First Edition

BLOCK 4
ENDOCRINE SYSTEM,
GENITOURINARY SYSTEM &
AUTACOIDS

COPYRIGHT MBBS NOTES DATO FARID FADZILAH

HORMONES & HORMONE ANTAGONISTS

A. Anterior Pituitary Hormones

1. Enumerate growth hormone preparations and IGF-1 preparation. **
2. Enumerate growth hormone release inhibitors and growth hormone antagonist. **
3. Describe the pharmacological actions of growth hormone. **
4. Describe the therapeutic uses of the following: growth hormone preparations, growth
hormone antagonist, growth hormone release inhibitors and IGF-1 preparation. **
5. List the adverse effects of the following: growth hormone preparations, growth
hormone antagonist and growth hormone release inhibitors. **
6. Enumerate prolactin inhibitors. **
7. Describe the therapeutic uses and adverse effects of bromocriptine. **
8. Describe the therapeutic uses of various gonadotropin preparations. **
9. Describe the adverse effects of gonadotropins. **
10. Enumerate GnRH agonists. ***
11. Explain the mechanism of action of GnRH agonists. ***
12. Explain the rationale for combining GnRH agonists with androgen receptor antagonists
in prostatic carcinoma. ***
13. Describe other therapeutic uses of GnRH agonists with their route of administration **
14. Describe the adverse effects of GnRH agonists. *
15. Enumerate GnRH antagonists. *
16. Describe the advantages of GnRH antagonists over GnRH agonists. *
17. Describe the therapeutic uses of GnRH antagonists. *

B. Thyroid & Anti-Thyroid Drugs

1. Describe the thyroid hormone biosynthesis and indicate the sites of action of various
anti-thyroid drugs. ***
2. Classify antithyroid drugs based on chemistry and mechanism of action. ***
3. Describe the mechanism of action of thioamides. ***
4. Describe the important pharmacokinetic features of thioamides. ***
5. Describe the therapeutic uses of thioamides. ***
6. List the adverse effects of thioamides. ***
7. List the thyroid and non-thyroid uses of iodine/iodides. *** (Tripathi)
8. Explain the role of iodides in the preoperative preparation for thyroidectomy. ***
9. Describe the adverse effects of iodides. ***
10. Discuss the role of radioactive iodine in the treatment of hyperthyroidism. ***
11. Explain the role of beta blockers in the management of hyperthyroidism. ***
12. List the drugs used in management of thyroid storm. ***
13. Describe the role of each drug used in the management of thyroid storm. ***
14. List the drugs used in the management of thyrotoxicosis during pregnancy. ***
(Katzung)
15. List thyroid hormone preparations. ***
16. Describe the uses of thyroid hormone preparations. ***
17. List the adverse effects of thyroid hormone preparations. ***
18. Describe the pharmacological differences between levothyroxine sodium and
liothyronine. *** (Katzung)
19. Describe the important pharmacokinetic features of thyroid hormone preparations. **
(Katzung)
20. Describe the precautions to be taken during the administration of thyroid hormone
preparations. ** (Katzung)
C. Insulin & Other Anti-Diabetic Drugs
1. Describe the chemistry, bio-synthesis, secretion and mechanism of action of insulin.
***
2. List the sources of insulin preparations. ***
3. Classify insulin preparations based on their duration of action. ***
4. Explain the characteristic features of regular insulin. *** (Katzung)
5. Explain the characteristic features of following insulin preparations: insulin lispro, NPH
insulin, insulin glargine and insulin detemir. ** (Katzung)
6. Describe various insulin treatment regimens. ** (Katzung)
7. List insulin delivery systems. ** (Katzung)
8. Describe the management of complications of insulin therapy. ***
9. Explain the drug interaction between insulin and beta blockers. ***
10. Classify oral anti-diabetic drugs based on their chemistry. ***
11. Explain the mechanism of action of sulfonylureas. ***
12. Describe the adverse effects of sulfonylureas. ***
13. Describe the important drug interactions of sulfonylureas. ***
14. Describe the important features of various sulfonylureas. **
15. Describe the mechanism of action of repaglinide/nateglinide. ***
16. Describe the role of repaglinide and nateglinide in the management of diabetes. ***
17. Explain the mechanism of action of biguanides. ***
18. List non-diabetic uses of metformin. ***
19. Describe the adverse effects of biguanides. ***
20. List the contraindications for biguanides. ***
21. Describe the mechanism of action of thiazolidinediones. ***
22. Describe the role of thiazolidinediones in diabetes. ***
23. List the adverse effects of thiazolidinediones. ***
24. Describe the mechanism of action of - glucosidase inhibitors. ***
25. List the adverse effects and contraindications of - glucosidase inhibitors. ***
26. Describe the mechanism of action of incretin-mimetics, dipeptidyl peptidase-4
inhibitors, amylin-mimetic drugs and sodium-glucose cotransporter-2 inhibitors. **
27. Explain the role of incretin-mimetics, dipeptidyl peptidase-4 inhibitors, amylin-mimetic
drugs and sodium-glucose cotransporter-2 inhibitors in diabetes. **
28. Choose a suitable anti-diabetic drug for the following: mild diabetes, mild diabetes
with obesity, mild diabetes with COPD, mild diabetes with high risk for hypoglycaemia
and postprandial hyperglycemia. ***
D. Adrenocortical Steroids & Their Analogues
1. Classify glucocorticoids based on their duration of action. ***
2. Enumerate mineralocorticoids. ***
3. Compare the relative glucocorticoid and mineralocorticoid activity of various
glucocorticoids. ***
4. Describe the mechanism of action of corticosteroids at cellular level. ***
5. Describe the important pharmacokinetic features of corticosteroids. ***
6. Explain the pharmacological actions of corticosteroids. ***
7. Explain the therapeutic uses of corticosteroids. ***
8. Describe the adverse effects of corticosteroids. ***
9. Describe the effects of long-term steroid therapy on HPA axis. ***
10. Describe the measures to minimize HPA axis suppression. ***
11. Describe the important contraindications of glucocorticoids. ***
12. State two examples each of steroids which are administered as ***
a) Inhaled steroids
b) Eye/ear drops
c) Dermatological preparations
d) IV/IM injections
e) Intra-articular injections

E. Gonadal Hormones
a) Oestrogens, Progestins & Contraceptives
1. Enumerate natural and synthetic estrogens. ***
2. Describe the principal actions of estrogens on: sex organs, secondary sex
characters and metabolism. ***
3. Describe the mechanism of action of estrogen. ***
4. Describe the advantages of transdermal estradiol over oral estrogens. ***
(Tripathi)
5. Explain the benefits and risks of Hormone Replacement Therapy (HRT). ***
(Tripathi)
6. Describe the current status of HRT. *** (Tripathi)
7. Describe the dosage of estrogen in HRT. ** (Tripathi)
8. Describe the role of progestin in HRT. *** (Tripathi)
9. Describe the other therapeutic uses of estrogens. **
10. Describe the adverse effects of estrogens. ***
11. Enumerate Selective Estrogen Receptor Modulators (SERMs). ***
12. Discuss the role of clomiphene citrate in infertility. ***
13. Explain the rationale for each therapeutic use of tamoxifen and raloxifene. ***
14. Describe the adverse effects of tamoxifen and raloxifene. ***
15. Describe the therapeutic use of fulvestrant. *
16. Enumerate aromatase inhibitors. **
17. Describe the therapeutic uses of aromatase inhibitors. **
b) Progestins
1. Enumerate progestins. ***
2. Describe the principal actions of progesterone on: target organs, body
temperature and metabolism. ***
3. Describe the mechanism of action of progesterone. ***
4. Explain the therapeutic uses of progesterone. ***
5. Describe the adverse effects of progesterone. ***
6. Enumerate antiprogestins. ***
7. Explain the therapeutic uses of mifepristone. ***List the adverse effects of
mifepristone. ***
8. Enumerate Selective Progesterone Receptor Modulators (SPRM). **
9. List the therapeutic uses of Selective Progesterone Receptor Modulators
(SPRM). **

c) Contraceptives
1. List the various groups of oral contraceptive (OC) preparations with examples
for each. ***
2. Describe the regimen of combined pills used for contraception. ***
3. List the advantages and disadvantages of phased regimens and mini pills. **
(Tripathi)
4. Describe the regimens used in postcoital contraception. ***
5. List different types of injectable contraceptive preparations with examples. ***
6. List the advantages and disadvantages of injectable contraceptive preparations.
***
7. List hormonal drug delivery systems used for contraception. **
8. Explain the mechanism of action of hormonal contraceptives. ***
9. Describe the health benefits of hormonal contraceptives. ***
10. Describe the adverse effects of hormonal contraceptives. ***
11. List the contraindications of hormonal contraceptives. ***
12. Describe the drug interactions of OCPs that may lead to contraceptive failure.
***
13. Describe the mechanism of action of centchroman. *
14. List the drugs used as male contraceptives. *
 d) Androgens & Drug Treatment Of Erectile Dysfunction
1. Enumerate androgen preparations. ***
2. Describe principal actions of testosterone and dihydrotestosterone on different
target organs. ***
3. Describe the mechanism of action of androgens. ***
4. Describe the therapeutic uses of androgens. ***
5. Describe the adverse effects of androgens. ***
6. Enumerate anabolic steroids. ***
7. Describe the therapeutic uses of anabolic steroids. ***
8. Describe adverse effects of anabolic steroids. ***
9. Describe the mechanism of action of danazol. **
10. Describe the therapeutic uses of danazol. **
11. List the adverse effects of danazol. **
12. Explain the role of flutamide / bicalutamide in the treatment of prostatic
cancer. ***
13. Enumerate 5- reductase inhibitors. ***
14. Describe the therapeutic uses of 5- reductase inhibitors. ***
15. List the adverse effects of 5- reductase inhibitors. ***
16. Enumerate drugs used for erectile dysfunction. ***
17. Explain the role of phosphodiesterase-5 inhibitors in the treatment of erectile
dysfunction. ***

PARATHYROID HORMONE (PTH), VITAMIN D, CALCITONIN & DRUGS AFFECTING CALCIUM BALANCE

A. Calcium
1. Describe the therapeutic uses of various calcium preparations. *** (Tripathi)
2. List the adverse effects of calcium. *** (Tripathi)

B. Parathyroid Hormone
1. Describe the actions of PTH on: bone, kidney and intestine. **
2. Explain the role of teriparatide in the treatment of osteoporosis. **
3. Describe the therapeutic uses of cinacalcet. **

C. Calcitonin
1. Describe the actions of calcitonin on: bone and kidney. **
2. Describe the therapeutic uses of calcitonin. **
3. List the adverse effects of calcitonin. **

D. Vitamin D
1. Describe the actions of vitamin D on: intestine, bone and kidney. ***
2. Describe therapeutic uses of various vitamin D preparations. ***

E. Bisphosphonates
1. Classify bisphosphonates (bPNs) based on their potency. **
2. Describe the mechanism of action of bPNs. **
3. Describe the therapeutic uses of bPNs. **
4. Explain the adverse effects of bPNs. **
5. List the drugs used in the treatment of osteoporosis. ***
OXYTOCIN & OTHER DRUGS AFFECTING UTERUS

1. List oxytocics. ***

2. Describe the mechanism of action of oxytocin. ***
3. Describe the pharmacological actions of oxytocin. ***
4. Describe the important pharmacokinetic features of oxytocin. ***
5. Describe the therapeutic uses of oxytocin. ***
6. List the adverse effects of oxytocin. ***
7. Explain why oxytocin is preferred over ergometrine/PGs for uterine inertia. ***
8. Describe the obstetric uses, adverse effects and contraindications of ergot alkaloids. ***
9. List tocolytics acting through different mechanisms. ***
10. Describe the role of beta-2 agonists as tocolytics. **

AUTACOIDS

A. Drug Therapy Of Migraine

1. Enumerate drugs used in the treatment of mild, moderate and severe migraine. ***
2. Enumerate drugs used for the prophylaxis of migraine. ***
3. Describe the role of following drugs in migraine: triptans, ergot alkaloids. **
4. Describe the other therapeutic uses of ergot alkaloids. *
5. Describe the adverse effects and contraindications of the following: sumatriptan and
ergot alkaloids. ***

B. Anti-Histaminics
1. Enumerate first generation and second generation antihistaminics. ***
2. Describe the therapeutic uses of antihistaminics. ***
3. Describe the adverse effects of antihistaminics. ***
4. Describe the advantages of second generation antihistaminics over the first generation
antihistaminics. ***

C. Prostaglandins
1. Explain the therapeutic uses of different prostaglandin preparations. ***
2. List the adverse effects of prostaglandins. ***
HORMONES &
HORMONE
ANTAGONISTS
 ANTERIOR PITUITARY HORMONES

CLASSIFICATION OF ANTERIOR PITUITARY HORMONES

Somatotropin
Growth hormone
Somatrem
preparation
Sermorelin

Mesacermin
IGF-1 preparation
Mesacermin rinfabate

Somatostatin
Growth hormone releasing Optreotide
inhibitor Sandostatin
Lancreotide

