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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 - PowerPoint PPT Presentation
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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