Endocrine pharmacology

Human Endocrine System

Principal organs -Hypothalamus, Pituitary gland (two lobes), Pineal gland, Thyroid gland, Parathyroid glands (4), Thymus gland, Adrenal glands, Pancreas (islets of Langerhans), Langerhans), Ovaries or Testes.

Endocrine System
A) Function 1) control systems, maintain homeostasis (control chemical and water balance in body) 2- Regulation of growth and development.(control embryonic development ) 3- Control of reproductive system processes (ovulation, mestruation, mestruation, maintanence of pregnancy) 4- Effects on Behavior (modification, modulation, initiation of specific patterns) 5- influence sexual behavior, stimulate growth and maturation of the gonads

Posterior Pituitary
a) Oxytocin - stimulates uterine contractions, milk ejection reflex in the mammary glands b) ADH - antidiuretic hormone, stimulates retention of water action blocked by caffeine

Adrenal Glands (on top of kidneys) - hormones in the fight/fright response

a) Glucocorticoids - raises glucose levels in the blood, stimulates glucose production b) Epinephrine - complement supply from the sympathetic system function is to give the body an energetic boost, increase metabolic rate, dilates bronchioles in the lungs, increases heart rate, etc. Target - most systems of the body c) Mineralocorticoids - retention of ions

Pancreas (at junction of stomach and small intestine)

a) Insulin - lowers blood sugar levels (secreted by beta cells) Target organs - liver, skeletal, adipose (fat) tissues b) Glucagon - increases blood sugar levels (secreted by alpha cells) Target organs - liver, skeletal, adipose (fat) tissues

Male gonads - testes (pelvic region on men)

a) testosterone, maintain secondary sexual characteristics, stimulate sperm production

Female gonads - ovaries (pelvic region of women)

a) estrogen and progesterone, maintain secondary sexual characteristics, regulate reproductive cycle

Hormones
Hormones are chemical messengers that are produced by the endocrine glands and are carried by the bloodstream. They actually act as "messengers" to coordinate functions of various body parts. Most hormones are proteins consisting of amino acid chains. Some hormones are steroids. .

Functions controlled by hormones include: activities of entire organs growth and development reproduction sexual characteristics usage and storage of energy levels of fluid, salt and sugar in the blood

Types of Hormones
There are two main classes (chemical groups) into which hormones fall: 1. steriods (in vertebrates sythesized from cholesterol by adrenal cortex, testis, ovary and placenta) [examples: cortisol, estradiol] cortisol, estradiol] 2. non-steroid non- amines [epinephrine and norepinephrine] norepinephrine] - peptides [oxytocin, ADH] [oxytocin, - proteins [growth hormone, insulin] - glycoproteins [FSH, TSH]

Adrenal steroids

Adrenal steroids
The adrenal gland consists of the cortex and the medulla. The latter secretes epinephrine, whereas the cortex, synthesizes and secretes two major classes of steroid hormonesthe adrenocorticosteroids (glucocorticoids and mineralocorticoids. mineralocorticoids. and the adrenal androgens.

The adrenal cortex is divided into three zones that synthesize various steroids from cholesterol and then secrete them . The outer zona glomerulosa produces mineralocorticoids (for example, aldosterone), aldosterone), which are responsible for regulating salt and water metabolism. Production of aldosterone is regulated primarily by the renin-angiotensin system . reninThe middle zona fasciculata synthesizes glucocorticoids (for example, cortisol), cortisol), which are involved with normal metabolism and resistance to stress. The inner zona reticularis secretes adrenal androgens (for example, dehydroepiandrosterone. dehydroepiandrosterone.

Mechanism of action
They bind to specific intracellular cytoplasmic receptors in target tissues, the receptorreceptorhormone complex then translocates into the nucleus where it acts as a transcription factor to turn genes on or off, depending on the tissue ( this mechanism take a time for the effect to be obvious )

Pharmacological action
Promote normal intermediary metabolism Carbohydrate metabolism: (increase gluconeogenic enzymes) metabolism: gluconeogenesis is increased and peripheral glucose utilization may be decreased (insulin antagonism) so that hyperglycaemia and sometimes glycosuria result. Latent diabetes becomes overt. Protein metabolism: anabolism (conversion of amino acids to metabolism: protein) is decreased but catabolism continues unabated or even faster, so that there is a negative nitrogen balance with muscle wasting. stimulate lipolysis .