Growth hormone antagonist Pegvisomant

Bromocriptine
Prolactin inhibitor Dopamine
Cabergoline

Nafarelin
Goserelin
Triptorelin
GnRH agonist Buserelin
Deslorelin
Histrelin
Leuprolide

Cetrorelix
Ganirelix
GnRH antagonist
Abarelix
Degarelix
GROWTH HORMONE

PHARMACOLOGICAL ACTION
Attainment of normal adult size
Increases size and mass of all body parts except brain and eyes
For development of sex organ, both growth hormone and gonadotropin are needed
Anabolic action on muscle (protein) increase in muscle mass
Catabolic action on lipid reduction in central adiposity
Anabolic and growth promoting effect of growth hormone are indirect & are mediated by
activating insulin-like growth factor type 1 (IGF-1) at open epiphyses of long bones that
causing bone growth

METABOLISM
Growth hormone reduces insulin sensitivity, hence decreases utilization of glucose by muscle
and increases glycogenolysis which increases glycogen level
Growth hormone increases protein synthesis & promotes positive N2 balance increases
cellular uptake of amino acids
Growth hormone initially has insulin-like effect, followed by antagonist effect to insulin
Diabetogenic effect decreased uptake of glucose into tissue and increased release of
glucose from the liver
Increases mobilization of free fatty acids from adipose tissue (lipolysis), thus predisposing
formation of ketone bodies especially among diabetic patients
GROWTH HORMONE PREPARATION

DRUGS
Somatotropin, Somatrem, Sermorelin

INTRODUCTION
Human pituitary growth hormone such as Somatotropin is no longer used
Recombinant human growth hormone (rhGH) is most commonly used nowadays
The longer acting preparation are now available: Somatropin and Somatrem (both of them are
equipotent to Somatotropin)
Sermorelin: synthetic form of growth hormone preparation

THERAPEUTIC USES
Somatotropin S.C. permits many children with short stature to achieve normal adult height
Somatotropin S.C. to treat adult onset growth hormone deficiency, which is usually due to
damage to hypothalamus or pituitary caused by tumour, infection or radiation therapy
Used for increasing height of girls with Turner syndrome (failure of ovary to respond to
pituitary hormone)
Used for AIDS-related muscle wasting
Potent anabolic agent approved for management of burn injuries
Sometimes it gets abused by athletes
Used for its anti-aging effects, but does not reverse manifestation of normal aging
Short bowel syndrome, usually associated with malabsorption growth hormone promotes
intestinal growth and improve patient condition

ADVERSE EFFECTS
Pain at site of injection
Precipitation of type 2 diabetes
Induction of insulin resistance
Arthralgia in hand and wrist
Carpal tunnel syndrome
Myalgia
Fluid retention and headache due to intracranial hypertension (visual change, nausea,
vomiting)
Patients with Turner syndrome have high risk of otitis media
Lipodystrophy
Peripheral oedema (due to fluid and sodium retention)
Glucose intolerance
Scoliosis in children

CONTRAINDICATION
Cancer and other critically ill patients (increased morbidity)
IGF-1 PREPARATION

DRUGS
Mesacermin, Mesacermin rinfabate

MESACARMIN
Combination of recombinant human IGF-1 with recombinant human IGF binding protein-3
Given by subcutaneous injection

THERAPEUTIC USES
Replacement of IGF-1 deficiency that is not responsive to exogenous growth hormone
(Somatropin treatment)
IGF-1 deficiency occur due to :
Mutation of growth hormone receptor with aberrant growth hormone signaling
Development of antibody against growth hormone
Deficiency IGF binding protein-3

ADVERSE EFFECTS
Hypoglycaemia
Intracranial hypertension
Reversible rise in liver enzymes
Lymphoid tissue hypertrophy including enlarged tonsil
Lipohypertrophy (presumably secondary to activation of insulin receptor)
GROWTH HORMONE RELEASE INHIBITORS

DRUGS
Somatostatin, Optreotide, Sandostatin, Lancreotide

SOMATOSTATIN
Primarily inhibits secretion of growth hormone
Also inhibits TSH from anterior pituitary, insulin from pancreas and gastrin from stomach
Use of Somatostatin is limited due to:
Very short half-life
Lack of specificity for inhibiting only growth hormone
Growth hormone rebound after discontinuation
Therapeutic uses:
Prevents bleeding from oesophageal varices
Prevents upper gastrointestinal bleeding from haemorrhagic gastritis, peptic ulcer,
intestinal/pancreatic fistula or from hypersecretory tumour of intestinal tract
Diabetic ketoacidosis acts as an adjuvant
Acromegaly (limited use)
Adverse effects:
Nausea
Diarrhoea
Dyspepsia
Steatorrhoea

OCTREOTIDE
Long acting analogue of Somatostatin
More potent than Somastostatin in inhibiting growth hormone release
Twice potent in reducing insulin secretion
Chance to get hyperglycemia as side effect is less compared to Somatostatin due to its weak
inhibitor of insulin secretion
Therapeutic uses:
Reduce symptoms due to growth hormone-secreting pituitary tumour eg. acromegaly
AIDS-associated diarhoea
Breast cancer
Cushings syndrome
Insulinoma
Bleeding in oesophageal varices and peptic ulcer (as it decreases mucosal blood flow)
Control symptoms in patients having carcinoid syndrome, VIP-secreting tumour,
gastrinoma, secretory diarrhoea associated with diabetes or irritable bowel syndrome
Adverse effects:
Nausea
Diarrhoea
Steatorrhea
Abdominal pain
Gall stones
Sinus bradycardia
SANDOSTATIN
Slow release formulation of Octreotide
Adverse effects:
Abdominal pain
Nausea
Steatorrhoea
Gall stones (due to biliary stasis)
Long term use may lead to conduction defect and vitamin B12 deficiency

LANCREOTIDE
Similar to Octreotide
Therapeutic uses:
Used to treat thyroid tumor
Longer acting formulation used to treat acromegaly

GENERAL THERAPEUTIC USES

Acromegaly
Watery diarrhoea
Hypokalaemia
Achlorhydria
Diabetic diarrhoea
Somastostatin receptor scintigraphy using radiolabel Octreotide
Useful in localizing neuroendocrine tumor having Somatostatin receptor
and helps to predict response to Octreotide therapy
Acute control of bleeding from oesophageal varices

GROWTH HORMONE ANTAGONIST

PEGVISOMANT
Prevents peripheral growth hormone binding to its receptor and suppresses serum IGF-1 level
After its attachment with growth receptor, it allows its dimerization but blocks the ongoing
conformational changes that activate signal transduction
However, formation of specific antibody limits its long term efficacy
Therapeutic uses:
Acromegaly
Highly effective alternative for use in patient who have not respond to Somatostatin
analogue either as sole therapy
As temporary measure while waiting for radiation therapy receives increased
scrutiny as first line therapy
Adverse effects:
Elevation of hepatic transaminase
Lipohypertrophy at injection site
PROLACTIN INHIBITORS

DRUGS
Bromocriptine, Dopamine, Cabergoline

BROMOCRIPTINE
Semi-synthetic ergot derivative
Acting as a potent Dopamine agonist mainly at D2 receptor
Weak -adrenergic blockade

THERAPEUTIC USES
It relieves symptoms of parkinsonism that result from Dopamine deficiency in nigrostriatal
pathway
Acromegaly reduces growth hormone level, but less effective than Octreotide and
Lancreotide
Restless leg syndrome
Hyperprolactinemia
Dopamine is the main factor controlling prolactin secretion
Hence, Bromocriptine (Dopamine agonist) effectively reduces the secretion of
prolactin

ADVERSE EFFECTS
Nausea and vomiting (due to stimulation of Dopamine receptor in CTZ)
Postural hypotension (due to -adrenergic blockade)
Constipation
Hallucination
Confusion
Psychosis
Behavioural alteration
Nasal congestion
Headache
Digital vasospasm
 GnRH PREPARATION

DRUG
Gonadrelin

THERAPEUTIC USES
Diagnostic use
Amennorhoea and infertility (due to deficient production of GnRH by pituitary)
Hypogonadotropic hypogonadism in males delay puberty or defective spermatogenesis or
oligozoospermia
Cryptochidism
To aid in vitro fertilization to induce simultaneous maturation of several ova and to
precisely time ovulation

ADVERSE EFFECTS
Ovarian hyperstimulation : polycystic ovary, pain in lower abdomen, ovary bleeding
Ovary enlargement: ascites and rupture
Spontaneous abortion
Precocius puberty in children
Gynaecomastia in male
Multiple pregnancy
Headache
Oedema
Allergic reaction
GnRH AGONISTS

DRUGS
Nafarelin, Goserelin, Triptorelin, Buserelin, Deslorelin, Histrelin, Leuprolide

MECHANISM OF ACTION

Pulsatile administration Continuous therapy

Increases FSH and LH Initially, increases gonadotropin secretion.
Later, after 2 weeks of therapy:
Ovulation down regulation of GnRH receptor due to their
prolonged occupation by GnRH

Decreases FSH and LH

Suppression of ovulation and suppression of
spermatogenesis

DRUGS ADMINISTRATION ROUTE THERAPEUTIC USES

Nafarelin Nasal spray Endometriosis, uterine fibroid, precocious puberty
Goserelin S.C. injection Endometriosis, uterine fibroid, prostate carcinoma
Triptrorelin I.M. depot injection Prostate cancer
Buserelin Nasal spray Endometriosis, prostate carcinoma
Leuprolide I.M. depot injection Endometriosis, uterine fibroid, precocious puberty,
prostate cancer
Histrelin S.C. injection Prostate carcinoma, precocious puberty

GENERAL THERAPEUTIC USES

Prostatic carcinoma
Precocious puberty
Breast cancer in pre-menopausal women
Uterine fibroid
Endometriosis
Polycystic ovarian disease
Control ovarian hyperstimulation in assisted reproduction

ADVERSE EFFECTS
Hot flushes, headache and nausea
Osteoporosis
Breast atrophy
Vaginal dryness
Loss of libido
GnRH ANTAGONISTS

DRUGS
Cetrorelix, Abarelix, Ganirelix, Degrarelix

MECHANISM OF ACTION
Competitively block GnRH receptor in anterior pituitary
Inhibit FSH and LH release without initial stimulation
Males: decrease testosterone level, useful in advance prostate cancer
Female: to suppress endogenous LH surge during controlled ovarian hyperstimulation and to
suppress oestrogen release from ovary

THERAPEUTIC USES
Advanced prostate cancer
GnRH antagonist is preferred over GnRH agonist because it does not cause initial
increase (flare up) in gonadotropin secretion and does not cause histamine release
So it does not exacerbate cancer symptoms initially and does not cause anaphylactoid
reaction
Uterine fibroid and endometriosis
As an adjuvant during in vitro fertilization (IVF)

RATIONALE OF COMBINING GnRH AGONIST WITH ANDROGEN RECEPTOR ANTAGONIST IN

PROSTATIC CARCINOMA
GnRH antagonist does not cause initial increase (flare up) in gonadotropin secretion, but it will
directly decrease GnRH secretion (hence decrease oestrogen secretion)
GnRH antagonist does not exacerbate cancer symptom initially
GnRH antagonist does not cause anaphylactoid reaction
GnRH agonist decreases testosterone level if it is administered as I.M. depot injection for 1-2
weeks

ADVANTAGES OF GnRH ANTAGONIST OVER GnRH AGONIST

Immediate gonadotropin suppression by competitive antagonism, so duration of
administration become shorter
Carry lower risk of ovarian hyperstimulation syndrome and multiple pregnancy
Achieve more complete suppression of endogenous gonadotropin secretion than GnRH
agonist
 THYROID & ANTI-THYROID DRUGS

THYROID HORMONE BIOSYNTHESIS

Step 1: Uptake of iodine; iodide trapping by follicular cells
Step 2: Synthesis of thyroglobulin and oxidation of iodides
Step 3: Iodination of tyrosine
Step 4: Coupling of MIT and DIT
Step 5: Secretion and release of T3 and T4
Step 6: Transportation of T3 and T4 into plasma and their binding protein
Step 7: Peripheral activation of T3 and T4 & metabolism of thyroid hormone
CLASSSIFICATION OF ANTI-THYROID DRUGS
a) Based on chemistry

Classification Drugs Mechanism of action

Thioamide Propylthiouracil Inhibit thyroid peroxidase which is required

derivatives Carbimazole for oxidation of I- (Step 2)
Methimazole Inhibit iodination of tyrosine (Step 3)
Inhibit coupling of MIT/DIT to form thyroid
hormone production (Step 4)

Radioactive iodine 131

Iodine Emits -rays (for tracer studies) and -
particles
-particles destroy thyroid parenchyma
destructive effect causes pyknosis and
necrosis fibrosis of thyroid follicular cells
(without damaging neighbouring tissue)

