pharmacology tutorials - endocrinology ii

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Endocrinology Tutorials II -Adrenal corticosteroids -Drug affecting calcium balance -Androgens & anti-androgens -Estrogens -Progestins -Contraceptives -Oxytocin & tocolytics - Vasopressin

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Page 1: Pharmacology Tutorials - Endocrinology II

Endocrinology Tutorials II

-Adrenal corticosteroids -Drug affecting calcium balance -Androgens & anti-androgens -Estrogens -Progestins -Contraceptives -Oxytocin & tocolytics - Vasopressin

Page 2: Pharmacology Tutorials - Endocrinology II

CORTICOSTEROIDS

1. Classify Glucocorticoids. Short Acting

Hydrocortisone Intermediate acting

Cortisone Prednisolone Methylprednisolone Triamcinolone

Long acting Dexamethasone Betamethasone

2. What are the metabolic actions of Glucocorticoids?

Carbohydrates: decreased uptake and utilisation of glucose accompanied by increased gluconeogenesis; this causes a tendency to hyperglycaemia. Proteins: increased catabolism Lipids: a permissive effect on lipolytic hormones and a redistribution of fat

3. How do glucocorticoids mediate the anti-inflammatory and immunosuppressive

action? Induction of Lipocortin in macrophages & endothelium Reduction in COX2 levels Reduction of expression of genes for cytokines Reduced production of acute phase reactants Affects leukocyte functions

4. What are the advantages of prednisolone over hydrocortisone?

Four times more potent No fluid retention Less pituitary-adrenal axis suppression when alternative day regimen is given

5. What are the uses of Glucocorticoids?

Replacement uses: Acute adrenal insufficiency Addison’s disease Congenital adrenal hyperplasia Thyroid strom

Immunosuppression: Inflammatory arthritis Collagen vascular diseases Allergic reactions Autoimmune diseases Bronchial asthma Retrobulblar neuritis, keratitis

Page 3: Pharmacology Tutorials - Endocrinology II

Transverse myelitis Ulcerative colitis, Crohn’s disease Organ transplantation Steroid dependant nephrotic syndrome Septic shock Other uses: Cerebral edema Premedication in cancer therapy

6. Name the diagnostic use of glucocorticoids.

Dexamethasone is used in the dexamethasone suppression test useful in the diagnosis of Cushing syndrome.

7. How do glucocorticoids benefit Preterm labour?

Glucocorticoids induce fetal lung maturity, decrease interventricular haemorrhage and decreases the risk of necrotising enterocolitis associated with preterm labour.

8. Name the infections where glucocorticoids are used under antibiotic cover?

TB meningitis, Lepra reactions, Severe pyogenic meningitis, Pneumocyctis carini & neurocysticercosis

9. What are the side effects of glucocorticoid therapy?

Fluid retention Cushingoid syndrome Hyperglycemia Avascular necrosis of femur Posterior subcapsular cataract (Systemic therapy) Glaucoma (Topical therapy) Growth retardation Osteoporosis Muscular weakness Peptic ulceration Delayed wound healing Susceptibility to infection

10. Describe cushingoid habitus? (refer diagram)

Page 4: Pharmacology Tutorials - Endocrinology II

11. What is the major concern when stopping Glucocorticoids for a patient? Suppression of HPA axis occurs when used for more than two weeks. When a patient is on long term glucocorticoids, the adrenal cortex undergoes atrophy due to suppression of the HPA axis. When the patient is suddenly stopped of his medication, he might develop an acute adrenal crisis. Hence glucocorticoids must withdrawn gradually.

12. What will you do if a patient on long term glucocorticoids develops infection?

Start antibiotics. Don’t stop glucocorticoids. The glucocorticoid dose may need to be increased as infection is a stress and the patient has to tide over the condition.

13. What will you do if a patient on long term glucocorticoids has to undergo surgery?

Surgery is a stress. Increase the dose of glucocorticoids.

