1. Dr. Areej M. Al-Taweel Pharmacognosy Department Pharmacognosy Department

2. Prolactin (Prl) Structure: It is a single polypeptide chain composed of 199 amino acid residues. It has three disulfide bonds. amino acid residues. It has three disulfide bonds.Secretion: Prolactin is secreted by the anterior pituitary. Prolactin is secreted by the anterior pituitary.Level: Starts early in the fetal stages. Starts early in the fetal stages. Decline shortly after birth and remain low in males. Decline shortly after birth and remain low in males. In female increase with pregnancy reach maximum In female increase with pregnancy reach maximum level at term and remains high during lactation. level at term and remains high during lactation.

3. Regulation: Regulation: Inhibited: Prolactin-inhibiting hormone [PIH] (dopamine) Inhibited: Prolactin-inhibiting hormone [PIH] (dopamine) secreted by the hypothalamus. secreted by the hypothalamus. PRH and TRH has a stimulatory effect on prolactin release PRH and TRH has a stimulatory effect on prolactin release Disorders: Hyperprolactinemia: hypersecretion of prolactin by lactotroph cells. Causes: Tumors in the lactotrophes. Hypothyroidism associated with high level of TRH. Hypothalamus or Anterior Pituitary disorders. Sympotoms: In females: Galactorrhea, disruptions in the normal menstrual period, Infertility. In males: Galactorrhea, Infertility. Dopamine agonists: Bromocriptine (Parlodel®) Treatment: Dopamine agonists: Bromocriptine (Parlodel®)

4. Gonadotropic Hormones They includes: 1- Luteinizing Hormone (LH). 2- Follicle-Stimulating Hormone (FSH). 3- Chrionic Gonadotropin (CG). Structures: - They are glycoproteins.

5. Secretion:  LH and FSH are secreted from the Gonadotropes of the Anterior Pituitary.  CG secreted by the placenta. (7 days after ovulation) & remains in the urine & blood of pregnant women up to the end of pregnancy Regulation:  Stimulation: Gonadotropin-Releasing Hormone from the hypothalamus (GnRH).  Inhibition: Feed back mechanism by sex hormones.

6. Physiological effects: In Males:  LH: Stimulate production of androgens.  FSH: Enhance normal sperm production. In Females:  LH: Induce Ovulation and stimulate Progesterone production.  FSH: Enhance production of Estrogen.

7. Uses: Diagnostic uses: Diagnosis of Pregnancy: CG in Urine or Blood. Diagnosis of Pregnancy: CG in Urine or Blood. Prediction of Ovulation: LH 36 hr before Ovulation. Prediction of Ovulation: LH 36 hr before Ovulation. Reproductive system disorder in males and females. Reproductive system disorder in males and females. Therapeutic uses: Male infertility. Male infertility. Female infertility. Female infertility. Cryptorchidism. Cryptorchidism. Function of CG & uses: 1- Diagnosis of pregnancy 1- Diagnosis of pregnancy 2- Diagnosis of ectopic pregnancy 2- Diagnosis of ectopic pregnancy 3- Prediction of spontaneous abortion. 3- Prediction of spontaneous abortion.

9. Estrogens Natural Estrogens: Natural Estrogens: Female Sex Hormones (Estrogens and Progestins) Sex Hormones

10. Structure Activity Relation Ships  Aromatic ring with C-3-OH is essential for activity.  Steroidal structures is not essential for activity.  Alkylation of the aromatic ring decrease the activity.  Unsaturation of ring B decreases the activity.  17α- and 16 position when modified enhance the activity.

11. Physiological Effects Development of the female sexual organs. Development of the female sexual organs. Development of the female secondary sex characters. Development of the female secondary sex characters. Control of the menstrual cycle. Control of the menstrual cycle.Uses Birth control pills. Birth control pills. Failure of ovarian development. Failure of ovarian development. Menstrual disturbances. Menstrual disturbances. Postmenopausal osteoporosis. Postmenopausal osteoporosis. Prostate cancer. Prostate cancer. Side Effects Nausea, vomiting and diarrhea. Nausea, vomiting and diarrhea. Sodium and water retention. Sodium and water retention. Inhibition of ovulation in large doses. Inhibition of ovulation in large doses.

12. Steroidal Estrogenic Drugs Estradiol: Most active natural estrogen. Most active natural estrogen. Very short duration of action. Very short duration of action. Mainly used for local effect on the uterus. Mainly used for local effect on the uterus. Ethinyl estradiol: 15- 20 more potent than estradiol orally. 15- 20 more potent than estradiol orally.

