Thyroid and Anti-Thyroid Drugs

Question 1

What is the role of follicular cells and parafollicular cells of the thyroid gland?

Answer 1

Follicular Cell: secretes the thyroid hormones

Parafollicular Cell: Secretes Calcitonin

Question 2

What is the function of the thyroid gland?

Answer 2

Take up iodine and convert it into thyroid hormones

Question 3

What is the iodine pathway?

Answer 3

Covalently bound to tyrosine residues in the thyroglobulin molecules via thyroperoxidase
–peroxidase enzymes are responsible for oxidationg, organification, and in addition to iodide coupling reactions of MIT and DIT
MIT + DIT = triiodothyronine (referred to as T3)
DIT + DIT = Thyroxine (referred to as T4)
Proteases digest iodinated thyroglobulin, releasing the hormones T4 and T3

Question 4

What is reverse triiodothyroine (reverse T3 or rT3)?

Answer 4

Isomer of T3

• –derived from T4 through the action of deiodinase
• -clinically silent, may come about during stressful situations

Question 5

What are the physiological effects of Thyroxine (T4)?

Answer 5

1. Increases BMR via Na/K ATPase activity (increase in RR, body temp and O2 consumption)
2. Potentiates the effects of catecholamines (increases sympathetic activity of beta effects) – increase in CO and HR
3. Promotes brain (CNS) development
4. Promotes bone growth synergistically with GH
5. Increases gluconeogensis, glycogenolysis and lyposis
6. LDL receptors expression: decrease in hypothyrodism and increase in hyperthyroidism

Question 6

What are the Pharmacokinetics of thyroid hormones?

Answer 6

Most circulating T3 is formed from deiodination of T4 in the peripheral tissue, liver, kidney

• -this enzyme also present in pituitary gland, brain and in brown fat
• -some T3 is released from thyroid

Question 7

Explain the role of Thyroxin-Binding Protein (TBG) – which is a transport protein for T3 and T4

Answer 7

TBG decreased in hepatic failure and increased in pregnancy and oral contraceptive pills (OCP)
–normal thyroid gland produces over 90% of T4 and about 10% T3
–T3 has a greater affinity to receptors so therefore it is much more potent than T4
Only free forms of T3 and T4 are active

Question 8

What are the physiological controls of thyroid gland?

Answer 8

The pituitary gland is regulated by hypothalamus (TRH)

• -thyroid gland is under the control of the pituitary gland (TSH)
• -negative feedback is from T3 and T4 to the hypothalamus and pituitary gland

Question 9

what factors affect the hypothalamus- pituitary axis?

Answer 9

Hypothalamus: stimulating — cold, acute psychosis, circadian and pulsatile rhythms ; inhibitory – severe stress
On TRH: inhibitory are corticoids/dopamine and somato-statin

Question 10

What is the mechanism of action of thyroid hormones?

Answer 10

Signaling mechanism is via TRH-IP3 mediated ; TSH-cAMP mediated and the T3 and T4 binds with the receptor in the nucleus

• -binds with intracellular receptors that control the gene expression with RNA formation and protein synthesis
• -protein synthesized depends on tissues involved (Na/K ATPase in the and Beta 1 receptor in the heart)

Question 11

What are the two thyroid hormones?

Answer 11

Thyroxine (T4)

Triiodothyronine (T3)

Question 12

What are the various thyroid hormone preparations?

Answer 12

1. Levothyroxine (T4) longer half life (T4 is converted to T3 in target tissues such as liver, kidneys, etc)
2. Liothyronine (T3) short half life ( T3 is 10 x more potent than T4)
   Uses:
   –cretinism (due to thyroid hormone synthesis enzyme defect) , adult hypothyroidism (myxedema)
   AE: tremors, tachy, arrhythmias, and heat intolerance

Question 13

P450 enzymes induction can increase the metabolism of the thyroid hormones (T3 and T4), what drugs induce P450 enzymes?

Answer 13

Rifampin
Phenobarbital
Phenytoin

Question 14

What are the primary, secondary and tertiary causes of hypothyroidism?