14. Name the glucocorticoids that are used as Inhalational steroids for asthma pharmacotherapy?

Beclomethasone, Budesonide and Flunisolide, Mometasone & Triamcinolone

15. Mention the drugs used for mineralocorticoid replacement? Fludrocortisone Desoxycorticosterone acetate

16. Mention antagonists of adrenocortical hormones.

Glucocorticoid synthesis inhibitors Aminoglutethimide Metyrapone Ketoconazole Trilostane Mifepristone Mitotane Mineralocorticoid antagonists Spironolactone Eplerenone

DRUGS AFFECTING CALCIUM BALANCE

Calcium:

Physiological roles:

Nerve excitability

Cell membrane integrity and adhesion

Excitation contraction coupling in all types of muscle, endocrine and exocrine glands

and release of neurotransmitters

Intracellular second messenger for hormones

Coagulation mechanism

Page 5: Pharmacology Tutorials - Endocrinology II

Major constituent of bones and teeth

Plasma calcium level is maintained by 3 hormones, PTH, calcitonin and calcitriol. Normal

plasma calcium level is 9-11mg/dl. About 50% of this is in ionized form and determines the

physiological functions. In hypoalbuminemia, total calcium levels are reduced while the

concentration of Ca2+ is usually normal.

Uses of Calcium:

1. Tetany: 10-20ml of calcium gluconate i.v over 10 min for the immediate

management, followed by infusion. Muscle spasms are reduced with infusion over 6

hrs (50-100ml). Supportive therapy with i.v fluids and oxygen is indicated.

2. As dietary supplement: in postmenopausal pregnant and lactating women.

In pregnancy and lactation: 1.5g

Women 25-50yr and 51-60yr if taking HRT: 1.0g

Women 51-65yr not taking HRT: 1.5g

3. Osteoporosis: For both prevention and treatment of osteoporosis. Calcium and vit

D3 have adjuvant role to HRT/raloxifene/bisphosphonate therapy. The efficacy of

these supplements still remains controversial. The Woman Health Initiative Study

(WHI) showed that the overall risk of fractures was same in both in the treated and

placebo group.

Parathyroid Hormone:

The secretion of PTH is stimulated by low plasma calcium levels and inhibited by rise in

calcium levels. PTH tends to increase the plasma calcium levels. Prolonged hypocalcemia

results in hypertrophy and hyperplasia of parathyroid glands.

It increase the plasma calcium levels by

Bone: Increasing the calcium resorption from bone

Kidneys: Increasing the calcium reabsorption from distal tubule in kidneys

Intestines: Increases the absorption of calcium from intestine indirectly by increasing the

formation of vit D

Teriparatide:

Recombinant preparation of 1-34 residues of amino terminal of human PTH has been

approved for treatment of severe osteoporosis.

It is injected s.c once daily for the treatment of osteoporosis in women.

Teriparatide is the only agent which stimulates bone formation whereas

bisphosphonates and estrogens check bone resorption.

Page 6: Pharmacology Tutorials - Endocrinology II

It is also used for to differentiate pseudo and true hypoparathyroidism. To

differenfiate pseudo

from true hypoparathyroidism. Teriparatide is given i. v: if plasma calcium level fails

to rise, then it is pseudohypoparathyroidism.

Calcitonin:

It is secreted by the para follicular ‘C’ cells of the thyroid gland. The actions of calcitonin are

just the opposite of PTH. It tends to reduce plasma calcium levels by inhibiting the bone

resorption. Calcitonin inhibits proximal tubular calcium and phosphate reabsorption by

direct action kidney.

Uses: Hypocalcemic states, postmenopausal osteoporosis and paget’s disease

VITAMIN D:

Active form of vit D is called Calcitriol. Vitamin D3 is cholecalciferol- synthesized in the skin

upon exposure to UV rays. 25-OH D3 is released in blood and finally activated in kidney by

hydroxylation. The final hydroxylation step is the rate limiting step. Vitamin D is practically

considered as a hormone because it is synthesized in body, needs to be activated for action

on specific receptors and finally it is subjected to feedback regulation by the plasma Ca2+

level.

Actions: Increases the absorption of calcium and phosphate from the intestine. The

receptors are located intracellularly similar to that of steroids. On ligand binding, Vitamin D

receptors are internalized and leads to increased transcription of specific mRNA.

Increases bone resorption and plasma calcium levels. It also enhances the tubular

reabsorption of calcium and phosphate in the kidney.

Use:

1. Prophylaxis and treatment of nutritional vit D deficiency

2. Treatment of metabolic rickets

3. Senile and postmenopausal osteoporosis

Page 7: Pharmacology Tutorials - Endocrinology II

4. Hypoparathyroidism

5. Fanconi syndrome

Bisphosphonates: These drugs prevent bone resorption and currently are used for

prevention of osteoporosis. They are also used for the management of hypercalcemia and

metabolic bone diseases.

