DRUGS AFFECTING THE THYROID AND PARATHYROID Introduction o Thyroid gland secretes 3 hormones essential for proper regulation of metabolism Thyroxine T4 triiodothyronine T3 and calcitonin o T4 and T3 contain iodine Ingested iodine is absorbed in GI tract enters circulation and is taken up iodide pump by the thyroid gland follicular cells for hormone synthesis Thyroid gland o Goiter used to be common until the discovery of I o Structure of the follicles T3 and T4 are synthesized from thyroglobulin in the follicle cells and stored in the colloid Proteolytic cleavage of storage protein thyroglobulin releases active hormones T4 and T3 Physiologic Effects of Thyroid Hormones o Diffuse effect no specific target organ or tissue o Regulate long term functions Growth and maturation Central nervous system function Basal metabolic rate Cardiovascular function Temperature regulation o Through actions on T3 receptor regulates gene expression o Thyroid hormones regulate gene function by binding to the T3 receptor turning on off protein synthesis T3 and T4 have the same physiological actions as T4 is converted to T3 T4 is more stable than T3 T3 is active and can turn on genes in cells T3 is more potent T3 binds to a receptor in the nucleus and turns on or off genes o Regulation of Hormone release and TRH Thyrotropin Releasing hormone is released from the hypothalamus TRH causes thyrotropin TSH Thyroid Stimulating Hormone release from the pituitary TSH stimulates I uptake and T4 T3 secretion from thyroid cells by activating TSH receptors in the follicle cells cells T3 binds to T3 receptors in hypothalamus and pituitary to inhibit TRH and TSH release Feedback inhibition TSH binds to TSH receptors and promotes I uptake and release of T3 T4 from Thyroglobulin THS stimulates I uptake and T4 T3 secretion from thyroid cells by activating TSH receptors in the follicle T3 binds to T3 receptors in hypothalamus and pituitary to inhibit TRH and TSH release Feedback inhibition Thyroid Diseases o Hyperthyroidism o Grave s Disease o Thyrotoxicosis o Thyroid Storm o Most severe form can be fatal Hypothyroidism Gull s Disease Myxedema symptoms Swelling of hands and feet can be fatal o Thyroid mass Goiter o Body Temperature o Heart Rate o Nervousness o Body Weight o Exophthalmia Bug eyes o Tremor Monitoring levels Thyroid mass Body Temperature Heart Rate Lethargy Puffy dry skin brittle hair In infants mental retardation Cretinism stunted growth o Direct Indirect measurements of T4 and T3 Radio immune assay RIA for T4 Thyroid Hormone Binding ratios for Thyroxine Binding Globulin measures free binding sites on the blood protein that normally binds T4 o TSH monitoring diagnosis TSH level is measured in serum of patient Primary hyperthyroidism 0 1 mIU L Primary hypothyroidism 10 mIU L TSH sensitive Assay s TSH is primary screening tool for thyroid disorders Hypothalamus Pituitary Thyroid Agents for the treatment of Hypothyroidism o Clinical approach Hormone replacement therapy o Thyroid tablets Formerly made from powdered animal thyroids example Armour Thyroid Less predictable response o Synthetic preparations Levothyroxine T4 is the standard treatment Usual treatment regimen 50 mg daily P O for 1 2 weeks increase or decrease as needed after that usual maintenance dose about 150 mg day Liothyroxine T3 Tablets 5 25 50 mg e g CYTOMEL Liotrix T3 T4 mixed e g 1 4 THYROLAR Patient care considerations o Start with low dose and increase as needed especially with angina patients o Monitor heart function hormone level o Contraindicated in patients with acute MI hyperthyroidism o Needs to be taken for life o Best absorption in a single daily dose on an empty stomach Antibodies bind to the TSH receptor in order to release way too much thyroid hormone This makes production in the automatic on position Pathology of Hyperthyroidism o Occurrence Graves disease Autoimmune disease Toxic adenoma Thyrotoxic storm o Treatment Rationales for drug therapy Block synthesis of T3 T4 Destroy excess thyroid tissue Increase metabolism of T3 T4 o 1a Block synthesis of T3 T4 with massive amounts of I mechanism not well understood referred to as Wolff Chaikoff effect temporary effect due to thyroid compensation and rebound effects formulations need 6 mg day for effect o Lugol s solution 5 I2 o Sodium iodide 10 NaI o Usual dose is 50 150 mg day and 10 KI Adverse reactions Allergic reactions are common in persons allergic to seafood particularly shellfish o 1b Blockers of Thyroid Peroxidase act as a more active substrate than TG o Iodism aches and pains in the joints metallic taste in the mouth a Drugs Propylthiouracil PTU and methimazole MMI BRAND NAMES Tapazole Northyx Prototype b Naturally occurring Goitrin in turnips or cabbage seeds c Slow onset body must deplete stores in thyroid d Avoid during pregnancy breastfeeding 131I treatment e MMI adverse Reactions less than 5 of patients 1 Rash pruritis arthralgia 2 Rare agranulocytosis hepatitis or other liver toxicity Patient considerations CBC test for agranuloctyosis Liver kidney thyroid function tests as well Follow any symptoms of immunosuppression o 2 Stimulators of deiodination a Propranolol but not other beta blockers and phenytoin b Act to decrease T3 and T4 in tissue c Some iodinated compounds have opposite effect Amiodarone antiarrhythmic drug or Iopanoic acid increase T3 and T4 d Propranolol slows heart during thyroid storm o 3 I used to destroy excess thyroid alternative to surgery a Dose calculated on body mass b 131I gives off gamma and beta rays short T1 2 of 8 days c Taken up and trapped in thyroid radiation destroys tissue d Must not be used in pregnant women will destroy fetal thyroid as well e Also used to detect tumors in liver and adrenals f Bodily fluids and waste will be radioactive g Often leads to hypothyroidism MMI effects Parathyroid Hormone o The primary function of the parathyroids is to maintain adequate o Parathyroid hormone levels of calcium in the extracellular fluid from bone PTH leads to mobilization of calcium o Elevated levels of PTH may lead to metabolic bone disease o Normal serum Calcium 4 5 5 8 mEq L or 8 5 10 5 mg dL o Rising serum calcium causes decreased PTH and increasedcalcitonin release o Falling serum calcium causes increased PTH Effects of PTH on Calcium o Increased release from bone o Increased readsorption in kidney with less retention of phosphate o Increased absorption in gut This is an indirect effect due to production of a vitamin D derivative