Iodides Aqueous KI High iodide concentration limits its own

solution transport (Step 1)
Lugols iodine Limits thyroid hormone release (Step 5)
Reduces thyroid blood flow

Iodinated contrast Oral ipodate Inhibits 5-deiodinase (DID-I and DID-II)

media Ipanoic acid enzymes, hence prevent conversion of T4 to
Diatrizoate (I.V.) T3 in the liver, kidney, pituitary gland and
brain

b) Based on mechanism of action

Inhibits hormone synthesis (anti-thyroid drugs): Propylthiouracil, Methimazole,
Carbimazole
Inhibits iodide trapping (ionic inhibitors): Thiocyanates, Perchlorates, Nitrates
Inhibits hormone release: Iodine, iodides of Na+ and K+, Organic iodide
Destroys thyroid tissue Radioactive iodine (131Iodine, 125Iodine, 123Iodine)
 THIOAMIDES

MECHANISM OF ACTION
Inhibit thyroid peroxidase which is required for oxidation of I- (Step 2)
Inhibit iodination of tyrosine (Step 3)
Inhibit coupling of MIT/DIT to form thyroid hormone production (Step 4)

IMPORTANT PHARMACOKINETIC FEATURES

Methimazole (an active metabolite of Carbimazole) is more potent than Propylthiouracil
Short plasma t1/2 which is 2-6 hours
Selectively accumulated in thyroid gland
Quickly absorbed orally
Widely distributed
Metabolized in the liver and excreted in urine
Carbimazole can enter into the milk and crosses placental barrier hence can cause foetal
hypothyroidism

THERAPEUTIC USES
Hyperthyroidism
Thyrotoxic crisis
Surgical subtotal thyroidectomy

ADVERSE EFFECTS
Pruritic or urticarial rash
Vasculitis
Arthralgia
Cholestatic jaundice
Lupus-like reaction
Agranulocytosis
 IODINES & IODIDES

THERAPEUTIC USES OF IODINE & IODIDES

Pre-operative preparation for thyroidectomy in Graves disease makes the thyroid gland
becomes less vascular and more compact for easier operation
Thyroid storm Lugols iodine or iodine containing radiocontrast media
Prophylaxis of endemic goitre Iodized salt
Antiseptics Tincture iodine, Povidone iodine

ROLE OF IODIDES IN THE PRE-OPERATIVE PREPARATION FOR THYROIDECTOMY

Make the gland less vascular and more compact easier to operate on
-blocker given adjunctively to prevent effects of thyrotoxicosis

ADVERSE EFFECTS OF IODIDES

Hypersensitivity
Chronic iodine toxicity (iodism) is characterized by:
Acneiform rash
Swollen salivary glands
Stomatitis
Metallic taste
Bleeding disorders
Conjunctivitis

RADIOACTIVE IODINES

ROLE OF RADIOACTIVE IODINE IN THE TREATMENT OF HYPERTHYROIDISM

131Iodine is most commonly used
123Iodine is for diagnostic use
131Iodine emits -rays and -particles
It gets accumulated in thyroid gland -particles destroy thyroid parenchyma

THERAPEUTIC USES
Hyperthyroidism due to Graves disease
Toxic nodular goitre

ADVANTAGES
Simple, convenient and inexpensive
No surgical risk, scar or injury to parathyroid glands or recurrent laryngeal nerve
Once hyperthyroidism is controlled, cure is permanent
DISADVANTAGES
Hypothyroidism
Long latent period of response
Contraindicated in pregnancy foetal thyroid destroyed, causing cretinism and other
abnormalities if given during 1st trimester
Not suitable for young patients more likely to develop hypothyroidism
Risk of thyroid carcinoma (rare)

ROLE OF -BLOCKERS IN THE MANAGEMENT OF HYPERTHYROIDISM

In hyperthyroism, there is up-regulation of 1 receptors in myocardium
This increases sensitivity of heart to catecholamines
Non-selective -blockers eg. Propranolol are used along with anti-thyroid drugs to:
Prevent thyrotoxicosis-induced tachycardia, tremors, sweating and anxiety
Inhibit peripheral conversion of T4 to T3
Pre-operative use before subtotal thyroidectomy
While awaiting response of Carbimazole and 131Iodine

ROLE OF DRUGS USED IN THE MANAGEMENT OF THYROID STORM

Drugs Role

Propylthiouracil Blocks thyroid hormone synthesis

Blocks peripheral conversion of T4 to T3

Collosal iodine Blocks thyroid hormone release

Sodium ipodate Blocks thyroid hormone release

Blocks peripheral conversion of T4 to T3

Propranolol Controls increased sympathetic activity and CVS manifestations

Blocks peripheral conversion of T4 to T3

Diltiazem Used if patients have complications like asthma or heart failure

Hydrocortisone Protects patients against shock

Blocks peripheral conversion of T4 to T3

DRUGS USED IN THE MANAGEMENT OF THYROTOXICOSIS DURING PREGNANCY

Propylthiouracil with lower dose because it does not cross placental barrier, greater plasma
binding protein and less transferred to foetus
Thyroid supplement
Methimazole risk of foetal scalp defect
 THYROID HORMONE PREPARATIONS

DRUGS
Levothyroxine sodium (T4)
Liothyronine sodium (T3)

THERAPEUTIC USES
Hypothyroidism
Myxoedema coma
Hypothyroidism during pregnancy
Subclinical hypothyroidism
Endemic goitre
Endemic cretinism
Empirical use in refractory anaemia, menstrual disorder, chronic and non-healing ulcer
Papillary carcinoma by suppressing TSH

ADVERSE EFFECTS
Tachycardia
Palpitation
Cardiac arrhythmias
Tremors
Weight loss
Headache
Diarrhoea
Insomnia
Heat intolerance

IMPORTANT PHARMACOKINETIC FEATURES

Oral bioavailability of Levothyroxine sodium is 75%
Severe hypothyroidism reduces oral absorption
Administered in empty stomach to avoid food interference
Reduced absorption: Sucralfate, Fe3+, Ca2+, proton pump inhibitors
Increased metabolism: CYP-3A4 inducers like Rifampicin, Phenytoin, Carbamazepine
PHARMACOLOGICAL DIFFERENCES

Levothyroxine sodium (T4) Liothyronine sodium (T3)

Half-life Long (7 days) Short (1 day)
Potency Less potent More potent (3-4 times)
Dosing Once daily dosing Multiple daily dosing
Cost Low High
Laboratory Easy Difficult
measurement of
serum level
Cardiotoxicity Lower risk Higher risk
Other advantages Stability Short-term suppression of TSH
Content uniformity Special situation:
Lack allergenic foreign protein Severe myxoedema
Produces both T3 and T4 Myxoedema coma
(intracellular conversion) Thyroid carcinoma surgery
Preferred Yes No

PRECAUTIONS TO BE TAKEN DURING THE ADMINISTRATION

Myxoedema and Low level of thyroid hormone protects heart against increasing
coronary artery disease demands that could result in angina and MI in older patients
Correction of myxoedema must be done cautiously to avoid provoking
arrhythmia, angina and acute myocardial infarction

Myxoedema coma Give all drugs I.V. because patient absorbs poorly from other routes
Large pool of empty T3 and T4 binding sites must be filled before free
thyroxine takes action

Pregnancy Given early and adequate, important for foetal brain development

Administration Avoid food such as bran, soy and coffee & drugs that will impair its
absorption
Administered in empty stomach

Monitoring Children should be monitored for normal growth and development

It takes 6-8 weeks to reach steady-state level in blood
In children: restlessness, insomnia, accelerated bone maturation and
growth may be signs of thyroxine toxicity
In adults: increased nervousness, heat intolerance, episodes of
palpitation and tachycardia, or unexplained weight loss may be the
presenting symptoms

Reduced absorption Sucralfate, Fe3+, Ca2+, proton pump inhibitors

Increased metabolism CYP-3A4 inducers like Rifampicin, Phenytoin, Carbamazepine

 INSULIN & OTHER ANTI-DIABETIC DRUGS

DIABETES MELLITUS
Chronic metabolic disease
Either no or inadequate insulin secretion with or without concurrent impairment of insulin
action (important to determine because each need different treatment)
Types:
Type 1: insulin dependent diabetes mellitus
Type 2: non-insulin dependent diabetes mellitus
Type 3: others
Type 4: gestational diabetes mellitus

INSULIN

INTRODUCTION
Discovered in 1921 by Banting and Best
Synthesized by the -cells of pancreas
Pre-pro-insulin (a single chain polypeptide precursor) pro-insulin insulin (formed by
removal of the C-peptide from pro-insulin by proteolysis)
C-peptide (connecting peptide) in pro-insulin can produce immunogenic reaction, but also
acts as a marker for insulin level as it is produced alongside insulin
Insulin consists of two peptide chains called A and B chains which are connected by a
disulphide bridges
REGULATION OF INSULIN SECRETION
There is always a minimal level of insulin level throughout our body at all time
Regulated by chemical, hormonal and neural mechanisms

1) Chemical mechanism
Stimulates beta cells and release of insulin
Glucose:
First phase (within 2 minutes, brief)
Second phase (delayed, more sustained)
Mechanism of action:
Glucose enter pancreatic beta cells by glucose transporter (GLUT2)

ATP produced (glycolysis)

Block ATP-sensitive potassium channels

Lead to depolarization

Promotes or activates voltage gated calcium channel (influx of Ca2+)

Promotes exocytosis of insulin
Others: amino acids, fatty acids and ketone bodies

2) Hormonal mechanism
Glucagon-like peptide 1 (GLP-1)
Glucose-dependent insulinotropic polypeptide (GIP)
Vasoactive intestinal peptide (VIP)
Pancreozymin-cholecystokinin

Stimulate Beta Cells Insulin

Inhibit Inhibit
Alpha Cells `` Stimulate
Delta (D) Cells
Glucagon Somatostatin
Inhibit

3) Neural mechanism
Adrenergic 2 decreases insulin release
Cholinergic-muscarinic stimulates insulin release
 Chemical mechanism of insulin secretion

MECHANISM OF ACTION OF INSULIN

Insulin binds to insulin receptor on alpha subunits

Depolymerization (come close together)

Phosphorylate tyrosine residues of insulin receptor substrate protein (IRS-1 & IRS-2)

IRS molecules bind to and activate other kinases

Generation of various second messengers

Activation or inhibition of enzymes involved in metabolic action of insulin rapid actions;
Activation of transcription factors, proliferation and differentiation of specific cells long term effects
ACTIONS OF INSULIN
Insulin has profound effect on metabolism of carbohydrates, fat and protein
Facilitates entry of glucose into all cells in the body except RBCs, WBCs, liver and brain
DNA-mediated synthesis of glucose transporter and enzyme of amino acid metabolism
Growth regulation

Inhibits glycogenolysis
Gluconeogenesis
Liver Promotes glycogen synthesis
Lipogenesis
Decreases protein breakdown

Stimulates glucose uptake and oxidation

Adipose tissue Promotes formation and storage of triglycerides
Inhibits lipolysis

Increases protein synthesis

Stimulates glucose uptake
Muscles Glycogen synthesis
Glycolysis
Inhibits protein breakdown
SOURCES OF INSULIN
Bovine and porcine insulin
Conventional insulin preparation
Disadvantages: allergy, resistance
Highly purified insulin preparations
Single peak insulin
Monocomponent insulin
Human insulin: recombinant DNA technology

INSULIN PREPARATION

Rapid and Insulin lispro

Taken 0-5 minutes
ultra-short Insulin aspart
before meal
acting Insulin glulisine

Taken 30 minutes before Regular insulin (human insulin)

Short acting
meal Prompt insulin zinc suspension or semi Lente

Insulin zinc suspension or Lente

Intermediate Does not need to be
Neutral protamine hagedorn (NPH) human
acting given with meal
insulin

Extended insulin zinc suspension or Ultra Lente

Does not need to be Insulin glargine
Long acting
given with meal Insulin etermir
Protamine zinc insulin (PZI)
CHARACTERISTIC FEATURES

Soluble, crystalline zinc insulin (zinc is given for stability), short acting
Forms hexamer (hexameric in nature):
This leads to delayed onset because of slow absorption due to the
large size hence prolonged time to peak injection
Given through subcutaneous injection where they are diluted by
interstitial fluid to form dimers, then monomers and then being
absorbed (monomerization)
Subcutaneous injection onset of 30-45 minutes, peak around 2-3 hours,
duration of 5-8 hours
Regular insulin
If administered at meal time leads to early post-prandial hyperglycaemia
and late postprandial hypoglycaemia
Because of delayed onset, it needs to be given 30-45 minutes before meal
time
Can be administered by I.V. route
Advantages of I.V.: useful for diabetic ketoacidosis, after surgery and acute
infections
Dose-dependent onset and duration of action, variability of absorption
hence mismatching of insulin supply with need may occur

-chain: proline (B28B29), lysine (B29B28)