First generation: Etidronate, Tiludronate

Second generation: Pamidronate, Alendronate and ibandronate

Third generation: Zoledronate, risedronate

Mechanism of action:

Acceleration of apoptosis of osteoclasts

Disruption of cytoskeleton and ruffled border of osteoclasts

Interference with the mevalonate pathway and isoprenoid lipid synthesis seen

especially with second and third generation drugs

Uses of bisphosphonates:

Osteoporosis: Second and third generation drugs (alendronate and risedronate) are

useful for the prevention and treatment of postmenopausal, age related, idiopathic

and steroid induced osteoporosis in both men and women. The use of

bisphosphonates reduces the risk of both vertebral and hip fracture by 47-56%.

Paget’s disease

Hypercalcemia of malignancy: A common complication of malignancy with altered

consciousness. Pamidronate or Zoledronate are the most effective and commonly

used drugs. Oral bisphosphonates are not useful. The use of furosemide is

recommended before i.v infusion of bisphosphonates.

Osteolytic bone metastasis

Adverse effects: Esophagitis: Seen with the use of bisphosphonates. Hence patient is

advised to sit straight after taking tablet for atleast 30min and to take plenty of water.

Osteonecrosis of the jaw: Serious side effect reported with the use of bisphopsphonates.

Page 8: Pharmacology Tutorials - Endocrinology II

ANDROGENS:

These hormones produce secondary sexual characters in a castrated male. Natural

androgens include Testosterone and dihydrotesterone. Synthetic androgens include

methyltestosterone and fluoxymesterone. Testosterone is produced by the interstitial cells

of Leydig under the influence of LH. It exerts negative feedback at the level of both pituitary

and hypothalamus maintaining the plasma levels.

Uses: Testicular failure

Hypopituitarism

AIDS related muscle wasting

Hereditary angioneurotic edema

Anabolic Steroids: Synthetic androgens with higher anabolic activity and lower androgenic activity. Ex: Nandrolone, Stanzolol, Oxymetholone and methandienone.

Uses:

Catabolic states

Renal insufficiency

Osteoporosis

DANAZOL

It is an impeded androgen analogue. It is an orally active ethisterone derivative having weak androgenic, anabolic and progestational acivities. It binds to androgen receptor and induces some mRNA production and inhibits the secretion of gonadotropins from pituitary in both men and women.

Uses:

Endometriosis: marked improvement in 75% of cases. Prompt relief of dysmenorrhea, pain and dyspareunia occurs. Therapy for 3-6 months results in prolonged relief.

Menorrhagia

Fibrocystic Breast disease

Hereditary angioneurotic edema

Side effects: Complete amenorrhoea

Androgenic side effects like acne, hirsutism deepening of voice, loss of libido in men, hot flashes and night sweats.

Page 9: Pharmacology Tutorials - Endocrinology II

ANTI ANDROGENS:

1. Inhibitors of testosterone secretion:

Analogues of GnRH effectively inhibit testosterone secretion by inhibiting LH secretion. Ex:Goserelin and Nafarein

GnRH receptor antagonists: ganirelix and abarelix used in prostate cancer.

2. Androgen Receptor Antagonists:

Flutamide, bicalutamide and nilutamide; primarily used for the treatment of prostate cancer in combination with GnRH analogues for the treatment of metastatic prostate cancer.

Spironolactone: It has anti androgenic action and inhibits the synthesis of testosterone. Spironolactone can be used in women to treat hirsutism

Cyproterone acetate: Weak anti androgen and a progestin. It is moderately effective in reducing hirsutism alone or in combination with an oral contraceptive

3. 5-α reductase inhibitors:

Finasteride: Inhibits Ty II and Dutasteride inhibits both Ty I and II of 5-α reductase

These drugs block the conversion of testosterone to dihydrotestosterone, especially in the male external genitalia and are used to treat benign prostatic hyperplasia.

Finasteride is approved for use in the treatment of male pattern baldness

Estrogens

Q) How is estrogen secreted in the body?

L.H. theca cells androgens estrogens

F.S.H. granulosa cells aromatase

Q) What are the uses of estrogens?

Primary amennorhoea – e.g. turner’s syndrome.p

As hormone replacement therapy in menopausal women to decrease the symptoms.

