Chapter 38

Thyroid & antithyroid drugs

Right Lobe Left Lobe

Thyroglobulin 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 is a large glycoprotein, – each molecule of which contains about 115 residues Thyroid homones

• The thyroid gland secretes: (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

Iodine intake

 Iodide is ingested by food, water, …

 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

3) Iodine iodinates tyrosine residues of thyroglobulin to form monoiodotyrosine (MIT) and (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 / - 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: – • increase the metabolic clearances of T4 and T3; • decreasing their half-lives; *

– ( 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 (, , )

– 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 thyroid hormone synthesis ….Hashimoto’s thyroiditis

– Goiter due to Iodide deficiency: Daily iodide intake is 150–200 mcg….iodized salt are excellent sources of iodine in the diet

1The anemia of hyperthyroidism is usually caused by increased red blood cell turnover. The anemia of hypothyroidism may be due to decreased production rate, decreased iron absorption, decreased folic acid absorption, or to autoimmune pernicious anemia. LDH, lactic dehydrogenase; AST, aspartate aminotransferase. Clinical Features of Hypothyroidism

Puffy Eyes Lethargy Forgetfulness/Slower Thinking Enlarged Thyroid (Goiter) Mood irritability Deepening of Voice Depression Inability to Concentrate Difficulty Swallowing Dry and brittle hair, brittle nails Decrease HR, CO, prolonged PR interval Dry, Patchy Skin Menstrual Irregularities/ Heavy Period Weight Gain Infertility/Impotence Cold Intolerance Decrease appetite and bowel Elevated Cholesterol & TG’s movement/Constipation Anemia: decreased erythropoiesis Muscle Weakness/ Decrease drug metabolism Cramps Increased warfarin requirements Decrease renal blood flow & GFR..impaired water excretion Management of Hypothyroidism

• There are no drugs that specifically augment the synthesis or release of thyroid hormones

• The only effective treatment for hypothyroidism is to administer the thyroid hormones themselves as replacement therapy

• Combination levothyroxine plus liothyronine has not been found to be superior to levothyroxine alone (once daily) Management of Hypothyroidism

• Drug-induced hypothyroidism

– can be treated by simply removing the depressant agent if possible…..or levothyroxine (if can not stop it)

• amiodarone-induced hypothyroidism,

– levothyroxine therapy may be necessary even after discontinuance because of amiodarone's very long half-life Management of Hypothyroidism

 Infants and children  require more T4 per kilogram of body weight than adults.

 Older adults (> 65 years of age)  may require less thyroxine for replacement than younger adults.

 Thyroxine administration:  should be administered on an empty stomach (eg, 30 minutes before meals or 1 hour after meals)  ….interactions with certain foods (eg, bran, soy, coffee) and drugs can impair absorption

SPECIAL CASES: Myxedema and Coronary Artery Disease

• Myxedema frequently occurs in older persons, often associated with underlying coronary artery disease

• The low levels of circulating thyroid hormone actually: – protect the heart against increasing demands (that may result in angina pectoris or MI)

• So….correction of myxedema, in patients with coronary artery diseae, >>>>> must be done cautiously to avoid provoking arrhythmia, angina, or acute MI Management of Hypothyroidism

 In younger patients or those with very mild disease,  full replacement therapy may be started immediately…..monitor for normal growth and development.

 Serum TSH and FT4 should be measured at regular intervals  It takes 6–8 weeks after starting a given dose of thyroxine to reach steady-state levels in the bloodstream

Adverse effects

• The toxicity of thyroxine is directly related to the hormone level (i.e., symptoms of hyperthyroidism)

• In children: – restlessness, – insomnia, – and accelerated bone maturation and growth

• In adults: – increased nervousness, – heat intolerance, – episodes of palpitation and tachycardia, – or unexplained weight loss may be the presenting symptoms

Adverse effects

 Chronic overtreatment

 may develop osteoporosis ,especially in elderly, increased bone turn over.

 In older patients,

 the heart is very sensitive to the level of circulating thyroxine, and if angina pectoris or cardiac arrhythmia develops,

 >>>>>it is essential to stop or reduce the dose of thyroxine immediately Drug interactions a. Drugs may interfere with thyroid hormones absorption (e.g. cholestyramine, iron and calcium supplements, aluminum hydroxide)

b. CYP450 enzyme inducer (eg, rifampin, phenobarbital, carbamazepine, phenytoin, protease inhibitors)

c. Inhibition of 5'-deiodinase (e.g. Beta-blockers)

d. Changes in TBG concentration: I. Increased TBG: Estrogens, tamoxifen, heroin, methadone, fluorouracil II. Decreased TBG: Androgens & glucocorticoids

Drug interactions

• Thyroid hormone & sympathomimetic agents – increase the risk of coronary insufficiency in patients with CAD

• Thyroid hormones & coumarins – increase the effect of the anticoagulant – Because of ……increase catabolism of vit. K–dependent clotting factors – (lower doses of coumarins are required)

• Initiation of thyroid hormone therapy in patients with DM – ….increase the requirement for insulin or oral hypoglycemic agents