Very low propensity to self-associate to form dimers
Stabilize into hexamers
After subcutaneous injection it quickly dissociates into monomers
Insulin lispro
(hence rapidly absorbed)
Onset of 5-15 minutes, peak around 1 hour
Provides post-prandial insulin replacement
Less risk of post-prandial hypoglycaemia

Onset of action is delayed by combining insulin and protamine

Onset of 2-5 hours, duration of 4-5 hours
Proteolytic tissue enzymes degrade protamine permit insulin
NPH insulin
absorption
Action is highly unpredictable
Variability of absorption

Attachment of two arginine molecules to -chain carboxyl terminal

Substitution of glycine for asparagine (A21)
Soluble in acidic medium
Subcutaneous injection precipitates in body pH insulin molecules
Insulin glargine slowly dissolve away from the crystalline depot low and continuous level
Should not be mixed with other insulin
Long acting, peakless insulin
Action is maintained for 11-24 hours provides basal insulin replacement
Administered once daily
 B30 threonine X: Myristic acid attached to B29 lysine
Increases self-aggregation and albumin binding
Insulin determir Dose-dependent onset of action of 1-2 hours and duration of action >24
hours
Administered twice daily to obtain a smooth background insulin level

NPH + Lispro/Aspart/Glulisine insulin (acutely mixed)

Mixture of Premixed formulations: Neutral protamine lispro (NPL) + Lispro (50%/50%;
insulin 75%/25%)
Neutral protamine aspart (NPA) + Aspart insulin

INSULIN TREATMENT REGIMEN

Post-prandial insulin requirement level control
Basal insulin requirement level control

Conventional insulin therapy

One injection/day to many injection/day
Intermediate or long acting insulin alone or with short or rapid acting insulin or pre-mixed
insulin
Sliding-scale regiment adjustable administration and usage of treatment depending on
meal consumption
For basal requirement, we have long acting and short acting
Long acting: once daily before breakfast
Short acting: twice daily before morning and maybe before lunch
For post prandial controls, we have regular and rapid acting
Regular acting: 30-45 minutes before meal
Rapid acting: immediately after meal
30:70 mixture of regular and NPH insulin
Injected subcutaneously before breakfast and dinner
Insulin glargine once daily before breakfast or bedtime + 2-3 mealtime injections of rapid
acting insulin (Lispro/Aspart insulin)
Intensive insulin therapy
Total daily requirement of insulin is assessed by testing urine or blood glucose levels
Requirement varies in different patients calculation has to be individualized
Half the total daily insulin dose covers basal insulin requirements
Remainder includes post-prandial and other high blood sugar corrections
Meal or snacks requirement is calculated by considering carbohydrates content of meal,
current plasma glucose levels and target glucose level
High blood sugar correction formula predicted fall in plasma glucose after 1U of rapid
acting insulin (diurnal variation in insulin sensitivity can be considered)
Devices:
Continuous subcutaneous insulin infusion devices (CSII)
Insulin pumps
Portable pen injectors
Advantages:
Greater flexibility in diet
Provides round the clock euglycaemia
Reduces the occurrences and slows the progression of diabetic complications
Delays end organ damages

INSULIN DELIVERY SYSTEMS

Inhaled insulin
Implantable pumps
External artificial pancreas
Intra-peritoneal or oral insulin

COMPLICATIONS OF INSULIN THERAPY

Hypoglycaemia
Signs and symptoms:
Autonomic symptoms
Dizziness, headache and fatigue
Hypoglycaemic unawareness can lead to coma and death
Prevention: Diabetic cards and sugar supply
Treatments:
Mild oral glucose, Dextrose
Severe 50 ml of 50% Dextrose I.V.
Glucagon 0.5-1.0 mg subcutaneous/intramuscular injection
Local reactions: lipodystrophy, swelling and erythema
Allergy
Insulin resistance
Insulin requirement is increased to >100 U/day
Development of IgG anti-insulin antibodies

DRUG INTERACTION BETWEEN INSULIN & -BLOCKERS

Delayed recovery from hypoglycaemia because the glycogenolysis is block (through 2
receptors)
Masking of warning signs of hypoglycaemia (through 1 receptors)
ANTI-DIABETIC DRUGS

CLASSIFICATION
Sulfonylureas
First generation: Tolbutamide, Chlorpropramide
Second generation: Glibenclamid, Glipizide, Gliclazide, Glimepiride
Meglitinide analogues: Repaglinide, Nateglinide
D-phenylalanine derivatives: Nateglinide
Biguanides: Metformin, Phenformin
Thiazolidinedines: Rosiglitazone, Pioglitazone
Alpha glucosidase inhibitors: Acarbose, Miglitol, Vaglibose

SULFONYLUREAS

DRUGS
First generation: Tolbutamide, Chlorpropramide
Second generation: Glibenclamid, Glipizide, Gliclazide, Glimepiride

IMPORTANT FEATURES
Stimulates insulin release from pancreatic -cells
Chronic administration sensitize target tissue to the action of insulin, inhibit hepatic
gluconeogenesis and decrease glucagon levels
Not effective in type 1 diabetes mellitus because there is no functioning -cells
Glimepiride and Gliclazide have extra anti-oxidant action

MECHANISM OF ACTION
Sulfonylurea binds to SUR1

Inhibits ATP sensitive K+ channels

Depolarization of -cells

Stimulates voltage gated calcium channels

Increase influx of Ca2+

Degranulation occurs and increase release of stored insulin from -cells
ADVERSE EFFECTS
Hypoglycaemia lower incidence with Glipizide, Gliclazide, Glimepiride
Hypersensitivity reaction
Weight gain
Nausea
Vomiting
Contraindicated in pregnancy
Chlorpropramide cholecystatic jaundice, photosensitivity, haematologic toxicity, alcohol
intolerance (hence not used anymore)

DRUG INTERACTIONS
Salicylates/Sulphonamides X Sulfonylureas Displacement from plasma binding site
Warfarin/Ketoconazole X Sulfonylureas Decrease metabolism of Sulfonylureas (increased
toxicity)
Phenytoin/Rifampicin X Sulfonylureas Enzyme induced (hence increased efficacy)
Propanolol X Sulfonylureas Mask the effect of diabetes (autonomic response) severe
hypoglycaemia

MEGLITINIDE ANALOGUES

DRUGS
Repaglinide, Nateglinide

MECHANISM OF ACTION
Meglitinide analogue binds to SUR1

Inhibits ATP sensitive K+ channels

Depolarization of -cells

Stimulates voltage gated calcium channels

Increase influx of Ca2+

Degranulation occurs and increase release of stored insulin from -cells

ROLE IN THE MANAGEMENT OF DIABETES MELLITUS

Rapid onset and shorter duration of action
Controls post-prandial hyperglycaemia
Lower risk of serious hypoglycaemia
Used in type 2 diabetes mellitus alone or in combination with other anti-diabetics
 BIGUANIDES

DRUGS
Metformin, Phenformin

MECHANISM OF ACTION
Suppress hepatic gluconeogenesis
Promote peripheral uptake and utilization of glucose reduce insulin resistance
Retard intestinal absorption of glucose
Promote insulin binding to its receptor

THERAPEUTIC USES OF METFORMIN

Anorectic action
Treat hirsutism
Enhances infertility in patients with polycystic ovarian syndrome (PCOS)

ADVERSE EFFECTS
Gastrointestinal adverse effects: metallic taste, anorexia, nausea
Lactic acidosis
Vitamin B12 deficiency
Rarely causes hypoglycaemia

CONTRAINDICATIONS
Peripheral neuritis
Renal and hepatic diseases
Asthma
Chronic obstructive pulmonary disease (COPD)
Congestive heart failure
Alcoholics
THIAZOLIDINEDIONES

DRUGS
Rosiglitazone, Pioglitazone

MECHANISM OF ACTION
Activate peroxisome proliferators activated receptor gamma (PPAR-)
Hence promote transcription of insulin responsive genes

ROLE IN DIABETES MELLITUS

Increase insulin sensitivity and reverse insulin resistance
Increase the number of GLUT-4 receptor hence promote peripheral glucose uptake and
utilization
Suppress hepatic gluconeogenesis
Reduce HbA1C level
Increase HDL cholesterol level
Decrease triacylglycerol level

* Use in combination with Sulmetformin

ADVERSE EFFECTS
Plasma volume expanders
Can lead to oedema and weight gain
Hepatic dysfunction
Glitazones + Insulin precipitation of congestive heart failure

-GLUCOSIDASE INHIBITORS

MECHANISM OF ACTION
Competitive inhibitors of -glucosidase and -amylase
Decrease digestion and absorption of polysaccharide
Used as an adjuvant

ADVERSE EFFECTS
Hypokalaemia
Gastrointestinal adverse effects

CONTRAINDICATIONS
Intestinal bowel disease
Intestinal obstruction
OTHERS

MECHANISM OF ACTION

Drug: Exenatide (synthetic GLP-1)

Stimulate insulin secretion
Incretin mimetics Decrease glucagon release
Slow gastric emptying decrease nutrient absorption
Decrease appetite (acting on hypothalamus)

Drugs: Sitaglipin, Vildaglipin

Dipeptidyl peptidase-4 Inhibit dipeptidyl peptidase-4
inhibitors Hence, prevent degradation of GLP-1 and other Incretins
prolonging their action

Drug: Pramlintide (synthetic amylin analogue)

Anorectic action
Amylin mimetics Inhibit glucagon secretion
Delay gastric emptying
Reduce post-prandial hyperglycaemia

Sodium-glucose co- Drugs: Dapaglifozin, Serglifozin

transporter-2 Decrease the amount of glucose reabsorption from the proximal
inhibitors convoluted tubule and increase its urinary excretion

ROLE IN DIABETES MELLITUS

Incretin mimetics reduce post-prandial hyperglycaemia
Dipeptidyl peptidase-4 inhibitors adjuvant in type 2 diabetes mellitus
Amylin mimetics adjuvant in type 1 and type 2 diabetes mellitus
 ADRENOCORTICAL STEROIDS & THEIR ANALOGUES

CLASSIFICATION OF GLUCOCORTICOIDS
Short acting (8-12 hours): Hydrocortisone, Cortisone
Intermediate acting (12-36 hours): Prednisone, Prednisolone, Methylprednisolone,
Triamcinolone
Long acting (36-72 hours): Betamethasone, Dexamethasone

MINERALOCORTICOIDS
Fludrocortisone
DOCA (Deoxycorticosterone acetate)

COMPARING RELATIVE GLUCOCORTCOIDS & MINERALOCORTICOIDS ACTIVITY

a) Hydrocortisone
Glucocorticoids : Mineralocorticoids = 1 : 1 (equal action)
Rapid acting and short duration of action
Used in acute adrenal insufficiency
b) Prednisolone
More potent and more selective Glucocorticoids actions
Glucocorticoids : Mineralocorticoids = 5 : 0.8
Intermediate duration of action
c) Dexamethasone
Very potent and highly Glucocorticoids
Glucocorticoids : Mineralocorticoids = 30 : 0)
Long acting
No fluid retention due to no Mineralocorticoids activity

MECHANISM OF ACTION OF CORTICOSTEROIDS AT CELLULAR LEVEL

Glucocorticoids

Bind to cytotoxic glucocorticoids receptor

Steroid-receptor complex translocate to nucleus

Bind to the GRE on regulatory region of genes

Transcription of specific mRNA

Regulation of protein synthesis

Hormonal response
IMPORTANT PHARMACOKINETIC FEATURES OF CORTICOSTEROIDES
All steroids except DOCA are absorbed orally
Glucocorticoids can also be given I.V., I.M. or topically
Cortisol has high first pass metabolism
90% are bound to the plasma proteins
Corticosteroids are metabolized by hepatic microsomal enzymes and excreted in urine

ADMINISTRATION OF STEROIDS
Inhaled steroids: Beclomethasone, Budesonide
Eye drops: Prednisolone, Dexamethasone
Dermatological preparations: Prednisolone, Triamcinolone
I.V/. I.M. injections: Hydrocortisone, Prednisolone, Methylprednisolone
Intra-articular injection: Hydrocortisone acetate, Prednisolone acetate, Triamcinolone,
Dexamethasone acetate

PHARMACOLOGICAL ACTIONS OF CORTICOSTEROIDS

Carbohydrates and Decrease peripheral utilization of glucose

protein metabolism Promote gluconeogenesis
Promote glycogen deposition on the liver
Enhance protein breakdown and mobilization of amino acids from
peripheral tissue (muscle, connective tissue and skin)
Increase blood glucose level and diabetes-like state, worsen the
already pre-existing diabetic state
Protein wasting

Fat metabolism Permissive action on lypolytic effects of Growth hormone, Adrenaline

and Thyroxine
Redistribution of body fat from the peripheral stores to the central
locations of the body (back of neck, shoulders, abdomen and face)

Calcium metabolism Decrease Ca2+ ion uptake from the gut

and electrolyte balance Increase Ca2+ ion excretion through kidney
Cause fluid retention (Na+ ion and water reabsorption)
Promote K+ ion excretion

