1. Thyroid Drugs
Kaukab Azim, MBBS, PhD

2. 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

3. Thyroid Hormones Thyroid hormones:
Thyroxine T4 (90%)
Triiodothyronine T3
Thyroid gland also secretes Calcitonin – serum calcium lowering hormone

4. 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.

5. 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)

6. 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

7. Thyroid hormone synthesis
TBP T3
& Free T4 & T3
(Iodide Organification)
4. Coupling

8. Metabolism of thyroid hormones
Outer ring
Inner ring
(T4)
5’-deiodinase
(4X potent than T4)

9. 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

10. 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.

11. Hypothyroidism
Clinical manifestations: Lethargy, wt. gain, bradycardia, constipation, cold intolerance, menstrual irregularities
Cretinism (congenital hypothyroidism)
Myxedema coma: most extreme manifestations of untreated hypothyroidism

12. 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)

13. 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

14. Hyperthyroidism Treatment 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)

15. 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
KI = Potassium iodide

16. Propylthiouracil, Ipodate, beta blockers, cortocosteroids
(-)
Anion Inhibitors
T4 T3
5’-deiodinase
(-)
Propylthiouracil, Ipodate, beta blockers, cortocosteroids

17. 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

18. 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

19. Thioamides: Adverse drug reactions
Common: Maculopapular Rash, Arthralgia, vasculitis
Serious side effect: Agranulocytosis

20. 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

21. 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

22. Anion Inhibitors
Perchlorate(ClO4-), Pertechnetate (Tco4-), Thiocyanate (SCN-)
competitively block the uptake of iodide
Adverse effect: Aplastic anemia

23. 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

24. Thyroid storm Rx Propranolol /Esmolol / Diltiazem
Iodide/ipodate – ipodate also block the T4 to T3 conversion
Propylthiouracil
Hydrocortisone – blocks the T4 to T3 conversion

25. Qs