13. Nonsteroidal Estrogens Diethylstilbestrol: The trans form is the active one. The trans form is the active one.Advantages: As active as Estradiol. As active as Estradiol. Longer duration of action. Longer duration of action. Orally active Orally active Cheap. Cheap.Disadvantages: Increase the risk of uterine cancer. Increase the risk of uterine cancer.Uses: Treatment of prostate cancer. Treatment of prostate cancer.

14. Progestins Progesterone in the major natural progestin. Progesterone in the major natural progestin. Secretion: By the ovary mainly the corpus luteum during the second half of the menstrual cycle. Physiological Effects: Development of the endometrium. Development of the endometrium. Development of the mammary gland during pregnancy. Development of the mammary gland during pregnancy.

15. Structure Activity Relation-ships: Steroidal nucleus essential for activity. Steroidal nucleus essential for activity. Removal of the 19 CH 3 increase activity. Removal of the 19 CH 3 increase activity. Unsaturation of ring B or C increase the activity. Unsaturation of ring B or C increase the activity. Have some androgenic activity. Have some androgenic activity. Removal of the keto function remove androgenic activity. Removal of the keto function remove androgenic activity.

16. Progestrogenic Drugs Lynestrenol: Semisynthetic progestin with pure progestrogenic activity. Semisynthetic progestin with pure progestrogenic activity. Lynestrenol

17. Uses: Contraceptive pills. Contraceptive pills. Uterine bleeding. Uterine bleeding. Prevention of abortion. Prevention of abortion. Amenorrhea, dysmenorrhea, endometriosis. Amenorrhea, dysmenorrhea, endometriosis. Endometrial, renal and breast carcinoma. Endometrial, renal and breast carcinoma. Side Effects: Nausea, vomiting, irregular bleeding, edema, weight gain. Nausea, vomiting, irregular bleeding, edema, weight gain.

18. Female Oral Contraceptive Sequential Preparations: Estrogens for 16 days then Estrogen and Progesterone for 5- 6 days. Estrogens for 16 days then Estrogen and Progesterone for 5- 6 days. 98- 99% successful. 98- 99% successful. Combination Preparation: Estrogens and Progesterone from the beginning to the end in small doses. Estrogens and Progesterone from the beginning to the end in small doses. 99- 100% successful. 99- 100% successful.Mechanism: The above two types inhibit both FSH and LH so prevent ovulation. The above two types inhibit both FSH and LH so prevent ovulation.

19. Female Oral Contraceptive (Cont.) Minipills: Small doses of Progesterone from the beginning to the end. Small doses of Progesterone from the beginning to the end. 97- 98% successful. 97- 98% successful.Mechanism: Alter the structure of the Endometrium. Alter the structure of the Endometrium. Increase consistency of the cervical mucus. Increase consistency of the cervical mucus.

20. Male Sex Hormones (Androgens) Natural Androgens: Natural Androgens:

21. Physiological Effects Development of the male sexual organs and male secondary sex characters. Development of the male sexual organs and male secondary sex characters. Anabolic effect. Anabolic effect.Uses Replacement therapy in cases of hypogonadism. Replacement therapy in cases of hypogonadism. Anabolic effect. Anabolic effect. Side Effects Side Effects Sodium and water retention leads to edema. Sodium and water retention leads to edema. Hepatic dysfunction. Hepatic dysfunction.

22. Structure Activity Relation-ships: Steroidal nucleus essential for activity. Steroidal nucleus essential for activity. The C-3 and C-17 oxygenation increase the activity. The C-3 and C-17 oxygenation increase the activity. Oxidation of C-17 to carbonyl eliminates activity. Oxidation of C-17 to carbonyl eliminates activity. C-17 esters prolonged the activity. C-17 esters prolonged the activity. Trans A/B ring junction is essential for activity. Trans A/B ring junction is essential for activity. 17  -substitutions render compounds orally active. 17  -substitutions render compounds orally active.

23. Androgenic Drugs 17  -methyltestosterone: Orally active. Orally active. Prolonged action. Prolonged action. Androgenic and anabolic effects. Androgenic and anabolic effects. Synthetic Anabolic Steroids: Norethandrolone Orally active. Orally active. Anabolic effects. Anabolic effects. C-10 CH 3 group removed to C-10 CH 3 group removed to eliminate androgenic effect. eliminate androgenic effect.

