1. Drugs used in the management of thyroid disorders

Question 1

Biosynthesis of T4 and T3

Answer 1

1. Uptake of iodide from the blood into the thyroid follicular cell via the Na/I symporter.
2. The iodide is transported into the follicle colloid via Pendrin
3. Oxidation of iodide by thyroid peroxidase
4. Iodination of tyrosyl residues on thyroglobulin to form mono or di-iodotyrosyl residues by thyroid peroxidase (organification)
5. Coupling of 2 diiodotyrosyl residues or 1 monoiodotyrosyl residue with a diiodotyrosyl residue to form T4 and T3 respectively.
6. Endocytosis of colloid from the follicular lumen containing thyroglobulin
7. Fusion with lysosomes
8. TSH increases the activity of thiol endopeptidases, which selectively cleave thyroglobulins yielding hormone containing intermediates
9. Processed by exopeptidases to release T4 and T3.

Question 2

What is the Wolff-Chaikoff effect?

Answer 2

1. The Wolff–Chaikoff effect is an autoregulatory phenomenon.
2. During initial iodine exposure, excess iodine is transported into the thyroid gland by the sodium–iodide symporter.
3. This transport results in transient inhibition of thyroid peroxidase and a decrease in the synthesis of thyroid hormone.

Question 3

Causes of hypothyroidism

Answer 3

1. Primary hypothyroidism → due to failure of thyroid gland itself
   • Chronic autoimmune thyroiditis (Hashimoto thyroiditis); Antibodies directed against thyroid gland, specifically thyroid peroxidase
   • Iodine deficiency
   • Drugs such as amiodarone
2. Central hypothyroidism (secondary hypothyroidism)
   • Due to pituitary failure → Diminished TSH secretion, resulting in lower thyroid hormones
   • Hypothalamic failure → Diminished thyrotropin-releasing hormone, resulting in lower thyroid hormones
3. Congenital Hypothyroidism

Question 4

Symptoms of hypothyroidism

Answer 4

1. Fatigue and lethargy
2. Mental slowness
3. Dry skin
4. Weight gain
5. Irregular menses
6. Hair loss

Question 5

Drugs used in the management of hypothyroidism

Answer 5

1. Levothyroxine (L-T4)

2. Liothyronine (L-T3)

Question 6

Onset of action of levothyroxine (L-T4)

Answer 6

Oral: 3 to 5 days
IV: 6 to 8 hours

Question 7

Onset of action of liothyronine (T3)

Answer 7

3 hours

Question 8

Half-life of levothyroxine (L-T4)

Answer 8

6 to 8 days

Question 9

Half-life of liothyronine (L-T3)

Answer 9

0.75 days

Question 10

How long should thyroid function be monitored during levothyroxine therapy?

Answer 10

6 to 8 weeks

Question 11

Reasons for persistently elevated TSH levels after levothyroxine therapy

Answer 11

Inadequate dosing, poor compliance, malabsorption, drug or food interaction

Question 12

What precipitates myxedema coma and how would a patient with myxedema coma present?

Answer 12

Myxedema coma occurs as a result of long-standing, undiagnosed or undertreated hypothyroidism and is usually precipitated by a systemic illness (infection, heart attack, etc)

Primary signs and symptoms of myxedema coma is altered mental status and low body temperature, hypoglycemia, low blood pressure

Question 13

Adverse reactions of levothyroxine (T4) or liothyronine (T3)

Answer 13

1. In adults, overdosing can cause cardiac arrest, hypertension, palpitations, tachycardia, anxiety, heat intolerance, hyperactivity, insomnia, irritability and weight loss. In children overdosing can cause insomnia, restlessness, accelerated growth and bone maturation,
2. Long term use of high dose L-T4 has been associated with increased bone resorption and reduced bone mineral density, especially in post-menopausal women.

Question 14

Levothyroxine dosage modifications with estrogen hormone replacement therapy

Answer 14

Increase in levothyroxine dose maybe required due to increased thyroxine-binding globulin levels, which then binds levothyroxine and reduces the amount available for action

Question 15

What is observed in subclinical hypothyroidism

Answer 15

Raised TSH with normal serum thyroid hormone levels → progress to overt hypothyroidism

Question 16

How should levothyroxine be dosed in elderly patients

Answer 16

Levothyroxine dose requirement gradually decreases with age due to age-related decreases in thyroxine degradation and in lean body mass.

Question 17

How should levothyroxine be dosed in pregnant patients

Answer 17

30 to 50% increase in dose of levothyroxine during pregnancy, as early as the first 4-6 weeks of gestation

Question 18

How should levothyroxine be dosed in patients with ischemic heart diseases

Answer 18

1. Due to the positive inotropic and chronotropic effects of thyroid hormone on the heart, starting a full dose of levothyroxine could precipitate acute coronary syndrome in hypothyroid patients with silent ischaemic heart diseases.
2. Therefore, newly diagnosed hypothyroid patients with ischemic heart disease should be started on a small dose of levothyroxine and slowly up titrated every 4–6 weeks until euthyroidism is achieved.