Cardiovascular system Directly stimulate cardiac output

Permissive role pressor effects of Adrenaline and Angiotensin-II
Cautiously used in hypertensive

Blood cells Decrease circulating lymphocytes, eosinophils and basophils

Increase RBC, platelets and neutrophils in circulation
Anti-inflammatory Suppress early components of inflammation (oedema, pain, hat, fibrin
effect deposition) and late components of inflammation (collagen synthesis,
wound healing)
Induce production of lipocortin

Arachidonic acid Glucocorticoids

Stimulates production

Phospholipase A2 Lipocortin
Inhibit

Prostaglandins, Leukotrienes,
Plasma activating factor

Lipocotin blocks production and release of inflammatory cytokines (IL-

1, IL-6, TNF-)
Suppress fibroblast proliferation
Impair recruitment of leucocytes at the site of inflammation
Reduce the number of lymphocytes (T cells and B cells)
Decrease IgE-dependent release of histamine leukotrienes from
basophils reduced capillary permeability

Immune response Suppress cell-mediated immunity (delayed hypersensitivity, graft

rejection)
Inhibit genes that codes for the cytokines IL-1 to IL-6 (most
important being IL-2), and IFN-gamma reduces T-cell proliferation
Interfere with the function of complement and NK-cells
Suppress humoral immunity
THERAPEUTIC USES OF CORTICOSTEROIDS
A) Endocrine Diseases
1. As replacement therapy
a) Acute adrenal insufficiency (Addisonian crisis):
Symptoms: dehydration, weakness, lethargy, hyponatremia,
hyperkalaemia, severe hypertension
Using Hydrocortisone I.V. along with adequate maintenance of fluid and
electrolyte balance
b) Chronic adrenal insufficiency
Hydrocortisone orally
May be supplemented with Fludrocortisone
c) Congenital adrenal hyperplasia
Genetic deficiency of 21--hydroxylase enzyme which is involved in
glucocorticoids precursor conversion to cortisol (cortisol production)
Leads to a shift to androgenic pathway which leads to excess of
androgen lead to masculinization
Treatment involve Hydrocortisone orally

2. As diagnosis for Cushings syndrome

Dexamethasone suppression test

Normal suppression of cortisol Failure of suppression of cortisol

production after administration of production after administration of
Dexamethasone due to negative Dexamethasone due to
feedback mechanism hypersecretion of ACTH or Cortisol

HPA axis is intact Pituitary or adrenal tumours

B) Non-Endocrine Diseases
1. Anti-inflammatory therapy:
Rheumatoid arthritis
Osteoarthritis
Acute gouty arthritis
Ulcerative colitis
Crowns disease
Allergic conjunctivitis
Iridocyclitis
Eczematous skin lesions

2. Bronchial asthma
Inhaled or systemic glucocorticoids Fluticasone, Beclomethasone
Moderate to severe asthma
3. Severe allergic reactions
Anaphylactic shock + adrenaline + asthma
Angioneurotic oedema
Chronic urticarial
Hay fever

4. Immunosuppressive therapy
Collagen vascular disease: systemic lupus erythematosus, polyarthritis nodosa,
sarcoidosis
Skin grafts and organ transplant
Nephrotic syndrome Prednisolone
Haemolytic anaemia
Idiopathic thrombocytopenic purpura
Myasthenia gravis
Autoimmune disease
Chronic demyeliting polyneuropathies

5. Stimulation of lung maturation of foetus

Glucocorticoids given to mother to speed up preterm foetus lung
development
Preferred drug is Betamethasone because of less placental metabolism and less
maternal binding protein

6. Infective diseases
Pneumocystis jirovecii pneumonia
MAC (mycobacterium avium complex) infection used only as an adjuvant
drug to decrease the inflammatory reaction

7. Malignancies
Leukaemia
Hodgkins and other lymphomas

8. Cerebral oedema
Dexamethasone or Betamethasone
ADVERSE EFFECTS OF CORTICOSTEROIDS
Cushings syndrome
Fragile skin
Hirsutism
Acne
Myopathy and muscle wasting
Hyperglycaemia and a diabetic-like state (glycosuria)
Susceptibility to infections:
Latent TB reactivation due to immunosuppressant activity
Delay wound healing due to decreased collagen synthesis
Peptic ulcers:
Due to decreased prostaglandin production
Due to increased gastrin and pepsin perforation and bleeding
Ocular effects: cataract, glaucoma
Osteoporosis and osteonecrosis due to Ca2+ resorption, decreased absorption and decreased
formation
Growth retardation is seen in children
Foetal abnormalities: intrauterine growth retardation, gestational diabetes, pre-eclampsia
CNS side effects: euphoria, manic depressive, psychosis, insomnia, nervousness

EFFECT OF LONG TERM STEROID THERAPY ON HPA AXIS

Suppression of HPA axis
Abduction withdrawal causes flare up of the underlying disease
Precipitate withdrawal syndrome: fever, arthralgia, malaise, anorexia, myalgia
Subjected to stress acute adrenal insufficiency (severe hypotension, shock, coma, death)

MEASURES TO MINIMIZE HPA AXIS SUPPRESSION

Gradual withdrawal of steroids
Use shorter acting steroids for shorter period of time
Alternate day of therapy
2/3rd of the dose in the morning and another 1/3rd in the evening to mimic the normal
secretion of cortisol
Local preparation is used whenever possible

CONTRAINDICATIONS OF GLUCOCORTICOIDS
Peptic ulcers
Osteoporosis
Hypertension
Epilepsy
Diabetes mellitus
Herpes simplex keratitis mask the evidence of disease progression
Irreversible loss of vision and cloudiness of cornea (corneal opacity)
 OESTROGENS

CLASSIFICATION
Natural steroidal oestrogens: Estradiol benzoate, Estradiol crypionate, Estradiol enanthate,
Estradiol valarate
Synthetic steroidal oestrogens: Ethinyl estradiol, Mestranol, Quinesterol, Tibolone
Synthetic non-steroidal oestrogens: Diethylstilbesterol (Stilboesterol), Dienesterol,
Chlorotrianisene, Methallenestril
Conjugated oestrogens: Sodium estrone sulfate, Sodium equiline sulfate

PRINCIPAL ACTIONS

Fallopian tubes, uterus and vagina pubertal growth and development &
thickening and cornification of vaginal epithelium
Sex organs Mammary glands pubertal growth & proliferation of ducts and stroma
Uterine endometrium proliferation
Cervix watery secretion to facilitate sperm penetration
Growth of hair as per female pattern (axillary, pubic)
Secondary sex
Distribution of fat as per female contours
characteristics
Pigmentation of nipples and genital organs
Anabolic effect
Weak diabetogenic action, glucose intolerance
Metabolism
Maintain bone mass and decrease bone resorption by antagonizing
osteoclastogenic effects of PTH and IL-6

MECHANISM OF ACTION
Oestrogens bind strongly to sex hormone binding globulin (SHBG) 90%
Free oestrogens enter cells and bind to 2 types of oestrogen receptors
ER-: uterus, vagina, breast, hypothalamus, pituitary, blood vessels
ER-: prostate gland
Sequence of events:
Oestrogen binds to oestrogen receptor (ER)

Release ER from stabilizing proteins (heat shock proteins or Hsp90)

Receptor-hormone complex binds oestrogen response elements in the nucleus

Transcription and translation of mRNA

Protein synthesis
Non-genomic effects: rapid stimulation of endothelial nitric oxide synthase (eNOS) to provide
vasodilatation and cardioprotective effects
Oestrogens stimulate progesterone receptor (PR) synthesis & potentiate target tissue
responses due to progesterone
ADVANTAGES OF TRANSDERMAL ESTRADIOL OVER ORAL OESTROGENS
Beneficial effects of transdermal Estradiol on menopausal symptoms, bone density, vaginal
epithelium and plasma gonadotropin level
However, serum lipid profile is less marked
Milder systemic side effects
Avoid high hepatic delivery plasma levels of TBG, CBG, angiotensinogen and clotting factors
are not elevated hence risk of thromboembolic phenomena may not increase

BENEFITS OF HORMONE REPLACEMENT THERAPY (HRT)

Menopausal symptoms and atrophic changes (primary indication)
Prompt and complete response of vasomotor symptoms
Improves general physical, mental and sexual well being
Genital and dermal atrophic changes arrested
Solves vulvar and urinary problems
Relieves local symptoms
Osteoporosis and fracture
Restores Ca2+ balance
Prevents further bone loss and excess fracture risk
CVS events
Ostrogen improves HDL:LDL ratio
Retards atherogenesis
Reduces arterial impedance
Increases NO and PGI2
Prevents hyperinsulinaemia reduces hypertension, cardiovascular diseases,
coronary artery disease, myocardial infarction, stroke
Cancer protective effect on colorectal carcinoma

RISKS OF HORMONE REPLACEMENT THERAPY (HRT)

CVS events
Progestin in older women with pre-existing cardiovascular diseases, increased risk
of venous thromboembolism and myocardial infarction
No secondary prophylaxis of coronary artery disease in long term
Cognitive function and dementia
Cause slight deterioration
Incidence of dementia doubled
Cancer
Oestrogens enhance growth of breast cancer
Induce endometrial hyperplasia
Progestin irregular uterine bleeding
Long term: endometrial carcinoma
Oestrogen slight increased risk of gallstones
Migraine progestin triggers migraine
CURRENT STATUS OF HRT
Main indication of HRT: vasomotor and other symptoms in peri-menopausal period
Young women + premature menopause deserve HRT
Hysterectomized women have oestrogen alone; while with intact uterus, oestrogen and
progestin are given
Peri-menopausal women are given cyclical HRT rather than continuous HRT
HRT is not the best option to prevent osteoporosis and fractures
HRT affords no protection against CVD, conventional dose combined HRT may even increase
risk of venous thromboembolism, myocardial infarction and stroke
HRT does not protect against cognitive decline; may increase the risk of dementia
Combined HRT increases risk of breast cancer, gall stones and migraine
Used at smallest effective dose and shortest duration
Transdermal HRT may have certain advantages over oral HRT
The need for HRT should be assessed in individual women and not prescribed routinely

DOSAGE OF OESTROGEN IN HRT

Lower than in contraception
Conjugated oestrogen: 0.625 mg/day/cyclically (3 weeks treatment with 1 week gap) or
continuously
Lower dose: 0.3-0.45 mg/day
Progestin 2.5 mg/day is added for 10-12 days for each month

ROLE OF PROGESTIN IN HRT

Attenuates metabolic and CVS benefits of oestrogen
Blocks increased risk of dysfunctional uterine bleeding and endometrial carcinoma by
oestrogen stimulation on endometrium
OTHER THERAPEUTIC USES OF OESTROGENS
Post-menopausal hormone replacement therapy (ERT)
ERT in primary ovarian failure
Primary ovarian failure due to ovarian dysgenesis or hypopituitarism
Oestrogen in cyclical pattern given
Progesterone is added during last week of every month to induce menstrual bleeding
when puberty develops
Dysfunctional uterine bleeding
Due to chronic anovulatory cycles (disruption of follicular and luteal phase)
Progestin is given cyclically to stop bleeding
Oestrogen as an adjuvant
Dysmenorrhoea
Menstrual bleeding with discomfort and pain
First line drugs: NSAIDs
Cyclical oestrogen therapy (with progestin) provides benefits
Acne and hirsutism
Cyclical oestrogen (with progestin) suppress ovarian production of androgens by
inhibiting gonadotropin release from pituitary
Not a suitable treatment for boys
Rarely used nowadays
Carcinoma of prostate
Use of oestrogen is outdated
GnRH agonists with/without androgen antagonist is preferred

ADVERSE EFFECTS OF OESTROGENS

Males:
Gynaecomastia
Feminization
Decrease libido
Females:
Breast tenderness, migraine, headache, nausea
Withdrawal bleeding, amenorrhoea, endometrial hyperplasia
Risk of breast cancer, increased incidence of vaginal and cervical adenocarcinoma in
female offspring
Both sexes:
Gall stones and gall bladder disease
Hepatic dysfunction
Predisposition to thromboembolic disorders
Precipitation of diabetes and fluid retention
 SELECTIVE OESTROGEN RECEPTOR MODULATORS (SERMs)

INTRODUCTION
SERMs are non-steroidal synthetic agents whose agonist or antagonist activities on oestrogen
receptor (ER) are tissue selective
Examples: Clomiphene, Tamoxifen, Doloxifen, Toremifen, Fulvestrant, Raloxifene, Ormeloxifen

CLOMIPHENE CITRATE

ROLE IN INFERTILITY
Clomiphene is an orally active SERM with both agonist and antagonist properties
Mechanism of action:
Acts as a competitive antagonist of ER in hypothalamus

Fails oestrogens negative feedback effects on GnRH release

GnRH release

FSH and LH secretion

Facilitates ovulation (treat infertility due to anovulation)
Not used in primary ovarian or pituitary failure
Also used to treat male infertility due to oligozoospermia increased gonadotropin secretion
promotes testosterone secretion and spermatogenesis

