Thyroid gland The thyroid gland consits of two lobes & is situated in the lower neck The thyroid gland secretes three main hormones: thyroxine (T4), triiodothyronine (T3) and calcitonin T4 and T3 are critically important for normal growth and development and for energy metabolism Calcitonin is involved in the control of plasma Ca2+ .

3,5,3’-Triiodothyronine (T3) Thyroxine (T4) The principal hormones of the thyroid gland are the iodine-containing amino acid derivatives of thyronine (T4 and T3) O OH I NH2 O OH I NH2 3,5,3’-Triiodothyronine (T3) Thyroxine (T4)

Synthesis, storage, release, and interconversion of thyroid hormones Uptake of iodide ion (I-) by the gland by the sodium/iodide symporter (NIS) Oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin Coupling of iodotyrosine residues to generate the iodothyronines Resorption of the thyroglobulin colloid from the lumen into the cell Proteolysis of thyroglobulin and the release of T4 and T3 into the blood

Na+ Extracellular space Follicle cell colloid space I- I- Io I- K+ T3, T4 I- Na+ K+ Follicle cell Extracellular space colloid space Exocytosis I- T3, T4, DIT, MIT Proteolysis T T T T Io peroxidase I- Thyroglobulin Organification T T 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 More than 99% of the circulating thyroid hormones are protein bound, primarily thyroxin-binding globulin (TBG) T4 is produced in the greatest amounts, but T3 is four times more potent in activity T4 is converted into T3 in the tissues, especially in the liver, & this process may be an additional site for regulation

Summary of thyroid hormone kinetics Variable T4 T3 Volume of distribution 10 L 40 L Daily production 75 mcg 25 mcg Metabolic clearance per day 1.1 L 24 L Half-life (biologic) 7 days 1 day Serum levels   Total 4.810.4 mcg/dL 62-134 nmol/L 79-149 ng/dL 1.2-23 nmol/L Free 0.7-1.86 ng/dL 9-24 pmol/L 145- 348 pg/dL 2.2-5.4 pmol/L Amount bound 99.96% 99.6% Biologic potency 1 4 Oral absorption 80% 95%

Control of thyroid function Cold Acute psychosis Circardian & pulsatile rhythms + _ Stress Hypothalamus + TRH _ SST _ - Dopamine Corticoids Anterior pitutary gland - + TSH _ I- (high) Thyroid gland + I- (low) T3 & T4

Effects of Thyroid Hormones Growth & development Thyroid hormone is critical for the development and functioning of nervous, skeletal, and reproductive tissues during infancy and childhood Thyroid hormone plays a critical role in brain development during the period of active neurogenesis (up to 6 months postpartum) The absence of thyroid hormone during the period of active neurogenesis leads to irreversible mental retardation (cretinism)

Effects of Thyroid Hormones Metabolic effects: increase in the metabolism of carbohydrates, fats and proteins Calorigenic effect: increased O2 consumption & heat production Cardiovascular effects: thyroid hormone influences cardiac function

Hypothyroidism The most common cause of hypothyroidism is chronic antoimmune (Hashimoto’s thyroditis) resulting in thyroid atrophy or goiter

Thyroid preparations Thyroid preparations may be synthetic (levothyroxine, liothyronine, liotrix) or of animal origin (desiccated thyroid, Thyroid (USP)) 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

Levothyroxine (T4) 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) Has limited therapeutic applications and is not used for maintenance thyroid hormone replacement therapy because of: shorter half-life and duration of action Cost Difficulty in monitoring by conventional lab methods hormone activity and consequent greater risk of cardiotoxicity

Liotrix 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

Adverse effects The toxicity of thyroxine is directly related to the hormone level (i.e., symptoms of hyperthyroidism) Careful monitoring of individual infants and dosage adjustment are necessary during early weeks and months of life to prevent prolonged hyperthyroxinemia Premature synostosis with and without brain dysfunction: associated with T4 doses In children: restlessness, insomnia, and accelerated bone maturation and growth

Hyperthyroidism Hyperthyroidism refers to excess synthesis and secretion of thyroid hormones by the thyroid gland Goal of treatment: Inhibit synthesis of the hormone Block the release of the hormone from the follicle

Inhibition of thyroid hormone synthesis Thioamides Agents: propythiouracil (PTU) and methimazole (MMI) Used in the management of hyperthyroidism and thyrotoxic crisis and in the preparation of patients for surgical subtotal thyroidectomy Since the synthesis rather than the release of hormones is affected, the onset of these agents is slow (3-4 weeks) before stores of T4 are depleted

Thioamides Prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification Block coupling of the iodotyrosines Inhibit the peripheral deiodination of T4 and T3 (mainly propylthiouracil) Pharmacodynamics

Thioamides- ADRs Maculopapular pruritic rash Most serious: agranulocytosis (0.1-0.5% of patients Rare: urticarial rash, vasculitis, a lupus-like reaction

Iodides The effects of iodide on the thyroid gland are complex: Inhibit hormone release, possibly through inhibition of thyroglobulin proteolysis (major) Inhibit organification Decrease the size and vascularity of the hyperplastic gland Improvement in symptoms occurs rapidly—within 2–7 days

Iodide Iodide use is restricted to short term therapy and should not be used alone: thyroid gland will escape from the iodide block in 2–8 weeks, and its withdrawal may produce severe exacerbation of thyrotoxicosis

Iodides- ADRs Acute life threatening angioedema and laryngeal Swollen salivary glands Soreness of the teeth and gum Mucous membrane ulcerations Conjunctivitis Rhinorrhea Drug fever Metallic taste Bleeding disorders Anaphylactoid reactions (rare)

Radioactive Iodine (131I) 131I is taken up and trapped in the same manner as I-: β- particle emissions, which destroy thyroid tissue Advantages: easy administration, effectiveness, low expense, and absence of pain Major disadvantage is the development of hypothyroidism