24. Adrenal Gland

25. Adrenal cortex secretes: - Mineralocorticoids (mainly aldosterone) - Glucocorticoids (mainly cortisol) Adrenal medulla secretes: - Epinephrine and lesser amounts of norepinephrine. Adrenal Gland

26. Secretion: Adrenal cortex of the adrenal gland. Adrenal cortex of the adrenal gland.Regulation: Stimulation: ACTH. Stimulation: ACTH. Inhibition: Feed back Mechanism. Inhibition: Feed back Mechanism. Steroidal Hormones (Adrenocorticosteroids, Adrenocorticoids, Corticosteroids, Corticoids)

27. Classification of corticosteroids

28. Physiological Functions and Pharmacological Effects of corticosteroids :  Carbohydrates and Proteins Metabolism: Stimulate glucose formation in the brain. Stimulate glucose formation in the brain. Decrease peripheral utilization of glucose. Decrease peripheral utilization of glucose. Promote storage of glucose in the liver. Promote storage of glucose in the liver. Promote gluconeogenesis. Promote gluconeogenesis.  Lipids Metabolism: Redistribution of body fat (Buffalo hump, Moon face). Redistribution of body fat (Buffalo hump, Moon face). Enhance lipolyses of Triglycerides. Enhance lipolyses of Triglycerides.  Electrolyte and Water balance: Enhance reabsorption of sodium and water into plasma. Enhance reabsorption of sodium and water into plasma. Increase urinary excretion of potassium. Increase urinary excretion of potassium.

29.  Blood Picture: Increase hemoglobin and Red blood cells. Increase hemoglobin and Red blood cells. Decrease white blood cells. Decrease white blood cells.  Anti-inflammatory effects: Suppress inflammations regardless to their cause. Suppress inflammations regardless to their cause.  Immunosuppressive Effects: Decrease immunity as a result of decrease the WBC’s. Decrease immunity as a result of decrease the WBC’s.

31. Disease States (abnormalities of adrenal cortex function): Addison’s disease: Rare syndrome 1/100,000 due to Hypoadrenalism. Rare syndrome 1/100,000 due to Hypoadrenalism.Causes: Atrophy of adrenal gland. Atrophy of adrenal gland. Tuberculoses (result of infectious disease ). Tuberculoses (result of infectious disease ). Low level of ACTH. Low level of ACTH.Symptoms: Weakness, fatigue, depression and irritability. Weakness, fatigue, depression and irritability. Anemia and low blood pressure. Anemia and low blood pressure. Loss of sodium and dehydration. Loss of sodium and dehydration. Low blood sugar. Low blood sugar. Excess pigmentation on skin. Excess pigmentation on skin. Nausea and vomiting. Nausea and vomiting.

32. Cushing’s disease: Rare syndrome 2- 5/Million due to Hyperadrenalism. Rare syndrome 2- 5/Million due to Hyperadrenalism.Causes: Tumor of the Adrenal Cortex. Tumor of the Adrenal Cortex. Tumor of the Pituitary gland. Tumor of the Pituitary gland.Symptoms: Alteration of fat distribution. Alteration of fat distribution. Hypertension. Hypertension. Osteoporosis. Osteoporosis. Growth retardation. Growth retardation. Decrease Immunity. Decrease Immunity.

33. Conn’s syndrom: Conn’s syndrom:Causes: Conn's syndrome is a disease of the adrenal glands involving excess production of aldosterone (hyperaldosteronism). Conn's syndrome is a disease of the adrenal glands involving excess production of aldosterone (hyperaldosteronism).Symptoms: Hypertension. Hypertension. Alkalosis. Alkalosis. Polyuria. Polyuria. Edema. Edema.

34. Adrenocorticoid Drugs Systemic Corticosteroids : * They can be administered by IV, IM, oral, topical or by inhalation. * They can be short, intermediate or long-acting. Cortisone and Cortisone acetate: Can be given orally or by IM injection. Can be given orally or by IM injection. Acetate has longer duration of action. Acetate has longer duration of action. Drug of choice in replacement therapy. Drug of choice in replacement therapy. Cortisone acetate

35. Fludrocortisone: Fludrocortisone:  9  -fluorocortisone.  10 times more active than cortisone as antiinflammatory.  300- 800 times more active as mineralocorticoids. Prednisone and Prednisolone: Prednisone and Prednisolone:  They are Δ 1 corticoids.  3, 4 times more active than cortisone and hydrocortisone.  Prepared by microbial dehydrogenation (Corynebacterium simplex) or chemically using SeO 2.