1.Conjugated estrogens (0.625 mg), isolated from pregnant mare’s urine.

+ medroxy progesterone acetate (for 10 days, to counteract the estrogenic

proliferative activity on endometrium.)

No need to add progestin if hysterectomy is done.

2. phytoestrogen- soya beans, flax seeds

3. SERMs- partially estrogenic in some tissues and anti-estrogenic in some. e.g. tamoxifene- antiestrogenic- breast, estrogenic- bone, endometrium.

Page 10: Pharmacology Tutorials - Endocrinology II

PROGESTINS

Q) What are the uses of progestins?

DUB- nor ethisterone, 5-10 mg orally, 6 hrly OR i.m. hydroxy progesterone caproate, 100 mg stops bleeding within 24 hrs. Other drugs used in DUB- O.C. pills, NSAIDs, iron;folic acid.

Dysmenorrhea- progestins, O.C. pills

Diagnosis of the etiology in cases of amenorrhoea-progesterone withdrawal test. Differentiates hypogonadotrophic hypogonadism from hypergonadotrophic hypogonadism.

Endometriosis- acts by suppressing ovarian function.

Fibrocystic disease of breast.

Postponement of menstruation.

Endometrial carcinoma.

CONTRACEPTIVES

Q) What is the mechanism of action?

Inhibits gonadotrophin release

Thickens cervical mucous

Unreceptive endometrium

Modifies tubal contractions.

Q) What are the preparations?

1st gen.- levonorgestrel- 250 mcg. ; ethinyl estradiol-50 mcg.

2nd gen.- levonor.- 150 mcg ; E2- 30 mcg

3rd gen.- desogestrel(has potent anti ovulatory action)- 150 mcg ; E2- 20 mcg

They are started on the 5th day of cycle, given for 21 days. Iron and folic acid supplement given for remaining 7 days.

In tri/bi phasic pills, estrogen content remains constant, progestin levels are progressively increased. It decreases the total hormone content. Indicated when a risk factor is present.

Q) Why is progestin added in OC pills?

1. It increases the certainty of ovulation suppression. 2. Ensures predictable withdrawal bleeding. 3. Modifies cervical mucus. 4. Decreases the estrogenic mediated endometrial proliferation.

Q) What are the non-contraceptive benefits of OC pills?

1. Less menstrual blood loss; less anaemia. 2. Decreases the incidence of menorrhagia, dysmenorrhea, pre-menstrual syndrome,

acne.

Page 11: Pharmacology Tutorials - Endocrinology II

3. Lowers incidence of benign breast disease, ovarian Ca., tubal pregnancy.

Q) How can oral antibiotics like tetracycline cause failure of contraception?

By suppressing flora, they prevent deconjugation of the estrogen excreted in bile, hence decreasing the entero hepatic circulation.

And rifampicin?? By inducing the metabolizing enzyme.

Q) what are the adverse effects of OC pills?

Estrogen component-

1. Venous thrombosis (its not seen in HRT doses)

Increases the clotting factors, platelet aggregation.

Decreases anti thrombin III and plasminogen activator.

2. Salt and water retention, hypertension.

3. Precipitates migraine.

4. Increases the risk of endometrial Ca. , breast Ca.

5. Increases the risk of gall stones( increased cholesterol excretion)

6. Carbohydrate intolerance/ diabetes.

Progesterone component - (pto)

Weight gain, hirsutism, acne, chloasma, mood swings, raised HDL, hypertension.

Q) What are the contraindications?

Absolute-

H/O- thrombo embolic/ coronary/ cerebrovascular disease

HTN, hyperlipidaemia

Liver disease

Suspected malignancy of genitals/ breast.

Porphyria

Impending major surgery(to avoid thrombosis)

Relative

Diabetes

Obesity

Smoking

Undiagnosed vaginal bleeding

Age more than 35 years

Migraine

Uterine leiomyoma

Page 12: Pharmacology Tutorials - Endocrinology II

Q) What are the drugs used for post coital contraception?

OC pills( 2 pills followed by 2 more after 12 hrs, within 72 hrs of coitus; yuzpe

method)

Levonorgestrel {0.75 mg twice in 12 hrs within 72 hrs}

Mifepristone , 10 mg within 72 hrs.

Copper containing IUCD within 5 days.

