1 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.
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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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Metabolism of Thyroid hormones
Drugs that inhibit deiodination: • Beta blockers • High dose propylthiouracil • Corticosteroids
– inhibit the 5’-deiodinase activity necessary for conversion of T4 to T3 resulting in low T3 and high 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) • 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
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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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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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Iodides:Potassium iodide, Lugol’s solution
– 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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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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Anion Inhibitors
Perchlorate(ClO4-), Pertechnetate
(Tco4-), Thiocyanate (SCN-)
– competitively block the uptake of iodide
• Adverse effect: Aplastic anemia
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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
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Thyroid storm
Rx• 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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