36. Triamcinolone: Triamcinolone: 9  -fluoro, 16  -hydroxyprednisolone. 9  -fluoro, 16  -hydroxyprednisolone. Activity equal to prednidolone but with less mineralocorticoid activity. Activity equal to prednidolone but with less mineralocorticoid activity. Dexamethasone: Dexamethasone: 9  -fluoro, 16  -methylprednisolone. 9  -fluoro, 16  -methylprednisolone. 5- 7 times more active than prednidolone. 5- 7 times more active than prednidolone. Betamethasone: Betamethasone: 9  -fluoro, 16  -methylprednisolone. 9  -fluoro, 16  -methylprednisolone. Slightly more active than Dexamethasone. Slightly more active than Dexamethasone.

37. Topical Corticosteroid: Beclomethasone 9  -chloro, 16  -methylprednisolone. 9  -chloro, 16  -methylprednisolone. 9  -chloro analog of Betamethasone. 9  -chloro analog of Betamethasone. Topical activity 500 times more than Betamethasone. Topical activity 500 times more than Betamethasone. Inhaled Corticosteroids: Beclomethasone 17, 21-dipropionate (BDP): Prodrug metabolized to more active 17-BMP. Prodrug metabolized to more active 17-BMP. 17-BMP is 30 times more active than BDP. 17-BMP is 30 times more active than BDP. Topical activity 500 times more than Betamethasone. Topical activity 500 times more than Betamethasone.

38. Clinical uses Hypoadrenalism. Hypoadrenalism. Rumatic diseases. Rumatic diseases. Renal diseases. Renal diseases. Collagen diseases. Collagen diseases. Ocular diseases. Ocular diseases. Skin diseases. Skin diseases. GIT inflammation. GIT inflammation. Liver diseases. Liver diseases.

39. Side effects Due to Prolonged use: Fluid and electrolyte disturbances, edema and hypertension. Fluid and electrolyte disturbances, edema and hypertension. Hyperglycemia and glucosuria. Hyperglycemia and glucosuria. Peptic ulcer. Peptic ulcer. Increase susceptibility to infections. Increase susceptibility to infections. Myopathy Myopathy Growth arrest Growth arrest Osteoporoses Osteoporoses Withdrawal Symptoms: Rapid withdrawal after prolonged use leads to sever hypoadrenalism. Rapid withdrawal after prolonged use leads to sever hypoadrenalism.

40. Numbering System of Steroidal ring:

41. Pancreas

42. Site of Secretion: Site of Secretion: Pancreas contains:  -cells  -cells Glucagons Glucagons  -cells  -cells Insulin Insulin  -cells  -cells Somatostatin Somatostatin Pancreas

43. Structure: Peptide hormone composed of two chains of amino acids. Peptide hormone composed of two chains of amino acids. Chain A composed of 21 amino acid residues. Chain A composed of 21 amino acid residues. Chain b composed of 30 amino acid residues. Chain b composed of 30 amino acid residues. The two chain are connected by two disulfide bonds. The two chain are connected by two disulfide bonds. Insulin

44.  It stimulates skeletal muscle fibers to * take up glucose and convert it into glycogen. * take up amino acids from the blood and convert them into protein.  Acts on liver cells * Stimulating them to take up glucose from the blood and convert it into glycogen.  Acts on fat (adipose) cells to stimulate the uptake of glucose and the synthesis of fat. Function of insulin

45. Regulation: Stimulated by: Glucose, Amino acids, Fatty acids and ketone bodies. Glucose, Amino acids, Fatty acids and ketone bodies. Vagal nerve and  2 -adrenergic receptors stimulation. Vagal nerve and  2 -adrenergic receptors stimulation. Inhibited by:  2 -adrenergic receptors stimulation.  2 -adrenergic receptors stimulation. Exogenous somatostatin Exogenous somatostatin low CHO diet low CHO diet Drugs as thiazides. Drugs as thiazides.

46. Glucagons Site of Secretion:  -cells of the pancreas. Site of Secretion:  -cells of the pancreas. Structure: Polypeptide composed of 29 amino acid residues. Structure: Polypeptide composed of 29 amino acid residues. Action: Action: Glucagon acts on the liver where it stimulates: * conversion of glycogen into glucose (glycogenolysis) * fat and protein into intermediate metabolites that are ultimately converted into glucose (gluconeogenesis) In both cases, the glucose is deposited in the blood.  Glucagon secretion is stimulated by low levels of glucose in the blood ( during periods of fasting) and inhibited by high levels.