Increase resistance to stress:

increase blood glucose ( provide energy ) increase blood pressure ( potentate vasoconstricter effect of adrenergic system on blood vessela) vessela)

Alter blood cell levels in plasma

Decrease in eosinophils , basophils, monocytes and basophils, lymphocytes by redistributing them to lymphoid tissue from the circulation . The decrease in circulating lymphocytes and macrophages compromises the body's ability to fight infections. However, this property is important in the treatment of leukemia In contrast to this effect, they Increase blood levels of hemoglobin , erythrocytes, platelets and polymorphonuclear leukocytes .

AntiAnti-inflammatory action The most important therapeutic property of the glucocorticoids is their ability to dramatically reduce the inflammatory response and to suppress immunity by 1- Lowering the number and inhibition of peripheral lymphocytes and macrophages role 2- Indirect inhibition of phospholipase A2 through elevation of lipocortin which blocks the release of arachidonic acid from the cell membrane . 3- In addition, interference in mast cell degranulation results in decreased histamine and capillary permeability.

Effects on other system

Excessive level of glucocorticoids stimulate gastric acid and pepsin production . Bone loss .(Osteoporosis (reduction of bone protein matrix) occurs, .(Osteoporosis growth slows in children). Myopathy leads to weakness . - Fat deposition: this is increased on shoulders, face and abdomen. AntiAnti-vitamin D action . -Reduction of hypercalaemia chiefly where this is due to excessive absorption of calcium from the gut (sarcoidosis, vitamin D (sarcoidosis, intoxication). -Urinary calcium excretion is increased and renal stones form. -Suppresion of hypothalamic / pitutary adrenocortical feedback system (with delayed recovery) occurs with chronic use, so that abrupt withdrawal leaves the patient in a state of adrenocortical insufficiency

Mineralocorticoids
Help to control the bodys water volume and concentration of electrolytes specially sodium and potassium . Aldosterone acts on kidney tubules and collecting ducts, causing a reabsorption of sodium, bicarbonate, and water. Conversely, aldosterone decreases reabsorption of potassium, which, with H+, is then lost in the urine.

Commonly used corticosteroids

Short acting glucocorticoids ( 8-12 hours ) 8 Hydrocortisone cortisone

Intermediate acting glucocorticoids (18-36 hours ) (18 Prednisolone Prednisone Methylprednisolone trimcinolone

Long acting glucocorticoids ( 1-3 days ) 1 Betamethasone Dexamethasone Paramethasone

Miniralocorticoids
Fludrocortisone ( strong salt retaining effect Deoxycorticosterone ( only salt retaining effect )

Pharmacokinetics
- They are readily absorbed from GIT , selected compound can be given IV, IM, Topically or as an aerosol . - Greater than 90% of absorbed corticosteroids are 90% bound to plasma protein mostly to corticosteroidcorticosteroidbinding globulin (CBG) and the remainder to albumin . - They are metabolized in the liver their metabolites conjugated to glucuronic acid or sulfate which are excreted in the urine .

Figure :

Routes of administration and elimination of corticosteriods.

Therapeutic Uses I- Anti-inflammatory and anti-allergy Antianti2- contact dermatitis, hives, drug allergies etc 3- Asthma ( Inflammatory condition of the airways Beclomethasone (inhaled) focuses the drug to the site.

(NOT FOR REVERSAL OF AN ACUTE ATTACK )

4- Transplant rejection 5- Autoimmune disorders ( Rheumatoid arthritis, ulcerative colitis .

Therapeutic Uses
II- Other Uses II1- Replacement Therapy (Primary adrenal insufficiency (Addisons disease) and Secondary adrenal insufficiency 2- Diagnostic (Dexamethasone suppression test) (Dexamethasone 3- Stimulation of lung maturation in the fetus Up to 34 weeks gestation 4- Shock 5- Spinal cord injury 6- Anti-neoplastics agent Anti-

Adverse Effects
1- Osteoporosis (Common side effect of long-term therapy longDue to direct actions on osteoblasts and impaired Ca absorption. Increased protein catabolism resulting from gluconeogenesis can consume the protein matrix of bones. 2- Skeletal muscle wasting and weakness (Results from increased protein catabolism associated with gluconeogenesis. gluconeogenesis. 3-Increased appetite 4- Inhibition of growth in children Protein catabolism in bones 5- Delayed wound healing Results from increased protein catabolism in the skin

Adverse Effects
6- Peptic Ulceration (Suppression of PG synthesis). 7- Hyperglycemic action (Decreased glucose tolerance and insulin responsiveness. 8- Moon face and buffalo hump 9- Increased susceptibility to infection Catabolic effect on lymphoid tissue. 1010- Suppression of the Hypothalamic-Pituitary Axis Hypothalamic-

Withdrawal of corticosteroid Withdrawal from these drugs can be a serious problem, because if the patient has experienced HPA suppression, abrupt removal of the corticosteroids causes an acute adrenal insufficiency syndrome that can be lethal. This, coupled with the possibility of psychologic dependence on the drug and the fact that withdrawal might cause an exacerbation of the disease, means the dose must be tapered according to the individual, possibly through trial and error. The patient must be monitored carefully.

