients are made euthyroid and then operated.
4. Hyperthyroidism in pregnancy: Propylthiouracil is the preferred drug in 1st trimester as it poorly crosses the placental barrier. During 2nd and 3rd trimester, the patient is switched to carbimazole. In lactating mothers, though only a negligible amount of propylthiouracil is
   secreted in the milk, due to toxicity, methimazole (10–30 mg/day) is used.
5. With radioiodine: Radioiodine treatment requires about 3 months for the response. Antithyroid drugs may be employed till then to control hyperthyroidism.
6. Thyroid storm: A thyroid storm or thyrotoxic crisis is a sudden, severe exacerbation of thyrotoxicosis and can be life-threatening.

Trigger factors:

• Stress, infections, trauma, surgery, and inadequately treated thyrotoxic patients may cause into thyroid storm.
• Symptoms include fever, tachycardia, nausea, vomiting, diarrhea, profuse sweating, confusion, restlessness, pulmonary edema, CCF, and may lead to coma and death.

Treatment of thyroid storm:

• Propylthiouracil 400–600 mg stat orally or rectally enema to block the hormone synthesis (alternative carbimazole 20 mg).
• 6–10 drops of oral/rectal potassium iodide or Lugol’s iodine inhibit the release of hormones from the thyroid gland.
• IV hydrocortisone 50 mg repeated every 6 hours helps to combat shock and also blocks the conversion of T₄ to T₃.
• Propranolol (1–2 mg slow IV or 40–60 mg oral QID) is used to rapidly control the symptoms, particularly cardiovascular symptoms. It also impairs the conversion of T₄ to T₃.
• If propranolol is contraindicated, diltiazem 60–120 mg TDS may be used to control hypertension and tachycardia.
• Inhibit thyroid hormone release and peripheral conversion of T₄ to T_3.
• Tepid sponging, sedation, IV fluids, and supportive therapy.
• Peritoneal dialysis may be required to clear the plasma thyroxine.

Iodides

Question 8. Write a short essay on iodides.
Answer:

Iodides:

Administration of iodides inhibits the synthesis and release of thyroid hormones.

WolffChaikoff effect: It is an autoregulatory effect, T₃ and T₄ levels fall and in thyrotoxic patients, the symptoms subside in 1–2 days.

• The gland becomes firm, less vascular, and shrinks in size over a period of 10–14 days.
• These effects may be used to quickly reduce thyroid hormone levels as in thyroid storm but the effect decreases after 14–15 days (known as thyroid escape).

Jod-Basedow effect:

• Jod-Basedow effect is iodine-induced hyperthyroidism seen in patients with thyroid abnormalities. It may also be produced by iodine-containing drugs like amiodarone.
• Iodides are administered orally as Lugol’s iodine or as potassium iodide solution—3 drops 3 times a day. Iodine is converted into iodides in the intestine which is then absorbed.

Iodides Uses:

1. Preoperative preparation for thyroidectomy: Iodine is started 10 days prior to surgery to make the thyroid gland firm and less vascular.
2. Thyroid storm: Iodides act rapidly to reduce the release of thyroid hormones.
3. Prophylaxis: Iodide or iodate is added to common salt to prevent endemic goiter.
4. Protection against radioactivity: Potassium iodide given prophylactically following a nuclear accident protects the thyroid from radioactive iodine (by Wolff-Chaikoff effect)
5. Antiseptic: Iodine has antimicrobial properties including antifungal effects.
6. Expectorant: Potassium iodide is used in cough.

Iodides Preparations:

Lugol’s iodine (5% iodine in 10% potassium iodide solution).

• For topical use: Povidone-iodine (5–10% solution).
• Tincture of iodine:  Tincture of iodine(2% iodine with 2.4% sodium iodide).

Iodides Adverse effects:

• Including allergic reactions like skin rashes, conjunctivitis, rhinitis, vasculitis, swelling of the lips and salivary glands, fever, and lymphadenopathy.
• Chronic overdose can cause iodism with a metallic taste, excessive salivation, lacrimation, burning sensation in the oral cavity and throat, running nose, sore throat, cough, headache, and rashes.

Iodine overdose: Acute toxicity with iodine can be fatal (3–4 g—fatal dose).

Signs and symptoms: Iodine is a powerful irritant and vesicant.

• Nausea, vomiting, diarrhea, and an unpleasant metallic taste.
• Vesication, desquamation, and corrosion of skin and mucous membrane with brownish-yellow stains.
• Corrosion and perforation of mouth, throat, and GI tract.
• Nephritis and renal failure.
• Delirium, stupor.
• Inhalation produces edema of the glottis and pulmonary edema.
• Anaphylactic reactions can occur.

Iodides Treatment:

• Starch or flour solution was given orally (30 g per liter of water). Milk is also helpful.
• Sodium thiosulphate the antidote is given orally (1–5% solution). This will convert iodine to iodide which is relatively harmless.
• Skin lesions—treated with 20% alcohol.
• Supportive therapy.
• Induction of vomiting or stomach wash is contraindicated.

Iodism:

• Iodism is chronic poisoning with iodide salts and is characterized by erythema, urticaria, acne, stomatitis, conjunctivitis, rhinorrhea, parotid swelling, lymphadenopathy, anorexia, and insomnia.
• Treatment—intake of sodium chloride → chloride competes with iodide for excretion at the level of the renal tubules and promotes excretion of iodides.

Radioactive Iodine

Question 9. Write briefly on radioactive iodine.
Answer:

Radioactive Iodine:

• ¹³¹Igiven orally as a solution is rapidly absorbed and is concentrated by the thyroid in the follicles. It emits both γ and β rays.
• The γ rays pass through the thyroid tissue, while β particles penetrate only 0.5–2 mm of the tissue which it destroys only the thyroid tissue without damaging the surrounding structures.
• ¹³¹Ihas a half-life of 8 days but the radioactivity is present up to 2 months. It is given as a single dose; clinically the effect is seen after 1–2 months but the peak effect is seen in 3–6 months.

Radioactive iodine Uses:

• Hyperthyroidism (3–10 millicuries)
• Toxic nodular goiter
• Thyroid carcinoma—when surgery is not possible.
• Diagnostic tests—small doses used (in microcurie doses).
• Patients should be instructed to dispose of the urine carefully in the toilet and flush it with enough water.
• Patients should be kept away from children and pregnant women for 2–3 days.

Radioactive iodine¹³¹I Advantages:

• Administration is simple
• Convenient—given as an outpatient.
• Surgery and its associated risks and morbidity can be avoided.
• Less expensive when compared to surgery.

Radioactive iodine¹³¹I Disadvantages:

• Long time (3 months) taken for maximum response.
• Risk of hypothyroidism—after months → needs follow-up and replacement therapy with hormones.
• Risk of thyroid carcinoma—since radiation can be carcinogenic, there is a risk of secondary carcinoma (though uncommon). Hence, its use is restricted to adults.

Question 10. Explain why propranolol is used in hyperthyroidism.
Answer:

β-adrenergic blockers:

• Many of the symptoms of hyperthyroidism are sympathetic overactivity as there is increased tissue sensitivity to catecholamines in hyperthyroidism.
• β- adrenergic blockers like propranolol relieve symptoms like palpitation, tremors, nervousness, sweating, and myopathy.
• They also inhibit the peripheral conversion of T₄ to T₃ in higher doses. They only provide symptomatic relief and are used as adjuvants. They are very useful in controlling the symptoms of thyroid storm.

Ionic inhibitors:

• Interfere with the concentration of iodine by the thyroid gland. Thiocyanate and perchlorate inhibit the organification of iodine.
• Food items like cabbage; drugs like sodium nitroprusside and cigarette smoking increase the concentration of thiocyanate in the blood and may result in hypothyroidism.

Drugs That Influence Thyroid Function:

• Amiodarone, an antiarrhythmic drug that contains iodine—can cause hypothyroidism or hyperthyroidism, chemical thyroiditis, and thyrotoxicosis.
• Phenytoin, carbamazepine, phenobarbitone, rifampicin, and protease inhibitors cause microsomal enzyme induction → ↑ ↑ metabolism of  T₃ and T₄
• Cholestyramine and cholestipol bind → ↓ ↓ absorption of thyroid hormones in the gut.
• Proton pump inhibitors, ciprofloxacin, and sucralfate → ↓ ↓ T4 absorption.
• Lithium and amiodarone inhibit the synthesis and release of thyroid hormones.
• Sulfonamides inhibit the coupling reaction.
• Drug-induced hypothyroidism or hyperthyroidism is best treated by stopping the drug.

Corticosteroids

Corticosteroids Overview:

• Corticosteroids are hormones produced in the cortex of the adrenal gland. They are glucocorticoids, mineralocorticoids, and a small amount of androgens.
• Cortisol is the major glucocorticoid, while aldosterone is the major mineralocorticoid. The secretion of the adrenal cortex is under the control of ACTH, secreted by the anterior pituitary and this is in turn regulated by
• CRF and plasma corticosterone levels . This is termed hypothalamic-pituitary-adrenal axis.

Structure and biosynthesis:

The corticosteroids have a cyclopentanoperhydrophenanthrene (steroid) ring. They are synthesized in the adrenal cortex from cholesterol under the influence of ACTH.

In a normal person, every day about 10–20 mg of hydrocortisone (maximum in the early morning) and 0.125 mg of aldosterone are secreted. They are also released in response to stress.

Glucocorticoids

Question 11. Name/list the glucocorticoids. Describe their actions and mechanism of action.
Answer:

Glucocorticoids include:

• Hydrocortisone or cortisol (natural glucocorticoid)
• Prednisolone
• Triamcinolone
• Dexamethasone
• Betamethasone
• Paramethasone

Hydrocortisone has both glucocorticoid and mineralocorticoid activity.

Glucocorticoid Actions:

• Glucocorticoids (GC) influence several systems in the body.
• They enable the body to handle stress. Apart from direct effects, glucocorticoids also have other actions in coordination with other hormones or regulators and are called permissive effects.

1. Metabolic effects: Glucocorticoids have effects on carbohydrate, protein, and fat metabolism.

• Glucocorticoids increase blood glucose levels.
• Increase protein breakdown—are catabolic hormones; they reduce muscle mass.
• Promote lipolysis and fat is mobilized from the extremities and is deposited over the face, neck, and shoulder, described as ‘moon face’, ‘fish mouth’, and ‘buffalo hump’, respectively.

2. Anti-inflammatory and immunosuppressive effects:

• Glucocorticoids have profound anti-inflammatory properties which is the basis for their beneficial effects in several conditions.
• They are also immunosuppressants. Glucocorticoids:
• Suppress the development of inflammatory responses to all types of stimuli like chemical, mechanical, and immunological stimuli.
• Inhibit both early and late manifestations of inflammation. Inhibition of late responses like capillary proliferation, collagen deposition, fibroblastic activity, and scar formation may delay wound healing.
• Inhibit migration depress the function of the leukocytes and macrophages and inhibit the release of chemical mediators of inflammation. The ability of these cells to respond to antigens is decreased.
• Even a single dose of glucocorticoids decreases the number of WBCs—lymphocytes, monocytes, eosinophils, and basophils decline.
• Induce the synthesis of a protein—lipocortin which inhibits phospholipase A2 thereby decreasing the production of prostaglandins and leukotrienes. GC also suppresses the production of COX-2 in the inflammatory cells.
• Suppress production of cytokines (IL-6 and IL-b) which play a key role in inflammation.

Immunosuppressant effect:

Glucocorticoids suppress cell-mediated immunity, prevent manifestations of allergy and inflammation, and prevent homograft rejection. Large doses also inhibit antibody production.

3. CVS: Glucocorticoids reduce capillary permeability, thereby reducing fluid exudation and maintaining the tone of arterioles. They have a positive inotropic effect on the heart. Prolonged use can cause hypertension.

4. Skeletal muscle: Essential for normal muscular activity.

5. CNS: GC is required for the normal functioning of CNS. Deficiency results in apathy and depression, while large doses result in restlessness, anxiety, and sometimes psychosis. Large doses may increase intracranial pressure.

6. GIT: ↑ Secretion of gastric acid and pepsin in the stomach → may worsen the acid peptic disease.

7. Calcium metabolism: GC inhibits absorption and increases the renal excretion of calcium— they antagonize the effect of vitamin D on calcium absorption.
Bone resorption takes place.

8. Formed elements of blood: Their lymphocytic effect is useful in lymphomas, but they increase the number of platelets and RBCs.

9. Kidney: They are essential for maintaining normal GFR.

10. Fetal lungs: They have a vital role in the development of fetal lungs and stimulate the production of surfactants.

Mineralocorticoid Actions:

Glucocorticoids have a weak mineralocorticoid action but many synthetic glucocorticoids are free of this activity.

Mineralocorticoid Mechanism of Action:

• Glucocorticoids bring about their effects by activating the glucocorticoid receptors which are nuclear receptors but in an inactivated state, they are found in the cytoplasm.
• Corticosteroids enter the cells by simple diffusion, bind to specific receptors present in the cytoplasm, and activate them.
• The drug-receptor complex then moves into the nucleus where it binds to specific sites on DNA (called glucocorticoid response elements or GRE) and induces the synthesis of specific mRNA. Such mRNA regulates the synthesis of new proteins which bring about the hormone effects.

Mineralocorticoid Pharmacokinetics:

Glucocorticoids are well absorbed orally. Biological half-life is longer because of their mechanism of action. They are metabolized by microsomal enzymes in the liver

Relative potency of some corticosteroids:

Question 12. Write short notes on preparations of glucocorticoids.
Answer:

Glucocorticoids Preparations:

Glucocorticoids are given by many routes—orally, parenterally, topically, by inhalation, and nasal spray. They may also be injected intra-articularly. Synthetic analogs are more potent than hydrocortisone and have less or no mineralocorticoid activity.

