Thyroid and antithyroid.pptx

THYROID HORMONE & ANTI-THYROID DRUGS PREPARED BY Syed Waqas ali shah LECTURER DEPARTMENT of Pharmacy Cusit, Peshawar. THYROID GLAND  To normalize;  Growth and development  Body temperature  Energy levels SYNTHESIS, STORAGE A...

THYROID HORMONE & ANTI-THYROID DRUGS PREPARED BY Syed Waqas ali shah LECTURER DEPARTMENT of Pharmacy Cusit, Peshawar. THYROID GLAND  To normalize;  Growth and development  Body temperature  Energy levels SYNTHESIS, STORAGE AND SECRETION OF THYROID HORMONES The functional unit of the thyroid is the follicle. Each follicle consists of a single layer of epithelial cells around a cavity, which is filled with a thick colloid containing thyroglobulin.  Thyroglobulin is a large glycoprotein, contains tyrosine residues.  Surrounding the follicles is a dense capillary network and the blood flow through the gland is very high in comparison with other tissues. TRANSPORT OF THYROID HORMONES  T 4 and T 3 in plasma are reversibly bound to protein, primarily thyroxine-binding globulin (TBG) PERIPHERAL METABOLISM OF THYROID HORMONES The primary pathway for the peripheral metabolism of thyroxine is deiodination. Deiodination of T 4 may occur by monodeiodination of the outer ring, producing 3,5,3’-triiodothyronine (T 3 ), which is three to four times more potent than T 4. Deiodination may occur in the inner ring, producing 3,3’,5’-triiodothyronine (reverse T 3 , or rT 3 ), which is metabolically inactive. IODIDE METABOLISM The recommended daily adult iodide (I – ) ∗ intake is 150 mcg (200 mcg during pregnancy).  Iodide, ingested from food, water, or medication The thyroid gland removes about 75 mcg a day from this pool for hormone synthesis, and the balance is excreted in the urine. REGULATION OF THYROID FUNCTION Thyrotrophin-releasing hormone (TRH), released from the hypothalamus in response to various stimuli Releases thyroid-stimulating hormone (TSH; thyrotrophin) from the anterior pituitary TSH acts on receptors on the membrane of thyroid follicle cells,. controls all aspects of thyroid hormone synthesis, including: the uptake of iodide by follicle cells,  the endocytosis and proteolysis of thyroglobulin  the actual secretion of T3 and T4  the blood flow through the gland  The production of TSH is also regulated by a negative feedback effect of thyroid hormones on the anterior pituitary gland; T3 is more active than T4 in this respect. ACTIONS OF THE THYROID HORMONES The physiological actions of the thyroid hormones fall into two main categories: Those affecting metabolism  Those affecting growth and development EFFECTS ON METABOLISM:  The thyroid hormones produce a general increase in the metabolism of carbohydrates, fats and proteins, and regulate these processes in most tissues such as heart, kidney, liver and muscle. There is an increase in oxygen consumption and heat production, which is manifested as an increase in the measured basal metabolic rate (BMR). EFFECTS ON GROWTH AND DEVELOPMENT:  influencing growth hormone production and potentiating its effects on its target tissues. ABNORMALITIES OF THYROID FUNCTION HYPERTHYROIDISM (THYROTOXICOSIS) HYPOTHYROIDISM HYPERTHYROIDISM (THYROTOXICOSIS): Excessive secretion and activity of the thyroid hormones, resulting in a high metabolic rate, an increase in skin temperature and sweating, and heat intolerance.  Two common hyperthyroidism are;  Diffuse toxic goitre (also called Graves’ disease or exophthalmic goitre)  Toxic nodular goitre  Nervousness,  Tremor,  Tachycardia  Increased appetite associated with loss of weight occur. HYPOTHYROIDISM:  myxedema. fatigue; constipation; weight gain; cold intolerance; a deep voice, and dry, pale, cool skin  in early life results in irreversible mental retardation and dwarfism.  dwarfism a disorder characterized by shorter than normal skeletal growth. It can be genetic.. Achondroplasia is a common form of short-limbed dwarfism.  