TAMOXIFEN

THERAPEUTIC USES
ER antagonist in breast cells, blood vessels and some peripheral sites
ER agonist in uterus, bone, liver and pituitary
Used to treat breast carcinoma (pre- and post-menopausal women)
It up-regulates TGF- (down-regulation of TGF- associated with progression of malignancy)
Prevents post-menopausal osteoporosis and improves bone density
Up-regulation of TGF- (this cytokine keeps a balance between osteoblast and osteoclast)
Improvement of lipid profile, thus lowering coronary artery disease risk (ER agonist actions on
liver)

ADVERSE EFFECTS
Increased risk of endometrial cancer and deep vein thrombosis due to ER agonist effects on
uterus and blood coagulation factors
Hot flushes, vomiting, menstrual irregularities
Anorexia, mild leucopenia, mild ocular effects
RALOXIFENE

THERAPEUTIC USES
Anti-oestrogenic effects on breast and endometrial tissue
Oestrogenic effects on bone, lipid metabolism and blood coagulation
Treatment and prevention of osteoporosis in post-menopausal women
Maintains favorable lipid profile
Reduces risk of breast cancer (in ER positive)

ADVERSE EFFECTS
Hot flushes
Leg cramps
Increased risk of deep vein thrombosis and pulmonary embolism due to oestrogenic effect
on blood coagulation
No risks of endometrial carcinoma (does not stimulate endometrial proliferation)
Does not relieve menopausal hot flushes

FULVESTRANT

THERAPEUTIC USES
Pure anti-oestrogen
Treats Tamoxifen-resistant breast cancer
Down regulates ER by promoting degradation of ER by proteasomal enzymes
AROMATASE INHIBITORS

CLASSIFICATION
Aminoglutethimide
Non-steroidal agent: Anastrozole, Letrozole, Fadrozole, Vorozole
Selective steroidal: Formestane, Exemestane

MECHANISM OF ACTION
Aromatase inhibitors stop the production of oestrogen in post-menopausal women
They work by blocking the enzyme aromatase, which turns the hormone androgen into small
amounts of oestrogen in the body
This means that less oestrogen is available to stimulate the growth of hormone-receptor-
positive breast cancer cells
Aromatase inhibitors can't stop the ovaries from making oestrogen, so aromatase inhibitors
only work in post-menopausal women

THERAPEUTIC USES
ER expressing breast carcinoma which is resistant to Tamoxifen
Adjunct to androgen antagonist in precocious (premature) puberty
Excessive aromatase syndrome
 PROGESTINS

CLASSIFICATION

Hydroxyprogesterone acetate (I.M.)

Medroxyprogesterone acetate (I.M./oral)
Megestrol acetate (oral)
Progesterone analogues
Dihydrogesterone (oral)
Nomegestrol (oral)
Micronized natural progesterone

Norethindrone (Norethisterone)
Norethynodrel
19-nortestosterone Lynestrenol (Ethinyl estrenol)
Oral
derivatives Allylestrenol
Norgestrel
Levonorgestrel

Newer 19- Desogestrel

nortestosterone Norgestimate Oral
derivatives Gestodene

PRINCIPAL ACTIONS

Fallopian tubes, uterus and vagina inhibition of uterine

contraction; growth and development
Uterine endometrium induce secretory phase in oestrogen-
primed endometrium
Sex organs
Mammary glands development of alveo-lobular secretory
system of breast for lactation
Cervix viscous, scanty mucous secretion as a barrier to
sperm penetration
Body temperature thermogenic
basal insulin level and insulin response to glucose
fat deposition and appetite
Metabolism
HDL & LDL
Stimulates respiration
Catabolic actions
MECHANISM OF ACTION
89% progesterone bound to corticosteroid binding globulin and serum albumin
Free progesterone enters cell and binds to progesterone receptors (PR- and PR-)
Sequence of events:
Progesterone binds to PR

Release PR from stabilizing proteins (heat shock proteins or Hsp90) proteins

Receptor-hormone complex binds progesterone response elements (in the nucleus)

Transcription and translation of mRNA

Protein synthesis
Progesterone inhibits synthesis of ER to limit tissue response to oestrogen

THERAPEUTIC USES
Hormone replacement therapy (HRT)
Dysfunctional uterine bleeding
Endometriosis
Inoperable endometrial carcinoma
Treat pre-menstrual tension
Diagnosis for oestrogen secretion and endometrial responsiveness
Treat premature labour and infertility

ADVERSE EFFECTS
Breast engorgement
Rise in body temperature
Headache
Fluid retention
Depression and irritability
Acne
Weight gain
Decreased libido
Irregular menstrual cycle and breakthrough bleeding
Increased risk of thromboembolism
19-nortestosterone derivatives HDL exhibit atherogenicity
 ANTI-PROGESTINS

DRUGS
Mifepristone, Onapristone, Gestinone

THERAPEUTIC USES
Termination of pregnancy
Block progesterone support to endometrium endometrial shedding
Release prostaglandin induce uterine contraction
Progesterone secretion decrease cervix softened favorable condition for
abortion
As contraceptive
Emergency contraception
Also taken 2 days after mid-cycle to prevent conception
For softening of cervix softening and dilation of cervix prior to surgical abortion
For induction of labour induction of labour following intrauterine foetal death
Endometriosis
Uterine fibroids (leiomyomas)
For progesterone-dependent brain neoplasm (meningioma)
For progesterone-dependent breast cancer
Cushings syndrome anti-androgenic and anti-glucocorticoid activities

ADVERSE EFFECTS
Failed abortion
Prolonged bleeding (which stops spontaneously)
Abdominal cramps
Vomiting
Diarrhoea
Anorexia

SELECTIVE PROGESTERONE RECEPTOR MODULATORS (SPRMs)

DRUGS
Ulipristal acetate, Asoprisnil, Proellex (CDB-4124)

THERAPEUTIC USES
Emergency contraception (Ulipristal)
Uterine leiomyoma
Endometriosis
Asoprisnil and Proellex
Fibroid tumours
Breast cancer
 CONTRACEPTIVES

ORAL CONTRACEPTIVES

CLASSIFICATION
Combination pills (oestrogen + progestin)
Ethinyl estradiol (30 g) + Norgestrel (30 g)
Ethinyl estradiol (30 g) + Levonorgestrel (150 g)
Ethinyl estradiol (50 g) + Norgestrel (0.5 mg)
Mestranol (50 g) + Norethindrone (1 mg)
Ethinyl estradiol (30 g) + Desogestrel (150 g)
Mini pills (progestin-only pills):
Norethindrone (350 g)
Norgestrel (75 g)
Post-coital (after morning) pills:
Levonorgestrel
Ethyl estradiol
Levonorgestrel
Mifepristone
Ulipristal (SPRM)
Centchroman: Non-hormonal oestrogen receptor antagonist

REGIMEN OF COMBINED PILLS USED FOR CONTRACEPTION

Tablet Levonorgestrel 0.25 mg + Ethinyl estradiol 50 g
Dispense 63 tablets
Take one tablet daily for 21 days, starting on 5th day of menstruation
Next course to be started after a gap of 7 days
Review after 3 months

PHASE REGIMEN
Advantages:
Triphasic regimen permits reduction of total steroids without compromising efficacy by
mimicking normal hormonal pattern in menstrual cycle
Recommended for women:
>35 years
No withdrawal or breakthrough bleeding while on monophasic pill
When other risk factors are present
Higher efficacy (98-99.9%)
Disadvantages:
No withdrawal or breakthrough bleeding while on monophasic pill
MINI PILLS
Advantages:
Eliminate oestrogen and its associated long term risks
Alternative for women contraindicated to oestrogen
Disadvantages:
Irregular menstrual cycle
Ovulation in 20-30%
Lower efficacy (96-98%)

REGIMENS USED IN POST-COITAL CONTRACEPTION

1) 2 tablets of progestin Levonorgestrel (0.75 mg each)
First tablet taken as soon as possible (within 48 hours of coitus)
Second tablet taken after 12 hours
2) Single tablet progestin Levonorgestrel (1.5 mg) taken once within 48 hours of coitus
3) Ethinyl estradiol (50 g each) + Levonorgestrel (250 g each)
Take two tablets each within 72 hours of coitus
Next two tablets after 12 hours
4) Mifepristone (600 mg) single dose taken within 72 hours of coitus
5) Ulipristal (SPRM) single dose 30 mg taken within 5 days

INJECTABLE CONTRACEPTIVES

PREPARATIONS
Depot medroxyprogesterone acetate
DMPA
Depot Provera
Combined oestrogen-progestin injectable contraceptives
Estradiol valerate + 17-hydroxy progesterone caproate
Estradiol crypionate + DMPA

ADVANTAGES
No need for daily ingestion of pills (as it is long acting)
Highly effective (I.M. as only solution)
Useful in patient where complications is a problem, heavy menstrual bleeding and ostrogen
contraindicated (eg. migraine, thromboembolism, edema, hypertension, diabetes mellitus)
Provide single defined and predictable bleeding every month (combined oestrogen +
progesterone)

DISADVANTAGES
Complete disruption of menstrual bleeding pattern or total amenorrhoea (more common with
DMPA)
Not suitable for adolescent girls and lactating mothers
DMPA is restricted to women who unlikely to use others effectively
 HORMONAL DRUG DELIVERY SYSTEMS USED FOR CONTRACEPTION
1. Oral
2. Injectable depot
3. Norplants (subcutaneous implants)
4. Intrauterine inserts

HORMONAL CONTRACEPTIVES

MECHANISM OF ACTION
Inhibition of gonadotropin release from pituitary by reinforcement of normal feedback
inhibition
Progestin frequency of LH secretory pulse
Oestrogen FSH secretion Inhibit LH surge no ovulation
Minipill and progestin-only injectable attenuate LH surge but less consistently
irregular ovulation
Thicken cervical mucus secretion hostile sperm penetration due to progestin action (all
methods except post-coital pill)
Hyperproliferation, hypersecretory or atrophic endometrium unsuitable for implantation
(especially mini pills and post-coital pill)
Uterine and tubal contractions disfavour fertilization
Dislodge a just implanted blastocyst or interfere with fertilization or implantation

HEALTH BENEFITS
Oestrogen-progesterone pill reduces risk of functional ovarian cysts, ovarian cancer,
endometrial cancer, fibrocystic breast disease and bleeding uterine fibroids
More regular menses, with reduced blood loss, less premenstrual tension and dysmenorrhoea
Lower incidence of ectopic pregnancy, endometriosis and pelvic inflammatory disease
Iron deficiency anaemia and rheumatoid arthritis (less common)
Combined pills with newer progestins (Desogestrel) lack androgenic side effects, hence
safer for women suffering from weight gain, acne, hirsutism or LDL
Combined pill (oestrogen + anti-androgen Cyproterone acetate) is useful to treating acne and
hirsutism
ADVERSE EFFECTS

Mild adverse effects (withdrawal is not needed)

Oestrogenic effects:
Nausea and migraine
Breast tenderness
Mild oedema
Withdrawal bleeding
Progestogenic effects:
Increased appetite and weight gain
Acne and mild hirsutism
Decreased libido
Increased body temperature

Moderate (warrant discontinuation)

Oestrogenic effect:
Vertigo
Leg and uterine cramps
Precipitation of diabetes
Progestogenic effect:
Breakthrough (spotting) bleeding
Monilial vaginitis (urethral dilatation and bacteriuria)
Amenorrhea (even after stoppage)

Serious (needs stoppage of the drug)

Oestrogenic effects (mainly):
Thromboembolism
Cholecystic jaundice and cholelithiasis
Hepatic adenoma
Higher progestin content:
Risk for MI and cerebrothrombosis
Risk for cancer (controversial)

CONTRAINDICATIONS
Pregnancy (risk of congenital limb deformities)
Genital carcinoma
Masculinization of female and cryptorchism in male offspring
Thromboembolic disorder
Hepatic, renal and gall bladder diseases
Breast carcinoma
Undiagnosed vaginal bleeding
Diabetes mellitus
Obesity
Hypertension
Porphyria
Epilepsy (oral contraceptives decrease seizure threshold)
DRUG INTERACTIONS OF OCPS THAT MAY LEAD TO CONTRACEPTIVE FAILURE
a) Enzyme inducers
Increase metabolism of oestrogenic and progestational components
Drugs: Phenytoin, Phenobarbitone, Primidone, Carbamazepine, Rifampicin, Itonavir
b) Suppression of intestinal microflora
Deconjugation of oestrogen excreted in bile fails
Enterohepatic circulation interrupted
Blood level falls
Drugs: Tetracyclines, Ampicillin

MECHANISM OF ACTION OF CENTCHROMAN

It is a non-steroidal oestrogen antagonist or selective oestrogen receptor modulators (SERMs)
Potent competitive antagonist at peripheral oestrogen receptors & suppress proliferative
stage of endometrium
Accelerates ovum transport without affecting ovulation