• Thyroid hormone & cardiac glycosides – …..larger doses of digoxin may be required SPECIAL CASES: Hypothyroidism and Pregnancy

• Hypothyroid women frequently have: – anovulatory cycles – and are therefore relatively infertile until restoration of the euthyroid state

• Widespread use of thyroid hormone for infertility, – although there is no evidence for its usefulness in infertile euthyroid patients

• During pregnancy: Adequate daily dose of thyroxine because of; – early development of the fetal brain depends on maternal thyroxine – and coz elevated TBG levels SPECIAL CASES: Myxedema Coma • is an end state of untreated hypothyroidism associated with: – progressive weakness, – stupor, – hypothermia, – hypoventilation, – hypoglycemia, – hyponatremia, water intoxication, – shock, and death • …mortality rate 60-70%

• Medical emergency….the patient is treated with: – i.v loading dose of levothyroxine; – tracheal intubation – and mechanical ventilation may be required Hyperthyroidism

• Hyperthyroidism refers to excess synthesis and secretion of thyroid hormones by the thyroid gland

– ….T3, T4 , FT4, and FT3 are elevated – while TSH is suppressed – Radioiodine uptake is usually markedly elevated as well

• Thyrotoxicosis is the term applied to any condition caused by elevated levels of circulating free thyroid hormones

Hyperthyroidism • It is associated with a number of disease states, including: – Graves’ disease, – toxic adenoma, – or toxic goiter

• Graves’ disease: autoimmune disorder in which the – antibody (TSH-R [stim] Ab) is directed against the TSH receptor site on the thyroid cell membrane – and activate adenylate cyclase in the same manner as TSH – Spontaneous remission occurs – but some patients require years of antithyroid therapy

Hyperthyroidism

• Toxic Uninodular Goiter & Toxic Multinodular Goiter: – occur often in older women with nodular goiters

– FT3 or T3 is strikingly elevated (FT4 may be normal)

– Single toxic adenomas can be managed with either • surgical excision • or with radioiodine therapy

– Toxic multinodular goiter is best treated with: • methimazole or • followed by subtotal thyroidectomy 1The anemia of hyperthyroidism is usually caused by increased red blood cell turnover. The anemia of hypothyroidism may be due to decreased production rate, decreased iron absorption, decreased folic acid absorption, or to autoimmune pernicious anemia. LDH, lactic dehydrogenase; AST, aspartate aminotransferase. Signs and Symptoms of Hyperthyroidism

Nervousness/Tremor Mental Disturbances/ Irritability Difficulty Sleeping Difficulty Swallowing Bulging Eyes/ Vision Changes Palpitations/ Enlarged Thyroid (Goiter) Tachycardia, increase CO, SV, angina, arrhythmias Frequent Bowel Movements Heat Intolerance Menstrual Irregularities/ Increased Sweating Light Period Warm, Moist Palms

Impaired Fertility Weight loss / Increase appetite First-Trimester Miscarriage/ Excessive Vomiting in Pregnancy Hyperglycemia, decrease FA, TG’s, cholesterol Increase erythropoiesis / anemia Increase drug metabolism, decrease warfarin requirements Sudden Paralysis Hyperthyroidism

• The three primary methods for controlling Graves’ disease hyperthyroidism are:

– antithyroid drug therapy,

– surgical thyroidectomy,

– and destruction of the gland with radioactive iodine

Thyredectomy

• A near-total thyroidectomy is the treatment of choice for patients with:

– very large glands

– or multinodular goiters

• Patients are treated with antithyroid drugs

– until euthyroid (about 6 weeks) before surgery

• About 80–90% of patients

– will require thyroid supplementation following near-total thyroidectomy Hyperthyroidism • Antithyroid Drug Therapy:

– the only Tx that leaves the thyroid gland intact (advantage)

– but require long period of Tx (12-18 months) (disadvantage)

– with 50-70% incidence of relapse (disadvantage)

1) Inhibit synthesis of the hormone

2) Inhibit iodide uptake

3) Block the release of the hormone

4) Remove/destroy part of the thyroid by surgery or radiation Inhibition of thyroid hormone synthesis: thioamides • Agents: propylthiouracil and methimazole

• Thionamides are the primary and major drugs used to decrease thyroid hormone production

• Methimazole: – 10x more potent than propylthiouracil – and can be given once daily

• Uses – in the management of hyperthyroidism – and thyrotoxic crisis – and in the preparation of patients for surgical subtotal thyroidectomy Thioamides- MOA 1) Prevent hormone synthesis by inhibiting the -catalyzed reactions and blocking iodine organification

2) Block coupling of the iodotyrosines

3) Inhibit the peripheral deiodination of T4 and T3 (mainly propylthiouracil)

• 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

• They do not block uptake of iodide by the gland

Thioamides- ADRs I. Most common: maculopapular pruritic rash (antihistamine)

II. Most serious: agranulocytosis (sore throat, high fever….discontinue Tx)

III. Rare: urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy, hypoprothrombinemia, exfoliative dermatitis, polyserositis, cholestatic jaundice (methimazole), hepatitis (propylthiouracil) and acute arthralgia