• Hydrocortisone, the chief natural glucocorticoid is used orally and parenterally; in emergencies, hydrocortisone hemisuccinate is used intravenously.
  • Dose: For replacement, 20 mg in the morning, and 10 mg in the afternoon orally.
• Pharmacotherapy 100 mg IV solution followed by 100 mg infusion every 8 hours.
• Prednisolone has potent glucocorticoids with mild mineralocorticoid activity. It is the most commonly used glucocorticoid.
  • Dose: 5–60 mg
• Prednisolone acetate 1% eye drops.
• Methylprednisolone is similar to prednisolone and is used as a retention enema in ulcerative colitis and for high-dose pulse therapy.
  • Dose: 4–32 mg 0.1%, cream, 80,160 mg inj.
• Triamcinolone, dexamethasone, and betamethasone have no mineralocorticoid activity but have selective and potent glucocorticoid effects.
• Triamcinolone: 4–20 mg. Dexamethasone and betamethasone: 0.5–5 mg oral, 4–20 mg IV/IM inj; eye drops 0.01%.

Deflazacort:

• Deflazacort is a newer glucocorticoid with no mineralocorticoid activity.
•  It is particularly useful in children due to fewer adverse effects (less growth retardation) on long-term use.
• Dose: 6–30 mg.

Glucocorticoids Special preparations:

Glucocorticoids are administered by local routes to deliver the drug directly to the site of action so that the dose requirement is reduced.

• Topical preparations: Several glucocorticoids like hydrocortisone, triamcinolone, dexamethasone, and betamethasone are available for topical use as creams, ointments, and nasal and eye drops. Some of them also contain antibiotics.
• Inhalation: Beclomethasone dipropionate, budesonide, fluticasone, and mometasone furoate are available as aerosols for inhalation in bronchial asthma.
• Nasal spray: Beclomethasone, triamcinolone, budesonide, flunisolide, and mometasone are available as nasal sprays for use in allergic rhinitis.
• Ophthalmic preparations: Should be used carefully as immunosuppression may promote the growth of microorganisms.
• Enema: Hydrocortisone is available as an enema for use in ulcerative colitis.

Adverse Effects Of Glucocorticoids

Question 13. Explain briefly the adverse effects of glucocorticoids/prednisolone.
Answer:

Adverse effects of glucocorticoids are dependent on the dose, duration of therapy, and the relative potency of additional mineralocorticoid effects. Whenever possible, they should be used topically to avoid systemic effects. Single doses are harmless while short courses are well tolerated. Prolonged use is associated with toxicity.

Glucocorticoids Adverse effects are:

1. Cushing’s syndrome:

• With the characteristic appearance of the moon face, supraclavicular hump, truncal obesity, muscle wasting, myopathy, thinning of the limbs and skin, easy bruising, and purple striae.
• Cutaneous atrophy at the site can occur on prolonged topical use. Fine hair grows over the face, trunk, and thighs; weight gain can occur; acne may appear.

2. Hyperglycemia: Increased protein breakdown and neo-glucogenesis result in hyperglycemia
and diabetes mellitus may be precipitated

3. Increased susceptibility to infections:

• Increased susceptibility to infections and severity of any infection may be more because of immunosuppression.
• Opportunistic infections may occur.
• Previously dormant tuberculosis may become active.

4. Osteoporosis: Especially of the vertebrae is more common in the elderly.

5. Avascular:

• Avascular necrosis of the bone due to restriction of blood flow through bone capillaries may cause joint pain, stiffness, and restriction of movement.
• The head of the femur, humerus, and distal part of the femur may be affected. Growth in children may be suppressed.

6. Peptic ulceration: On prolonged therapy especially when used with other ulcerogenic drugs (for example, NSAIDs)

7. Mental disturbances:

• Alterations in behavior can occur with high doses of steroids.
• Symptoms may range from insomnia, anxiety, nervousness, mood changes, euphoria, psychosis, or depression.

8. Cataract: Cataract and glaucoma may follow long-term use of glucocorticoids → should undergo eye examinations for these.

9. Delayed wound healing: Steroids may delay wound healing.

10. Other effects: Include raised intracranial pressure, convulsions, hypercoagulability of the blood, and menstrual disorders.

Question 14. Explain HPA axis suppression by glucocorticoids. Mention the measures to avoid or reduce it.
Answer:

1. HPA axis suppression:

• Depends on the dose, duration, and time of administration.
• > 2 weeks use → HPA axis suppression is likely and on continued use adrenal cortex gradually atrophies due to feedback inhibition. If steroid administration is suddenly stopped, acute adrenal insufficiency results.
• Hence after prolonged use, steroids should be tapered before withdrawal to allow the HPA axis to recover.
• Before surgery or general anesthesia, a proper drug history is to be taken. If the patient has received long-term glucocorticoids within the previous 6 months, prophylactic hydrocortisone should be given to avoid shock.
• If the patient is exposed to minor stress, steroid supplements should be given.
• 2 weeks of use of >20 mg hydrocortisone/day needs tapering of the dose.

Measures to reduce HPA axis suppression:

• The lowest effective dose of a glucocorticoid for the shortest possible period to be used.
• To be given in a single morning dose.
• Administration on alternate days is associated with least/no HPA axis suppression and should be followed especially when long-term steroids are needed.

2. Mineralocorticoid effects:

Salt and water retention and edema add to weight gain; hypokalemia and hypertension are rare with drugs having selective glucocorticoid activity.

 Hydrocortisone And Dexamethasone:

HPA axis suppression of glucocorticoids Uses:

Question 15. Explain the uses of glucocorticoids.
Answer:

Replacement Therapy:

Acute adrenal insufficiency is an emergency condition.

• Precipitating factors—infection, trauma, stress, or sudden withdrawal of steroids.
• Symptoms—nausea, vomiting, weakness, hypotension, dehydration, hyponatremia, and hyperkalemia.
• Treatment—hydrocortisone hemisuccinate 100 mg bolus given immediately followed by IV 100 mg infusion every 4–6 hours. The dose may be repeated depending on the patient’s condition. Once the patient recovers, to be switched over to oral preparations.
• Immediate correction of fluid and electrolyte balance is important. When acute adrenal insufficiency is not confirmed, dexamethasone (4 mg IV) should be used in place of hydrocortisone because dexamethasone does not interfere with the estimation of cortisol levels for diagnosis.
• Primary adrenal insufficiency (Addison’s disease)—oral hydrocortisone 20–40 mg daily is given with additional mineralocorticoid.
• Congenital adrenal hyperplasia is characterized by impaired synthesis of corticosteroids due to deficiency of some enzymes involved in the synthesis.
• Hydrocortisone is given daily at 0.6 mg/kg and if mineralocorticoids are also deficient, fludrocortisone (0.2 mg/day) may be added.

2. For Diagnostic Purposes:

• Dexamethasone suppression test for the diagnosis of Cushing’s syndrome.
• Dexamethasone inhibits the release of corticotrophin-releasing hormone (by negative feedback) but does not interfere with the measurement of endogenous glucocorticoid levels in the plasma.
• Suppression of cortisol production indicates that the HPA axis is intact.

3. Pharmacotherapy:

Glucocorticoids have been used in many nonendocrine conditions where they may even be lifesaving. Their anti-inflammatory activity is the basis for their use in many of these conditions, while immunosuppressive effects help in some.

1. Rheumatoid arthritis: In progressive disease, steroids are given with NSAIDs. If 1–2 joints are involved, intra-articular injections are preferred. If multiple joints are involved, systemic steroids are used.
2. Osteoarthritis: Steroids are given as intra-articular injections in acute exacerbations with strict aseptic precautions. A minimum of 3 months interval should be given between two injections of steroids into the joint.
3. Rheumatic carditis: Severely ill patients not responding adequately to NSAIDs require glucocorticoids in addition.
4. Acute gout: When treatment with NSAIDs has not been successful and colchicine is not tolerated, a short course of prednisolone is used orally or as an intra-articular injection.
5. Allergic diseases: Allergic diseases like angioneurotic edema, hay fever, serum sickness, contact dermatitis, urticaria, drug reactions, and anaphylaxis—steroids are indicated.
6. Shock: Severe inflammatory reaction may be the cause for septic shock. An infusion of hydrocortisone 100 mg over 8 hours for 5–7 days may be life-saving in such patients.
7. Bronchial asthma:
   • Acute exacerbations—a short course of oral prednisolone.
   • Status asthmaticus—intravenous hydrocortisone hemisuccinate 100–200 mg repeated after 8 hours or methylprednisolone 60 mg every 6 hours followed by oral prednisolone 40–60 mg per day for 5 days or till the patient recovers. Prednisolone should then be tapered.
   • Chronic asthma: Inhalational steroids and in more severe cases low dose oral prednisolone is used. COPD exacerbations are treated with short courses of prednisolone.
8. Collagen diseases: Like polyarthritis nodosa, lupus erythematosus, polymyositis, Wegener’s granulomatosis, and other rheumatoid disorders respond to glucocorticoids—the first-line drugs and may be life-saving.
9. Eye diseases: Allergic conjunctivitis, uveitis, optic neuritis, and other inflammatory conditions are treated with glucocorticoid eye drops or ointment. Long-term use can increase IOP which should be monitored. In ocular infections, steroids are contraindicated.
10. Renal diseases: In renal diseases, like nephrotic syndrome, GC is the first-line drug. Prednisolone is given for 6 weeks and tapered over another 6 weeks.
11. Skin diseases: Atopic dermatitis, seborrheic dermatitis, inflammatory dermatoses, and other local skin conditions are treated with topical steroids.
12. Gastrointestinal diseases: Mild inflammatory bowel diseases like ulcerative colitis, and Crohn’s disease are treated with steroid retention enema while severe cases need oral prednisolone.
13. Liver diseases: Steroids are useful in autoimmune chronic active hepatitis and may be tried in alcoholic hepatitis.
14. Hematologic disorders: Like purpura and hemolytic anemia having immunological etiology respond to steroids. They reduce the autoimmune destruction of erythrocytes in hemolytic anemia.
15. Cerebral edema: Large doses of dexamethasone or betamethasone reduce cerebral edema occurring in some malignancies.
16. Malignancies: Because of their lymphocytic effects and inhibition of cell proliferation, steroids are used in the treatment of acute lymphocytic leukemia and lymphomas—as a component of combination chemotherapy. Steroids are used for rapid symptomatic relief in other malignancies like breast cancer.
17. Lung diseases: Diseases like aspiration pneumonia respond. GCs useful in the prevention of infant respiratory distress syndrome—they help in faster lung maturation and production of surfactants. Also used for the treatment of acute respiratory distress syndrome (ARDS).
18. Organ transplantation: For prevention and treatment of graft rejection, high doses of prednisolone are started at the time of surgery with immunosuppressive agents.
19. Thyroid storm: Glucocorticoids inhibit the peripheral conversion of T₄ to T₃.
20. Others: Glucocorticoids are useful in:
    • Sarcoidosis to induce remission.
    • Pneumocystis jiroveci pneumonia in patients with AIDS—GC reduces the risk of respiratory failure and decreases mortality.

Precautions And Contraindications

Question 16. List the contraindications of glucocorticoids.
Answer:

Glucocorticoids should be monitored particularly on long-term use for the development of diabetes mellitus, peptic ulcer, hypertension, osteoporosis, and exacerbation of dormant tuberculosis.

Steroids should be used with caution in:

• Peptic ulcer
• Infections particularly varicella
• Ocular infections particularly viral infections
• Psychoes
• CCF
• Renal Failure
• Pancreatitis
• Hypertension
• Diabetes Mellitus
• Osteoporosis
• Epilepsy
• glaucoma
• Myopathy
• Hepatic Diseases

Contraindications Glucocorticoids Drug Interactions:

• Drugs like erythromycin, ketoconazole, cyclosporine, and isoniazid → inhibit the metabolism of glucocorticoids resulting in an increase in the plasma
• Microsomal enzyme inducers like phenobarbitone and rifampicin → ↑ ↑ rate of metabolism of glucocorticoids.

Mineralocorticoids

The most important natural mineralocorticoid is aldosterone, synthesized in the zona glomerulosa of the adrenal cortex. Small amounts of desoxycorticosterone is also released which also has some glucocorticoid activity.

Mineralocorticoids Actions:

• Mineralocorticoids promote sodium and water retention by distal renal tubules with loss of potassium.
• They act by binding to the mineralocorticoid receptor.

Mineralocorticoids Adverse effects: Include weight gain, edema, hypertension, and hypokalemia.

Fludrocortisone:

• Has predominantly mineralocorticoid properties and is used for replacement therapy in aldosterone deficiency as in Addison’s disease.
• Although aldosterone is the principal natural mineralocorticoid, it is not used therapeutically since it is not effective orally. Floricort 100 mg tab.

Mineralocorticoid antagonists:

Mineralocorticoid antagonists include spironolactone and eplerenone.

Female Sex Hormones

Physiological Consideration:

• At puberty, the ovary begins its cyclic function which stretches over 30–40 years characterized by regular episodes of uterine bleeding.
• The hypothalamus releases the GnRH in pulses which stimulates the release of FSH and LH from the anterior pituitary.
• At the beginning of each cycle, a number of follicles begin to enlarge in response to FSH. After 5–6 days, one of the follicles begin to develop more rapidly.
• The granulosa cells of this follicle multiply and under the influence of LH and FSH, synthesize estrogens.
• Estrogen inhibits FSH release, resulting in regression of the smaller follicles. The ovarian follicle consists of an ovum surrounded by a fluid-filled antrum, lined by granulosa and theca cells.
• Just before the midcycle, the estrogen secretion reaches a peak, stimulating a brief surge in FSH and LH levels which results in ovulation by around the 14th day of the cycle.

Estrogens

The estrogens are produced by the ovaries, placenta and in small amounts by the adrenals, and testes, and by peripheral aromatization of the androgens. The major estrogens are estradiol, estrone, and estriol. Synthetic nonsteroidal estrogens are diethylstilbestrol, dienestrol and hexestrol.

Estrogen receptors:

Estrogen receptors are nuclear receptors and are of two types—ER-α and ER-β.

