Thyroid and Antithyroid Drugs

Question 1

BIOSYNTHESIS OF THYROID HORMONES?

Answer 1

The major steps in the synthesis, storage, and release of thyroid
hormones are :
1. Uptake of iodide ion (I–
) by the thyroid gland.
2. Oxidation of iodide to iodine.
3. Iodination of tyrosyl groups of thyroglobulin.
4. Coupling of iodotyrosine residues to generate the thyroid
hormones.
5. Resorption of the thyroglobulin colloid from the lumen into
the cell.
6. Proteolysis of thyroglobulin and the release of thyroxine and
triiodothyronine into the blood.

Question 2

THYROID HORMONES - MOA?

Answer 2

Thyroid hormones enter cells and bind to thyroid hormone
receptor (TR) in the nuclei.
The hormone–receptor complex then binds to DNA and increases or decreases the expression of a variety of different genes that code for proteins that regulate cell function.
T3 acts more rapidly and is more potent than T4. This is
because T3 is less tightly bound to plasma proteins than is T4, but binds more avidly to thyroid hormone receptors.

Question 3

PHYSIOLOGICAL EFFECTS OF THYROID HORMONES?

Answer 3

↑Metabolic Rate
Synergism with Catecholamines
Normal Growth
and Development

Question 4

METABOLISM OF THYROID HORMONES?

Answer 4

Thyroid hormones are metabolized by the following
mechanism:
 Deiodination (the most important mechanism).
 Glucuronidation.
 Sulfation.

Question 5

Describe Deiodination?

Answer 5

Deiodination of T4 by 5′deiodinase enzymes results in the production of either T3 which is more potent than T4 or reverse
T3 [rT3] which is metabolically inactive.
 Inhibition the 5′-deiodinase results in low T3 levels in the serum.
 5′deiodinase enzymes are inhibited by:
1. Drugs such as propylthiouracil, propranolol,
corticosteroids, and amiodarone.
2. Severe illness and starvation.
3. Iodinated compounds such as the radiographic agents iopanoic acid and ipodate.

Question 6

Describe T4 and T3 role in the GIT?

Answer 6

 T4 and T3 are also conjugated in the liver to form sulfates
and glucuronides.
 These conjugates enter the bile and pass into the intestine where they are hydrolyzed, and some are thereafter reabsorbed (enterohepatic circulation), but others are excreted in the stool.
 In the intestine, Bile acid sequestrants (e.g. cholestyramine)
bind to and prevent the enterohepatic cycling of thyroid hormones.

Question 7

Describe the consequences of induction in relation to Thyroid enzyme metabolism?

Answer 7

 Deiodinase and UDP-glucuronosyltransferase enzymes are
inducible enzymes.
 Enzyme inducers (e.g. rifampin) increase the metabolism of
both T3 and T4.
 Patients dependent on T4 replacement medication may
require increased dosages to maintain clinical effectiveness if they are also on an enzyme inducer.

Question 8

MANIFESTATIONS OF HYPOTHYROIDISM?

Answer 8

Clinical manifestations of hypothyroidism include goiter, muscle weakness, dry coarse skin, lethargy, cold intolerance, decreased sweating, cold skin, thick tongue, coarse hair, yellowish tint of the
skin, and delayed DTRs.

Question 9

CAUSES OF HYPOTHYROIDISM?

Answer 9

 Hashimoto’s thyroiditis the most common cause of
hypothyroidism in the USA while iodine deficiency is the most common cause worldwide.
 Other causes of hypothyroidism include thyroidectomy, external neck irradiation, radioactive iodine therapy and
drug induced.

Question 10

Drugs that may cause hypothyroidism?

Answer 10

Drugs that may cause hypothyroidism include thioamides,
iodides, amiodarone, lithium, aminoglutethimide, rifampin,
tyrosine kinase inhibitors (e.g., imatinib, sunitinib, sorafenib),
interleukin 2, interferon-α, and sulfonylureas.

Question 11

General management of hypothyroidism?

Answer 11

 Hypothyroidism is treated by thyroid hormone replacement.
 Available thyroid preparations are classified into:
A. Synthetic preparations including:
1. Levothyroxine (T4).
2. Liothyronine (T3).
3. Liotrix (mixture of T4 and T3).
B. Natural preparations of animal origin (desiccated
thyroid).

Question 12

LEVOTHYROXINE VS. LIOTRIX?