Low metabolic rate  Slow speech  Deep hoarse voice  Lethargy  Bradycardia  Sensitivity to cold  Mental impairment HORMONE REPLACEMENT THERAPY IN HYPOTHYROIDISM THYROID HORMONES There are no drugs that boost the synthesis or release of thyroid hormones. The only effective treatment for hypothyroidism, unless it is caused by iodine deficiency (which is treated with iodide), is to administer the thyroid hormones themselves as replacement therapy. THYROID PREPARATIONS Synthetic compounds identical to the natural hormones are as followed;  Levothyroxine (synthetic T4)  Liothyronine (synthetic T3) PHARMACOKINETICS  Thyroxine is absorbed best in the duodenum and ileum. Oral bioavailability of L-thyroxine averages 80% & T 3 is almost completely absorbed (95%). Synthetic levothyroxine is the preparation of choice for thyroid replacement and suppression therapy because of its stability, low cost, long half-life ,which permits once- daily administration.  Liothyronine (T 3) is three to four times more potent than levothyroxine, it is not recommended for routine replacement therapy because of its shorter half-life (24 hours), which requires multiple daily doses; its higher cost; and the greater difficulty of monitoring its conventional laboratory tests. Liothyronine has a faster onset but a shorter duration of action, and is generally reserved for acute emergencies such as the rare condition of myxoedema coma,  Levothyroxine, as the sodium salt in doses of 50– 100 µg/day, is the usual first-line drug of choice. MECHANISM OF ACTION Thyroid hormones act mainly through a specific nuclear receptor, Thyroid hormone receptor (TR).  Two distinct genes, TRα and TRβ, code for several receptor isoforms that have distinct functions. T4 may be regarded as a prohormone, because when it enters the cell, it is converted to T3 by 5’ deiodiase (5’DI), which then binds with high affinity to TR This interaction is likely to take place in the nucleus, where TR isoforms generally act on target genes which then activates transcription, resulting in generation of mRNA and protein synthesis ADVERSE EFFECTS overdose signs and symptoms of hyperthyroidism there is a risk of precipitating angina pectoris, cardiac dysrhythmias or even cardiac failure. The effects of less severe overdose causes bone reabsorption is increased, leading to osteoporosis. ANTI-THYROID DRUGS IN HYPERTHYROIDISM ANTI-THYROID DRUGS Hyperthyroidism may be treated pharmacologically or surgically. Reduction of thyroid activity and hormone effects can be treated by agents that Interfere with the production of thyroid hormones, Modify the tissue response to thyroid hormones.  Or by glandular destruction with radiation or surgery. ANTI-THYROID DRUGS 1- THIOAMIDES:  Propylthiouracil  Methimazole  Carbimazole 2- ANION INHIBITORS:  Perchlorate (ClO 4 – )  Thiocyanate (SCN –) 3- IODIDES: 4- RADIOACTIVE IODINE:  131I 5- ADRENOCEPTOR-BLOCKING AGENTS:  Metoprolol,  Propranolol,  Atenolol 1- THIOAMIDES  Methimazole and propylthiouracil are major drugs for treatment of thyrotoxicosis.  Carbimazole, which is converted to methimazole in vivo, is widely used.  Methimazole is about ten times more potent than propylthiouracil and is the drug of choice in adults and children.  black box warning(serious adverse reactions or special problems occur, particularly those that may lead to death or serious injury assigned by FDA) about severe hepatitis, The black box warning states that in patients newly diagnosed with hyperthyroidism and requiring drug therapy, propylthiouracil should be reserved for those who cannot tolerate methimazole (the other approved antithyroid medication), radioactive iodine therapy, or surgery. propylthiouracil can be use during the first trimester of pregnancy, in thyroid storm, and in those experiencing adverse reactions to methimazole (other than agranulocytosis or hepatitis).  