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Chapter 38 Thyroid & Antithyroid Drugs

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Chapter 38 Thyroid & Antithyroid Drugs Chapter 38 Thyroid & antithyroid drugs Right Lobe Left Lobe Thyroglobulin Thyroid gland Structure: • The thyroid gland consists of two lobes & is situated in the lower neck • The functional unit of the thyroid gland is the follicle • Each follicle consists of a single layer of epithelial cells (follicular cells) around a cavity, >>> • the follicle lumen, which is filled with a thick colloid containing thyroglobulin – Thyroglobulin is a large glycoprotein, – each molecule of which contains about 115 tyrosine residues Thyroid homones • The thyroid gland secretes: triiodothyronine (T3) thyroxine (T4)…iodothyronines • The thyroid gland also secretes calcitonin • T3 and T4 are critically important for: – normal growth and development, – normalize body temp. – normalize energy levels • Calcitonin is involved in the control of plasma Ca2+ (Ch. 42) Synthesis, storage, release, and interconversion of thyroid hormones Iodine intake Iodide is ingested by food, water, medication… rapidly absorbed (best absorbed in the duodenum and ileum) The daily intake is: 150mcg (200mcg during pregnancy) The thyroid gland removes 75mcg daily Synthesis, storage, release, and interconversion of thyroid hormones 1) Iodide ion (I-) is uptaken by the follicular cell (Na/I- symporter)…that incorporate it into active thyroid hormone. 2) Iodide is oxidized by thyroidal peroxidase into iodine 3) Iodine iodinates tyrosine residues of thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT)….iodine organification 4) Two molecules of diiodotyrosine combine to form L- thyroxine (T4 ); one MIT and one DIT combine to form T3 (Coupling) 5. Proteolysis of thyroglobulin and the release of T4 and T3 into the blood Na+/I- symporter - Thiocyanate / Perchlorate - T3, T4 Na+ I Extracellular space K+ Na+ Exocytosis I- T3, T4, DIT, MIT Proteolysis Follicle cell colloid space T T Pendrin T T o peroxidase - Thyroglobulin I I T T Organification DIT T4 T MIT T4 T3 DIT T Coupling T MIT T MIT Thyroglobulin with monoiodotyrosines (MIT) & diiodotyrosines (DIT) Synthesis, storage, release, and interconversion of thyroid hormones • In the blood thyroid hormones are 99% bound to plasma protein, – primarily thyroxin-binding globulin (TBG) • T4 – is secreted solely from the thyroid gland – and is produced in the greatest amounts • T3: – 20% of T3 is produced in the gland, – the majority of T3 is formed from the breakdown of T4 in peripheral tissues (liver) by 5-deiodinase • T3 is 4X more potent in activity 1. Amiodarone 2. Radiocontrast media 3. β-blockers 4. Corticosteroids 5. Starvation - T4 R R T3 rT3 Monodeiodination Monodeiodination of in the inner ring the outer ring, produces 3,3',5'- producing 3,5,3'- triiodothyronine triiodothyronine (T3) R = (reverse T3, or rT3), which is metabolically inactive Table 38-1. T4 highly TGB bound © The McGraw-Hill Companies, Inc., 2010 Table 38-2. © The McGraw-Hill Companies, Inc., 2010 Control of thyroid function Cold _ Stress Acute psychosis + Circardian & pulsatile rhythms Hypothalamus TRH _ SST + _ - Anterior pitutary Dopamine gland Corticoids - TSH + _ I (high) Thyroid gland I (low) + T3 & T4 Pharmacokinetics • Absorption of thyroid hormones is modified by intraluminal factors such as food, drugs, gastric acidity, and intestinal flora – …change from oral to parenteral Tx. (I.V) • T4..(80% absorbed), T3 (95%) • Strict high regulation: – Hyperthyroidism • increase the metabolic clearances of T4 and T3; • decreasing their half-lives; * – (hypothyroidism opposite) Pharmacokinetics • Drugs that induce hepatic microsomal enzymes – increase T4 and T3 metabolism; – conc. remain normal in euthyroid patients….compensatory increase in thyroid function • Similarly, if TBG increase by pregnancy, estrogens, or oral contraceptives – ….initial shift of hormone from free to bound state – and decrease in its rate of elimination – until the normal hormone concentration is restored Figure 38–4. 1 4 Active 2 transport 3 © The McGraw-Hill Companies, Inc., 2010 Mechanism of Hormone Action • Most actions of thyroid hormones seem to be mediated by nuclear receptors – T3 binds to high-affinity nuclear receptors, – which then bind to specific DNA sequences (thyroid hormone response elements, TREs) in the promoter/regulatory regions of target genes, – which may repress or promote the transcription of the associated thyroid hormone-responsive genes Effects of Thyroid Hormones 1. Growth & development • critical for the development and functioning of : – nervous, skeletal, and reproductive tissues – ….directly by protein synthesis & indirectly by potentiation of GH • Thyroid hormone plays a critical role in brain development – The absence of thyroid hormone during the period of active