• Thioamides cross the placental barrier, caution when using these drugs in pregnancy • (propylthiouracil is preferable in pregnancy…more protein bound) ANION INHIBITORS

• Monovalent anions: – – perchlorate (ClO4 ), – – (TcO4 ), – and (SCN–) • MOA: – can block uptake of iodide by the gland….competitive inhibition of the iodide transport mechanism

• Effects may be overcome by large doses of iodides…..unpredictable effectiveness

• N.B: rarely used clinically because it is associated with aplastic anemia

Inhibition of hormone release: IODIDES

• The effects of iodide on the thyroid gland are complex:

1) Inhibit hormone release, possibly through inhibition of thyroglobulin proteolysis (major) 2) Inhibit organification 3) Decrease the size and vascularity of the hyperplastic gland

• In susceptible individuals, iodides can: • induce hyperthyroidism • or precipitate hypothyroidism Iodides

• Clinical Uses

1. Treatment of severe thyrotoxicosis or thyroid crisis when a rapid decrease in plasma T4 and T3 is desirable

1. ….Improvement in symptoms occurs rapidly—within 2–7 days

2. Preoperative preparation of patients about to undergo total or subtotal surgical thyroidectomy

1. …..decrease vascularity and size of the hyperplastic gland

Iodide

• Iodide should not be used alone coz over time, the beneficial effects disappear, even with ongoing therapy – Hypersecretion of thyroid hormone and thyrotoxicosis may return at the previous or a more severe intensity

• Iodide use should be initiated only after onset of thioamide treatment & not used if radioactive iodine therapy is planned

• Chronic use of iodides in pregnancy should be avoided….cross the placenta….fetal goiter Iodides- ADRs

• Iodism: are uncommon and reversible: a. Acneiform rash (similar to that of bromism) b. Swollen salivary glands c. Mucous membrane ulcerations d. Conjunctivitis e. Rhinorrhea f. Drug fever g. Metallic taste h. Bleeding disorders i. Anaphylactoid reactions (rare) Radioactive Iodine (131I) • The only isotope used for treatment of thyrotoxicosis – ….orally in solution as sodium 131I, – it is rapidly absorbed, – concentrated by the thyroid, – and incorporated into storage follicles

• 131I is taken up and trapped in the same manner as I-.

• The ablative effect depends on emission of β rays, which

destroy thyroid tissue...T1/2 of 5 days

• Within few weeks, destruction of the thyroid parenchyma is evidenced by: – epithelial swelling and necrosis, – follicular disruption, – edema, – and leukocyte infiltration Radioactive Iodine (131I) • Advantages:

– easy administration,

– effectiveness,

– low expense,

– and absence of pain

• Major disadvantage

– is the development of hypothyroidism…replacement with T4

• Should not be administered to pregnant women or

nursing mothers…..crosses the placenta to destroy the fetal thyroid gland and is excreted in breast milk Adrenergic receptor blocking drugs

• Rationale: reduction of sympathetic manifestations of thyrotoxicosis (thyroid storm)

• Applicable drugs:

 Beta adrenoceptor blockers without intrinsic sympathomimetic activity (, metoprolol, atenolol)

 Beta blocker cause improvement of symptoms but do not alter thyroid hormone levels

 Patients suffering from asthma: CCB (diltiazem)

 At high doses propranolol inhibit conversion of T4 to T3 SPECIAL PROBLEM: thyroid storm • Sudden acute exacerbation of all thyrotoxicosis symptoms; life- threatening syndrome; vigorous management: 1. Propranolol (diltiazem) control severe CV manifestations

2. Release of thyroid hormones from the gland is retarded by the administration of potassium iodide solution

3. Hormone synthesis is blocked by the administration of propylthiouracil or methimazole (orally or rectally)

4. Hydrocortisone protect the patient against shock and block the

conversion of T4 to T3

5. Supportive therapy essential to control fever, heart failure, and any underlying disease that may have precipitated the acute storm

6. Rarely: peritoneal dialysis to lower circulating thyroxine levels SPECIAL PROBLEM: Subacute Thyroiditis

• Subacute thyroiditis:

– Destruction of thyroid parenchyma – during acute viral infection of the thyroid gland – with transient release of stored thyroid hormones • These transient episodes of thyrotoxicosis are called spontaneously resolving hyperthyroidism

• Supportive therapy: – β-adrenoceptor blocking for tachycardia – and NSAIDs to control local pain and fever

• Corticosteroids may be necessary in severe cases to control the inflammation

SPECIAL PROBLEM: thyrotoxicosis & pregnancy

• Women in childbearing period with severe disease should have – definitive therapy with 131I or subtotal thyroidectomy prior to pregnancy

• If thyrotoxicosis develops during pregnancy, radioiodine is contraindicated (crosses the placenta and may injure the fetal thyroid) – In the first trimester…propylthiouracil – Mid trimester….subtotal thyroidectomy performed safely.

• Most patients are treated with propylthiouracil during the pregnancy (lower dose)