Pharmacology of Thyroid Drugs

Describe anatomy of the thyroid gland (1)

Sits on the trachea, two lobes joined by isthmus. Each lobe is 2.5-4 cm long, 1.5-2 cm wide and 1-1.5 cm thick. Adult gland weighs 10-20 g. Enlarged during - adolescence, pregnancy, lactation, later portion of menstrual cycle

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Describe anatomy of the thyroid gland (2)

Blood supply from superior and inferior thyroid arteries. Arise from external carotid artery, subclavian artery, blood flow 4-6 mL/min/g tissue

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Where are the parathyroid glands located?

They are embedded within the thyroid gland (produce PTH, involved in Ca metabolism)

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What are the functions of the thyroid gland? (1)

Makes thyroid hormones (thyroxine/T4 and tri-iodothyronine/T3) and calcitonin (involved in Ca metabolism). Development (neural development of foetus, growth in young child). Metabolism (controls basal metabolic rate/BMR)

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What are the functions of the thyroid gland? (2)

Concentrates iodine for incorporation into thyroid hormones. Contains 60-65% of body iodine

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Describe the structure of thyroid hormones

Contains tyrosine residues. Pre-cursors are MIT and DIT. T4 can be converted to T3 in the periphery by the removal of iodine. Reverse T3 (lacks 5 iodine rather than 5' iodine)

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Describe the cell structure of the thyroid gland (1)

Thyroid consists of follicles. Follicular cells surround organelles/colloids. C-cells (parafollicular cells) produce calcitonin. Follicular cells - basement membrane, uptake of iodine in cells

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Describe the cell structure of the thyroid gland (2)

Tyrosine enters cell. Protein synthesis produces thyroglobulin, secreted into IC space, into colloid. Thyroglobulin (where thyroid hormones are made/breakdown of thyroglobulin). Release of thyroid hormones - re-uptake of thyroglobulin into lysosomes

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What is the consequence of an underactive thyroid

Accumulation of thyroglobulin

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What is the consequence of an overactive thyroid?

Proliferation and enlargement of follicular cells, little colloid

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Outline the control of synthesis for the hormones (1)

Input, hypothalamus, release hormone, pituitary, release tropic hormone, release of thyroid hormone, reaches target to achieve effects. Thyroid hormone can feedback to pituitary and hypothalamus

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Outline the control of synthesis for the hormones (2)

Hypothalamus releases TRH to anterior pituitary, release TSH into blood supply and reaches thyroid gland (receptor), cause release of T4 (mainly) and T3. T4 (pro-hormone converted to T3). Effects mediated by T3 rather than T4

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Outline the control of synthesis for the hormones (3)

T3 feedback to pituitary and hypothalamus (suppress release of TSH and TRH)

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Describe the regulation of synthesis (1)

Hypothalamus releases TRH (consists of 3 amino acids). TRH stimulates anterior pituitary to produce TSH which stimulates gland to synthesis/release thyroid hormones

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Describe the regulation of synthesis (2)

Main hormone released is T4 which is converted to T3 in the periphery. T3 is more potent at thyroid receptors than T4. T3 acts on thyrotrophs to decrease release of TSH and decrease TRH release

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Describe the synthesis of thyroid hormones (1)

Uptake of amino acids, thyroglobulin. Active uptake of iodide into follicular cells, oxidised, added to tyrosine entities with thyroglobulin (storage). Re-uptake of thyroglobulin

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Describe the synthesis of thyroid hormones (2)

Release T3 and T4 (lipid soluble, diffuse out of cell, towards capillaries) - little evidence for exocytosis. Iodine reused

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Describe the effects of TSH on thyroid follicular cells (1)

TSH acts on receptors, GPCR, causes increase in cAMP, stimulate production of thyroglobulin (across apical membrane to colloid), more iodine uptake into cell (Na overload prevented by Na-K pump)

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Describe the effects of TSH on thyroid follicular cells (2)

Thyroid peroxidase (TPO) in the presence of hydrogen peroxide, traps iodine (large conc gradient from EC to IC). Iodine pumped into colloid via pendrin. TPO catalysis addition of iodine to tyrosine residues once iodine is pumped into colloid.