thiocarbamide (S–C– N) group is essential for antithyroid activity. PHARMACOKINETICS: Given orally Carbimazole is rapidly converted to its active metabolite methimazole, which is distributed throughout the body water and has a plasma half-life of 6–15 h. Forpropylthiouracil, giving every 6–8 hours 100 mg dose can inhibit iodine by 60% for 7 hours. 30 mg dose of methimazole exerts an antithyroid effect for longer than 24 hours, a single daily dose is effective in the management of mild to severe hyperthyroidism. Both methimazole and propylthiouracil cross the placenta and also appear in the milk, After degradation, the metabolites are excreted in the urine. MECHANISM OF ACTION: The major action is to prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification.  In addition, they block coupling of the iodo-tyrosines.  Propylthiouracil and (to a much lesser extent) methimazole inhibit the peripheral deiodination of T 4 and T 3  Onset of these agents is slow, often requiring 3–4 weeks before stores of T 4 are depleted. ADVERSE EFFECTS: The most dangerous unwanted effect is neutropenia and agranulocytosis. Patients must be warned to report symptoms (especially sore throat) immediately and have a blood count. Rashes and other symptoms including headaches, nausea, jaundice and pain in the joints, can also occur. 2- ANION INHIBITORS perchlorate (ClO 4 – ), pertechnetate (TcO 4 –) , and thiocyanate (SCN –) Can block uptake of iodide by the gland through competitive inhibition of the iodide transport mechanism. The major clinical use for potassium perchlorate is to block thyroidal reuptake of I – in patients with (eg, amiodarone-induced hyperthyroidism). However, potassium perchlorate is rarely used clinically because it is associated with aplastic anemia. MECHANISM OF ACTION:  Iodides have several actions on the thyroid. Theyinhibit organification and hormone release and decrease the size and vascularity of the hyperplastic gland. The main uses of iodine/iodide are for the preparation of hyperthyroid subjects for surgical resection of the gland. 4- RADIOACTIVE IODINE: 131Iis the only isotope used for treatment of thyrotoxicosis (others are used in diagnosis). PHARMACOKINETICS: Administered orally in solution as sodium  131 I, it is rapidly absorbed, concentrated by the thyroid, and incorporated into storage follicles. Its therapeutic effect depends on emission of β rays with an effective half-life of 5 days.  It is given as one single dose, but its cytotoxic effect on the gland is delayed for 1–2 months. MECHANISM OF ACTION: It is taken up and processed by the thyroid in the same way as the stable form of iodide, eventually becoming incorporated into thyroglobulin. The isotope emits both β and γ radiation. The γ rays pass through the tissue without causing damage, but the β particles have a very short range; they are absorbed by the tissue and exert a powerful cytotoxic action that is restricted to the cells of the thyroid follicles, resulting in significant destruction of the tissue. ADVERSE EFFECTS: Hypothyroidism will eventually occur after treatment with radioiodine, particularly in patients with Graves’ disease, but is easily managed by replacement therapy with T4. Radioiodine is best avoided in children and also in pregnant patients because of potential damage to the fetus. 5- ADRENOCEPTOR-BLOCKING AGENTS  Beta blockers without intrinsic sympathomimetic activity (eg, metoprolol, propranolol, atenolol) are effective therapeutic adjuncts in the management of thyrotoxicosis since many of these symptoms mimic those associated with sympathetic stimulation. Propranolol has been the β blocker most widely studied and used in the therapy of thyrotoxicosis. Beta blockers cause clinical improvement of hyperthyroid symptoms but do not typically alter thyroid hormone levels. Propranolol at doses greater than 160 mg/d may also reduce T 3 levels approximately 20% by inhibiting the peripheral conversion of T 4 to T 3.