Q) What are the injectable contraceptives?

DMPA, injected deep i.m., provides contraception for 3 months.

Levonorgestrel implant, a drug delievery system, lasts 5 years.

Q) What is centchroman?

It is a non steroidal estrogen antagonist (SERM) developed in India. Acts as anti implant

agent by disturbing motility and inhibiting decidualization.

Q) What is mifepristone?

Progesterone antagonist, causing menstrual bleeding(in non pregnant), and decidual

necrosis, cervical dilatation and detachment of conception(in pregnant).

USES:

Post coital contraceptive (10 mg)

1ST trimester MTP (600 mg)

Cushing’s syndrome (has anti glucocorticoid action at higher doses).

Q) What is clomiphene?

Potent anti estrogen with mild estrogenic effect of its own. It competes with

estrogen for receptors in pituitary and hypothalamus, breaks the negative feedback,

causes FSH,LH release and thereby ovulation.

Started on the 5th day of menses, 50 mg for 1 week.

Q) What is letrozol?

Aromatase inhibitor, used for ovulation induction.

Q) What is gossypol?

Male contraceptive, acts by inhibiting spermatogenesis, but can cause hypokalaemia.

Q) What is danazol?

Anti gonadotrophic, eliminates midcycle LH,FSH surge. Also inhibits estrogen synthesis.

Page 13: Pharmacology Tutorials - Endocrinology II

Induces hypoestrogenic, hypo progestational state.

Uses-

Endometriosis, benign breast disease, ITP.

Posterior Pituitary Hormones

1. What are the posterior pituitary hormones? Oxytocin &Vasopressin (Anti- diuretic hormone)

2. What are the major actions of oxytocin?

Uterine muscle contraction (both the frequency and force of estrogen primed uterus), expression of formed breast milk by contraction of the myoepithelial cells and weak anti-diuretic.

3. What are the uses of Oxytocin? Induction of labour, Augmentation of labour, to reduce post-partum

hemorrhage, breast engorgement.

4. What are the side effects of Oxytocin? Uterine hyper stimulation Fetal distress, Placental abruption, fetal death Fluid retention leading on to hyponatremia Hypotension on bolus injection

5. Name the oxytocin receptor antagonist?

Atosiban

6. Name the other drugs acting on the uterus? a. Ergometrine b. Methylergometrine c. Misoprostol (PG E1) d. Carboplast (PG F2a)

7. Name the drugs used as tocolytics.

Beta-agonists (Terbutaline, ritodrine) Calcium channel blockers (Nifedipine) Magnesium sulfate Atosiban Indomethacin

8. What are the advantages of using ergometrine over oxytocin for PPH? Ergometrine acts to contract the entire uterus. Oxytocin contracts the upper

segment preferentially and tends to relax the lower segment. Ergometrine also has a longer half-life than oxytocin.

Page 14: Pharmacology Tutorials - Endocrinology II

9. Name the receptors for vasopressin and their actions?

V1 is present predominantly in the vascular system and mediate the pressor action. V2 is present in the kidneys and mediate water reabsorption. They are also present in the liver and mediate the release of factor VIII and vWf. V3 (previously V1b) is present in the neural structures.

10. What are the vasopressin analogues? Lypressin, Desmopressin, terlipressin, felypressin.

11. What are the uses of vasopressin analogues?

Diabetes insipidus Initial treatment of bleeding oesophageal varices Prophylaxis against bleeding in haemophilia & von Willebrand disease(e.g. before tooth extraction) Trelipressin is used in Hepatorenal syndrome. Felypressin is used as a vasoconstrictor with local anaesthetics. Desmopressin is used for persistent nocturnal enuresis in older children and adults.

12. What are the side effects of vasopressin?

Headache, nausea, abdominal cramps, rarely allergic reactions, hyponatremia and seizures. Iv vasopressin may cause spasm of coronary vessels and precipitate angina. Desmopressin does not have vasopressor action. Nasal irritation and ulceration may occur following nasal spray.

13. What routes are desmopressin given? Intravenous, subcutaneous, nasal spray and oral. (Vasopressin not effective

orally)

14. What are vasopressin antagonists and their uses? Non selective

Conivaptin V1 selective antagonist – Used in Congestive heart failure and ypertension

Relcovaptan V2 selective antagonist – Used in SIADH

Lixivcaptan Mozavaptan Tolavaptan