Estrogen Distribution:

• ER-α—female reproductive tract, breast, blood vessels, and hypothalamus.
• ER-β—ovaries and prostate.

Estrogens Mechanism of action:

Estrogens bring about their effects by stimulating the specific estrogen receptors on the target cells. The estrogen receptor complex moves to the nucleus and binds to the estrogen response elements (EREs) which are present on the target gene and bring about the synthesis of specific proteins involved in the effects of estrogen.

Estrogens Actions:  Estrogens are required for:

• Normal maturation of the female reproductive tract.
• Development of secondary sexual characters in the female.
• Stimulation of preovulatory endometrium.
• Maintenance of normal structure of the skin and blood vessels in women.
• The integrity of the skeleton: Estrogens inhibit the resorption of bone and maintain bone mass.
• They promote the fusion of epiphyses.

Metabolic effects:

• Estrogen promotes the retention of sodium, nitrogen, and fluid in the tissue.
• Estrogens decrease plasma LDL cholesterol and raise HDL cholesterol and triglycerides.
• Estrogens increase the coagulability of the blood.

Estrogens Pharmacokinetics:

• Natural estrogens are metabolized rapidly in the gut—not effective orally; they have a short t½. Synthetic estrogens are orally effective and are longer-acting. All estrogens get absorbed through the skin and mucous membranes.
• Estrogens are metabolized by conjugation in the liver. They also undergo enterohepatic circulation.

Estrogens Adverse Effects:

1. Nausea, breast tenderness, migraine headaches, hyperpigmentation, hypertension, and cholestasis (gallstones are common) may be seen. In men, gynecomastia and feminization can occur.
2. Estrogen therapy can cause postmenopausal uterine bleeding and endometrial hyperplasia. Estrogen should be given cyclically and progesterone added—to allow withdrawal bleeding and also to avoid endometrial hyperplasia.
3. Cancers: Increased incidence of endometrial and breast cancers is reported on long-term use of only estrogens. Therefore, it should be combined with progesterone.
4. Teratogenicity: When given to a pregnant lady, estrogens (diethylstilbesterol) may cause:
   • In female children → increased risk of vaginal and cervical cancers.
   • In male children → genital abnormalities.

Estrogens Uses: 

1. Replacement therapy:
   • In primary hypogonadism: Estrogen started at 11–13 years of age on the diagnosis of hypogonadism stimulates the development of secondary sexual characters and menstruation. It also requires progestins at appropriate times to induce menstruation.
   • Postmenopausal syndrome: Due to decreased estrogen production at menopause, hot flashes, anxiety, fatigue, sweating, and muscle and joint pain are common.
2. Senile vaginitis: Estrogen cream used topically reverts the changes in vaginal cytology.
3. Osteoporosis: In postmenopausal osteoporosis, estrogens restore calcium balance but need to be given for a long time. SERMs are preferred over estrogens for this purpose.
4. Hormonal contraceptives: Estrogens are used with progestins.
5. Dysmenorrhea: Estrogens combined with progestins suppress ovulation and such anovulatory cycles are painless.
6. Dysfunctional uterine bleeding: Estrogens are used as adjuvants to progesterone.
7. Carcinoma prostate: It is an androgen-dependent tumor. Estrogens antagonize the action of androgens, suppress androgen production, and are useful for palliative therapy.
8. Acne: Secretion of androgens at puberty results in acne. Though estrogen helps to reduce acne, it should be avoided since safer topical drugs are available.

Contraindications: Estrogen-dependent tumors, liver disease, and thromboembolic disorders.

Therapeutic uses of estrogens and progestins:

Selective Estrogen Receptor Modulators (Serms) And Anti-Estrogens:

Question 17. Write a short essay on SERMs/tamoxifen/raloxifene. What are SERMs? Name them and write their uses.
Answer:

Tamoxifen is an agonist, antagonist or partial agonist depending on the site. Raloxifene, toremifene and ormeloxifene have actions similar to tamoxifen and are all termed selective estrogen receptor modulators (SERMs). SERMs have tissue-selective estrogenic activities, i.e

Tamoxifen: Tamoxifen is a nonsteroidal SERM. To its tissue selective activity on the estrogen receptor, tamoxifen:

• Inhibits the proliferation of breast cancer cells.
• Stimulates the proliferation of the endometrium—agonistic effect.
• Reduces bone resorption.
• Decreases total cholesterol and LDL (but no effect on HDL or triglycerides).
• Increases the risk of deep vein thrombosis and pulmonary embolism.

Tamoxifen is effective orally and has a long duration of action (4–11 days); metabolized by microsomal enzymes in the liver and undergoes enterohepatic circulation.

Side effects include hot flashes, nausea, vomiting, anorexia, vaginal dryness, bleeding, cataract, and skin rashes. Tamoxifen increases the risk of endometrial cancer because of its agonistic activity on the uterus. Also, it almost doubles the risk of thromboembolism.

Tamoxifen Uses:

• Palliative treatment of advanced breast cancer in postmenopausal women with estrogen receptor-positive tumors.
• Tamoxifen has been tried for the prophylaxis of breast cancer in high-risk women.

Raloxifene:

• Raloxifene nonsteroidal SERM acts as an estrogen receptor agonist in the bone and improves bone density in postmenopausal women. Raloxifene has antiresorptive effects on the bone, reduces bone loss, and may even help to gain bone mass.
• Raloxifene also lowers LDL and total cholesterol.

• It acts as an estrogen antagonist in the breast due to which it reduces the incidence of breast cancer. Raloxifene does not stimulate uterine endometrial proliferation hence no risk of carcinoma uterus.
• Raloxifene has poor oral bioavailability, has a t½ of 28 hours, metabolized by glucuronidation and excreted through the gut.’
• Dose: 60 mg/day.

Raloxifene Adverse effects:  Hot flushes, leg cramps, and an increased risk of deep vein thrombosis and pulmonary embolism.

Raloxifene Uses: Prevention and treatment of postmenopausal osteoporosis.

Toremifene:

Toremifene has actions similar to tamoxifen and is used in the treatment of metastatic breast cancer in postmenopausal women.

Ormeloxifene or centchroman:

• Ormeloxifene has antagonistic effects on the estrogen receptors in the uterus and breast tissue.
• It can cause headaches, nausea, weight gain, a rise in BP, and prolonged menstrual cycles.

Ormeloxifene Uses: Dysfunctional uterine bleeding and is a popular contraceptive

Clomiphene Citrate

Question 18. Write brief/short notes on clomiphene citrate.
Answer:

Clomiphene citrate an antiestrogen, binds to the estrogen receptors—ER-α and ER-β and acts as a competitive inhibitor of endogenous estrogens. Like tamoxifen, it is also a partial agonist.

Clomiphene opposes the negative feedback of endogenous estrogens on the hypothalamopituitary axis resulting in increased gonadotrophin secretion (FSH and LH levels increase) and thereby induces ovulation. Thus in women with polycystic ovarian syndrome and anovulatory cycles, clomiphene effectively induces ovulation.

Side effects: Include ovarian hyperstimulation resulting in multiple pregnancies and ovarian cysts; also causes hot flashes, headaches, and skin rashes, and could increase the risk of ovarian tumors.

Clomiphene Citrate Uses:

1. Infertility: Infertility due to ovarian disorders—clomiphene is given orally 50 mg daily for 5 days starting from 2–5 days of the cycle; the course may be repeated for a few cycles till ovulation occurs.
2. In vitro fertilization: Clomiphene-induced ovulation is also useful in in vitro fertilization.
3. Cyclofenil: Cyclofenil is structurally similar to clomiphene and can be used to induce ovulation.

Selective Estrogen Receptor Down Regulators:

Fulvestrant:

• Fulvestrant an estrogen receptor antagonist has an affinity for both ER-α and ER-β receptors and blocks them.
• It acts as an antagonist in all tissues with estrogen receptors. The estrogen receptors are also degraded and downregulated because of which it is also called selective estrogen receptor down regulators (SERDs).
• It is given as IM depot preparation of 250 mg once a month.
• It can cause headaches, hot flashes, and nausea.

Fulvestrant Uses: Breast cancer resistant to tamoxifen.

Estrogen Synthesis Inhibitors

• GnRH agonists administered continuously suppress the biosynthesis of estrogens.
• Aminoglutethimide inhibits the synthesis of all steroids by inhibiting the activity of aromatase an enzyme involved in steroidogenesis.

• Aromatase inhibitors (AI): Aromatase is the enzyme that catalyses the final step in the synthesis of estrogen from testosterone.

Formastane and exemestane are steroid compounds that irreversibly inhibit aromatase, while anastrozole, letrozole, vorozole, and fadrozole are not steroids and the aromatase inhibition is reversible.

Antagonists of sex hormones and their uses;

Aromatase Inhibitors Advantages :

• Both circulatory and local estrogen levels drastically decline.
• Suppress even tamoxifen-resistant breast tumors.
• Do not increase the risk of thromboembolism or endometrial cancer.
• Orally effective.
• Anastrazole is long-acting.
• Exemastane in addition has weak androgenic activity.

Aromatase Inhibitors Uses:

Aromatase inhibitors are first-line drugs or adjuvants following mastectomy as well as for palliation in advanced breast cancers in postmenopausal women.

Progestins

Progesterone is the natural progestin synthesized in the ovary and placenta. It is also synthesized by the testis and adrenals where it acts as a precursor of various steroid hormones (see under corticosteroids). Synthetic progestins differ from natural progesterone in some properties.

Progestins Actions:

• Uterus: The secretory changes in the endometrium like increased tortuosity of the glands are due to progesterone. In pregnancy, decidual changes in the endometrium and maintenance of pregnancy (Progestin = favors pregnancy) require progesterone.
• Cervix: The watery cervical secretions are changed to a viscid scanty secretion by progesterone.
• Vagina: Vaginal epithelium changes to that seen in pregnancy.
• Mammary gland: Along with estrogen, progesterone is responsible for the development of the secretory apparatus in the breast and prepares the gland for lactation.
• Body temperature: An increase in the body temperature by 1°C during the luteal phase beginning at ovulation is due to progesterone.

Progestins Pharmacokinetics:

• Natural progesterones are rapidly absorbed but undergo high first-pass metabolism.
• Synthetic progestins are orally effective and have a longer t½.

Progestins Adverse effects:

• Headache, breast engorgement, rise in body temperature, edema, acne, and mood swings may be seen. Progesterone is teratogenic.
• Some progestins (nortestosterone derivatives) can cause virilization of the female fetus.
• Progestins with androgenic activity may cause weight gain, acne, and hirsutism.

Progestins Uses:

• Contraception
• Hormone replacement therapy (HRT): Progestins are combined with estrogens in HRT of postmenopausal women (given cyclically). Estrogen administration increases the risk of endometrial cancer—supplementing it with progestin counters this risk.
• Ovarian suppression: Progestins are used to suppress ovulation in Dysmenorrhea, endometriosis, Dysfunctional uterine bleeding (DUB), and Premenstrual syndrome.
• Threatened or habitual abortion: Efficacy.
• Endometrial carcinoma: High doses used in metastasis.
• To delay premature labor: Progestins have been tried and the results are encouraging.
• Endometrial hyperplasia: Progesterone administration for a long time—up to 1 year is used to suppress endometrial hyperplasia.
• Diagnostic: To test for estrogen secretion in women with amenorrhea, progesterone for 5 days should be followed by withdrawal bleeding, if estrogen levels are normal.
• Postponement of menstruation: The administration of progesterone in the 2nd half of the menstrual cycle prolongs the luteal phase and thereby postpones the beginning of menstruation. Norethisterone 5 mg is given orally—started early in the second half of the menstrual cycle. Higher doses are needed if started in the latter part of the second half of the cycle.

Other Progesterone Derivatives:

Danazol:

• Danazol is a derivative of 17α-methyltestosterone. It has weak progestational, androgenic, and glucocorticoid activities.
• It inhibits the midcycle surge (but not the basal secretion) of FSH and LH in women. This reduction of ovarian function results in atrophic changes in the endometrium.

Danazol Uses:

• Danazol is primarily used in the treatment of endometriosis. It is also used in menorrhagia, fibrocystic disease of the breast, and gynecomastia.
• Tried in some disorders of allergic etiology like idiopathic thrombocytopenic purpura, angioedema, hemophilia, and Christmas disease.

Danazol Side effects: Hot flushes, edema, weight gain, acne, headache, adrenal suppression, and hepatotoxicity.

Antiprogestins And Progesterone Receptor Modulators

Mifepristone:

• Mifepristone has anti progestational as well as anti-glucocorticoid activity. It binds to the progesterone receptors and blocks the actions of progesterone.
• It is a progesterone receptor modulator—acts as both a competitive antagonist and a partial agonist of progesterone receptors.
• When given in early pregnancy—abortion occurs.

Mifepristone Mechanisms of Action:

• Mifepristone blocks the progesterone receptors in the uterus which causes decidual breakdown; the blastocyst gets detached, and HCG and progesterone secretions fall.
• This in turn increases prostaglandin levels and stimulates uterine contractions. It also softens the cervix and facilitates the expulsion of the blastocyst.
• If given during the follicular phase—mifepristone prevents the midcycle surge of gonadotrophins and delays ovulation.
• Has luteolytic properties → may act as an emergency contraceptive.
• Mifepristone is also an antagonist at glucocorticoid receptors because of which it may be useful in Cushing’s syndrome, endometriosis, and breast cancer.

Mifepristone Pharmacokinetics: Given orally but bioavailability is low; t½ long (20–40 hours); excreted through the gut.

Mifepristone  Adverse effects:

• Nausea, vomiting, headache, and uterine cramps are common. Severe bleeding and infection can occur and require caution and immediate treatment.
• When used for termination of pregnancy, there is about a 1% chance of failure—curettage should be done in such cases.