neurogenesis (up to 6 months postpartum) leads to irreversible mental retardation and dwarfism (cretinism= neonatal hypothyroidism) Effects of Thyroid Hormones 2. Cardiovascular effects: thyroid hormone influences cardiac function by direct and indirect actions: • Thyroid hormones directly: – increase the expression of genes of the sarcomeric myosin heavy chains – >>>…increase heart contraction • Thyroid hormones indirectly: – indirectly alter the sensitivity of the cardiac myocyte responsiveness to catecholamines, possibly due to changes in expression of myocardial β-adrenergic receptors Effects of Thyroid Hormones 4. Metabolic effects • The thyroid hormones produce a general increase in the metabolism of – carbohydrates, – fats, – proteins – and vitamins, • and regulate these processes in most tissues Effects of Thyroid Hormones 5. Calorigenic effect • Most peripheral tissues (heart, skeletal muscle, liver, and kidney) are stimulated markedly by thyroid hormone to – increased O2 consumption – & heat production • Several organs, including – brain, – gonads, – and spleen, – are unresponsive to the calorigenic effects of thyroid hormone Generally: hyperthyroidism cause: tremor, excessive sweating, Anxiety & nervousness Thyroid preparations • Thyroid preparations may be: – synthetic (levothyroxine, liothyronine, liotrix) – or of animal origin (desiccated thyroid) • There is no significant difference in the qualitative response of the patient with hypothyroidism to triiodothyronine, thyroxine, or desiccated thyroid. • However, there are obvious quantitative differences Thyroid preparations • Major indications: 1) hormone replacement therapy in patients with hypothyroidism or cretinism 2) TSH suppression therapy in patients with thyroid cancer and occasionally those with nontoxic goiter Levothyroxine (T4) (oral & parenteral) • It is the preparation of choice for maintenance of plasma T4 and T3 concentrations for thyroid hormone replacement therapy in hypothyroid patients • Its long half-life (7 days) allows for convenient once daily administration • Since much of the T4 is deiodinated to T3; thus, administration of T4 produces both hormones Liothyronine (T3) (oral & parenteral) • It is not used for maintenance thyroid hormone replacement therapy because of: 1) shorter half-life and duration of action 2) Cost 3) Difficulty in monitoring by conventional lab methods 4) Hormone activity and consequent greater risk of cardiotoxicity • Most appropriate use: a. short-term suppression of TSH in patients undergoing surgery for thyroid cancer b. Initial therapy of myxedema and myxedema coma (absorption and conversion impaired, T4 delayed onset) Liotrix (oral) • 4:1 mixture of levothyroxine sodium and liothyronine sodium • Based on the idea of combining T4 and T3 in replacement therapy so as to mimic the normal ratio secreted by the thyroid gland • It does not appear that liotrix offers any therapeutic advantage over levothyroxine alone • Too expensive Dessicated Thyroid (thyroid extracts) (oral) • The use of desiccated thyroid rather than synthetic preparations is never justified….. – protein antigenicity, – product instability, – variable hormone concentrations, – and difficulty in laboratory monitoring >>>>>>> far outweigh the advantage of lower cost • Shelf life of synthetic hormone preparations is ~2 years (stored in dark bottles to minimize spontaneous deiodination) • Shelf life of desiccated thyroid is not known with certainty….its potency is better preserved if it is kept dry Abnormalities of thyroid function Hypothyroidism • Hypothyroidism is manifested largely by a reversible slowing down of all body functions…diagnosed by elevated TSH in the serum and low free thyroxine • In infants and children, – striking retardation of growth and development that results in dwarfism and irreversible mental retardation Table 38-3. © The McGraw-Hill Companies, Inc., 2010 Hypothyroidism • The laboratory diagnosis of hypothyroidism – the combination of a low free thyroxine and elevated serum TSH • Subclinical hypothyroidism – ….elevated TSH level – and normal thyroid hormone levels?? – >>>>>> hormone therapy considered for patients with very high TSH levels – >>>>>>>….close TSH monitoring is appropriate for those with lower TSH elevations • Pituitary failure (2ry hypothyroidism) – should be suspected in patients with low T4 and TSH levels Hypothyroidism • Hypothyroidism can occur with or without thyroid enlargement (goiter) • Tx goals: – restore thyroid hormone conc.; – provide symptomatic relief, – prevent neurologic deficits in newborn & infants – and reverse the biochemical abnormalities of hypothyroidism Hypothyroidism • NON-TOXIC GOITER: • Syndrome of enlargement of the thyroid gland without excessive thyroid hormone production – Enlargement is often due to TSH stimulation from inadequate
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