Hormones Introduction and Thyroid PDF

HORMONES Hormone is a substance of intense biological ac vity that is produced by specific cells in the body and is transported through circulation to act on its target cells. Hormones are secreted by endocrine or ductless glands....

HORMONES Hormone is a substance of intense biological ac vity that is produced by specific cells in the body and is transported through circulation to act on its target cells. Hormones are secreted by endocrine or ductless glands. Insuline Like GHRH GH Growth Factor I IGF-I THRH TSH Thyroxine CRH ACTH Glucocor coids Hypothalamus Male: Testosterone LH Females: GnRH FSH Female: Estrogen, Dopamine Progestrone Prolac n (-) Hypothalamic Anterior Pituitary Hormones Hormones Hormones released by target endocrine organs Therapeu cally Ac ve Drugs related to Hormones: I. HYPOTHALAMIC AND ANTERIOR PITUITARY HORMONES Hormones of the anterior and posterior pituitary are administered intramuscularly (IM), subcutaneously, or intranasally because they are pep de in nature. (destructed by proteoly c enzymes in the GIT) 1. Cor cotropin Used as a diagnos c tool for differen a ng between primary adrenal insufficiency (Addisons disease, associated with adrenal atrophy) and secondary adrenal insufficiency (caused by the inadequate secre on of ACTH by the pituitary) ACTH is also used in the treatment of infan le spasm (West syndrome). 1 HORMONES 2. Growth hormone (somatotropin) Synthe c human growth hormone is produced using recombinant DNA technology and is called somatotropin. It is used in the treatment of growth hormone deficiency or growth failure in children. (athletes misused this drug and they call this hormone as an aging drug.) 3. Somatosa n (growth hormone-inhibi ng hormone) It is not only inhibi ng the release of GH but, also, that of insulin, glucagon and gastrin. Octreo de is a synthe c octapep de analogue of somatosta n. They have found use in the treatment of acromegaly and in diarrhoea and flushing associated with carcinoid tumors. An intravenous infusion of octreo de is also used for the treatment of bleeding esophageal varices. ADR of octreo de treatment are diarrhea, abdominal pain, flatulence, nausea and steatorrhea Pegvisomant a GH receptor antagonist also used in acromegaly 4. Gonadotropin- releasing hormone (lutenizing hormone- releasing hormone) Gonadotropin releasing hormone (GnRH), also called gonadorelinis a decapep de obtained from hypothalamus. Pulsa le secre on of GnRH is essen al for the release of FSH and LH from the pituitary, whereas con nuous administra on inhibits gonadotropin release. A number of synthe c analogues, such as nafarelin, histrelin, leuprolide, goserelin act as agonists at GnRH receptors. These are effec ve in suppressing produc on of the gonadal hormones when administered con nuously and thus, are effec ve in the treatment of prosta c cancer, endometriosis, and precocious puberty. They are contra indicated in pregnancy and breast feeding. 5. Gonadotropins Gonadotropins are glycoproteins that are produced in the anterior pituitary. The regula on of gonadal steroid hormones depend on these agents. They find use in the treatment of infer lity in men and women. Chorionic gonadotropin (hCG) is a placental hormone structurally related to LH which is an LH receptor agonist. 6. Prolac n Prolac n is a pep de hormone similar in structure to GH, and is also secreted by the anterior pituitary. Its secre on is inhibited by dopamine. Prolac n primary func on is to s mulate and maintain lacta on.in addi on, it decreases sexual drive and reproduc ve func on. Hyper prolac nemia which is associated with galactorrhea and hypogonadism, is usually treated with D 2 receptor agonists, such as bromocriptine (synthe c ergot deriva ve) and cabergoline. II. HORMONES OF THE POSTERIOR PITUITARY They include vasopressin and oxytocin, are not regulated by releasing hormones. Instead, they are synthesised in the hypothalamus, transported to the posterior pituitary, and released in response to specific physiologic signals. 1. Oxytocin It is employed to s mulate uterine contrac on to induce or reinforce labor (injected iv for this purpose). Oxytocin causes milk ejec on. Although toxici es are uncommon when the drug is used properly, hypertension, uterine rupture, water reten on and 2 HORMONES fetal death have been reported. Oxytocin is contra indicated in abnormal fetal presenta on, fetal distress, and in premature births. 