Mifepristone Uses:

• Termination of pregnancy: Early pregnancy up to 9 weeks can be terminated with a single oral dose—600 mg of mifepristone followed 48 hours later by a prostaglandin to increase uterine contractions and facilitate expulsion of the blastocyst. The prostaglandin used may be oral misoprostol 400 mg or gemeprost 1mg vaginal pessary or sulprostone IM in. The combination has a success rate of >90%.
• Postcoital contraception: Mifepristone prevents implantation when given within 72 hours after coitus.
• Monthly contraception:
  • Mifepristone is used regularly in the late luteal phase—200 mg for 2 days after midcycle.
  • A single dose of 600 mg of mifepristone is taken on the 27th day of the cycle every month.
  • This should, not be used for long periods as a regular method of contraception.
• Uterine fibroids: Low-dose mifepristone 25–30 mg daily for 3 months reduces the size of the fibroid. This can be used to reduce blood loss till surgery is done.
• Ectopic pregnancy: Mifepristone is injected into the unruptured sac of ectopic pregnancy to discourage growth.
• Cervical ripening: In intrauterine fetal death given orally 1 day prior, mifepristone facilitates cervical ripening and softening of the cervix used for terminating intrauterine death.
• Cushing’s syndrome: Mifepristone is useful due to its anti glucocorticoid effects.

Mifepristone Contraindications:

• Women are on long-term glucocorticoid therapy because of its anti-glutocorticoid activity.
• Caution is required in women having anemia or receiving anticoagulants because it can cause heavy bleeding which could be dangerous.
• Onapristone: Onapristone i is a pure progesterone antagonist. Lilopristone is similar to mifepristone.
• Ulipristal:  A selective progesterone receptor modulator (SPRM) inhibits ovulation and has been approved for use as an emergency contraceptive.

Drugs Used In The Treatment Of Menopausal Symptoms:

Drugs used include: Hormonal agents and Nonhormonal agents

• Estrogen
• Tibolone
• Progesterone
• Clonidine
• Propranolol
• Veralipride
• SSRIs

Hormonal agents:

• HRT with estrogen reverses menopausal symptoms and reduces the risk of osteoporosis and cardiovascular disease, but using estrogen alone can increase the risk of endometrial carcinoma and may stimulate the growth of uterine fibroids.
• The addition of progestin counters these unwanted effects. Hence a combination of estrogen and progestin has been recommended for HRT at menopause.
• Various regimens with cyclic and continuous estrogens and progestins have been tried. If withdrawal bleeding is undesirable, the hormones are given continuously. They may be given orally or as transdermal patches or subcutaneous implants.
• HRT is now recommended only for women who undergo premature menopause and for the treatment of vasomotor symptoms of menopause.

Tibolone:

• Tibolone is a synthetic steroid that has effects like both estrogen and progesterone with weak androgenic properties. It is found to reduce the symptoms of estrogen deficiency in menopause with endometrial stimulation.
• Osteoporosis and vasomotor symptoms subside but it can cause weight gain.
• Dose: 2.5 mg daily.

Nonhormonal agents:

• Clonidine, an α-adrenergic agonist, and veralipride, a dopamine antagonist, can reduce hot flashes. Propranolol can be used to overcome palpitations.
• SSRIs like fluoxetine or sertraline may be tried for vasomotor symptoms.

Hormonal Contraceptives

• Millions of women around the world use hormonal contraceptives making them one of the most widely used drugs. When properly used, they are the most effective spacing methods of contraception.
• Regimen Estrogen + Progestin dose Duration (in days) and trade name combination and progesterone-only preparations.

Hormonal contraceptives include:

Combined Hormonal Contraceptives

• Combined pills contain low doses of estrogen and progestin. They are highly efficacious(success rate 98%). Ethinylestradiol and mestranol (in a dose of 20–50 mcg) are the estrogens used.
• Newer progestins like desogestrel and norgestimate cause the least side effects, ensure prompt withdrawal bleeding and also counter the increased risk of endometrial cancer due to estrogen

Oral Pills

1. Monophasic: The pill is started on the 5th day of the menstrual cycle, taken daily for 21 days followed by a gap of 7 days during which bleeding occurs. This is a monophasic regimen.
2. Biphasic: Estrogens for 10 days followed by progestin for the next 11 days. Because of the risk of endometrial cancer, biphasic pills are not preferred.
3. Triphasic: Low doses of estrogen with a progestin → very effective with least side effects.

Oral Pills Use:

• If a woman misses a pill, she should take 2 pills the next day and continue the course. If more than 2 pills are missed, then that course should be withdrawn, and an alternative method of contraception for that particular cycle, and the course on the 5th day of the next menstrual cycle.
• If the woman has conceived, pregnancy should be terminated as these hormones are teratogenic. However, recent studies have shown that in such low doses, the hormones are not teratogenic.

Parenteral Combined Contraceptives:

• Combined injectable contraceptives:  An estrogen with a progestogen is injected at monthly intervals. They are highly effective with side effects similar to progesterone-only implants. They are better tolerated but further reports of long-term effects on reversal of ovulation are yet to be available.
• Transdermal contraceptives: A transdermal patch containing progestin and ethinyl estradiol is applied once a week for 3 weeks and the next week withdrawal bleeding follows. It has the advantage of better compliance.
• Vaginal rings: Containing levonorgestrel are placed in the vagina for 3 weeks of the cycle and then removed for 1 week. The hormone is absorbed gradually through the vaginal mucosa. The advantage is the need for a low dose of the hormone because the first-pass metabolism is avoided.

Progestin-Only Contraceptives

Minipill: A low-dose progestin is taken daily without a gap (75 mg norgestrel). Estrogen and its accompanying long-term adverse effects are thus avoided, but efficacy is lower, menstrual cycles may be irregular and is, therefore, not popular.

Progestin injections: Depot preparations contain progestin and are given as:

• Intramuscular injections: Intramuscular injections at 3–6 months intervals, for example, Depot medroxyprogesterone acetate (DMPA) 150 mg every 3 months injected IM or norethisterone enantate 200 mg (NETEN).
• Ovulation: Ovulation is inhibited for about 14 weeks. Long-term use of DMPA reduces menstrual blood loss and risk of endometrial carcinoma.
• Subcutaneous implants: Capsules containing norgestrel are (NORPLANT capsules) implanted subcutaneously in the forearm or upper arm. A low dose of progestin is released and the effect can last up to 5 years. Since the progestin levels are low, adverse effects like altered lipoprotein and carbohydrate metabolism are insignificant.
• Intrauterine device: A progestagen impregnated with progesterone is introduced into the uterus. It releases a low dose of progesterone locally for up to 5 years (MARINA).

Parenteral Progestins Disadvantages:

• Amenorrhea is common.
• Unpredictable bleeding or spotting.
• Disruption of the menstrual cycle.
• Suppression of ovulation may continue up to 18 months after the last injection. Thus long time is required for the return of fertility.
• Suppression of estrogen secretion may result in reduced bone density—but is reversible.

Postcoital Contraceptives

Question 19. Write a short note on postcoital contraceptives.
Answer:

The following may be used for postcoital contraception:

1. Combination: Combination of low doses of estrogen and progestins—two tablets containing ethinyl estradiol (100 mg) and a progestin levonorgestrel 0.5 mg are given as soon as possible (within 72 hours of coitus 2 tablets of OVRAL-G). They can cause nausea and vomiting and have an efficacy of 90–98%. The dose is repeated after 12 hours. It is called the YUZPe method.
2. Levonorgestrel: Levonorgestrel alone is also effective and commonly used (iPILL—1.5 mg single dose within 72 hours after coitus).
3. Mifepristone: Mifepristone 600 mg prevents implantation when given within 72 hours after coitus, followed 48 hours later by 400 mg misoprostol to improve the success rate.
4. Methotrexate: Methotrexate (50 mg/m2) given orally or IM effectively induces abortion in the first trimester. Being a folic acid antagonist and also because its active metabolite gets concentrated in the placenta, methotrexate acts as an abortifacient. Misoprostol is added to promote uterine motility.
5. Ulipristal: Ulipristal 30 mg orally within 5 days of coitus is effective.
6. Insertion of an intrauterine device (IUD) like copper-T within 5 days of coitus can prevent implantation and thereby prevent pregnancy.
7. A high dose of estrogen (stilbestrol—25 mg daily for 5 days) was used earlier but this may cause severe nausea and vomiting and hence generally not preferred. If the pills are expelled in vomiting, they need to be repeated.

Postcoital pills act by preventing implantation. The earlier they are started the better their efficacy. If postcoital pills fail, pregnancy should be terminated by other methods because oral contraceptives are likely to be teratogenic. Postcoital contraception is used as an emergency method in situations following rape or contraceptive failure and should not be routinely used.

Mechanism Of Action Of Hormonal Contraceptives:

Combined pills act by multiple mechanisms

1. Estrogens suppress FSH release by negative feedback on the pituitary. As a result, the ovarian follicle fails to develop.
2. They prevent ovulation—by negative feedback on the hypothalamus. Progesterone decreases GnRH pulses and thereby midcycle LH surge which is essential for ovulation.
3. Progesterone renders the cervical mucus thick and unfavorable for sperm penetration.
4. They alter the uterine endometrium making it unfavorable for implantation.
5. OCs inhibit the coordinated contractions of the cervix, uterus, and fallopian tubes which are required for transport of the ovum, and sperm as well as for fertilization and implantation.

Postcoital Contraceptives Pharmacological Effects

• Hormonal contraceptives (HC) inhibit gonadotrophin secretion, and suppress ovarian function, and on prolonged use the size of the ovaries may be reduced.
• On stopping them, 95% of women have regular cycles in about 2–3 months. Cervical hypertrophy may be present and the cervical mucus gets thick and scanty.
• The endometrium shows glandular atrophy and,
  therefore, less menstrual bleeding. Slight enlargement of the breasts may be seen.
• An increase in the clotting factors 7, 8, 9, and 10 and a decrease in antithrombin 3.
• Carbohydrate absorption from the gut is slower while insulin levels are slightly increased.
• There is a slight increase in cardiac output, heart rate, and BP. Increased plasma renin activity with salt and water retention contributes to hypertension.
• All changes are reversible on stopping the HC.
• Skin pigmentation particularly on exposure to sun may be seen in some women.

Postcoital Contraceptives Adverse Effects:

Milder effects:

• Headache may be mild and may subside on continued treatment. Migraine headaches in some women may require HC discontinuation. Nausea, vomiting, edema, breast tenderness, amenorrhea, and irregular menstrual cycles may occur.
• Weight gain, acne, mood swings, and hirsutism may occur.

More severe side effects:

1. Cardiovascular effects: In women above 35 years, HCs may increase the coagulability of blood, and increase the risk of venous thrombosis and pulmonary embolism. The risk of thromboembolism is higher in women with predisposing factors like genetic susceptibility:
   • Myocardial infarction: Women with other risk factors for MI (like cigarette smoking, obesity, and diabetes mellitus) have a slightly higher chance of developing MI.
   • Cerebrovascular disease: The risk of stroke is marginally higher among older women.
   • Hypertension: High-dose preparations may lead to hypertension but the newer low-dose preparations are safer.
2. Cancers: Long-term use of HCs may increase the incidence of cervical and breast cancers— but the risk is not significant.
3. Cholestatic jaundice and gallstones: Genetically predisposed women may develop cholestatic jaundice and the incidence of cholecystitis, gallstones, cholangitis, and hepatic adenomas is higher.
4. Impaired glucose tolerance: HCs may impair glucose tolerance—but the newer low-dose preparations do not carry such risk.
5. Depression: Mood swings may be noted; depression can occur in a small percentage of women and when significant, HCs should be withdrawn.

Contraindications to cobined Pill:

• Thromboembolic and cerebrovascular disease
• Liver disease
• Breast cancers
• Used with caution in diabetes, hypertension, convulsive disorders, edema, and CCF.

Other Uses of Combined Preparations:

• Hormone replacement therapy: Discussed earlier.
• DUB: Progestin in preferred for DUB but, low dose combined preparations may be used.
• Endometriosis: Combined pills may be used continuously to induce atrophy of the endometriotic tissues. Amenorrhea is produced.
• Postponement of menstruation: Combined pills are started → 2 tablets daily 3–6 days prior to the expected date of menstruation and continued till desired. Menstruation occurs 2–3 days after stopping the drug. Higher doses may cause nausea and vomiting. Alternatively, start low dose combined pill on days 7–10 (1 tab daily) and continue throughout the cycle, and stop it when menstruation is desired.
• Premenstrual syndrome: OC pills are used to suppress ovulation and continue for 3–6 cycles.
• Dysmenorrhea: If analgesics cannot be used, OC pills may be given for 3–4 cycles.
• Idiopathic hirsutism: Cyclic therapy with combined pills is useful.

Benefits Of Combined Pills:

• An effective and convenient method of contraception.
• Reduced risk of ovarian cancers (reduced ovarian stimulation of gonadotrophins as ovulation is also suppressed).
• Reduced risk of endometrial cancers (progesterone antagonizes the endometrial proliferation induced by estrogens).
• Reduced incidence of pelvic inflammatory disease and ectopic pregnancy.
• Menstrual benefits—less menstrual blood loss, less iron deficiency, premenstrual tension, and dysmenorrhea are less intense.

Centchroman

• Centchroman or ormeloxifene (a SERM) a chroman derivative, is a nonsteroidal, nonhormonal, oral contraceptive developed in India. It has antiestrogenic and antiprogestogenic activity and acts by preventing implantation.
• The onset of action is quick (<60 minutes) and the duration of action is 7 days.

Preparations and dose:

30 mg twice a week for 3 months followed by once a week till contraception is desired (the tablet should be continued without withdrawing for menstruation).

• Saheli, Centron.
• Clinical Pearl

Centchroman Advantages:

• The success rate claimed is 97–99%.
• No side effects of HCs like nausea and effects on blood coagulation.
• Long t½ → once a week use.
• No teratogenicity, carcinogenicity, or mutagenicity was reported.
• Return of fertility is faster.
• Well-tolerated.

Centchroman Disadvantages:

• May cause prolongation of menstrual cycles (in 10% of women).
• May cause ovarian enlargement → avoided in polycystic ovaries.
• Should be avoided in renal and hepatic dysfunction, tuberculosis, and in lactation.

