1. Thyroid & Antithyroid Drugs
Dr. Naza M. Ali
Lec 3-4

2. Objectives: Thyroid physiology and function Regulation of synthesis
Biosynthesis of thyroid hormones
Mechanism of action
Pharmacokinetics
Hypothyroidism and treatment
Hyperthyroidism and treatment

3. Thyroid Gland Physiology
Consists of two lobes & is situated in the lower neck
Both T4 and T3 are produced within the follicular cells in the thyroid.
The gland is made up of multiple follicles that consist of a single layer of epithelial cells surrounding a lumen filled with thyroglobulin, which is the storage form of thyroid hormone.

4. Consists of two lobes & is situated in the lower neck

5. Thyroid gland function
Facilitates normal growth and development,
body temperature and energy levels.
Thyroid hormones are :Triiodothyronine ( T3), Tetraiodothyronine ( T4 )
These hormones contain 59% and 65% of iodine as an essential part of the molecule.
Calcitonin hormone is important in the regulation of calcium metabolism

6. Regulation of Hormone Synthesis
Regulation of hormone synthesis is by TSH from the anterior pituitary.
TSH is regulated by hypothalamic secretion of TRH

7. Feedback inhibition of TRH occurs with high levels of circulating thyroid hormone.
At pharmacologic doses, dopamine, somatostatin, or glucocorticoids can also suppress TSH secretion
Most of the hormone (T3 and T4) is bound
to thyroxine-binding globulin in the plasma.

9. Low circulating levels of thyroid hormones initiate the release of TSH and also TRH.
Rising levels of TSH promote increased iodide trapping by the gland and a subsequent increase in thyroid hormone synthesis.

11. Biosynthesis of Thyroid Hormones
Once taken up by the thyroid gland, iodide undergoes a series of enzymatic reactions that incorporate it into active thyroid hormone
1. The first step is the transport of iodide into the thyroid gland by the sodium/iodide symporter (NIS).
This can be inhibited by thiocyanate (SCN−)

12. 1. The first step is the transport of iodide into the thyroid gland
2. Oxidation to iodine ( I2 ) by a peroxidase
3. Followed by iodination of tyrosines on thyroglobulin.
4.Condensation of two diiodotyrosine residues gives rise to T4, whereas condensation of a monoiodotyrosine residue with a diiodotyrosine residue generates T3
5.The hormones are released following proteolytic cleavage of the thyroglobulin.

13. Biosynthesis of thyroid hormones

14. Mechanism of action of thyroid hormone
Both T4 and T3 must dissociate from thyroxine-binding plasma proteins prior to entry into cells, either by diffusion or by active transport.
In the cell, T4 is enzymatically deiodinated to T3, which enters the nucleus and attaches to specific receptors.
The activation of these receptors promotes the formation of RNA and subsequent protein synthesis, which is responsible for the effects of T4.

15. Pharmacokinetics
Both T4 and T3 are absorbed after oral administration.
T4 is converted to T3 by deiodinase in liver, kidney
Metabolized through the P450 system.

16. Calcium preparations, and aluminum-containing antacids can decrease the absorption of T4 but not of T3.
Interactions with certain foods (bran, soy, coffee) and drugs can impair its absorption
Thyroxine should be administered on an empty stomach ( 60 minutes before meals, or at bedtime).

17. Drugs that induce the P450 enzymes:
Phenytoin,
Rifampin, Phenobarbital
accelerate metabolism of the thyroid hormones

18. Hypothyroidism
A deficiency of thyroid hormones and a reversible slowing down of all body functions
In infants and children, there is striking retardation of growth and development that results in dwarfism and irreversible mental retardation.
Hypothyroidism can occur with or without thyroid enlargement (goiter).
The laboratory diagnosis is made by the combination of low free thyroxine and elevated serum TSH levels

19. The most common cause of hypothyroidism is Hashimoto’s thyroiditis, an immunologic disorder
In hypothyroidism
bradycardia,
poor resistance to cold,
mental and physical slowing (mental retardation ,dwarfism)

20. Treatment of hypothyroidism
It is treated with levothyroxine (T4)
is given once daily because of its long half-life.
Steady state is achieved in 6 to 8 weeks.
Dosage will vary depending on age and weight.
Infants and children require more T4 per kilogram of body weight than adults.
Toxicity
Nervousness, heart palpitations and tachycardia, intolerance to heat, weight loss.

21. Special Problems in Management of Hypothyroidism
Myxedema Coma
is an end state of untreated hypothyroidism.
is a medical emergency, treated in the intensive care unit
treatment of choice is to give a loading dose of
levothyroxine IV 300–400 mcg initially,
followed by 50–100 mcg daily

22. Hypothyroidism and Pregnancy
Hypothyroid women have anovulatory cycles
So the widespread use of thyroid hormone for infertility
In a pregnant hypothyroid patient receiving thyroxine,
It is important that the daily dose of thyroxine be adequate because early development of fetal brain depends on maternal thyroxine .