Inhibitors of adrenocorticoid biosynthesis

Several substances have proven to be useful as inhibitors of the synthesis of adrenal steroids: aminoglutethimide, aminoglutethimide, ketoconazole, ketoconazole, metyrapone, metyrapone, trilostane, trilostane, spironolactone, and eplerenone. spironolactone, eplerenone. Mifepristone competes with glucocorticoids for the receptor.

Endocrine pharmacology Sex steroids and their inhibitors

Figure : Summary of sex hormones

 Sex hormones

produced by the sex gonads are necessary for conception, embryonic maturation, and development of primary and secondary sexual characteristics at puberty. Their activity in target cells is modulated by receptors. The gonadal hormones are used therapeutically in replacement therapy, for contraception, and in management of menopausal symptoms. Several antagonists are effective in cancer chemotherapy. All gonadal hormones are synthesized from the precursor, cholesterol.
These hormones regulate the menstrual cycle (follicular phase , ovulatory phase and luteal phase) .

Estrogen
It is secreted from granulose cells of the follicles , the major ovarian estrogen is estradiol , estrone, and estriol . estrone, All most all estrogens in the blood is bound to sex hormone binding globulin Estradiol is 80X more potent than estrone, and it is estrone, 12X more potent than estriol. estriol. It can be given orally but their bio-availability is low biobecause of short half life and hepatic metabolism .

Pharmacological action
Normal female sexual development Capillary dilatation Fluid retention Protein anabolism Enhance deposition of fat . Inhibit bone resorption

Estrogens preparation
1- Natural estrogen from animal conjugated estrogen( premarin) 2- Synthetic estrogens
Stilbesterol used in Ca of prostate Ethinyl estradiol Mestranol

Clinical uses of estrogens

As replacement therapy in hypogonadism in girls . As a component of contraceptive preparation ( alone or in combination with progesterone) As replacement therapy in post menopausal women ( prevent osteoporosis, facial weakness and reduce vaginal dryness . Androgen dependent CA of prostate To inhibit lactation ( rare) To reduce sexual activity in male.

Contraindications of estrogens Pregnancy because it damage the fetus. In thromboembolic disease. CA of breast. Hypertension , migraine , diabetes mellitus and liver disease.

Adverse effects of estrogens

Nausea , vomiting and diarrhoea Breast tenderness Retention of salt and fluid (edema). Increase incidence of gall bladder formation Increase incidence of endomaterial carcinoma. Vaginal adenocarcinoma in female

Figure : Some adverse effects associated with estrogen therapy

Estrogen inhibitors
Tamoxifen It is a non steroidal that acts as a competitive inhibitors of estradiol by binding to the estrogen receptor . It is used in treatment of breast cancer in post menopausal women . main adverse effects Hot flush, nausea and vomiting .

Estrogen inhibitors
Clomiphene ( clomid) clomid) It is a partial agonist at estrogen receptors in the pituitary gland, it prevent the normal feedback inhibition and increase release of LH and FSH from pituitary which subsequently stimulate ovulation. It is used in treatment of infertility. main adverse effects Hot flush, ovarian enlargement multiple simultaneous births and visual disturbances .

Progesteron
It is synthesized in the ovary, testes and adrenal gland from circulating cholesterol, -It stimulate lipoprotein lipase activity and increase fat deposition, -It increase insulin response to glucose promotes glycogen storage in the liver,
Types of progestins

-Medroxyprogesterone acetate (provera) - Norethindrone - Norethindrone acetate

Therapeutic uses -Contraception ( alone or with estrogen) - Hormone replacement therapy

Adverse effects
Weight gain Depression Edema Acne Hypertension Thrombophlebitis Cholrestatic jaundice

Figure : Some adverse effects associated with progestin therapy.

Progestine inhibitors
- Mifepristone: -It is a competitive inhibitor of progestin at progesterone receptors. -It is used to induce abortion with prostaglandine E or F to increase myomaterial contraction . Adverse effects are heavy bleeding , nausea and vomiting anorexia and abdominal pain . Danazol ( Danocrine) It is a drug that acts as a partial agonist at progesterone , androgen and glucocorticoid receptors . It is used clinically in treatment of endometriosis . Their main adverse effects are weight gain , edema, acne, and reduced HDL cholesterol levels .