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Describe the effects of TSH on thyroid follicular cells (3)

Condensation reaction to produce T3 and T4. Increase in TSH stimulates re-uptake of thyroglobulin (115 tyrosine residues). MIT + DIT gives T3, DIT + DIT gives T4, with less iodine (more T3 made)

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Describe features of thyroid hormones and protein binding (1)

Thyroid hormones highly protein bound (T4 is 99% bound to protein, not active). Changes in protein binding. Decreased binding (more effect). Increased binding (less thyroid hormone active (hypothyroidism). More free T4 found in plasma (serum levels)

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Describe features of thyroid hormones and protein binding (2)

T3 more active than T3 (but T3 doesn't act on receptor). T4 more table than T3. 90% of T4 is converted to T3 and rT3 in periphery

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Describe features of thyroid hormones and protein binding (3)

Free (T4 - 0.04, T3 - 0.4). Thyroxine Binding Globulin (T4 - 70-75, T3 - 70-75). Albumin (T4 - 5-10, T3 - 25-30), Thyroxine binding pre-albumin (T4 - 15-20)

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What are the levels of thyroid hormones? (1)

T4 (total serum, 103 nM, free serum, 27 pM, body store, 1023 nmol, half life of 7 days, release 100 nmol/day). T3 (total serum, 1.84 nM, free serum, 4.3 pM, body store, 71 nmol, half life of 1 day, release 5 nmol/day, conversion of T4, 35)

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What are the levels of thyroid hormones? (2)

rT3 (total serum, 0.51 nM, free serum, 3.69 pM, body store, 62 nmol, half life of 0.2 days, release <5 nmol/day, conversion of T4, 45)

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Describe features of thyroid receptors (1)

TSH acts on TSH receptor, release of hormones into plasma, thyroid hormones has IC receptors (reason for protein bound hormones). Nuclear receptors, form a dimer with retinoid receptor. Formation of complex. T3 and T4 enter cell

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Describe features of thyroid receptors (2)

T4 de-ionated, switch on mRNA production, protein synthesis, slow responses

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Describe features of thyroid receptors (3)

Thyroid hormones interact with nuclear receptors. Thyroid hormone enters cells via diffusion/specific carrier. T3 enters nucleus and binds to thyroid receptor. Hormone receptor complex binds to thyroid hormone responsive element (TRE) on DNA

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Describe features of thyroid receptors (4)

Results in increased - mRNA production, protein synthesis, Na-K ATPase levels, ATP turnover, O2 consumption and number of adrenoceptors

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What are the effects of thyroid hormones? (1)

Increased O2 consumption/heat production, increased cardiac muscle contractility, increased sensitivity to catecholamines. Maintenance of hypoxic/hypercapnia drive in respiratory centre. Increase gut motility, increase erythropoiesis

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What are the effects of thyroid hormones? (2)

Increase bone turnover, increase protein turnover (decrease in muscle mass), increase cholesterol degradation, increase metabolic turnover of hormones and drugs

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What are the types of thyroid disease?

Primary (thyroid). Secondary (pituitary). Tertiary (hypothalamic). Under activity (hypothyroidism). Over activity (hyperthyroidism)

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What would be the test results for thyroid disease?

Hypothyroidism - low T3 and T4, elevated TSH. Hyperthyroidism - high T3 and T4, low TSH

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What is the prevalence of primary hypothyroidism?

More common in women

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What are the effects of a hypothyroid state?

Increase body weight, decrease O2 consumption, decrease heat production, decrease BMR, CNS depression (drowsiness), decrease in reflexes, decrease in sympathetic effects, cardiac effects (bradycardia, decrease in CO/BP), decrease in gut effects

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What are the effects of a hyperthyroid state?

Decrease body weight, increase O2 consumption, increase heat production, increase BMR, CNS excitability (insomnia), increase in reflexes, increase in sympathetic effects, cardiac effects (tachycardia, increase in CO/BP), increase in gut effects

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What are the signs symptoms of hypothyroidism?