2. Vasopressin (An diure c hormone) Vasopressin has both an diure c and vasopressor effects. In the kidney, they bind to V2 receptor to increase water permeability and reabsorp on in the collec ng duct. Thus the major use of vasopressin is to treat diabetes insipidus. It also finds use in the management of cardiac arrest and in controlling bleeding due to esophagal varices or colonic diver cula. Pressor effects are mediated by V1 receptor. The analogue desmopressin (intranasal or oral prepara on available) has minimal ac vity at the V1 receptor, making it largely free of pressor effects. This analogue is now preferred for diabetes insipidus and nocturnal enuresis and is longer ac ng than vasopressin. Agents that increase the effect of vasopressin: Non steroidal an - inflammatory drugs and carbamazepine, Nico ne (Nico ne enhances ADH secre on) Agents that decrease the effect of vasopressin: lithium, Ethanol (ethanol inhibits the secre on of ADH ) The V2 receptor antagonists: tolvaptan and demeclocycline SYNDROME OF INAPPROPRIATE ADH SECRETION (‘SIADH’): SIADH is a disease of impaired water excre on with accompanying hyponatremia and hypo-osmolality caused by the excessive level of Vasopressin. The clinical manifesta ons of plasma hypotonicity resul ng from SIADH may include lethargy, anorexia, nausea and vomi ng, muscle cramps, coma, convulsions, and death. Treatment of hypotonicity due to SIADH includes: water restric on intravenous administra on of hypertonic saline loop diure cs and drugs that inhibit the effect of vasopressin like demeclocycline, tolvaptan (oral and iv), conivaptan (iv) (note: glands with special duct to carry their secre ons are known as exocrine; eg: salivary, lachrymal) Hormone Pharmacologic Agent Uses GH Somatotropin dwarfism, osteoporosis ACTH Cor cotropin Infan le spasms (west syndrome) Cosyntropin As a diagnos c tool for differen a ng between primary and secondary adrenal insufficiency GnRH Leuprolide, Nafarelin, Endometriosis, Prostate carcinoma, precocious Histerelin, goserelin puberty FSH and LH Urofollitropin (FSH), Hypogonadal states, infer lity placental HCG (LH), menotropins (FSH and LH) Dopamine Pergolide, bromocrip ne Hyperprolac nemia Vasopressin Desmopressin Neurogenic (pituitary) diabetes insipidus, nocturnal enuresis, Hemophilia 3 HORMONES Thyroid hormones The thyroid gland, located in the anterior neck just below the cricoid car lage, consists of 2 lobes connected by an isthmus. Follicular cells in the gland produce the 2 main thyroid hormones- tetraiodothyronine (thyroxine, T4 ) and triiodothyronine (T3). Inerfollicular C cells produce the hormone calcitonin, which is chemically and biologically entirely different and is not considered as a thyroid hormone. Along with parathormone it regulates calcium metabolism. (calcitonin is released in response to hypercalcemia and lowers serum Ca levels (hypocalcemic effect). Parathormone has hypercalcemic effects. The thyroid gland facilitates normal growth and matura on by maintaining a level of metabolism in the ssues that is op mal for their normal func on. These hormones act virtually on every body ssues by combining with nuclear receptors and altering expression of a wide range of gene products. Thyroid hormone is required for normal brain and soma c ssue development in the fetus and neonates, and in people of all ages by regula ng protein, carbohydrate and fat metabolism. T3 is the most ac ve form in binding to nuclear receptor, T 4 has only minimal hormonal ac vity. However T4 is much longer las ng and can be converted to T 3 and thus serves as a reservoir for T3. Thyroglobin is the storage form of thyroid hormone. Hypothyroidism Hyperthyroidism symptoms Sensi vity to cold Intolerance to heat (poor resistance to cold) Diarrhea Cons pa on Tachycardia bradycardia Weight loss (body Mental and physical slowing was ng) Weight gain Nervousness Dry skin Heart palpita on Coarse hair Hyperglycemia Slowed speech Puffy face, hands, feet Decreased libido If untreated myxedema and coma will develop treatment Thyroxin (T4) Methimazole Triiodothyronine (T3) Propylthiouracil Iodide Radioac ve iodide Cretinism-hypothyroidism occurs in childhood Myxodema- hypothyroidism in adults. Drugs that cause hypothyroidism include 131I, Iodide, lithium and amiodarone. 