DRUGS USED AS MALE CONTRACEPTIVES

Testosterone undecanoate
Testosterone undecanoate + depot Medroxyprogesterone acetate (DMPA)
Gossypol
ANDROGENS & DRUG TREATMENT OF ERECTILE DYSFUNCTION

ANDROGENS

CLASSIFICATION
Natural androgens: Testosterone, Dihydrotestosterone, Dehydroepiandosterone,
Androstenedione
Synthetic androgens: Methyltestosterone, Fluoxymesterone, Testosterone undeconoate,
Mesterolone

PRINCIPAL ACTION

Sexual differentiation in foetus

Penile and scrotal growth in male child
Male reproductive system Growth of prostate and seminal vesicle
Spermatogenesis
Maintenance of sexual function in men
Govern changes in puberty
Appearance of pubic, axillary and beard hair
Secondary sexual
Male pattern baldness
characteristics
Growth of larynx and thickening of vocal cords
Masculinity
Feedback control of LH and FSH
Central nervous system Increase libido
Aggressiveness
Increase protein synthesis and decrease excretion of nitrogen
Decrease protein breakdown
Anabolic action
Na+ ion and water retention
Increase bone density, muscle mass and haeme synthesis
Increase liver synthesis of clotting factor, triglyceride lipase,
1-antitrypsin and haptoglobin
Metabolic effect
Decrease HDL
Accelerate erythropoiesis
Increase linear skeletal growth
Bones Closure of epiphysis
Increase bone density
Skin Increase activity of sebaceous gland (thicker and oilier skin)
Hirsutism
Deepening of voice
Frontal baldness
Female
Enlargement of clitoris
Prominent musculature
Suppression of ovulation and irregular menstruation
MECHANISM OF ACTION
Androgen bound to two major proteins: albumin (40%) and sex hormone binding gamma
globulin (58%)
2% are unbound or free, which is active and available for interaction with peripheral target
cells
It binds to intracellular androgen receptor, initiating a series of events of DNA transcription
and modification of protein synthesis leading to spermatogenesis, sexual differentiation,
sexual maturation at puberty, external virilisation and gonadotropin regulation
Androgen-receptor complex binds to DNA response element which cause multiple coactivator
proteins recruited resulting in transcription of mRNA for tissue specific protein synthesis

THERAPEUTIC USES

Therapeutic uses Explanation

1. Testicular failure
2. Hypopituitarism
3. AIDS-related muscle
wasting
4. Hereditary angioneuretic
oedema
5. Ageing
Either primary (in children) or secondary (later in life)
Hypogonadism is a feature of hypopituitarism
Improve weakness and muscle wasting
Increase synthesis of complement (C1) esterase inhibitor
Improve bone mineralization and muscle mass

ADVERSE EFFECTS
Virilisation, masculinization, hirsutism and frontal baldness of female
Shrunken breast and deepening of voice seen in female
Clitoral hypertrophy and menstrual irregularity
Acne
Sustained and painful erection
Oligozoospermia and infertility (decreased testosterone production)
Precocious puberty
Shortening of stature
Oedema
Cholestatic jaundice
Hepatic carcinoma and cirrhosis
Gynaecomastia (conversion of testosterone to oestrogen)
Lowering of HDL and increase in LDL
Pseudohermaphroditism in genetically female foetus
Prostatic neoplasm in elderly
 ANABOLIC STEROIDS

DRUGS
Nandrolone
Oxymetholone
Stanozolol
Methandienone

THERAPEUTIC USES

Therapeutic uses Explanation

1. Catabolic states (acute
illness, severe trauma, major
surgery)
2. Renal insufficiency
3. Osteoporosis
4. Suboptimal growth in boys
5. Hypoplastic, haemolytic and
malignancy associated
anaemia
6. Enhance physical ability in
athletes
Reduce nitrogen loss over short periods
Transient effect in elderly, under-nourished, debilitated
person
Reduce urea production thus reduce frequency of dialysis
treatment
In elderly male who is immobilized
Brief spurts in linear growth
Increased RBC count and hemoglobin %
Transient increase strength of exercised muscle

ADVERSE EFFECTS
Same as Androgens
Sport abuse:

Men Women Both

Testicular atrophy Inhibition of ovulation Cholestatic jaundice

Sterility Hirsutism Worsen lipid profile
Gynaecomastia Frontal alopecia
Acne
Deepening of voice
Increase aggressiveness
Psychotic symptoms
Increased risk of
coronary artery disease
 DANAZOL

MECHANISM OF ACTION
Suppress gonadotropin release from pituitary gland in both sexes
Inhibition of testicular and ovarian function
Mild androgenic, anabolic and progestational activity

THERAPEUTIC USES
Treatment of endometriosis, fibrocystic disease of breast and premenstrual tension syndrome
Prevents attack of hereditary angioneurotic oedema
Treat infertility in women
Prevent bleeding episodes in haemophilics

ADVERSE EFFECTS
Hot flushes
Loss of libido
Muscle cramps
Amenorrhoea

FLUTAMIDE

ROLE OF FLUTAMIDE IN TREATMENT OF PROSTATIC CANCER

Non-steroidal androgen receptor antagonist
Active metabolite 20-hydroxyflutamide inhibits testosterone and DHT binding to androgen
receptor
Blocks androgen action on accessory sex organ as well as pituitary gland
Use for treatment of prostatic carcinoma, hirsutism and frontal baldness
Cause hepatotoxicity and mild gynaecomastia

BICALUTAMIDE

ROLE OF BICALUTAMIDE IN TREATMENT OF PROSTATIC CANCER

Newer potent orally active androgen receptor antagonist
Administered as single dose
Used along with GnRH agonist or castration
Marked relief in bone pain and other symptoms due to metastasis
Cause side effects of hot flashes, chills, oedema and loose stools
 5--REDUCTASE INHIBITORS

DRUGS
Finasteride
Dutasteride
Turoseride
Bexlosteride
Izonstreride

THERAPEUTIC USES
Suppress DHT-mediated prostatic tumor growth and benign prostatic hyperplasia
Treat male pattern baldness
Obstructive urine flow used with -adrenoceptor antagonist eg. Terazosin

ADVERSE EFFECTS
Decreased libido
Decreased volume of ejaculation on prolonged used
Impotence
Skin rashes
Swelling of lips
 DRUG TREATMENT OF ERECTILE DYSFUNCTION

DRUGS
Phosphodiesterase-5 inhibitors: Sildenafil, Congeners, Tadalafil, Vardenafil
Intracavernosal injection therapy: Alprostadil
Transcutaneous application therapy: Glyceryl trinitrate, Papaverine, Minoxidil, Alprostadil
Herbal agents: Ginseng, Kava, Ginkgo biloba
Adjuvant drugs: Dapoxetine

ROLE OF PHOSPHODIESTERASE-5 INHIBITORS

Sexual arousal

Nitric oxide PDE-5 inhibitors

GTP
Guanylyl cyclase
cGMP 5-GMP
Protein kinase G PDE-5
2+
Decreased Ca

Smooth muscle relaxation

Penile erection

Sildenafil inhibits PDE-5 selectively and thus increases cGMP levels by inhibiting its breakdown
Potentiation of NO action
It is indicated for treatment of erectile dysfunction due to organic or psychogenic causes
No effect in the absence of sexual stimulation and should be taken approximately one hour
prior to the anticipated sexual activity

ADVERSE EFFECTS
Headache
Nasal congestion
Flushing
Mild decrease in blood pressure
Loose motion
Dizziness
Disturbance of colour vision

CONTRAINDICATION
Contraindicated in patient with concurrent use of organic nitrates as it is able to potentiate
the activity of NO
 PARATHYROID
HORMONE, VITAMIN D,
CALCITONIN & DRUGS
AFFECTING CALCIUM
BALANCE
 CALCIUM

PREPARATION
a) Oral preparation
Calcium gluconate
Calcium lactate
Calcium carbonate
Calcium dibasic phosphate
b) Parenteral preparation
Calcium gluconate
Calcium chloride

THERAPEUTIC USES

Therapeutic uses Drug preparation Explanation

Tetany Mild: oral calcium Reversing muscle spasm

Severe: Calcium gluconate Additional of I.V. fluid and
(injected I.V. follows with oxygen inhalation
slow I.V. infusion)

Dietary supplement Especially for growing children,

pregnant, lactating and
menopausal women
Reduce bone loss
Given to patients who has
bone fracture

Osteoporosis HRT, Raloxifene or Ensure calcium deficiency not

Alendronate occur
Calcium + Vitamin D
(adjuvant)

Dermatoses, paresthesias, Calcium gluconate (I.V.) Psychological, due to warmth

weakness and vague and subjective effects
complaint

ADVERSE EFFECTS
Constipation
Bloating
Excess gas (especially with Calcium carbonate)
 PARATHYROID HORMONE

ACTIONS OF PARATHYROID HORMONE

a) Bone
Acts on PTH receptor on osteoblasts and induces receptor activator of nuclear
factor for KB ligand (RANK-L)
Interacts with receptor activator of nuclear factor for KB receptor (RANK receptor)
on osteoclasts and osteoclast precursors
Increases the activity and the number of osteoclasts (cells responsible for bone
resorption) especially when PTH is in excess as in low to physiological dose it
increases bone formation
Active osteoclasts secrete acid and proteolytic enzymes which resorb bone matrix
PTH increases resorption of calcium from bone
b) Kidney
Acts directly to increase renal tubular reabsorption of Ca2+ ion
Increases renal tubular excretion of PO43+ ion
Results in decreased serum PO43+ ion and increased serum Ca2+
Stimulates conversion of calcifediol to calcitriol that amplifies effect of PTH
c) Intestine
Increases Ca2+ ion and PO43+ ion absorption through induction of calcitriol synthesis
Calcitriol enhances absorption of Ca2+ ion from enterocytes

TERIPARATIDE

Human recombinant PTH (rPTH)

Stimulates bone formation
Increases bone mineral density in individuals with history of fractures, osteopenia and
osteoporosis
Its effects are faster and markedly than oestrogens and bisphosphonates
S.C. injection 20 IU/day for 12-18 months
Laso being used as diagnosis to differentiate pseudohypoparathyroidism from true
hypoparathyroidism

CINACALCET

Calcimimetic drug
Calcium sensing receptor (CaSR) on parathyropid gland regulates PTH secretion
Cinacalcet activates CaSR and blocks PTH secretion by this mechanism
Therapeutic uses:
Treatment of secondary hyperparathyroidism in chronic renal failure
Treatment of PTH releasing parathyroid carcinoma
Adverse effect: hypocalcaemia
 CALCITONIN

ACTIONS OF CALCITONIN
d) Bone
Opposite effect of PTH
Inhibits process of bone resorption by direct inhibitory action on osteoclasts
Decreases their ruffled surface which form contact with the resorptive surface
Promotes deposition of post-prandial Ca2+ ion into the bone
e) Kidney
Inhibits proximal tubular Ca2+ ion and PO43+ ion reabsorption
Acts directly on the kidney

THERAPEUTIC USES
Pagets disease
Osteoporosis
Hypercalcaemic states:
Hyperparathyroidism
Hypervitaminosis D
Osteolytic bone metastasis
Hypercalcaemia of malignancy

ADVERSE EFFECTS
Nausea
Flushing
Tingling sensation in fingers
Altered taste
Allergic reaction
Interferes with action of Digoxin
 VITAMIN D

ACTIONS OF VITAMIN D
f) Bone
Induces RANK-L which presents on osteoblasts increases osteoblast-mediated
activation of osteoclasts
Promotes differentiation of osteoclast precursors
Helps in bone mineralization
Enhances reabsorption of Ca2+ ion and PO43+ ion
g) Kidney
Both calcitriol and calcifediol enhance proximal tubular reabsorption of both Ca2+
ion and PO43+ ion
h) Intestine
Vitamin D stimulates Ca2+ ion and PO43+ ion absorption
Calcitriol binds to its receptor which presents on gut and leads to selective increase
in synthesis of calcium channels
Acts directly on the basolateral membrane to modulate Ca2+ ion uptake across GIT
mucosa
Activation of vitamin D receptor promotes endocytic capture of Ca2+ ion and
transports it across duodenal mucosa cell in vesicular form

VITAMIN D PREPARATION
Alfacalcidiol and Dihydrotachysterol active in the absence of renal 1--hydroxylase
Calcipotriol causes lesser hypercalcaemia
Doxercalciferol and Paricalcitol lower PTH without significant rise in plasma Ca2+ ion level
Cholecalciferol
Ergocalciferol and Calcitriol

THERAPEUTIC USES
Renal rickets
Vitamin D dependent rickets Alfacalcidiol and Dihydrotachysterol
Vitamin D resistant rickets
Hypoparathyroidism
Psoriasis Calcipotriol
Secondary hyperparathyroidism with chronic renal disease Doxercalciferol and Paricalcitol
Prevent deficiency symptoms Cholecalciferol
Senile or post-menopausal osteoporosis
Faconi syndrome
 BISPHOSPHONATES (BPNs)