47. Somatostatin Site of Secretion:  -cells of the pancreas. Structure: Polypeptide. Action: Inhibits both Insulin and Glucagons secretion. Inhibits both Insulin and Glucagons secretion.

48. Diabetes Mellitus (Carbohydrates Intolerance) Types of Diabetes: Types of Diabetes:  Type 1 (Insulin-Dependent Diabetes) (IDDM): Autoimmune disease resulted in destruction of the  -cells. Autoimmune disease resulted in destruction of the  -cells. Treated by Insulin only. Treated by Insulin only. most commonly appears in childhood. most commonly appears in childhood.  Type 2 (Noninsulin-Dependent Diabetes) (NIDDM): Occurs in adults and usually associated with obesity. Occurs in adults and usually associated with obesity. Insulin level is high but there is resistance to its effects. Insulin level is high but there is resistance to its effects. Treatment by oral hypoglycemic drugs. Treatment by oral hypoglycemic drugs.

49. Symptoms of Diabetes Type 1: Occurs in acute manner. Occurs in acute manner. Polyphagia Polyphagia Polydipsia Polydipsia Polyuria Polyuria Weight loss Weight loss

50. Oral Hypoglycemic agents: Sulfonylurea: Increase the release of Insulin from the  -cells. Sulfonamides: Increase the release of Insulin from the  -cells. Biguanides (e.g. Metformin): Never produce hypoglycemia at any dose. Never produce hypoglycemia at any dose. Increase glucose utility by cells. Increase glucose utility by cells. Thiazolidinediones: Enhance Insulin action in liver, muscles and fat tissues. Enhance Insulin action in liver, muscles and fat tissues.

51. Diagnoses of Diabetes Serum Glucose level: Fasting Plasma Glucose (FPG) over 126 mg/dL. Fasting Plasma Glucose (FPG) over 126 mg/dL. Casual Plasma Glucose level over 200 mg/dL. Casual Plasma Glucose level over 200 mg/dL. FPG between 100- 125 mg/dL is called Impaired fasting Glucose (IFG) disorder (Precursor condition to Diabetes). FPG between 100- 125 mg/dL is called Impaired fasting Glucose (IFG) disorder (Precursor condition to Diabetes). Diagnosis Plasma Glucose Result (mg/dL) Normal 99 or below Pre-diabetes (impaired fasting glucose) 100 to 125 Diabetes126 or above

52. Complications of Diabetes mellitus : Eyes: Eyes: - Retinopathy. - Retinopathy. - Sorbitol increase osmotic pressure in the eyes leading to - Sorbitol increase osmotic pressure in the eyes leading to over hydration and cataract. over hydration and cataract. Kidney: Nephropathy. Kidney: Nephropathy. Atherosclerosis and vascular complications. Atherosclerosis and vascular complications. Neuropathy. Neuropathy. Infection. Infection. Gangrene of extremities Gangrene of extremities

53. Insulin: - Lowers blood glucose and stimulates the production of glycogen, fat, and protein. Glucagon: - Raises blood glucose by stimulating the breakdown of liver glycogen. - It also promotes lipolysis and the formation of ketone bodies.  The secretion of insulin is stimulated by a rise in blood glucose following meals.  The secretion of glucagon is stimulated by a fall in blood glucose during periods of fasting.

54. Hormones of posterior lobe of Pituitary gland

55. The posterior lobe is the source of 2 hormones:  Vasopressin (ADH)  Oxytocin (OT)

56. Antidiuretic Hormone (ADH) Function: - ADH is to conserve body water by reducing the loss of water in urine. - ADH binds to receptors on cells in the collecting ducts of the kidney and promotes reabsorption of water back into the circulation.

57. Diabetis insipidus DI (Hyposecretion of ADH) Sign & symptoms: polyuria (10-12 L/ day) Treatment: Synthetic vasopressin injection (Pitressin) This condition can arise from either of two situations: Hypothalamic diabetes insipidus: ■ Results from a deficiency in secretion of ADH from the posterior pituitary. ■ Causes of this disease include head trauma and infections or tumors involving the hypothalamus. Nephrogenic diabetes insipidus: ■ occurs when the kidney is unable to respond to ADH. ■ Most commonly, this results from some type of renal disease.

58. Function in female: Oxytocin -Stimulation of milk ejection - Stimulation of uterine smooth muscle contraction.