Clinical Pearl:

• For most indications, a combination of estrogen and progesterone is used.
• Fertility returns within 1–2 months of discontinuing OCPs. However, with injectable contraceptives, the return of fertility takes several months.
• Routine use of mifepristone—misoprostol as a regular method of contraception is not advisable.
• Birth control vaccines (hCG vaccines) are under trial.

Androgens

Physiological Considerations:

Androgens are produced chiefly in the testis and small amounts in the adrenal cortex. In females, small amounts of androgens are produced in the ovary and adrenal cortex. Androgens are synthesized from cholesterol

Androgens include:

• Natural: Testosterone, dihydrotestosterone.
• Synthetic: Methyltestosterone, fluoxymesterone, testosterone enanthate, testosterone cypionate.
• Anabolic steroids: Oxandralone, nandrolone decanoate, stanozolol, methandienone.

Testosterone is the most important natural androgen. In the adult male, 8–10 mg of testosterone is produced daily. Secretion is regulated by gonadotrophins and GnRH.

Androgens Physiological actions:

• In males, testosterone is essential for the development of secondary sexual characters and sex organs, for normal spermatogenesis, and for maintaining sexual function in men.
• Testosterone promotes bone growth, enhances muscle mass, protein synthesis, and positive nitrogen balance—has anabolic actions. It also promotes erythropoiesis.

Androgens Mechanism of action:

Androgens bind to androgen receptors on the target cells, similar to other steroids, the complex moves to the nucleus where it stimulates protein synthesis.

Designer Steroids:

Designer steroids are developed in an attempt to obtain compounds with more selective anabolic activity on the androgen receptors, for example, Norbolethone, desoxymethyltestosterone (DMT), and tetrahydrogestrinone. Designer steroids are, however, abused as they may not be detected by routine doping tests.

Androgens Pharmacokinetics:

• Testosterone is given parenterally (IM).
• Testosterone pellets implanted subcutaneously can act for 6–8 months. Topical preparations to be applied over the scrotum daily gel and transdermal patch.

Androgens Adverse effects:

• Masculinization and acne in females; hepatotoxicity, increased libido, and precocious puberty can occur in young boys.
• With large doses, of salt and water retention, suppression of spermatogenesis resulting in infertility can be seen.
• Feminizing effects like gynecomastia in men can occur as some androgens are converted to estrogens.

Androgens Uses:

• Testicular failure: For androgen replacement therapy in testicular failure.
• Other uses: Senile osteoporosis and carcinoma of the breast in premenopausal women.

Anabolic Steroids

Question 20. Short note: Anabolic steroids.
Answer:

Anabolic steroids are synthetic androgens with higher anabolic and low androgenic activity. These are believed to increase protein synthesis and muscle mass. But with higher doses, the relative anabolic activity is lost

Preparations Of Anabolic Steroids:

Anabolic Steroids Adverse effects:

Anabolic steroids are similar to those caused by androgens.

Anabolic Steroids Uses:

• Catabolic states: Anabolic steroids may help patients following surgery, trauma, prolonged illness, and debilitating conditions.
• Given during convalescence, the negative nitrogen balance is corrected, appetite improves and there is a feeling of well-being.
• Senile osteoporosis in elderly males responds by the formation of new bone tissue.
• Growth stimulation in children: Anabolic steroids promote linear growth in prepubertal boys, particularly in delayed puberty but the actual benefit on final height is not established.
• Other uses:
  • Chronic renal failure:  Anabolic steroids may reduce nitrogen load on the kidneys.
  • Anemia:  Refractory anemias with bone marrow failure may respond.
  • Testosterone production decreases with age and when replaced may show an improvement in all parameters including lean body mass but further studies are needed to prove long-term safety.

Abuse In Athletes

• Anabolic steroids enjoy a reputation for improving athletic performance. When combined with adequate exercise, the muscle mass increases.
• However, the dose used by athletes is very high and is associated with serious adverse effects like testicular atrophy, sterility, and gynecomastia in men and virilizing effects in women; increased aggressiveness, psychotic symptoms, and increased risk of coronary heart disease in both sexes.
• Moreover, there is no evidence that athletic performance improves. Hence the use of anabolic steroids by athletes has been banned and is medically not recommended.

Contraindications for the use of androgens:

• Pregnancy
• Carcinoma of prostate/breast in males
• Infants and children
• Renal/cardiac/liver disease.

Antiandrogens

Cyproterone acetate a derivative of progesterone competitively binds to androgen receptors and thus blocks the actions of androgens. It also has progestational activity.

Cyproterone is used:

• To treat severe hypersexuality in males,
• In carcinoma prostate and
• In female hirsutism—used along with estrogen.

Flutamide, bicalutamide, nilutamide and enzalutamide are potent competitive antagonists at androgen receptors. They can cause gynecomastia, mastalgia, and hepatotoxicity. These antiandrogens are used with a GnRH analog/leuprolide in the treatment of carcinoma prostate.

Finasteride and dutasteride inhibit the enzyme 5-alpha-reductase and inhibit the conversion of testosterone to its active metabolite.

Cyproterone Uses:

• Benign prostatic hypertrophy (BPH) to reduce the prostate size. They may be combined
• Male pattern baldness—fairly good results but it requires continued use as the effect may be reversed in 6–12 months after stopping the drug. Side effects include decreased libido and impotence.
• Finasteride with estrogen and cyproterone in the treatment of hirsutism.
• Prevention of prostatic cancer—dutasteride is tried as it is longer acting.

Male Contraceptives

• The requirement of a safe and effective chemical contraceptive in men has not been fulfilled largely because it is difficult to totally suppress spermatogenesis.
• Various compounds including testosterone with progestin, estrogens with progestins, and antiandrogens like cyproterone acetate have been tried, but are neither reliable nor safe.
• GnRH agonists and antagonists along with testosterone inhibit gonadotrophin secretion and are being studied. Gossypol, a cotton seed derivative, has been shown to produce oligozoospermia and impair sperm motility in Chinese studies.
• This effect is reversible in a few months. Hypokalemia is the major adverse effect.

Drugs Used In Male Sexual Impotence

Sexual impotence is the inability of a man to have satisfactory sexual intercourse due to the inability to have and maintain an erection. Very often it is psychological while in some cases there could be an organic cause. Nitric oxide is released which activates guanylyl cyclase leading to increased synthesis of cGMP resulting in smooth muscle relaxation in the corpora cavernosa.

Hence drugs that enhance cGMP are useful in patients with erectile dysfunction.

Drugs For Impotence

• PDE5 inhibitors: Sildenafil, vardenafil, tadalafil
• Others: Alprostadil, phentermine, yohimbine, SSRIs, testosterone

Sildenafil:

• Sildenafil (popular as Viagra) inhibits the enzyme phosphodiesterase-5 (PDE5) in the penis and thus prolongs the life of cyclic GMP.
• This causes relaxation of smooth muscle in the corpus cavernosum and vasodilation—both resulting in cavernosal engorgement and penile erection.
• Sildenafil is given orally.

Dose:

• 50–100 mg 1 hour before sexual activity.
• Suhagra, Adams Delite 25, 50, 100 mg tab.
• Tadalafil 10, 20 mg tab.

Sildenafil Adverse effects and precautions:

Due to vasodilation—headache, dizziness, and nasal stuffiness can occur. It potentiates the hypotensive action of nitrates and is contraindicated in patients on nitrates and in patients with coronary artery disease. Elderly men above 60 years need less dose (25 mg). Patients with liver and kidney disease, bleeding disorders, and elderly people are at a higher risk of toxicity. Several deaths have been reported in such patients.

Sildenafil Other uses:

• Pulmonary arterial hypertension and systemic hypertension.
• It could prevent cardiac remodeling in patients with IHD.
• Sildenafil has been tried in cystic fibrosis and Benign prostatic hyperplasia.

Alprostadil:

• Alprostadil is a PGE₁ analog that can be injected directly into the cavernous. It can also be used as a mini suppository placed in the urethra and it diffuses into the cavernosal tissue.
• Alprostadil is used in patients who do not respond to sildenafil or in whom sildenafil cannot be used.

Phentolamine:

• Phentolamine  An alpha-blocker, can also be injected into the cavernosal with or without papaverine—called phentolamine/papaverine-induced penile erection (PIPE therapy).
• However, it is not preferred because of the inconvenience of the route of administration and complications.

Insulin And Oral Antidiabetic Drugs

Diabetes mellitus (DM):

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia and altered metabolism of carbohydrates, lipids and proteins. It is a common condition affecting 1– 2% of the

population with a strong hereditary tendency.

DM is now classified into four types:

Prolonged complications of hyperglycemia are—premature atherosclerosis, retinopathy, nephropathy, and gangrene of the limbs.

Insulin:

In 1921, Banting and Best first obtained insulin in the form of pancreatic extract. In 1922, an extract containing insulin was first used on a 14-year-old boy Thomson suffering from severe diabetes mellitus with excellent response.

Chemistry, Synthesis, And Secretion:

• Insulin is a polypeptide synthesized from the precursor preproinsulin to proinsulin. Proinsulin is processed in the secretory granules to get insulin.
• Insulin has two peptide chains—A chain (21 amino acids) and B chain (30 amino acids) linked by disulfide bridges. Human insulin differs from bovine insulin by 3 amino acids and from porcine insulin by 1 amino acid → hence porcine insulin is closer to human insulin.
• Insulin is stored in granules in the β islet cells of the pancreas. The normal pancreas releases about 40–50 units of insulin every day. Basal insulin secretion is 0.5–1 U/hr and increases after meals up to 6 U/hr.
• The secretion is regulated by factors like food, hormones, and the autonomic nervous system.
• Hypokalemia inhibits insulin release. Blood glucose concentration is the main factor that determines insulin secretion.
• Glucose transporters are proteins present in different tissues. They are of 5 subtypes of GLUT1 to GLUT5.
• They mediate various functions, for example, GLUT4 present in muscle and adipose tissues promotes the uptake of glucose.

Actions Of Insulin:

Question 21. Explain briefly the actions, mechanism of action, and side effects of insulin.
Answer:

Carbohydrate metabolism:

• Insulin stimulates the uptake and metabolism of glucose in the peripheral tissues especially skeletal muscles and adipose tissue.
• It inhibits glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis.
• By the above actions, insulin lowers the blood glucose concentration.

Lipid metabolism:

• Insulin inhibits lipolysis in adipose tissue and promotes the synthesis of triglycerides. In diabetes, large amounts of fat are broken down.
• The free fatty acids so formed are converted by the liver to acetyl-COA and then ketone bodies. This results in ketonemia and ketonuria.
• Insulin indirectly increases lipoprotein lipase activity resulting in increased clearance of VLDL and chylomicrons. In insulin deficiency, there is hypertriglyceridemia.

Protein metabolism:

• Insulin facilitates amino acid uptake and protein synthesis and inhibits protein breakdown anabolic effect.
• In diabetes, there is an increased catabolic effect and negative nitrogen balance.

Insulin Mechanism of action:

• Insulin activates specific receptors present in almost all cells in the body.
• The insulin receptor is a glycoprotein made up of two α and two β subunits. Insulin binds to the α subunit of the receptors present on the surface of target cells. This binding stimulates tyrosine kinase activity in the β subunit.
• This in turn activates a series of phosphorylation and dephosphorylation reactions which stimulate or inhibit the enzymes involved in the metabolic actions of insulin.

Side Effects/Complications of Insulin Therapy

1. Hypoglycemia:

• Hypoglycemia is the most common complication of insulin therapy. It may be due to too large a dose, inappropriate time of administration, unusually small meals or vigorous exercise, or simply by intensive efforts to reduce hyperglycemia.
• Severe hypoglycemia may result in convulsions and coma due to cerebral glucopenia.

Treatment: Oral glucose or fruit juice like orange juice or in severe cases IV 50 mL of 50% dextrose promptly reverses the symptoms.

2. Allergy:

Due to the contaminating proteins—urticaria, angioedema, and rarely anaphylaxis can occur. It is rare with purified preparations and human insulin.

3. Lipodystrophy:

• Atrophy of the subcutaneous fat at the site of injection may be due to the immune response to contaminating proteins.
• Lipohypertrophy, i.e. enlargement of subcutaneous tissue can also occur due to the local action of insulin. Insulin absorption may be irregular in such areas.
• This can be prevented by frequently changing the sites of injection.
• Lipodystrophy is rare with purified preparations and human insulin.

4. Edema: Some severe diabetics develop edema which is self-limiting.

Preparations Of Insulin:

Question 22. Write a short note on insulin preparations.
Answer:

Preparations of insulin can be classified in 2 ways based on:

1. Duration of action
2. Source

• Insulins are destroyed by the acidic pH of gastric juice when given orally—hence all preparations are given subcutaneously. Doses are expressed as units.
• Regular insulin is soluble or plain insulin: Which is mixed with a small amount of zinc. It can be given by SC, IV, and IM injection but is the only insulin preparation that can be given IV.
  • The insulin molecules bind to form hexamers in the vial which on injection gradually dissociate into monomers to get absorbed.
  • Hence regular insulin should be administered 30 minutes before food. On IV use, the hexamers immediately dissociate into monomers and are, therefore, useful in emergencies

Preparations of Insulin:

• Intermediate and longer-acting preparations:
  • Intermediate and longer are obtained by mixing regular insulin with protamine or zinc.
  • Neutral protamine Hagedorn (NPH or isophane insulin) is neutral in pH with added protamine. It acts for 18–24 hours.
  • Protamine zinc insulin (PZI) has both protamine and zinc for a long duration of action.
  • Long-acting insulin analogs are preferred now.

Lente insulins:

• Insulin zinc suspension in different ratios and particle sizes results in lente preparations.
• Semilente is short-acting, lente is intermediate-acting and ultra lente is long-acting.