CLASSIFICATION
First generation: Etidronate, Tiludronate
Second generation: Pamidronate, Alendronate, Ibandronate
Third generation: Risendronate, Zolendronate

MECHANISM OF ACTION
Inhibit osteoclastic resorption of bones by binding to the hydroxyapatite crystals of bone
Osteoclasts attach to the bone matrix during resorption, BPNs released which then
internalized by endocytosis into the osteoclasts to accelerate their apoptosis
Also inhibit release of interleukins eg. IL-6 to suppress differentiation of osteoclast precursors
Overall, BPNs inhibit osteoclast-mediated resorption and promote bone remodeling by
increasing bone density
Second and third generation bisphosphonates affect the metabolic pathway for isoprenoid
lipid synthesis
BPNs inhibit prenylation of certain GTP-binding proteins involved in cytoskeletal organization,
membrane ruffling and vesicle movement
Cause inactivation of osteoclast, impaired vesicle fusion and enhance apoptosis

THERAPEUTIC USES
Osteoporosis as prophylaxis treatment
Reduce fracture rates
Treat hypercalcaemia due to malignancy
Pagets disease combined with Calcitonin
Osteolytic bone metastasis

ADVERSE EFFECTS
Gastric irritation
Oesophagitis
Flu-like symptoms (Ibandronate, Pamidronate)
Osteonecrosis of the jwas (high I.V. dose of Zolendronate)
Retrosternal pain
Leucopenia
Fever
Headache
DRUG TREATMENT OF OSTEOPOROSIS

1) Bisphosphonates
There are several different kinds of bisphosphonates
Some are taken by mouth, while others are given by intravenous injection (a slow
injection into a vein)
Pamidronate, Ibandronate and Zoledronate are all types of bisphosphonates
2) Teriparatide and parathyroid hormone
These help regulate calcium levels in your blood
They come in a 'pen' syringe and are injected under your skin
3) Denosumab
This is used for post-menopausal women who can't take bisphosphonates
Also used in men who develop osteoporosis as a result of treatments for prostate
cancer
4) Raloxifene
This is used to treat spinal osteoporosis in post-menopausal women following a
fracture
It is given in tablet form and taken daily
5) Calcitonin
This isnt often used in the UK, but it's available as an injection to reduce pain from
pelvic and vertebral fractures in the time shortly after they occur
It should only be used for a maximum of 4 weeks
6) Strontium ranelate
This is taken daily at least 2 hours before or after food
It comes as a powder which you mix with water
7) HRT (hormone replacement therapy)
It is mainly used as a short-term therapy for early post-menopausal women with
increased fracture risk who have troublesome menopausal symptoms
8) Calcium and vitamin D
Not getting enough calcium and vitamin D can increase your risk of fractures
You may be given supplements to help reduce your risk and to promote better
responses to other treatments for osteoporosis
OXYTOCIN & OTHER
DRUGS AFFECTING
UTERUS
 OXYTOCIN & OTHER DRUGS AFFECTING UTERUS

OXYTOCICS
Drugs or hormones used to enhance uterine contraction
List of oxytocics:
Hormone: Oxytocin
Ergot alkaloids: Ergometrine (Ergonovine), Methylergonovine, Dihydroergonovine
Prostaglandins: Dinoprostone (PGE2 analogue), Carboprost (PGF2 analogue),
Misoprostol (PGE1 analogue)

OXYTOCIN

MECHANISM OF ACTION
Oxytocin stimulates oxytocin receptor on myometrium and causes:
Depolarization of muscle fibre Ca2+ influx
IP3 mediated intracellular Ca2+ release
Increase in prostaglandin synthesis and release by the endometrium
All these cause myometrium contraction

PHARMACOLOGICAL ACTIONS
a) Breast
Contraction of myoepithelial cells surrounding mammary alveoli, leading to milk
ejection
b) Uterus
Oestrogen sensitizes uterus to oxytocin action while progesterone decreases the
sensitization pregnant uterus is most sensitive
Oxytocin increases contraction of upper segment of uterus (fundus)
Facilitates relaxation of cervix and lower segment of uterus (body)
c) Miscellaneous
Causes vasodilation decreased blood pressure, reflex tachycardia
Helps in closure of umbilical vessels at time of birth
Weak ADH-like action mild anti-diuretic effects
Released during sexual orgasm role in mating and parenting behaviour as oxytocin
receptors are also found in limbic system

IMPORTANT PHARMACOKINETIC FEATURES

t1/2 of 5 minutes
Not bound to plasma protein
Metabolized by liver and excreted through kidneys
THERAPEUTIC USES
Promotes milk ejection and results in breast engorgement
Initiation and augmentation of labour early vaginal delivery, uterine inertia, caesarean
section
Control of post-partum bleeding

ADVERSE EFFECTS
Foetal or maternal soft tissue injury
Rupture of uterus
Foetal asphyxia
Water intoxication if used with normal saline due to weak anti-diuretic effects, which is
serious in case of pre-eclampsia (hypertension in pregnancy with oedema or proteinuria)

WHY OXYTOCIN IS PREFERRED OVER ERGOMETRINE OR PROSTAGLANDINS FOR UTERINE INERTIA?

Oxytocin has short t1/2 and slow I.V. infusion, hence intensity of action can be controlled and
action can be quickly terminated
Low concentration allows normal relaxation in between contractions foetal oxygenation
does not disturbed, hence prevents foetal hypoxia occurrence
Lower segment of uterus is not contracted, hence foetal descent is not compromised
Uterine contractions are consistently augmented

ERGOT ALKALOIDS

OBSTETRIC USES
Management of 3rd stage of labour
Treat post-partum haemorrhage
Ensure normal involution (physiological shrinkage of uterus after labour)

ADVERSE EFFECTS
Nausea
Vomiting
Headache
Decreased milk secretion due to dopaminergic action, where there is inhibition of prolactin
release

CONTRAINDICATIONS
Angina pectoris
Myocardial infarction
History of cerebrovascular disease, transient ischaemic heart attack and hypertension
 TOCOLYTICS

TOCOLYTICS
Drugs used to enhance uterine relaxation
List of tocolytics:
2 agonists: Ritodrine, Salbutamol, Terbutaline, Orciprenaline, Isoxsuprine
Ca2+ channel blockers: Nifedipine
Others: Magnesium sulphate

INDICATIONS
To prevent premature labour
Arrest threatened abortion
Used in dysmenorrhea

ROLE OF 2 AGONISTS AS TOCOLYTICS

Bind to 2 receptors on myometrium and activate adenylyl cyclase
This increases cAMP level which then activates cAMP-dependent protein kinase
Hence decreases Ca2+ ion concentration, leading to muscle relaxation
AUTACOIDS
 DRUG THERAPY OF MIGRAINE

DRUGS USED IN THE TREATMENT OF MILD, MODERATE & SEVERE MIGRAINE

Simple analgesics (Paracetamol, Aspirin)

NSAIDs (Ibuprofen, Naproxen, Diclofenac, Mephenamic acid,
Indomethacin)
Mild
Simple analgesics + NSAIDs + Anti-emetics (Metoclopramide,
Domperidone, Prochlorperazine, Diphenhydramine,
Promethazine)

Moderate NSAIDs + Triptan/Ergot alkaloids + Anti-emetics

Triptan/Ergot alkaloids + Anti-emetics + Prophylaxis:

i. Propranolol or other blockers
Severe ii. Amitriptyline or other tricyclic anti-depressants (TCAs)
iii. Flunarizine or other Ca2+ channel blockers
iv. Valproate or Topiramate

DRUGS USED FOR THE PROPHYLAXIS OF MIGRAINE

blockers: Propranolol, Timolol, Metoprolol, Atenolol
Tricyclic anti-depressants: Amitryptyline
Ca2+ channel blockers: Verapamil, Flunarizine
Anti-convulsants: Valproic acid, Gabapentin, Topiramate
5-HT antagonists: Methysergide, Cyproheptadine
 TRIPTAN

ROLE IN MIGRAINE
Drugs: Sumatriptan, Rizatriptan
They are selective 5-HT1D/1B receptor agonists
They suppress nausea and vomiting caused by migraine
This is due to constriction of dilated cranial blood vessels, especially the arteriovenous shunts
in carotid artery
They divert blood away from brain parenchyma
Sumatriptan also reduces 5-HT release at blood vessels
It may inhibit inflammatory neuropeptide release around the affected vessels and
extravasation of plasma proteins across dural vessels
This suppress neurogenic inflammation of cranial vessels

ADVERSE EFFECTS OF SUMATRIPTAN

Tightness in head and chest
Feeling of heat and paresthesia in limbs
Dizziness
Weakness
Slight rise in blood pressure
Bradycardia
Coronary vasospasm
Myocardial infarction
Death
Rarely seizures and hypersensitivity reactions

CONTRAINDICATIONS OF SUMATRIPTAN
Ischaemic heart disease
Hypertension
Epilepsy
Hepatic or renal impairment
Pregnancy
 ERGOT ALKALOIDS

ROLE IN MIGRAINE
Drugs: Ergotamine (oral/sublingual), Dihydroergotamine (parenteral)
They are partial agonist/antagonist at 5-HT1D/1B receptors in cranial vessels
They act by constricting the dilated cranial vessels by constriction of carotid arteriovenous
shunt channels
They reduce neurogenic inflammation and leakage of plasma in dura mater

OTHER THERAPEUTIC USES

Ergotamine and Dihydroergotamine: migraine
Methysergide: migraine prophylaxis, carcinoid syndrome
Bromocriptine: parkinsonism, endocrine disorders
Ergometrine: uterine stimulant to prevent post-partum haemorrhage

ADVERSE EFFECTS
Nausea
Vomiting
Headache
Vasoconstriction

CONTRAINDICATIONS
Pregnancy
Peripheral vascular disease
Coronary artery disease
Hypertension
 ANTI-HISTAMINICS

ANTI-HISTAMINICS
They are H1-receptor antagonists
First generation anti-histaminics
Highly sedative: Dimenhydrinate, Diphenhydramine, Doxylamine, Hydroxyzine,
Promethazine
Moderate sedative: Pyrilamine, Cyproheptadine, Pheniramine, Clemastine
Mild sedative: Meclizine, Chlorpheniramine, Cinnarizine, Triprolidine
Second generation anti-histaminics: Astemizole, Fexofenadine, Cetirizine, Loratadine,
Desloratadine, Levocetirizine, Ebastine

THERAPEUTIC USES

H1-receptor antagonists Allergic rhinitis

Urticaria
Atopic dermatitis
Hay fever
Motion sickness
Anti-emetics
Nausea and vomiting due to pregnancy
Sleeping aids as sedatives

H2-receptor antagonists Gastroesophageal reflux disease (GERD)

(Cimetidine, Ranitidine,
Famotidine, Nizatidine)
Duodenal and gastric ulcer disease
NSAIDs-induced ulcers
Prevention of stress-related gastric bleeding
Prevention of ulcer recurrence
Zollinger-Ellison syndrome
Chronic urticarial

Histamine release inhibitors Bronchial asthma

(Cromolyn sodium, Allergic rhinitis
Nedocromil sodium) Conjunctivitis
ADVERSE EFFECTS
Sedation
Dry mouth
Urinary retention
Constipation
Drug allergy
Teratogenic effects hence avoided during pregnancy
Excitement
Hallucinations
Convulsions
Coma

ADVANTAGES OF 2ND GENERATION OVER THE 1ST GENERATION ANTI-HISTAMINICS

Absence of CNS depressant properties no psychomotor impairment
Higher H1 selectivity no anti-cholinergic side effects
Additional anti-allergic mechanism apart from histamine blockers (some also inhibits late
phase allergic reaction by acting on leukotrienes or by anti-platelet activating factor effect)
 PROSTAGLANDINS

THERAPEUTIC USES OF DIFFERENT PROSTAGLANDIN PREPARATIONS

Therapeutic uses Prostaglandin preparations

Abortion Dinoprostone, Carboprost, Misoprostol
Labour, cervical priming Dinoprostone
Post-partum haemorrhage Carboprost
Peptic ulcer Misoprostol, Enprostil
Prevent platelet aggregation Epoprostenol
Pulmonary hypertension Epoprostenol, Treprostinil
Patent ductus arteriosus Epoprostenol, Alprostadil
Peripheral vascular disease Beraprost
Glaucoma Latanoprost, Bimatoprost, Travoprost, Unoprostone
Male impotence Alprostadil
Reduce infarct size Iloprost
Bronchial asthma Aerosolized PGE2

ADVERSE EFFECTS OF PROSTAGLANDINS

Vomiting
Diarrhoea
Fever
Brochoconstriction
Hypotension
Syncope
Dizziness
Flushing
Anaphylactic shock
Cardiovascular collapse
Ductus fragility and rupture
Gastrointestinal tract discomfort
Hyperostosis (excessive growth of bone)
Bone pain in liver disease patients
Hypercalciuria
Renal Ca2+ oxalate stones
Blurred vision
Brown pigmentation of iris
Dryness of eyes