Question 19

Causes of hyperthyroidism

Answer 19

1. Graves’ disease
2. Hyperactive thyroid nodules
3. Increased iodine consumption
4. Increased thyroid hormone consumption
5. Inflammation and release of stored thyroid hormones

Question 20

Drugs used in the management of hyperthyroidism

Answer 20

1. Thioamides (anti-thyroid drugs)
2. High concentration of iodine
3. Radioactive iodine

Question 21

Examples of thioamides

Answer 21

1. Carbimazole

2. Propylthiouracil (PTU)

Question 22

MOA of thioamides

Answer 22

1. Thought to inhibit thyroid peroxidase enzyme (TPO) and interfere with the incorporation of iodine into tyrosyl residues of thyroglobulin (iodination)
2. Inhibit coupling of iodotyrosyl residues to form iodothyronines
3. Propylthiouracil (not carbimazole) also inhibits deiodination of T4 to T3.

Question 23

Plasma half-life of PTU

Answer 23

75 mins

Question 24

Plasma half-life of carbimazole

Answer 24

4-6 hours

Question 25

Therapeutic uses for thioamides

Answer 25

1. Graves disease
2. Thyroid storm
3. Overactive thyroid gland
4. To attain an euthyroid state rapidly in preparation for radioiodine therapy or thyroidectomy

Question 26

Adverse effects of thioamides

Answer 26

1. Agranulocytosis → if patient develops a sore throat, fever, or other signs or symptoms of infection, they should stop and have a complete blood count
2. Mild, occasionally purpuric, urticarial papular rash
3. Cholestatic jaundice with carbimazole
4. Severe liver injury and acute liver failure with PTU

Question 27

Usage of thioamides in pregnancy

Answer 27

Propylthiouracil may be the preferred agent during organogenesis, in the first trimester of pregnancy.

Switch from propylthiouracil to thiamazole for the second and third trimesters

Question 28

Examples of high concentrations of iodine/iodide

Answer 28

1. Lugol’s solution

2. Potassium iodide

Question 29

MOA of iodide

Answer 29

High concentrations of iodide can:

1. Suppress iodination of tyrosine and also coupling of monoiodotyrosyl and diiodotyrosyl residues thus inhibiting thyroid hormone synthesis
2. Can decrease thyroid gland size and vascularity when given over 1 to 2 weeks
3. Can be used to temporarily inhibit T4 and T3 synthesis and release into the circulation (useful in thyroid storm)

Question 30

Therapeutic uses of iodide

Answer 30

1. Preparation for thyroidectomy, as it reduces thyroid hormone synthesis and release, and reduces thyroid size and vascularity
2. Thyrotoxic crisis
3. Endemic goitre

Question 31

Contraindication in iodide

Answer 31

Pregnancy → may cause fetal goiter

Question 32

Adverse effects of iodide

Answer 32

1. Allergic reactions → angioedema, laryngeal edema → suffocation and rashes
2. Chronic intoxication with iodide (iodism) → metallic taste, GI intolerance, soreness of the teeth and gums, increased salivation, irritation of the eyes, along with lacrimation and rhinorrhoea, may also complain of a severe headache

Question 33

Examples of radioactive iodine

Answer 33

131 I → treatment

123 I → diagnostic purposes

Question 34

MOA if radioactive iodine

Answer 34

1. Radioactive iodine, like iodine is rapidly and efficiently trapped by the thyroid sodium-iodide transporter, into the follicular cells, from which it is slowly liberated.
2. Destructive β particles originate within the follicle and act almost exclusively on the follicular cells, with little or no damage to surrounding tissue.

Question 35

Therapeutic uses for radioactive iodine

Answer 35

1. Graves’ disease

2. Toxic nodular goiter

Question 36

Can radioactive iodine therapy be co-administered with thioamides

Answer 36

No, must stop thioamides at least 3 days before RAI as it may affect efficacy

Question 37

Advantages of radioactive iodine as compared to surgery

Answer 37

Less discomfort, low cost, hospitalisation not required, and patients can participate in their day-to-day duties

Question 38

Adverse effects of radioactive iodine

Answer 38

1. High incidence of delayed hypothyroidism
2. Small but significant increase in certain types of cancer, including stomach, kidney and breast. These tissues express the sodium iodine transporter (NIS)
3. Radioactive iodine therapy has been associated with worsening Graves’ ophthalmopathy
4. Adverse effects may set in 1 to 2 months after treatment
5. Main contraindication is for pregnant women
   - Concentration of isotope in the fetal thyroid
   - Exposure of fetal tissues to radiation

Question 39

How can beta blockers help the treatment of thyrotoxic storm

Answer 39

Control the peripheral effects of excess thyroid hormones, in addition to slightly decreasing T4 to T3 conversion

Question 40

How can glucocorticoids help in the treatment of thyrotoxic storm

Answer 40

1. Reduce T4 to T3 conversion and treat the potential risk of adrenal insufficiency due to severe thyrotoxicosis
2. Used in Graves’ ophthalmopathy to reduce the inflammation and swelling