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Thyroid Drugs Learning Objectives: By the end of the lecture the students should be able to : • Describes Physiology, synthesis and feed back control of thyroid hormone synthesis • Define Hypothyroidism and differentiate between Cretinism and Myxedema coma. • Explain the Drugs for the treatment of hypothyroidism . • • • • Understand the machanism, pharmacokinetic, indications and contraindications of LEVOTHYROXINE (synthetic analog of thyroid hormone). Thyroid Hormones Thyroid hormones: – Thyroxine T4 (90%) – Triiodothyronine T3 Thyroid gland also secretes Calcitonin – serum calcium lowering hormone Thyroid Hormones - Facts Thyroid hormones are required for the growth and development of all tissues. • Thyroid hormone is critical for nervous, reproductive and skeletal growth. • Thyroid deprivation in early life results in irreversible mental retardation. • • • Thyroid hormones also augment sympathetic system function primarily by increasing the number of adrenergic receptors. Hypothalamus-pituitary-thyroid axis TSH secretion by anterior pituitary is stimulated by hypothalamic TRH Feedback inhibition of TSH and TRH occurs with high levels of circulating thyroid hormones (T3 & T4) • • • • ● ● ● • Dopamine, Glucocorticoids and somatostatin can suppress TSH secretion Thyroid hormone synthesis Uptake of iodide by thyroid gland Oxidation of iodide Organification – Iodination of tyrosine residues on thyroglobulin – MITs and DITs Coupling – formation of T4 and T3 Proteolysis of thyroglubulin and secretion of thyroid hormones Conversion of T4 to T3 in peripheral tissues Thyroid hormone synthesis Thyroid hormones Mechanism of action T4 and T3 must dissociate from thyroxine binding globulin (TBG) in plasma before entering into the cells. • In the cells, T4 is deiodinated to T3 that enters nucleus and attaches to specific receptors which promotes mRNA and protein synthesis. Hypothyroidism Clinical manifestations: Lethargy, wt. gain, bradycardia, constipation, cold intolerance, menstrual irregularities • • • • • Cretinism (congenital hypothyroidism) Myxedema coma: most extreme manifestations of untreated hypothyroidism Synthetic Thyroid Hormone synthetic levothyroxine (synthetic T4) . synthetic liothyronine (synthetic T3) is 3-4x more potent not used alone for long term treatment secondary to short half life and large peaks in serum T3 levels Synthetic Thyroid Hormone(Levothyroxine T4) • reasons for its use: – – – – – – – stability content uniformity low cost lack of allergenic foreign protein easy laboratory measurements of serum levels long half-life (7days) once a day dosing Thyroid hormones Mechanism of action • • • • • • • T4 and T3 must dissociate from thyroxine binding globulin (TBG) in plasma before entering into the cells. In the cells, T4 is deiodinated to T3 that enters nucleus and attaches to specific receptors which promotes mRNA and protein synthesis. PHARMACOKINETICS Absorption – Absorption of orally administered T4 from the gastrointestinal (GI) tract ranges from 40% to 80%. The majority of the Levothyroxine dose is absorbed from the jejunum and upper ileum. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybean infant formula. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age. • • • • • • • • • • • • • • Distribution – Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA). The higher affinity of both TBG and TBPA for T4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 compared to T3. Many drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins Metabolism – The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately eighty-percent of circulating T3 is derived from peripheral T4 by monodeiodination. The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation. Elimination – Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of T4 is eliminated in the stool. Urinary excretion of T4 decreases with age. INDICATIONS AND USAGE • • Hypothyroidism – As replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology. Pituitary TSH Suppression – In the treatment or prevention of various types of euthyroid goiters , including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), multinodular goiter and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. CONTRAINDICATIONS • • • • Levothyroxine is contraindicated in: patients with untreated subclinical (suppressed serum TSH level with normal T3 and T4 levels) or overt thyrotoxicosis of any etiology and in patients with acute myocardial infarction. Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency since thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids Levothyroxine sodium is contraindicated in patients with hypersensitivity to any of the inactive ingredients in Levothyroxine sodium tablets. side effects • Hyperthyroidism due to therapeutic overdosage Seizures Hypothyroidism Children/infants Hypersensitivity to inactive ingredients drug interactions • • Levothyroxine increases the response to oral anticoagulant therapy. The therapeutic effects of digitalis glycosides may be reduced by Levothyroxine. • • Consumption of certain foods may affect Levothyroxine absorption thereby necessitating adjustments in dosing. Soybean flour (infant formula), cotton seed meal, walnuts, and dietary fiber may bind and decrease the absorption of Levothyroxine sodium from the GI tract. thanks