Insulin dose:

• The requirement for insulin should be calculated in each patient by monitoring blood glucose and glycosylated hemoglobin levels.
• Multiple doses of insulin control blood glucose better as compared to single bedtime doses.
• The daily requirement of insulin varies from 0.2 to 1.6 IU/kg. In obese patients, the requirement is higher.

Based on the source, insulins are grouped as:

1. Conventional preparations:

Conventional preparations Obtained from bovine and porcine pancreas have the disadvantages of being allergenic and poorly stable. Hence, are no more preferred.

2. Highly purified insulins:

Highly purified insulins are mostly porcine insulins purified by more developed purification techniques. The contaminating protein content is negligible. They are available in short- and long-acting forms and have the following advantages over conventional insulins:

• They are less antigenic
• More stable
• Lesser chances of resistance
• Lesser chances of lipodystrophy.

3. Human insulins:

Human insulins are the most commonly used insulins now—produced by recombinant DNA technology and available as regular and long-acting (NPH) preparations. Human insulin is less immunogenic and is absorbed more rapidly; the dose needed is lesser (~10%).

Question 23. Write brief/short notes on insulin analogs.
Answer:

1. Insulin analogs:

Minor modifications of the position of amino acids in the insulin molecule can give insulin analogs.

Such analogs have some advantages over original insulins like:

• Favorable pharmacokinetic profile
• Better blood glucose control than with natural insulins
• Rapid-acting analogs produce rapid insulin peaks which closely mimic physiological insulin release.

Rapid and short-acting insulin analogs act much faster than regular insulin.

When injected Such rapid peaks resemble the physiological release of insulin.

They are absorbed 3 times faster than human insulin—therefore, can be given subcutaneously 10 minutes before food; and have lesser chances of hypoglycemia. Insulin lispro, insulin aspart, and insulin glulisine are rapid- and short-acting with a maximum duration of action of 4–5 hours. Absorption is reliable.

• Insulin lispro: Insulin lispro differs from human insulin by the transposition of two amino acids— proline and lysine in the β chain—hence the name lispro. On SC administration, the onset of action is in 10–15 minutes and the peak effect is 1 hour. Glycemic control is better and 20– 30% lesser incidence of hypoglycemia compared to regular insulins.
• Insulin Aspart:  Insulin aspart is obtained by substituting aspartic acid in place of proline in the β chain.
• Insulin glulisine: Insulin glulisine is formed by substituting glutamic acid for lysine and lysine for asparagine. It is the analog used in insulin pumps. Both insulin aspart and glulisine are similar to insulin lispro.

2. Long-Acting Insulin Analogs:

Insulin glargine:

• Insulin glargine is a long-acting analog that acts for 24 hours. The effect is peakless but attains a broad plasma concentration plateau. Obtained by adding 2 arginine molecules to the beta chain and replacing glycine for asparagine.
• On SC injection, glargine molecules dissolve gradually and provide a low but steady concentration of insulin in the plasma over 24 hours.
• Insulin glargine should not be mixed with any other insulin in the syringe because it is acidic and there is a risk of loss of efficacy of the other drugs.

Insulin detemir:

• Insulin detemir is obtained by attaching myristic acid, a fatty acid, to the terminal lysine, and from the B30 position, the terminal threonine is removed.
• It has an onset of action of 1–2 hours and is given twice daily for smoother control of blood sugar and a lower incidence of hypoglycemic episodes. It should not be mixed with any other insulins.

Insulin degludec:

• Insulin degludec is similar to human insulin with minor modifications like the deletion of the last amino acid from the B chain and the addition of a glutamyl link from Lys B29.
• It is long-acting (>40 hr) and is also compatible with rapid-acting insulins—it can be mixed with them.

3. Insulin mixtures:

Mixtures of short-, intermediate- and long-acting preparations are given for rapid onset and long duration of action. Such readymade mixtures are available, for example, Glargine once a day + one dose of rapid-acting insulin like Lispro before each meal.

Insulin Delivery Devices

• Devices have been designed which make insulin administration more convenient. Pen injectors are small pen-size devices containing multiple doses of insulin and retractable needles and they can be carried.
• Insulin pumps (also called continuous subcutaneous insulin infusion or CSII) deliver appropriate doses of insulin on the basis of self-monitored blood glucose results. The set is inserted subcutaneously.

Alternative routes of insulin delivery have been studied—by inhalation, nasal spray, orally, rectally, and as subcutaneous pellet implants.

Insulin Delivery Devices Drug Interactions:

1. b-blockers + insulin

2. Salicylates, lithium, and theophylline precipitate hypoglycemia by increasing insulin secretion and β cell sensitivity to glucose.

3. Drugs that cause hyperglycemia—glucocorticoids, diuretics, diazoxide, phenytoin, and adrenaline → counter the effects of antidiabetics.

Treatment Of Diabetic Ketoacidosis

Question 24. Short note: Treatment of diabatic ketoacidosis.
Answer:

Diabetic ketoacidosis:

• Diabetic ketoacidosis is a medical emergency and can be life-threatening. It is more common in patients with IDDM.
• Ketoacidosis may be precipitated by infection, trauma, stress or high doses of glucocorticoids.
• Insulin deficiency results in severe hyperglycemia (600–800 mg/dL) and excessive production of ketone bodies.

Diabetic ketoacidosis  Clinical features:

• Metabolic acidosis, dehydration with loss of sodium and potassium in the urine causing electrolyte imbalance, nausea, vomiting, abdominal pain, confusion, impaired consciousness, and hyperventilation—may proceed to coma. Ketone bodies in blood and urine increased.

Diabetic ketoacidosis  Treatment:

• Correction of hyperglycemia: Intravenous regular (plane) insulin 0.1U/kg bolus followed by 0.1 U/kg/hour by continuous IV infusion till the patient recovers. Once the patient fully recovers, SC insulin should be administered 30 minutes before stopping the infusion.
• Correction of dehydration: Fluid and electrolyte replacement is important. Normal saline infusion—1 liter in the first hour and then based on the severity of dehydration.
• Correction of acidosis: Sodium bicarbonate may be needed in.
• Potassium: Rapid correction of hyperglycemia may result in the movement of potassium into the cells resulting in hypokalemia. 10–20 mEq /hour potassium chloride is added to the drip. When serum phosphate is also low, potassium biphosphate may be given to supplement both potassium and phosphorus. ECG monitoring is needed.
• Blood glucose: Blood glucose may come down to normal but ketosis requires a longer time to be corrected and requires adequate insulin. Hence when the blood glucose comes down to about 300 mg/dL, it may be needed to add glucose with insulin till the clearance of ketone bodies.

Treatment of hyperglycemic, hyperosmolar, nonketotic coma: Severe hyperglycemia and glycosuria result in severe dehydration and increased plasma osmolarity leading to mental confusion, sometimes convulsions and coma, and has a high mortality rate. The treatment is similar to ketoacidosis with immediate correction of fluid and electrolyte balance and regular insulin.

Question 25. What is insulin resistance? Write briefly on insulin resistance.
Answer:

Insulin resistance:

Insulin resistance is said to be present when the insulin requirement is increased to >200 U/day. Many consider insulin requirements of >100 U/day as resistance.

Keybox 1: Drugs that cause hyperglycemia and hypoglycemia.

• Drugs that can cause hyperglycemia
• Diazoxide, phenytoin, thiazides, b-adrenergic agonists
• Hormones—adrenaline, glucagon, thyroid hormones, glucocorticoids
• Drugs that can cause hypoglycemia
• Quinine
• Lithium
• Alcohol
• Pentamidine

Insulin resistance is said to be present when the insulin requirement is increased to >200 U/day. Many consider insulin requirements of >100 U/day as resistance.

• Acute resistance develops Quickly but it is of short duration and reversible. It may be precipitated by factors like infection, stress including emotional and physical stress (trauma, surgery), or drugs that cause hyperglycemia.
• Once the precipitating factor is treated, the requirement for insulin decreases.
• Chronic resistance develops over years of insulin use. It is due to the antibodies to insulin, contaminants and other added constituents like protamine.
• In the presence of resistance, change over to highly purified/human insulin, if the patient is receiving conventional insulin.
• Most patients need regular insulin for some time till the resistance is overcome.
• Other precipitating factors should be corrected. In some patients, immunosuppression with glucocorticoids like prednisolone may help. Pregnancy and hormonal contraceptives can induce insulin resistance.

Oral Antidiabetic Drugs

Question 26. Classify oral antidiabetic drugs. Write the mechanism of action and adverse effects of any two.
Answer:

The main disadvantage of insulin is the need for injection. The introduction of oral antidiabetics is a boon to millions of patients with early and mild diabetes mellitus.

Oral Antidiabetic Drugs Classification:

1.  Insulin secretagogues
   • Sulfonylureas (KATP channel blockers)
     • 1 generation: Tolbutamide
     • 2 generation: Glibenclamide, glipizide, gliclazide, glimepiride
   • Meglitinides: Repaglinide, nateglinide
   • GLP-1 analogs (subcutaneous): Exenatide, liraglutide, albiglutide, dulaglutide
   • DPP-4 inhibitors: Sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin
2. Biguanide: Metformin
3. Thiazolidinediones: Troglitazone, pioglitazone
4. Alpha glucosidase inhibitors: Acarbose, miglitol, voglibose
5. Amylin analog: Pramlintide (subcutaneous)
6. SGLT-2 inhibitors: Dapagliflozin, remogliflozin

Insulin Secretagogues:

Question 27. Write short notes on sulfonylureas.
Answer:

 1. Sulfonylureas:

• A sulfonamide derivative used for its antibacterial effects in typhoid patients produced hypoglycemia.
• This observation led to the development of sulfonylureas.
• These drugs increase insulin release → insulin secretagogues.

 Sulfonylureas Mechanism of action:

• Sulfonylureas reduce the blood glucose level by:
• Stimulating the release of insulin from the pancreatic β cells.
• Increasing the sensitivity of peripheral tissues to insulin.
• Increasing the number of insulin receptors.
• Suppressing hepatic gluconeogenesis.

Prolonged use reduces glucagon levels probably due to negative feedback from raised insulin levels.

• Sulfonylureas bind to the sulfonylurea receptors (SUR) which are nothing but the ATP-sensitive K⁺ channels (K_ATP) present on the cell membrane of the pancreatic beta cells.
• Sulfonylureas bind to the SUR1 subunit on the KATP and bring about the closure of these K⁺ channels (prevent K⁺ efflux) causing depolarization of the membrane.
• This in turn opens the voltage-dependent calcium channels, thereby leading to calcium influx.
• This calcium brings about the release of insulin that is stored in the granules of the beta cells.

 Sulfonylureas Pharmacokinetics:

• Sulfonylureas are well absorbed orally, extensively bound to plasma proteins (>90%), metabolized in the liver and some are excreted in the urine.
• Hence they should be avoided in patients with renal or liver dysfunction.

 Sulfonylureas Adverse effects: Second-generation agents have fewer adverse effects:

• Hypoglycemia is the most common side effect, least with tolbutamide due to short t½ and low potency.
• Nausea, vomiting, jaundice, and allergic reactions can occur.
• Sulfonylureas can precipitate a disulfiram-like reaction on the consumption of alcohol. Patients should be warned to avoid alcohol while on sulfonylureas.

 Sulfonylureas Drug Interactions:

First-generation agents:

• Tolbutamide is short-acting as it is rapidly metabolized in the liver, t½
• 4–5 hours and is, therefore, associated with a lesser risk of hypoglycemia but is rarely used now.

Second-generation agents: Second-generation agents when compared to the first-generation are

• More potent
• Have fewer side effects and
• Fewer drug interactions.

They can cause hypoglycemia → should be used cautiously, particularly in the elderly. Utmost caution is also required in patients with cardiovascular diseases. They are all contraindicated in renal and hepatic impairment.

Glibenclamide:

• Glibenclamide (glyburide) is longer acting—can be given once a day. It can cause hypoglycemia and rarely, flushing after alcohol consumption.
• It may be started with a low dose of 2.5 mg in the morning and increased to 5–10 mg once daily.
• Different formulations are available for controlled release and extended-release.

Glipizide:

• Glipizide has a short t½; food delays its absorption, hence should be taken 30 minutes before breakfast. It is less likely to cause hypoglycemia because of its short t½.
• Started with 5 mg/day the dose may be increased to 15 mg/day. It is metabolized in the liver; and contraindicated in renal and hepatic dysfunction.

Gliclazide:

• Gliclazide can be used in diabetes with renal dysfunction.
• It is found to delay the onset of retinopathy in diabetics.

Glimepiride:

• Glimepiride is longer-acting and can be given as a single morning dose starting with 1 mg.
• The dose may be increased to 4 mg daily but a maximum of 8 mg has also been given.

2. Meglitinides:

• Repaglinide and nateglinide are insulin secretogogues and like sulfonylureas, meglitinides increase the release of insulin by blocking the ATP-dependent K⁺ channels (sulfonylurea receptors) in the pancreatic β cells.
• Repaglinide and nateglinide are rapidly absorbed and have a rapid onset of action.
• They are metabolized in the liver by microsomal enzymes.
• Gastrointestinal disturbances are common with repaglinide. Both drugs can cause hypersensitivity reactions and hypoglycemia—but less with nateglinide.
• Nateglinide can be given even in patients with renal dysfunction.

Meglitinides Uses:

• Meglitinides can be used in type 2 diabetes mellitus either alone or with biguanides. They can also be used as alternatives to sulfonylureas a dose before each major meal.
• May be used in patients allergic to sulfonylureas (no sulfur in their structure).
• Meglitinides increase insulin release in the presence of glucose—therefore, the incidence of hypoglycemia is least with their use.
• Useful in patients with postprandial hyperglycemia (fast action and less hypoglycemia).

3. Glucagon-Like Peptide-1 (GLP-1) Analogs/Incretin Analogs:

Glucagon-like peptides (also called incretins) are released from the gut following oral glucose administration. GLP-1 acts on GLP–1 receptor and:

• Increases the insulin secretion
• Suppresses glucagon release
• Delays gastric emptying
• Reduces appetite
• May increase the beta cell mass and reduce HbA1c levels.