4 HORMONES T3 and T4 are metabolised through microsomal P450 systems. Drugs that induce P450 enzyme such as phenytoin, rifampin, phenobarbital accelerate the metabolism of thyroid hormones. TREATMENT OF HYPOTHYROIDISM: Levothyroxine: Mechanism of ac on: Hormone of thyroid gland Side effects: Anxiety, diarrhoea, weight loss, swea ng, insomnia, muscle cramps Drug interac ons: cholestyramine and sucralfate may reduce the ac on of levothyroxine. Levothyroxine may increase the effects of warfarin Iron salts may decrease absorp on of levothyroxine Be er on empty stomach and once daily administra on, usually. TREATMENT OF HYPERTHYROIDISM: 1. Inhibit hormone synthesis (An thyroid drugs): Propylthiouracil, methimazole,carbimazole. 2. Inhibit iodide trapping (ionic inhibitors): Thiocyanate(-SCN), perchlorates(-ClO4), nitrates(-NO3) 3. Inhibit hormone release Iodine, Iodides of Na and K, organic iodide 4. Destroy thyroid ssue: Radioac ve iodine (131I, 125I, 123I ) Compounds 1 & 2 together known as goitrogens. Methimazole Methimazole inhibits enzyme thyroperoxidase, which normally acts in thyroid hormone synthesis by oxidising the anion iodide to iodine Side effects: Agranulocytosis (Agranulocytosis or granulopenia, is an acute condi on involving severe and dangerous neutropenia), skin rashes, itching, abnormal hair loss, upset stomach, vomi ng Contraindicated in case of hypersensi vity , breast feeding Propylthiouracil During breas eeding, propylthiouracil is the treatment of choice because li le passes into breast milk. Mechanism of ac on: inhibit synthesis of thyroid hormone by blocking oxida on of iodine in thyroid gland Side effects: agranulocytosis, aplas c anemia, dermatological reac ons, hepa s, polyarthri s, alopecia, Drug interac on 5 HORMONES Use along with carbamazepine, clozapine, procainamide, primaquine, first genera on sulphonyl urea, methimazole-increases the risk of agranulocytosis. PTU inhibits peripheral deiodination of T4 to T3. Carbimazole does not inhibit. Radio iodine Mechanism of ac on: when swallowed it is concentrated in the thyroid gland. It emits mainly beta radia on (90%), which penetrates only 0.5mm of ssue and thus allows therapeu c effects on the thyroid without damage to the surrounding structures. Side effects: metallic taste, fever, Arthralgia, Diarrhea, Angioedema Drug interac ons Pregnant women should not be treated with radiiodine because it crosses the placenta. Notes: Goiter simply describes enlargement of the thyroid gland, regardless of cause. A goiter may be associated with hypothyroidism, hyperthyroidism, or normal thyroid func on. Graves disease, the immune system makes an an body called thyroid s mula ng immunoglobin (TSI), some mes called TSH receptor an body, which mimics TSH and the thyroid to make too much thyroid hormone. In some people with Graves disease, this an body is also associated with eye problems such as irrita on, bulging, and puffiness. PTU for the first trimester of pregnancy and switch to methimazole for the second and and third trimesters. Synthe c thyroxine is safe and necessary for the well being of the fetus if the mother has hypothyroidism. Thyrotoxic crisis (thyroid storm): Thyroid storm (thyrotoxic crisis) is a sudden exacerba on of hyperthyroidism caused by rapid release of thyroid hormone. It is fatal if not treated rapidly. In this crisis, unchecked hypermetabolism leads ul mately to dehydra on, shock, and death. Treatment: similar to that of uncomplicated hyperthyroidism; however, the doses are higher and given more frequently other treatments include propranolol, Potassium iodide (Lugol’s solu on) and Other suppor ve therapy includes rehydra on, cooling, an bio cs, rest, and seda on. Cinacalcet (Sensipar) is a calcimime c drug that acts as an agonist at the calcium-sensing receptor on the parathyroid gland that regulates PTH secre on. PTH release is inhibited when the calcium-sensing receptor is ac vated. Cinacalcet is used to treat hyperparathyroidism secondary to renal failure and hypercalcemia caused by parathyroid carcinoma. Sevelamer (Renagel) is a non ionic polymer that binds dietary phosphorus in the GI tract. Used to trat Hyperphosphatemia condi ons 6