Answer 12

 The use of the more expensive thyroxine and liothyronine
fixed-dose combination (liotrix) has not been shown to be more effective than T4 administration alone.
 Synthetic levothyroxine (T4) is the preparation of choice for thyroid hormone replacement therapy

Question 13

AE of thyroid replacement therapy?

Answer 13

 Thyroid replacement therapy may result in hyperthyroidism like
manifestation.
 Thyroid hormones can increase the risk of atrial fibrillation and osteoporosis.

Question 14

MANAGEMENT OF MYXEDEMA COMA?

Answer 14

 Myxedema coma is a severe and long-standing form of hypothyroidism.
 Cardinal features of myxedema coma are hypothermia, respiratory depression, and decreased consciousness.
 Management includes supportive measures and IV
levothyroxine. Liothyronine may be added until the patient is stable and conscious.

Question 15

MANAGEMENT OF HYPOTHYROIDISM

DURING PREGNANCY?

Answer 15

During pregnancy, adequate dose of levothyroxine is important
as early development of the fetal brain depends on maternal thyroxine.

A higher dose of levothyroxine is usually required in pregnant
patients. This is because of :
1. Increased serum concentration of Thyroxine-binding globulin (TBG) induced by estrogen.
2. Expression of 5′deiodinase 3 (D3) by the placenta.
3. Small amount of transplacental passage of
levothyroxine from mother to fetus.

Question 16

Management of Congenital hypothyroidism?

Answer 16

 Success in the treatment of congenital hypothyroidism
depends on the age at which therapy is started and the speed with which hypothyroidism is corrected.
 If levothyroxine is instituted within the first 2 weeks of life,
normal physical and mental development can be achieved.

Question 17

MANIFESTATIONS OF HYPERTHYROIDISM?

Answer 17

 Symptoms of hyperthyroidism include nervousness,
increased sweating, heat intolerance, palpitations, fatigue, weakness, weight loss with increased appetite, dyspnea.
 Signs of hyperthyroidism may include goiter with bruit over thyroid, tachycardia, skin changes and eye signs.

Question 18

Causes of Hyperthyroidism?

Answer 18

 Grave’s disease (toxic diffuse goiter) is most common cause
of hyperthyroidism.
 Other causes include toxic adenoma, toxic multinodular goiter, factitious hyperthyroidism and Drug-induced (iodides,
amiodarone, interleukin 2, interferon-α, lithium).

Question 19

The primary methods for controlling hyperthyroidism are:

Answer 19

1. Pharmacotherapy.
2. Destruction of the gland with radioactive iodine (RAI).
3. Surgical thyroidectomy

Question 20

Drugs used in the management of hyperthyroidism include:

Answer 20

 Thioamides.
 Iodides.
 β-adrenoceptor–blocking agents.
 Glucocorticoids.
 Bile acid sequestrants.

Question 21

Give 2 examples of Thioamides?

Answer 21

Thioamides include:

1. Methimazole.
2. Propylthiouracil (PTU).

Question 22

Thioamides MOA?

Answer 22

Thioamides inhibit the formation of thyroid hormones by:
 Inhibiting the thyroid peroxidase enzyme.
 Preventing oxidation of iodide to iodine.
 Interfering with the iodination of tyrosyl groups of thyroglobulin.
 Inhibiting the coupling of iodotyrosyl residues to form
thyroid hormones.

Question 23

Propylthiouracil vs methimazole differences moa?

Answer 23

 Propylthiouracil partially inhibits the peripheral deiodination of T4
to T3. Methimazole does not have this effect.
 Propylthiouracil is preferred over methimazole in the treatment of severe hyperthyroid and thyroid storm, where a decreased rate of T4 to T3 conversion would be beneficial.

Question 24

THERAPEUTIC USES OF THIOAMIDES?

Answer 24

Thioamides are used for the following indications:
 As definitive treatment for hyperthyroidism.
 In conjunction with radioactive iodine, to hasten recovery
while awaiting the effects of radiation.
 To control hyperthyroidism in preparation for surgical
treatment.

Question 25

Adverse Effects of THioamides?

Answer 25

 Urticarial rash (most common reaction).
 Agranulocytosis (The most serious reaction).
 Hepatotoxicity.
 Vasculitis.
 Teratogenicity.