Contraceptive
Types of contraceptive 1- Combination estrogen-progestin tablets in estrogenconstant doses throughout the menstrual cycle . 2- Combination estrogen-progestin tablets in estrogenwhich the progestin concentration slowly increased to mimic the natural cycle . 3- Progestin-only preparation . Progestin-

Adverse effects of combination oral contraceptives

- Formation of blood clots . - Increase risk of breast cancer - Breast tenderness - Headache - Gallbladder disease - Acne - Weight gain

 Adverse effects Most adverse effects are believed to be due to the estrogen component, but cardiovascular effects reflect the action of both estrogen and progestin. Major adverse effects: The major adverse effects are breast fullness, depression, fluid retention, headache, nausea, and vomiting. Cardiovascular: Including thromboembolism, thrombophlebitis, hypertension, increased incidence of myocardial infarction, and cerebral and coronary thrombosis. Carcinogenicity: Oral contraceptives have been shown to decrease the incidence of endometrial and ovarian cancer.

Absolute contraindication for combination oral contraceptive

pregnancy history of thromboembolic disease MI Coronary artery disease Cerebral vascular disease Congenital hyperlipidemia Breast or endometrial cancer

Androgens
The androgens are a group of steroids that have anabolic and/or masculinizing effects in both males and females. Testosterone [tess-TOSS-te-rone], the most important [tess-TOSS-te-rone], androgen in humans, is synthesized by Leydig cells in the testes and, in smaller amounts, by cells in the ovary of the female and by the adrenal gland in both sexes. Other androgens secreted by the testes are dihydrotestosterone (DHT), androstenedione, and androstenedione, dehydroepiandrosterone (DHEA) in small amounts.

Regulation of secretion of testosterone. DHT = dihydro testosterone; LH = luteinizing hormone

 Therapeutic uses
Androgenic effects: effects: Androgenic steroids are used for males with inadequate androgen secretion. [Note: Hypogonadism can be caused by testicular dysfunction (primary hypogonadism) or due to hypogonadism) failure of the hypothalamus or pituitary (secondary hypogonadism). hypogonadism). In each instance, androgen therapy is indicated.] Anabolic effects: effects: Anabolic steroids can be used to treat senile osteoporosis and chronic wasting associated with human immunodeficiency virus or cancer. They may also be used as adjunct therapy in severe burns and to speed recovery from surgery or chronic debilitating diseases.

 Endometriosis: Endometriosis: Danazol , a mild androgen, is used in the treatment of endometriosis (ectopic growth of the endometrium) and endometrium) fibrocystic breast disease. It inhibits release of FSH and LH but has no effect on the aromatase. aromatase. Adverse effects of danazol weight gain, acne, decreased breast size, deepening voice, increased libido, and increased hair growth . Danazol has been reported occasionally to suppress adrenal function. Unapproved use of androgen: androgen: Anabolic steroids are used to increase lean body mass, muscle strength, and endurance in athletes and body builders.

 . Adverse

effects

In females: females: Androgens can cause masculinization, with acne, growth of masculinization, facial hair, deepening of the voice, male pattern baldness, and excessive muscle development. Menstrual irregularities may also occur. Testosterone should not be used by pregnant women because of possible virilization of the female fetus. In males: males: Excess androgens can cause priapism, impotence, decreased priapism, spermatogenesis, and gynecomastia. Cosmetic changes such as gynecomastia. those described for females may occur as well. Androgens can also stimulate growth of the prostate. In children: children: Androgens can cause abnormal sexual maturation and growth disturbances resulting from premature closing of the epiphyseal plates.

 Antiandrogens
Antiandrogens counter male hormonal action by interfering with the synthesis of androgens or by blocking their receptors. For example, at high doses, the antifungal drug ketoconazole inhibits several of the cytochrome P450 enzymes involved in steroid synthesis.

Finasteride and dutasteride used for the treatment of benign prostatic hypertrophy, inhibit 5 reductase . The resulting decrease in formation of DHT in the prostate leads to a reduction in prostate size. Antiandrogens, such as flutamide , act as competitive Antiandrogens, inhibitors of androgens at the target cell. Flutamide is used in the treatment of prostatic carcinoma in males. Two other potent antiandrogens, bicalutamide and nilutamide antiandrogens, are effective orally for the treatment of metastatic prostate cancer.