Thyroid and Antithyroid Drugs

Question 1

Levothyroxine

Answer 1

Levothyroxine (T4) longer t 1⁄2; (T4 is converted to T3 in target tissues such as liver, kidneys etc.)

Question 2

Liothyronine

Answer 2

Liothyronine (T3) short t 1⁄2; (T3 is 10 X more potent than T4)

Question 3

Thyroid Hormone Uses

Answer 3

Thyroidhormone-Uses:

Cretinism (due to thyroid hormone synthesis enzyme

defect)

Adult hypothyroidism (Myxedema)

AE: Tremors, tachycardia, arrhythmias and heat intolerance.

Question 4

Rifampin, Phenobarbital, and Phenytoin

Answer 4

P-450 Enzyme induction can increase the metabolism of the thyroid hormones – T3 & T4

Question 5

Propythiouracil

Answer 5

Thioamide

Uses of Propylthiouracil:

1. PTU is reserved for patients who are intolerant to methimazole; who are not fit for surgery or 131 I (RAI)
2. It is also preferred in thyroid storm due to its ability to inhibit peripheral conversion of T4 to T3 and
3. PTU used in 1st trimester because of rare teratogenisity with methimazole.

Question 6

Methimazole

Answer 6

Thioamide

Methimazole is a teratogen –aplasia cutis congenita

Question 7

Thioamides

Answer 7

Propylthiouracil and Methimazole are referred as goitrogens due to their ability to cause goiter.

Both of them block iodination of thyroglobulin and inhibit coupling reaction of DIT with MIT (T3) & DIT joining with another DIT (T4). Hence, formation of T3 and T4 is reduced.

“I” transported into thyroid (Via Na+:I– symporter –NIS) thioamides inhibit thyroperoxidase (TPO)MIT + DIT ↓(T3), & DIT + DIT ↓(T4)

Oral rout of administration. They do not inhibit the preformed T4 / T3; as a result –slow onset of action. Takes 2-3 weeks for full effect.

PTU is a drug of choice in thyroid storm due to its inhibitory effect on 5’–deiodinase also that result in decrease peripheral conversion from T4 to T3.

But, Methimazole does not inhibit conversion from T4 to T3.

Methimazole given daily one dose unlike PTU 3 times a day.

Adverse Effects:

Thioamides are associated with rash and arthralgia; produce rare agranulocytosis, aplastic anemia, hepatotoxicity, hypoprothrombinemia and vasculitis.

Serious AE are much less with methimazole than with PTU; because of this methimazole is more preferred in clinical practice.

Question 8

Iodine and Iodide Salts

Answer 8

Large doses of iodide inhibit thyroid hormone synthesis (↓organification and release) via brief TPO inhibition. This effect is called as Wolff-Chaikoff effect.

Wolff-Chaikoff effect is gone after 10 - 14 days that can result in multinodular goiter, if large doses are continued (Jod-Basedow phenomenon).

Iodides decrease vascularity and size of the gland. They are used most often before surgery for easy thyroid excision.

They are used in conjunction with PTU, and b- blockers in thyrotoxic crisis.

Preparations are available as:

1. Lugol’s solution – a mixture of iodine & potassium

iodide.

2. Saturated solution of potassium iodide.

Adverse effects:

chronic iodide intoxication (iodism), anaphylactoid reaction –angioedema, swelling of larynx, eyelids; brassy taste, burning of teeth and gums; enlargement of parotid and maxillary glands.

Question 9

Radioactive Iodine

Answer 9

Radioactive iodine (131I) is taken up and sequestered by thyroid gland. The intracellular 131I damage the tissue through emission of toxic β-rays, no effect on other tissues.

Used in adults with hyperthyroidism, Graves’ disease –that has been refractory to other antithyroid drugs and persistent symptoms even after the subtotal thyroidectomy.

The desired effect may not be obtained due to the difficulties to determine the dose. Patients may develop hypothyroidism.

It is the only medical therapy produces permanent reduction in thyroid activity.

There is no evidence of causing any cancer.

Adverse effect: hypothyroidism.

It is contraindicated in pregnant women and nursing mothers.