Question 26

CHOOSING BETWEEN METHIMAZOLE AND PROPYLTHIOURACIL

Answer 26

 Methimazole is preferable to propylthiouracil except in the first trimester of pregnancy and thyroid storm.
 Compared to propylthiouracil, methimazole has less toxic
effects, a lower risk of serious liver injury, a longer half-life, and a long duration of action (can be administered once
daily).

Question 27

Iodides MOA?

Answer 27

 Iodides inhibit hormone release from the thyroid gland possibly through inhibition of thyroglobulin proteolysis and
transiently inhibit the organification of iodine (the WolffChaikoff
effect).
 Iodide should not be used alone, because the thyroid gland escapes from the iodide block in 2–8 weeks.

Question 28

CLINICAL USE OF IODIDES?

Answer 28

 Thyroid storm as iodides result in rapid improvement of thyrotoxic symptoms.
 Preoperative preparation for surgery as they decrease the size and the vascularity of hyperplastic thyroid glands.
 Radiation emergencies involving release of radioactive iodine
isotopes.

Question 29

ADVERSE EFFECTS OF IODIDES?

Answer 29

 Adverse reactions are uncommon.
 May precipitate hyperthyroidism (Jod-Basedow phenomenon) or hypothyroidism (failure to escape from the
acute Wolff-Chaikoff effect).
 Delay onset of thioamide therapy or prevent use of
radioactive iodine therapy for several weeks.
 Fetal goiter if used during pregnancy

Question 30

Thyroid hormone role in Beta receptors and consequences?

Answer 30

 Although they do not increase catecholamine levels, thyroid hormones increase the expression of β-adrenergic receptors and the signaling effectors to which they are linked.
 This results in catecholamine excess-like manifestations including hypertension, tachycardia, lid lag and retraction,
tremor, excessive sweating, anxiety, and nervousness,
resemble sympathetic nervous system overactivity.

Question 31

β-ADRENOCEPTOR–BLOCKING AGENTS role in thyroid hormone treatment?

Answer 31

 β-blockers are used extensively alleviate catecholamine
excess-like manifestations associated with hyperthyroidism
and thyroid storm.
 Propranolol inhibits the conversion of T4 to T3, resulting in
low T3 levels in the serum.
 Diltiazem and verapamil can be used to control tachycardia
in patients in whom β blockers are contraindicated.

Question 32

Glucocorticoids in thyroid therapy?

Answer 32

 Used in the management of thyroid storm as they inhibit the peripheral conversion of T4 to T3 and promote vasomotor
stability, and possibly treat an associated relative adrenal insufficiency.
 Used in the management of Grave’s ophthalmopathy and dermopathy

Question 33

Bile acid sequestrant use in thyroid therapy?

Answer 33

 Bile acid sequestrants are used in the management of
thyroid storm.
 In the intestine, Bile acid sequestrants (e.g., cholestyramine) bind to and prevent the enterohepatic cycling of thyroid
hormones.

Question 34

Radioactive Iodine in thyroid therapy?

Answer 34

 Generally, radioiodine therapy (RAI) utilizing 131I is the preferred treatment for hyperthyroidism.
 RAI destroys the thyroid parenchyma.

Question 35

RADIOACTIVE IODINE – ADVERSE EFFECTS?

Answer 35

 Hypothyroidism.
 Radiation thyroiditis.
 Exacerbate Grave’s ophthalmopathy.
 Destroys the fetal thyroid if used during pregnancy.

Question 36

What is a thyroid storm?

Answer 36

 Thyroid storm is a sudden and life-threatening acute
exacerbation hyperthyroidism.
 Occurs in patients who have hyperthyroidism and is
triggered by Infection, trauma, surgery, physical illness, and
severe emotional distress.
 Manifested by acute exacerbation of hyperthyroidism
manifestations and may be lead to vital instability and multi organ involvement.

Question 37

MANAGEMENT OF THYROID STORM?

Answer 37

Management includes supportive therapy, treating the underlying disease process that may have precipitated the
acute storm and the use of propylthiouracil, iodides,
propranolol, corticosteroids and bile acid sequestrants.

Question 38

MANAGEMENT OF THYROTOXICOSIS

DURING PREGNANCY?

Answer 38

 Propylthiouracil, which has a lower risk of teratogenicity
than methimazole, can be given in the first trimester, and then methimazole can be given for the remainder of the pregnancy to avoid potential liver damage.
 Alternatively, a subtotal thyroidectomy can be performed.
 RAI is contraindicated during pregnancy because it crosses
the placenta and may injure the fetal thyroid.