23. Drug-Induced Hypothyroidism
Amiodarone-induced hypothyroidism
levothyroxine therapy may be necessary

24. In hyperthyroidism (thyrotoxicosis)
Is the clinical syndrome that results when tissues are exposed to high levels of thyroid hormone
Most patients T3 & T4 are elevated / TSH is suppressed
Tachycardia , cardiac arrhythmias,
Body wasting,
Nervousness,
Tremor,
Excess heat production

25. Graves disease
An autoimmune disease that affects the thyroid, is the most common cause of hyperthyroidism.
which a defect in suppressor T lymphocytes stimulates B lymphocytes to synthesize antibodies to thyroidal antigens.

26. Treatment of hyperthyroidism
The goal of therapy is to decrease synthesis and/or release of additional hormone.
This can be accomplished by:
I. Removing part or all of the thyroid gland
II. Inhibiting synthesis of the hormones
III. Blocking release of the hormones from the follicle.

27. either surgically or by destruction of the gland
Removal of part or all of the thyroid:
either surgically or by destruction of the gland
by radioactive iodine 131 I
is selectively taken up by the thyroid follicular cells.
Most patients become hypothyroid as a result and require treatment with levothyroxine.

28. II. Inhibition of thyroid hormone Synthesis:
The thioamides methimazole & propylthiouracil are major drugs for treatment of thyrotoxicosis.
Carbimazole, which is converted to methimazole
Methimazole is about 10X more potent than PTU and is the drug of choice in adults and children.

29. Mechanism of action of PTU & methimazole
They inhibit both:
the oxidative processes required for iodination of tyrosyl groups and
the condensation (coupling) of iodotyrosines to form T3 and T4
PTU also inhibit peripheral deiodination
T4 & T3

30. PTU & methimazole are concentrated in the thyroid
[These drugs have no effect on the thyroglobulin already stored in the gland].

32. Observation of any clinical effects of these drugs may be delayed until thyroglobulin stores are depleted.
The thioamides are well absorbed from GIT
they have short half-lives.
PTU is given each 6-8 hours
Methimazole is administered in 3 equally divided doses each 8-hour intervals.

33. Both thioamides cross the placental barrier and are concentrated by the fetal thyroid,
Because of the risk of fetal hypothyroidism, both thioamides are classified as FDA pregnancy category D.
PTU is preferable during the first trimester of pregnancy because it is more strongly protein-bound.

34. PTU should be reserved for use during the first trimester of pregnancy.
Due to a black box warning about severe hepatitis

35. Carbimazole is associated with congenital malformations:
aplasia cutis (skin defect).

36. Both thioamides are secreted in low concentrations in breast milk but are considered safe for the nursing infant.
Adverse effects:
Agranulocytosis, rash, and edema.
liver toxicity or liver failure

37. Presents with extreme symptoms of hyperthyroidism.
Thyroid storm
Presents with extreme symptoms of hyperthyroidism.
The therapeutic options for thyroid storm are the same as those for hyperthyroidism, except that the drugs are given in higher doses and more frequently.
β-Blockers ( propranolol) are effective
IV is effective in treating thyroid storm.

38. An alternative in patients suffering from severe heart failure or asthma is the calcium-channel blocker, diltiazem.
Other agents used in the treatment of thyroid storm include:
PTU,
iodides,
iodinated contrast media (which rapidly inhibits the conversion of T4 to T3) and glucocorticoids (to protect against shock).

39. III. Blockade of Hormone Release:
A pharmacologic dose of iodide inhibits the iodination of tyrosines , but this effect lasts only a few days.
iodide inhibits the release of thyroid hormones from thyroglobulin by mechanisms not yet understood.

40. It is used to treat potentially fatal thyrotoxic crisis (thyroid storm) or prior to surgery, because it decreases the vascularity of the thyroid gland.
Iodide is not useful for long-term therapy, because the thyroid ceases to respond to the drug after a few weeks.

41. Iodide is administered orally.
Adverse effects
Sore mouth and throat,
Swelling of the tongue or larynx,
Rashes, ulcerations of mucous membranes
A metallic taste in the mouth.

42. Thyrotoxicosis during pregnancy
Treated with PTU with a dose of a minimum necessary for control of the disease (< 300mg/ d) , because it may effect the fetal thyroid gland.
Methimazole is an alternative but possible fetal scalp defects.

43. Amiodarone-Induced Thyrotoxicosis
About 3% of patients receiving will develop hyperthyroidism .
Two types of amiodarone-induced thyrotoxicosis
iodine-induced (type I), which often occurs in persons with ( multi- nodular goiter, Graves’ disease)
an inflammatory thyroiditis (type II) that occurs in patients without thyroid disease due to leakage of thyroid hormone into the circulation.
Treatment of type I requires therapy with thioamides, while type II responds best to glucocorticoids.
it is not always possible to differentiate between the two types,
thioamides and glucocorticoids are often administered together.