Signs - dry skin, hoarse voice, slow movements, coarse hair and skin, periorbital puffiness. Symptoms - cold intolerance, weight gain, constipation, slow reflexes, hypercholesterolaemia, hyperprolactinaemia

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Describe features of Hashimoto's thyroiditis (hypothyroidism) (1)

Affects 3% of population. Autoimmune disease (kills follicular cells). Antibodies to thyroglobulin or TPO. Causes - radiotherapy or surgery for hyperthyroidism, failure of delivery of thyroid hormones in foetus/cretinism

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Describe features of Hashimoto's thyroiditis (hypothyroidism) (2)

Treatment - thyroxine, low dose (T4, t1/2 of 6 days, effects last for 14 days). Monitor effectiveness of treatment by getting TSH back to within normal range. Measure every 3 months. Liothyronine (Na salt of T3, half life of 2-3 days, effects/8 days)

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Describe features of Hashimoto's thyroiditis (hypothyroidism) (3)

Monitor - increase thyroid hormone until TSH is suppressed back into normal range (other option T3 - not recommended)

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Describe features of myxoedema (hypothyroidism) (1)

Dietary iodine requirement (150 micrograms/day). Dietary deficiency (<50 micrograms/day). Non-toxic goitre. Treatment - iodine supplements

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Describe features of myxoedema (hypothyroidism) (2)

Goitrogen - suppresses hormone secretion. Increases TSH secretion (goitre - enlargement of gland), iodine in kelp (seaweed), breassicae (cabbage), cassava, lithium, some local drinking water, cough mixtures, decrease intake

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Describe features of myxoedema (hypothyroidism) (3)

High levels of iodine can suppress hormone production. Low iodine levels cause hypothyroidism, stimulation of gland to try to make hormones, more follicular cells, form goitre

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What are the signs and symptoms of hyperthyroidism?

Signs - tachycardia, tremor, thyroid bruit, eye signs, atrial fibrillation, pre-tibial myxoedema. Symptoms - nervousness/anxiety, sweating, heat intolerance, palpitations, fatigue, weight loss

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Describe features of thyrotoxicosis (hyperthyroidism) (1)

Graves' disease (diffuse toxic goitre). Autoimmune disease. TSaB (LATS) - produces prolonged stimulation of TSH receptors. Features - thyrotoxicosis, weight loss, sweating, tremor, tachycardia, nervous, diarrhoea, goitre

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Describe features of thyrotoxicosis (hyperthyroidism) (2)

Exophthalmos and upper lid retraction, pretibial myxoedema, thickening of skin over tibia due to deposition of glycosaminoglycans

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What is the treatment for hyperthyroidism? (1)

Anti-thyroid drugs (structures), carbimazole (converted to methimazole in the body), propyl thiouracil (inhibits TPO and also prevents peripheral conversion of T4 to T3). 4-8 weeks to become euthyroid

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What is the treatment for hyperthyroidism? (2)

Reduce dose to maintenance dose (monitor by measuring TSH and T4). Treat for 12-18 months. S/E - can suppress WBC production, neutropenia, agranulocytosis, report sore throat

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Describe other treatments for hyperthyroidism (1)

Patients with hyperthyroidism has exaggerated cardiac responses. Treat by decreasing size of gland (treat goitre)

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Describe other treatments for hyperthyroidism (2)

Radioiodine (PO, taken up into thyroid gland, incorporate into thyroid hormones, breaks down into non-radioactive iodine, beta kills cells/gamma emitter, t1/2 8 days, decay in 2 months, could become hypothyroid/treat with low dose thyroxine)

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Describe other treatments for hyperthyroidism (3)

Propranolol (block sympathetic effects of hormones/heart). Surgery/partial thyroidectomy (issue - high blood perfusion, could be come hypothyroid). Minimise blood loss/use prior to surgery- I2 in LUGOL's solution (reduce vascularity, 5% I2 + 10% KI)

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Describe other treatments for hyperthyroidism (4)

Guanethidine (noradrenergic neurone blocker). Eye drops for exophthalamus

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What are the signs of a thyroid storm?

Thyrotoxic crisis. Increase in thyroid levels. Signs - fever, tachycardia, agitation, nausea/vomiting/diarrhoea/jaundice

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What is the treatment for a thyroid storm?

Treatment - IV fluids (replace fluid from vomiting/diarrhoea), propranolol (effect on heart), hydrocortisone, oral iodine solution (prevent hormone production), propylthiouracil (prevent T4 to T3 conversion)

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Pharmacology of Thyroid Drugs

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