Question 10

Beta-Blockers

Answer 10

β-blockers are useful in controlling the nervousness, palpitation, fatigue, weight loss, heat intolerance and tremors associated with hyperthyroidism, short-term management in pregnancy, preoperatively, and thyroid storm. Partial agonists are not used.

• Propranolol, nonspecific beta blocker prevents conversion of T4 to T3.

• Esmolol, a short acting beta blocker can be used to control intra-operative thyroid storm.

• Alternativesto β-blockers in thyroid storm for patients with asthma are CCB, Diltiazem or Verapamil.

Question 11

Thyroid Storm

Answer 11

A life threatening medical emergency associated with extreme effects of hyperthyroidism.

It is caused by illness, surgery, and other stresses in patients suffering from thyrotoxicosis.

Beta-adrenergic blockers to manage CVS problems such as tachycardia, hypertension.

Propylthiouracil, I.V. sodium Iodine, and Glucocorticoids to inhibit peripheral conversion of T4 to T3.

Question 12

Diatrizoate and Iohexol

Answer 12

Iodinated Radiocontrast Media, like oral diatrizoate or oral/I.V. iohexol will suppress the conversion of T4 to T3 (5’-deiodinase) in the peripheral tissues, kidney and liver. It is useful in rapidly reducing (it has a fast onset of anti-thyroid action) the T3 concentration in thyrotoxicosis. Also may play a role in the inhibition of hormone release from thyroid gland.

Question 13

Thiocyanate, Perchlorate and Pertechnetate

Answer 13

Perchlorate, thiocyanate and pertechnetate inhibit iodide concentration in the gland by blocking the transportation. Potential for aplastic anemia.

Question 14

Other Antithyroid Drugs

Answer 14

A few drugs may provoke autoimmune or destructive inflammatory thyroiditis, inducing hypothyroidism.

1. Amiodarone: has structural similarity with thyroxine.

(a) Iodine associated hyperthyroidism may occur – can be treated with thiamides.
(b) Autoimmune mediated inflammatory version treated with steroids.
(c) Hypothyroidism: treated with levothyroxine

2. Interferon-α & Interleukin-2

3. Lithium inhibits release of hormones (hypothyroidism) and thyroid enlargement.

4. Goitrogens:
• Cabbage (contain thiocyanate)
• Cassava–contains carbohydrates + thiocyanate

5. Imatinib, Sunitinib (TKRI–Tyrosine Kinase Receptors decrease)

6. Aminoglutethimide, sulfonylureas.

Drugs that inhibits conversion of T4 to T3

1. Corticosteroids
2. Propranolol
3. Amiodarone

Question 15

Know this Facts

Answer 15

• Graves disease: antibodies produced in the disease activates thyroid gland TSH receptors.
• Thioamides (methimazole & propylthiouracil): prevent MIT and DIT to form T4 &T3. They cause hepatic damage, agranulocytosis, vasculitis and hypoprothrombinemia.
• Thyroid storm: β-blockers such as propranolol are used to control tachycardia and other CVS abnormalities. Propranolol is also used to inhibit T3 from T4. Other drugs used are: high doses of iodide and propylthiouracil.
• Iodides (Lugol’s iodine)inhibits synthesis, release of thyroid hormones and decrease the size and vascularity of the hyperplastic gland.
• Amiodarone is an antiarrhythmic agent. Its iodine contents could produce complex effects on thyroid hormones. It also inhibits peripheral conversion of T4 to T3
• I131 is only medical therapy that produces a permanent reduction in thyroid activity.

Question 16

Reverse T3

Answer 16

Reverse triiodothyronine (reverse T3 or rT3) is a molecule that is an isomer of T3.

It is derived from T4 through the action of deiodinase. rT3 binds to these receptors, thereby blocking the action of T3.

Under stress conditions, the adrenal glands produce excess amounts of cortisol. Cortisol inhibits the conversion of T4 to T3, thus shunting T4 conversion from T3 towards rT3.

It results in reduced body temperature, which slows the action of many enzymes, leading to a clinical syndrome, multiple enzyme dysfunction, which produces the effects seen in hypothyroidism. Effects include fatigue, headache, migraine, PMS, irritability, fluid retention, anxiety and panic.