Because GLP-1 cannot be used therapeutically due to its rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4), synthetic GLP-1 analogs like exenatide are used subcutaneously.

• Exenatide: Exenatide is given SC 30–60 minutes before food—dose 5–10 mg twice daily in type II DM.
• Liraglutide: Liraglutide, a longer-acting analog, is given once daily.
• Albiglutide and dulaglutide have a longer t½ for once-weekly injection.

• GLP-1 analogs can cause nausea, vomiting (self-limiting), diarrhea, and weight loss. One adverse effect of concern though rare is hemorrhagic pancreatitis which can be fatal.
• Should be avoided in patients with renal impairment as it can be worsened.
• Use: GLP-1 analogs are used as add-on drugs.

4. Dipeptidyl Peptidase-4 (DPP4) Inhibitors

• Dipeptidyl peptidase is an enzyme that degrades incretins. Sitagliptin is a DPP4 inhibitor—it increases incretin levels and thereby increases insulin secretion and decreases glucagon levels.
• Sitagliptin is orally effective (100 mg OD) and may be used alone or with other antidiabetic drugs. Adverse effects include headache, increased susceptibility to upper respiratory infections, and allergic reactions.
• Saxagliptin (2.5–5 mg OD) and linagliptin (5 mg OD) are longer-acting DPP4 inhibitors.

Biguanides

Question 28. Write a short essay on metformin/biguanides.
Answer:

Metformin in the biguanide in use. Biguanides lower blood glucose levels by insulin-like effects on the tissues (Keybox 2). The mechanism of action is not clear but could act as follows:

• Suppress hepatic gluconeogenesis by activation of an enzyme (AMP-activated protein kinase or AMPK)—this is the principal effect.
• Inhibit glucose absorption from the intestines.
• Stimulate peripheral uptake of glucose in tissues in the presence of insulin.
• Stimulate glycolysis in the tissues.
• Reduce plasma glucagon levels.
• Decrease appetite

Keybox 2: Biguanides.

Biguanides:

• Have insulin-like effects
• Do not cause hypoglycemia
• Weight reduction—due to anorexia
• Nausea, diarrhea, and metallic taste are transient
• Preferred in obese diabetics either alone or with sulfonylureas
• Contraindications in renal, hepatic, and unstable cardiac diseases

Biguanides Pharmacokinetics:

Metformin is well absorbed from the gut, has a duration of action of 6–8 hours, and is not metabolized but excreted unchanged in the urine.

Biguanides Adverse effects:

• Though phenformin is also a biguanide, it is not used because it causes lactic acidosis.
• Metformin is safer with a lower incidence of lactic acidosis but rarely can occur particularly in patients with renal and hepatic dysfunction.

It does not cause hypoglycemia since it is an euglycemic (or antihyperglycemic) agent.

• Nausea, diarrhea, and metallic taste are self-limiting.
• Anorexia is advantageous as it helps in reducing body weight. Long-term use may interfere with vitamin B₁₂ absorption— leading to vitamin B₁₂ deficiency B₁₂ levels should be checked once a year (Keybox 3).

Thiazolidinediones (Tzds):

Question 29. Explain briefly the actions, advantages, and disadvantages of pioglitazone/thiazolidinediones.
Answer:

Thiazolidinediones:

• Thiazolidinediones or glitazones like pioglitazone are agonists at the PPARγ receptors (gamma subtype of peroxisome proliferator-activated receptors).
• These are nuclear receptors present mostly in adipose tissue and also in muscle, liver, and other tissues.
• TZDs activate the PPARγ receptors and induce the synthesis of genes which increase insulin action. TZDs increase insulin-mediated glucose transport into muscle and adipose tissue. They also promote glucose utilization.

Keybox 3: Metabolic syndrome.

Metabolic syndrome:

• Metabolic syndrome is a prediabetic state and is associated with an increased risk of developing coronary heart disease.
• Criteria for metabolic syndrome:
• Triglycerides >150 mg/dL
• HDL cholesterol <40 mg/dL in men
• BP >130/85 mm Hg
• Fasting glucose >110 mg/dL
• Waist circumference: >30 inches men;>35 inches women

Thiazolidinediones Advantages:

• Reduce hepatic gluconeogenesis
• Once a day administration
• Low potential for hypoglycemia
• Increase HDL cholesterol
• No clinically significant drug interactions known so far.
• Reduce mortality.

Thiazolidinediones Disadvantages:

• 6–12 weeks of treatment is required to establish a maximum therapeutic effect.
• May cause weight gain and anemia.
• May cause edema and precipitate or worsen CCF.
• Liver function should be monitored regularly.
• Increased risk of bone fracture in postmenopausal women.

Pioglitazone is effective orally and is metabolized by hepatic microsomal enzymes and the metabolites are also active.

Thiazolidinediones Uses:

• As adjuvant to sulfonylureas/biguanides/insulin in type II diabetes mellitus.
• Troglitazone causes hepatotoxicity and rosiglitazone increases the risk of cardiac problems both are withdrawn.

Alpha-Glucosidase Inhibitors

• Monosaccharides like glucose and fructose are absorbed from the intestines while disaccharides and oligosaccharides are broken down into monosaccharides before being absorbed.
• This ‘breaking down’ is done by the enzymes α-glucosidases (for example, Sucrase, maltase, and glucoamylase) and α-amylases present in the intestinal wall.
• Acarbose, voglibose, and miglitol competitively inhibit the enzymes α-glucosidases and thereby prevent the absorption and delay the digestion of carbohydrates.

• Alpha-glucosidase inhibitors (AGIs) reduce postprandial blood glucose levels.
• AGIs do not cause hypoglycemia but due to other drugs, if hypoglycemia occurs, glucose should be given and not sucrose because sucrase is also inhibited.

Alpha-Glucosidase Inhibitors Adverse effects:

gastrointestinal disturbances including abdominal distention, flatulence, and diarrhea because of undigested carbohydrates reaching the colon and then getting fermented to fatty acids, and in the process gas is released.

Inhibitors Use:

In patients with predominantly postprandial hyperglycemia—either alone or with other oral antidiabetics or insulin.

Inhibitors  Contraindications: Patients with inflammatory bowel disease and renal failure.

Amylin Analogs

• Amylin—a polypeptide produced by the pancreatic beta cells, inhibits glucagon secretion, delays gastric emptying, and suppresses appetite.
• Pramlintide, a synthetic amylin analog, modulates postprandial glucose levels like amylin.
• Pramlintide has beneficial effects on HbA1C levels. Given subcutaneously it is rapidly absorbed and the dose of insulin or other antidiabetics should be reduced to avoid hypoglycemia.
• It should not be mixed with other drugs in the syringe. It can cause nausea, vomiting, and anorexia.
• Pramlintide can be used in both type I and type 2 DM.

Sglt-2 Inhibitors

• A large amount of glucose is reabsorbed from the proximal tubule by sodium-glucose cotransporter-2 (SGLT-2).
• Inhibition of SGLT-2 reduces the reabsorption of glucose and sodium and causes glycosuria.
• Dapagliflozin, remogliflozin, canagliflozin, empagliflozin, and sergliflozin are SGLT-2 inhibitors found to be useful in patients with diabetes. They are particularly useful when the patients also have hypertension.
• They do not cause hypoglycemia but could cause hypotension and increase the risk of urinary infection due to the presence of glucose in the urine. They should be avoided in the presence of low GFR.

Treatment Of Diabetes Mellitus

Aim of treatment:

• To keep the blood sugar within normal limits and prevent complications of diabetes. For patients with type 1, insulin is the only treatment as there is insulin deficiency due to the destruction of pancreatic β-cells.
• Sulfonylureas need functional β-cells for their action and therefore, are not useful in them.
• Mild type 2 may be controlled by diet, exercise, and weight reduction. When not controlled, an oral antidiabetic should be given. Most patients may require insulin sometime later in life.

Sugar Substitutes:

Question 30. Write briefly on artificial sweeteners/sugar substitutes.
Answer:

Sugar substitutes are nonsugars that are sweet but have minimum or no caloric value.

Saccharin sodium:

• Saccharin sodium is an artificial sweetener which is 500 times sweeter than sugar. It is excreted unchanged within 24 hours and has no caloric value.
• It is stable and nontoxic. Saccharin has an unpleasant aftertaste, while sodium saccharin does not have this disadvantage.

Aspartame:

• Aspartame is a sugar substitute that is 200 times sweeter than sugar.
• It is metabolized in the body like proteins and does not have the metallic aftertaste of saccharin.

Neotame:

Neotame an analog of aspartame, is sweeter than it and has better heat stability, and can be used while cooking.

Sucralose:

• Sucralose is a trichlorinated sucrose 600 times sweeter than sucrose.
• It is not absorbed and is excreted through the gut.

Glucagon

• Glucagon is synthesized in the alpha (A) cells of the pancreatic islets of Langerhans; like insulin, the secretion of glucagon is regulated by nutrients—chiefly glucose, paracrine hormones, and the autonomic nervous system.
• Fasting stimulates glucagon secretion. It is degraded in the liver, kidney, and plasma.

Actions: Glucagon increases blood glucose levels by glycogenolysis and gluconeogenesis in the liver. It evokes insulin release. It mobilizes stored fat and carbohydrates. Glucagon increases heart rate and force of contraction. It also relaxes the intestinal smooth muscles.

Glucagon Uses:

• Severe hypoglycemia—treatment of severe hypoglycemia due to insulin.
• Diagnostic uses—for diagnosis of IDDM.
• Radiology of the bowel—glucagon relaxes the intestinal smooth muscles.

Uterine Stimulants

Question 31. What are ecbolics? Compare oxytocin to ergometrine as ecbolics. Write a short note on oxytocin. Explain why oxytocin is preferred to ergometrine in labor.
Answer:

Drugs that stimulate uterine contractions are oxytocin, ergometrine, and prostaglandins. They are also called oxytocics or ecbolics. These drugs are useful in obstetrics.

Oxytocin:

• Oxytocin is a peptide hormone secreted by the posterior pituitary along with ADH.
• It is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus, transported along the axon, and stored in the neurohypophysis.
• It is released by stimuli, such as suckling, coitus, and parturition.

Oxytocin Actions:

• Oxytocin contracts the uterus. The fundus and the body contract, while the lower segment is relaxed.
• Both force and frequency of contractions are enhanced and there is full relaxation in between the contractions.
• This relaxation allows adequate blood supply to the fetus.

Oxytocin Mechanism of action:

• Oxytocin acts on oxytocin receptors which are G-protein-coupled receptors.
• The full-term uterus is highly sensitive to oxytocin because estrogen increases the number of oxytocin receptors and sensitizes the uterus to the effects of oxytocin.
• High doses produce sustained contractions, resulting in reduced blood flow to the fetus, fetal distress, and death.
• Synthetic oxytocin is used for therapeutic purposes—5 IU diluted in 500 mL glucose/saline infusion.

• Mammary gland:  Oxytocin facilitates milk ejection by contraction of the myoepithelium in the mammary alveoli. Suckling stimulates the release of oxytocin.
• Kidney: Oxytocin has mild antidiuretic effects.

Oxytocin Pharmacokinetics:

• Oxytocin is given as an IV infusion.
• It is metabolized by oxytocinase.

Oxytocin Adverse effects:

Large doses cause water intoxication and very powerful contractions.

Oxytocin Uses:

1. Induction of labor: Oxytocin is used to induce labor as in postmaturity or to augment labor when uterine contractions are inadequate. Oxytocin is the ecbolic of choice because of the following advantages:
   1. The upper segment of the uterus contracts while the lower segment relaxes which facilitates fetal expulsion.
   2. Relaxation in between contractions allows adequate blood supply to the fetus.
   3. Short t½ hence action can be easily controlled by monitoring the drip rate.
2. PPH: Oxytocin is now the preferred drug for the prevention and treatment of PPH.
3. Milk ejection: When milk ejection is impaired in nursing mothers, intranasal oxytocin spray can be used.
4. Abortion: As an alternative to induce mid-trimester abortion.

Question 32. What are the differences between oxytocin and ergometrine?
Answer:

Ergometrine:

Ergometrine and its derivative methylergometrine are uterine stimulants.

Actions on the uterus:

• Ergometrine is a powerful uterine stimulant. The force and frequency of uterine contractions are increased.
• All parts of the uterus including the fundus, body, and the lower segment contract. There is no relaxation in between contractions.
• A full-term uterus is more sensitive to the actions of ergometrine.
• Ergometrine also causes some vasoconstriction which helps to reduce bleeding from the uterus in the postpartum state. It brings about its effects by binding to serotonin receptors.

Ergometrine Pharmacokinetics:

• Ergometrine is rapid and short-acting.
• It can be given orally, IM, or IV.

Ergometrine Adverse effects: 

Include nausea, vomiting, vasospasm, visual disturbances, and rarely hypertension.

Ergometrine Uses:

• Postpartum hemorrhage: Ergometrine was used to control and prevent PPH but, oxytocin is now preferred.
• To hasten uterine involution: Ergometrine can be used.
• To prevent uterine atony: After cesarean section.

Comparison between oxytocin and ergometrine;

Prostaglandins:

• Prostaglandins are synthesized by the uterus and play a significant role in menstruation and labor.
• PGE₂ and PGF_2a stimulate the contraction of both pregnant and nonpregnant uterus though sensitivity is higher during pregnancy.
• They also soften the cervix and hasten dilatation (cervical ripening). PGs produced by fetal tissues mediate the initiation and progression of labor.

PGs used in obstetrics are:

• Dinoprostone (PGE₂)—intravaginal or extra-amniotic
  Carboprost (15 methyl PGF_2a )—deep IM
• Misoprostol, gemeprost, (PGE₁)—intravaginal

PGs  Adverse effects: 

Include nausea, vomiting, headache, fever, and diarrhea.

