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Thyroid Drugs

Kaukab Azim, MBBS, PhD

Learning Outcomes

By the end of the course the students should be able to discuss in detail

•Physiology, synthesis and feed back control of thyroid hormone synthesis

•Thyroid disorders:– Hypothyroidism

• Cretinism, Myxedema coma– Hyperthyroidism

• Thyroid storm

•Drugs for the treatment of hypothyroidism and hyperthyroidism 2

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Thyroid Hormones

• Thyroid hormones:– Thyroxine T4 (90%)– Triiodothyronine T3

• Thyroid gland also secretes Calcitonin – serum calcium lowering hormone

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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.

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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(High dose)

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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

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Thyroid hormone synthesis

4. Coupling

(Iodide Organification)

TBP

T4

T3

& Free T4 & T3

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Outer ring Inner ring

(T4)

Metabolism of thyroid hormones

5’-deiodinase

(4X potent than T4)

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Metabolism of Thyroid hormones

Drugs that inhibit deiodination: – Beta blockers – High dose propylthiouracil – Corticosteroids

• They inhibit the 5’-deiodinase activity necessary for conversion of T4 to T3 resulting in low T3 and high reverse T3 (rT3)

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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.

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Hypothyroidism

Clinical manifestations: – Lethargy – Wt. gain – Bradycardia – Constipation – Cold intolerance – Menstrual irregularities

• Cretinism (congenital hypothyroidism)• Myxedema coma: most extreme

manifestations of untreated hypothyroidism

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Drugs for Hypothyroidism

Levothyroxine (T4) • It is the treatment of choice for replacement

therapy in hypothyroid patients• It has a long half life ~7 days; once a day dose.

Triiodothyronine (T3)• Short half life (1 day)

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Drugs for Hypothyroidism

• T4 and T3 given orally.• T4 is better for long term replacement

therapy• I.V. administration in myxedema coma• During pregnancy, hypothyroid woman

require higher doses

Hyperthyroidism

• Clinical manifestation– Weight loss and with increase in appetite.– Nervousness and irritability.– Palpitations.– Heat intolerance and increased sweating.– Tremors.– Thyroid enlargement– Menstrual irregularities

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HyperthyroidismTreatment options:

• Surgical• Antithyroid drugs:

– By inhibiting uptake of iodine– By inhibiting synthesis– By inhibiting release of hormones from

thyroid• Medical destruction of thyroid tissue

– Radioiodine (I131)

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Drugs for hyperthyroidism

Thioamides: Propylthiouracil, Methimazole

Inhibit hormone synthesis

Iodide salts: KI, Lugol’s solution

Blocks hormone release

Iodinated contrast media: Ipodate

Inhibition of peripheral T4 to T3 conversion; inhibits hormone release

Anion inhibitors:Perchlorate, thiocyanate

block uptake of iodide by thyroid

Radioactive iodine (131I)

destruction of thyroid tissue

Beta-blocker: Propranolol, esmolol

Controls heart rate

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Anion Inhibitors(-)

T4 T3 5’-deiodinase

Propylthiouracil, Ipodate, beta blockers, cortocosteroids(-)

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1. Thioamides

Propylthiouracil, Methimazole• Inhibit hormone synthesis

– Acts by inhibiting thyroid peroxidase to block iodine organification and coupling reactions

• These are the major drugs for treatment of mild thyrotoxicosis and in preparation of patients for subtotal thyroidectomy

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Thioamides

• Slow onset of action (~ 4 weeks)• Propylthiouracil is relatively safe and

preferred in pregnancy• Methimazole is more potent and longer

acting than Propylthiouracil• Propylthiouracil also inhibits peripheral

deiodination of T4 and T3

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Thioamides: Adverse drug reactions

• Common: Maculopapular Rash, Arthralgia, vasculitis

• Serious side effect: Agranulocytosis

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2. Iodides:Potassium iodide, Lugol’s solution

• Mechanism of action – Inhibit hormone release – Inhibit organification– Decrease size and vascularity of the

hyperplastic gland.

• Effect is reversible and transient – not for long term as thyroid gland ‘escapes’ from its effect after 14 days

• Contraindicated in pregnancy: fetal goiter

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3. Iodinated contrast media

Ipodate and Iopanoic acid– They inhibit the peripheral conversion of T4

into T3 in the liver, kidney and brain– Inhibition of hormone release is an

additional mechanism

• Adjunctive therapy in the treatment of thyroid storm

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4. Anion Inhibitors

Perchlorate (ClO4-), Pertechnetate (Tco4

-), Thiocyanate (SCN-)

•competitively block the uptake of iodide•Adverse effect: Aplastic anemia

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5. Radioactive Iodine

• 131I is the only isotope used in treatment of thyrotoxicosis while others are used in diagnosis.

• Emission of beta particles – destroys the thyroid gland.

• Patients can become hypothyroid – managed with thyroxine (T4)

• Contraindications:– Pregnancy & lactation– Age <25 yrs

Thyroid storm• Clinical manifestation

– High fever often above 40°C– Fast and often irregular heart beat – Vomiting, diarrhea and agitation. – Heart failure and myocardial infarction may occur.– Death may occur despite treatment.

• Causes – Patients with known hyperthyroidism whose

treatment has been stopped or become ineffective,– Untreated mild hyperthyroidism who have

developed an intercurrent illness (such as an infection).

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Thyroid storm

Treatment

• Propranolol /Esmolol / Diltiazem

• Iodide/ipodate – ipodate also block the T4 to T3 conversion

• Propylthiouracil

• Hydrocortisone – blocks the T4 to T3 conversion

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Qs