PGs  Uses:

• Abortion: PGs are used as vaginal suppositories to induce mid-trimester abortion.
• Dinoprostone is given intravaginally or by the extra-amniotic route. Misoprostol is used with mifepristone in the termination of pregnancy up to 9 weeks. Gemeprost is given as vaginal pessary following mifepristone.
• PPH: Carboprost as an alternative to ergometrine.
• Cervical priming: Intravaginal gels prior to induction of labor.
• Induction of labor: PGs as alternatives to oxytocin.

Uterine Relaxants (Tocolytics)

Question 33. What are tocolytics? Name some tocolytics.
Or
Write a short note on tocolytics.
Answer:

Tocolytics:

Tocolytics are drugs that reduce uterine motility and relax the uterus. They are:

• b₂-adrenergic agonists: Salbutamol, terbutaline, ritodrine, and isoxsuprine.
• Oxytocin receptor antagonist: Atosiban.
• Cyclo-oxygenase inhibitors: Aspirin, indomethacin, and sulindac.
• Miscellaneous: Magnesium sulfate, ethyl alcohol, calcium channel blockers, nitroglycerine.

Salbutamol:

• Selective b₂-adrenergic agonists ritodrine and salbutamol relax the uterus and thereby suppress premature labor in a large number of cases. IV infusion is started at 10 mg per minute and the dose may be gradually increased up to 40 mg per minute.
• Alternatively, ritodrine IV infusion may be started at 50 mg per minute and gradually increased to 100 mg per minute till the contractions stop.\

Tocolytics  Adverse effects: 

• Including anxiety, palpitation, restlessness, headache, hypotension, arrhythmias, and hyperglycemia.
• b₂-agonists should be avoided in pregnant women with diabetes and heart diseases.

Atosiban:

Atosiban is an oxytocin receptor antagonist, effective as a tocolytic to delay preterm labor. It may be used as an alternative to b₂-adrenergic agonists as an IV infusion.

Intravenous magnesium sulfate:

• Intravenous magnesium sulfate is used as an alternative when b₂-agonists are contraindicated.
• High doses can cause significant CNS and respiratory depression.
• Magnesium sulfate is also used to suppress convulsions and control the BP in pre-eclampsia and eclampsia. A bolus dose of 2g is infused over 10–20 minutes followed by 1 g/L infusion.

Calcium channel blockers (CCBs):

Calcium channel blockers like nifedipine sublingual 10 mg repeated every 20 minutes for 3 doses relax the uterus but can reduce placental perfusion and hence CCBs are not preferred.

Ethyl alcohol:

• Ethyl alcohol given IV is a tocolytic but produces marked CNS depression.
• Though aspirin and indomethacin relax the uterus, they are not preferred as tocolytics because of the risk of closure of ductus arteriosus and other adverse effects.

Tocolytics Uses:  

To delay premature labor:

• Tocolytics may not always be successful. Uterine contractions may be controlled for 24–48 hours which should be utilized to prepare the fetus for preterm birth, i.e. by giving glucocorticoids to bring about early maturation of fetal lungs.
• In threatened abortion to inhibit uterine contractions.

Agents Affecting Bone Mineral Turnover

Question 34. Write a short note on the action and uses of calcium, vitamin D/calcitonin.
Answer:

Calcium and phosphorus are the most important minerals of the bone with 1–2 kg of calcium and 1 kg of phosphorus stored in it.

Calcium:

Calcium is essential for:

• Tissue excitability
• Muscular excitation-contraction coupling
• Secretion from glands
• Myocardial contractility
• Formation of bone and teeth
• Integrity of mucous membranes and cell membrane
• Normal blood coagulation

Calcium is absorbed from the small intestine by carrier-mediated active transport. Normally, about 30% of the dietary calcium is absorbed, while in Ca⁺⁺ deficiency, the absorption increases under the control of vitamin D. The normal plasma calcium level is 9–11 mg/dL. It is excreted in feces, urine, and sweat.

Calcium Adverse effects: Oral calcium can produce constipation

Calcium Uses:

• To prevent and treat calcium deficiency:
  • Calcium supplements are given orally in children, pregnant and lactating women, and in postmenopausal osteoporosis to prevent calcium deficiency.
  • Calcium 0.5–1g daily

Tetany: 5–10 mL IV calcium gluconate followed by 50–100 mL slow IV infusion promptly reverses the muscular spasm. The injection produces a sense of warmth. This is followed by oral calcium 1.5 g daily for several weeks.

• Osteoporosis: Calcium + vitamin D is given along with other drugs in the prevention and treatment of osteoporosis.
• Vitamin D deficiency rickets—calcium is given along with vitamin D.
• As an antacid—calcium carbonate is used.
• For the placebo effect—IV calcium is used in weakness, pruritus, and some dermatoses. The feeling of warmth produced by the injection could provide psychological benefits.

Phosphorus

• Phosphorus is present in many food items including milk, cereals, fish, meat, pulses, and nuts.
• The daily requirement of phosphorus is about 900–1,000 mg in adults. The human body contains about 500–600 g of phosphorus of which 75% is present in bones.

Phosphorus Physiological function:

• Phosphorus is necessary for the formation of bones and teeth, for phosphorylation reactions, for various enzymatic reactions, and are important for the structure.
• Function of the cells and for maintaining the acid-base balance in the plasma and the cells— phosphates are buffers.

Hypophosphatemia:

Hypophosphatemia Causes:

• Dietary phosphorus deficiency
• Hyperparathyroidism
• Long-term intake of aluminum-containing antacids
• Chronic alcoholism
• Vitamin D deficiency
• Diabetic ketoacidosis

Hypophosphatemia Clinical features:

Anorexia, muscular weakness, pain, abnormal bone mineralization, hemolysis, decreased myocardial contractility, and respiratory failure.

Hyperphosphatemia:

• Causes: Hypoparathyroidism, acromegaly, and renal failure.
• Clinical features: Hypocalcemia, bone resorption, and calcification of soft tissues.

Phosphorus Uses: 

• Phosphorus deficiency
• Chronic hypercalcemia (without hyperphosphatemia)

Hormones that infuence bone metabolism:

• Vitamin D
• Estrogens
• Parathormone
• Growth hormone
• Calcitonin
• Thyroid hormone
• Glucocorticoids

Parathyroid Hormone (Parathormone—PTH):

• Parathormone is a peptide secreted by the parathyroid gland. Secretion of PTH is regulated by plasma Ca⁺⁺ concentration—low plasma Ca⁺⁺stimulates PTH release, while high levels inhibit secretion.
• Parathormone maintains plasma calcium concentration by mobilizing calcium from the bone, promoting reabsorption of Ca⁺⁺ from the kidneys, and stimulating the synthesis of calcitriol which in turn enhances calcium absorption from the intestines.
• PTH stimulates the osteoblasts to induce a protein (RANK ligand) which enhances the number as well as activity of osteoclasts and stimulates bone modeling. PTH also promotes phosphate excretion.
• Hypoparathyroidism is characterized by low plasma calcium levels with its associated manifestations.
• Hyperparathyroidism which is most commonly due to parathyroid tumors produces hypercalcemia and deformities of the bone.
• PTH is used for the diagnosis of pseudohypoparathyroidism.

Teriparatide is a recombinant PTH found to be useful in the treatment of osteoporosis.

Vitamin D

Question 35. Describe briefly the action and uses of vitamin D.
Or
Write a short note on vitamin D.
Answer:

Vitamin D, a fat-soluble vitamin, is a prehormone produced in the skin from 7- dehydrocholesterol under the influence of ultraviolet rays. It is converted to active metabolites in the body which regulate plasma calcium levels and various functions of the cells.

Vitamin D Source:

• Diet—as ergocalciferol (vitamin D₂) from plants.
• Fish, liver, fish liver oils (cod, shark liver oil); milk.
• Cholecalciferol (vitamin D₃) is synthesized in the skin from 7-dehydrocholesterol.
• Cholecalciferol (vitamin D₃) is converted to 25-OHD₃ (calcifediol) in the liver.

Vitamin D  Mechanism of action:

Vitamin D is similar to glucocorticoids—it binds to the vitamin D receptors, the complex moves to the nucleus where it enhances the synthesis of specific mRNA and regulates protein synthesis.

Vitamin D Actions: The chief actions of calcitriol are:

• It stimulates calcium and phosphate absorption from the intestines.
• Mobilizes calcium from the bone by promoting osteoclastic activity.
• Increases reabsorption of Ca⁺⁺ and phosphate from the kidney tubules.
• Calcitriol is essential for normal bone mineralization, for skeletal muscles as well as for cellular growth and differentiation.
• Calcitriol may also act directly on the gastrointestinal mucosa to enhance Ca⁺⁺ uptake from the gut.
• Daily requirement 400 IU (10 mg).
• Vitamin D deficiency results in low plasma calcium and phosphate levels with abnormal mineralization of the bone; causes rickets in children and osteomalacia in adults.

Vitamin D  Pharmacokinetics:

Given orally, vitamin D is well absorbed from the small intestines in the presence of bile salts.

Vitamin D Preparations:

• Calciferol capsules: 25,000; 50,000 IU.
• Cholecalciferol granules: Oral 60,000 IU; 3,00,000 IU/mL, 6,00,000 IU/mL in.
• Shark liver oil with Vitamin D: 1000 IU/mL, Vitamin A—6,000 IU/ml.
• Calcifediol (25(OH)D₃), alfa calcidiol (1-α(OH)D3) and calcitriol (1,25(OH)2D3) are synthetic vitamin D analogs available for use.

Vitamin D Adverse reactions:

• High doses of vitamin D used for long periods result in hypervitaminosis D manifesting as generalized decalcification of the bones, hypercalcemia, hyperphosphatemia resulting in weakness, drowsiness, nausea, abdominal pain, thirst, renal stones and hypertension.
• Hypervitaminosis D in children is most often due to unnecessary vitamin D supplementation by parents.

Vitamin D Uses;

• Prophylaxis: 400 IU daily or 3 lakh IU every 3–6 months IM prevents vitamin D deficiency. Adequate dietary calcium and phosphate intake is necessary. In breastfed infants, from the first month onwards oral vitamin D supplements are needed.
• Nutritional rickets and osteomalacia 6 lakh units IM repeated after 4–6 weeks + calcium.
• Vitamin D-resistant rickets is a hereditary disorder with abnormality in renal phosphate reabsorption. Phosphate with vitamin D is found to be useful.
• Vitamin D-dependent rickets is due to calcitriol deficiency (inability to convert calcifediol to calcitriol) and is treated with calcitriol.
• Senile osteoporosis: Oral vitamin D supplements with calcium may be tried.
• Hypoparathyroidism: Calcitriol with Ca⁺⁺ supplements are beneficial.

Calcimimetics:

• Calcimimetics (calcium sensor mimetics) are drugs that activate calcium-sensing receptor (CaR) and mimic the actions of calcium.
• Cinacalcet is a calcimimetic that blocks the PTH secretion by activating the CaR in the parathyroid gland.
• It is given orally in secondary hyperparathyroidism due to chronic renal disease and in parathyroid carcinoma.

Calcitonin

• Calcitonin is a peptide hormone secreted by the parafollicular ‘C’ cells of the thyroid gland.
• Secretion is regulated by plasma calcium concentration and high plasma calcium stimulates calcitonin release.

Calcitonin Actions: Calcitonin lowers serum calcium and phosphate by its actions on the bone and kidney.

• It inhibits osteoclastic bone resorption and in the kidney, it reduces both calcium and phosphate reabsorption.
• In general, the effects are opposite to that of PTH. Calcitonin is used to control hypercalcemia, Paget’s disease, metastatic bone cancer and osteoporosis and to increase bone mineral density.
• Other hormones that regulate bone turnover are glucocorticoids and estrogens.
• Glucocorticoids antagonize vitamin D-stimulated intestinal calcium absorption and increase renal Ca⁺⁺ excretion.
• Estrogens reduce bone resorption by PTH and also increase calcitriol levels.
• Estrogens may also have a direct effect on bone remodeling.

Bisphosphonates

Question 36. Write a short note on bisphosphonates. Explain why bisphosphonates are used in osteoporosis.
Answer:

Bisphosphonates:

Bisphosphonates inhibit bone resorption. They are grouped into 3 generations based on the potency

Bisphosphonates Mechanism of action:

• Bisphosphonates concentrate at sites of acute bone remodeling.
• They have a high affinity for calcium, enter into the bone matrix, are taken up by osteoclasts, and then inhibit the osteoclasts resulting in reduced bone resorption.
• They also slow the formation and dissolution of hydroxyapatite crystals.
• Some bisphosphonates interfere with the mevalonate pathway which plays an important role in the functions of osteoclasts.

Bisphosphonates Adverse effects:

• The most common adverse effect is gastroesophagitis due to irritation—should be taken with a full glass of water (in a sitting position) or parenterally.
• Fever, flu-like symptoms, and hypocalcemia can occur. Headaches, body aches, and thrombophlebitis on IV infusion are common. Long-term use can lead to osteomalacia due to inhibition of bone mineralization.
• Higher doses can rarely cause osteonecrosis of the jaw.

Bisphosphonates Pharmacokinetics:

• Bisphosphonates are poorly absorbed—bioavailability ~10%.
• Food interferes with their absorption—hence give on an empty stomach.

Bisphosphonates Uses:

1. Osteoporosis: Given calcium and vitamin D for the prevention of postmenopausal osteoporosis in women and for osteoporosis in elderly men—they improve bone mineral density and reduce the risk of bone fractures.
2. Paget’s disease: Bisphosphonates relieve pain and induce remission.
3. Hypercalcemia of malignancies: Reuires immediate treatment—intravenous pamidronate infusion is useful in reducing plasma Ca⁺⁺ levels.

Denosumab: Denosumab an inhibitor of RANK ligand (RANKL) reduces bone resorption in patients with osteoporosis.

Agents Used In The Prevention And Treatment Of Osteoporosis

• Drugs may be used either to prevent bone resorption promote bone formation or a combination of both in the prevention and treatment of osteoporosis.
• These agents reduce the risk of fractures in patients with osteoporosis. Bone mineral density (BMD).