Answer 14

Primary (Thyroid): Hashimoto’s Thyroiditis (an autoimmune disorder) — anti - TPO (thyroperoxidase)
–causes radiation exposure, iodine deficiency, inadequate supplementation, drugs (lithium and aminodarone)
Secondary (Pituitary): Decreased TSH due to radiation, surgery or tumor
Tertiary (hypothalamus): Decreased TRH production

Question 15

How is dx made for hypothyroidism?

Answer 15

Increased TSH (if primary), decreased Total T4 , decreased free T4 and decreased T3 in blood

Question 16

What are the clinical features of hypothyroidism?

Answer 16

Lethargy, weight gain, cold intolerance, constipation, hair loss, carpel tunnel syndrome, poor memory and intellectual deterioration
Horse voice, puffy face, waxy skin, eyebrow hair loss, bradycardia, delayed relaxation DTRs
Queen Anne’s Sign: thinning of hair in the lateral third of eye brow

Question 17

Cretinism is cause of mental retardation with short stature, protruding umbilicus, pot belly, pale and puffy face and tongue protruding. What is the cause for this?

Answer 17

Lack of dietary iodine
—defect in T4 synthesis or developmental failure of thyroid
Screen and treat the patients, including congenital defect, with T4

Question 18

Moving on to Hyperthyroidism, what are some causes, how is a dx made, and what are the signs?

Answer 18

Dx: based on low TSH, increased total T4, increased free T4 and Increased T3 in the blood
Causes: Graves disease (ophthalmopathy and Pretibial myxedema due to thyroid stimulating antibodies against thyroid hormone receptors which causes the gland to produce excessive thyroid hormones), toxic multinodular goiter, toxic adenoma, molar pregnancy, postpartum thyrotoxicosis, post viral thyroiditis
PE: weight loss, heat intolerance, nervousness, palpitation, bowel frequency, insomnia, abnormal menses

Question 19

Moving on to the drugs for Hyperthyroidism. What are they?

Answer 19

Thioamides: propythiouracil and methimazole
Iodine and Iodide salts: lugol solution and potassium iodide
Beta Blocker: Propanolol and Esmolol
131I
Diatrizoate and Glucocorticoids

Question 20

First drug for Hyperthyroidism are the Thioamides (Propylthiouracil and Methimazole). what are some features of these drugs?

Answer 20

Referred to as Goitrogens due to their ability to cause goiter
MOA:
–block iodination of thyroglobulin and inhibit coupling reaction of DIT with MIT (T3) and DIT joining another DIT (T4)
–therefore T3 and T4 formation is reduced

Question 21

What is the MOA for Thioamides?

Answer 21

Iodine transported into thyroid via Na:I symporter (NIS) – the thioamides inhibit this —– thyroperoxidase (TPO) — MIT + DIT — decreases T3 and DIT + DIT (T4)
DO NOT INHIBIT PREFORMED T4/T3 – therefore a slow onset of action (2-3 weeks to take action)

Question 22

When is Propylthiouracil (PTU) used instead of Methimazole (This is preferred due to the less severe AE)?

Answer 22

DOC in thyroid storm due to its inhibitory effect on 5-deiodinase which results in decrease peripheral conversion from T4 to T3
Given 3 times a day
Reserved for patients who are intolerant to methimazole; who are not fit for surgery or radiation
Used in 1st trimester because of rare teratogenisity with methimazole.

Question 23

What are the adverse reactions of Thioamides?

Answer 23

Rash, Arthralgia
—rare: agranulocytosis, aplastic anemia, heptatotoxicity, hypoprothrombinemia, and vasculitis
Serious AE are much less with Methimazole
Methimazole is a teratogen: aplastic cutis congenita

Question 24

Next up are the Iodine and Iodine Salts in treatment of hyperthyroidism. How do these drugs work?

Answer 24

Large doses of iodine inhibit thyroid hormone synthesis (decrease organificantion and release) via brief TPO inhibition.
–called Wolff-Chaikoff Effect: gone after 10-14 days that can result in multinodular goiter, if large doses are continued ( Jod-Basedow Phenomenon)

Question 25

When are iodines and iodine salts used?

Answer 25

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 beta blockers in thyrotoxic crisis

Question 26

What iodine and iodine salt preparations are available?

Answer 26

1. Lugol’s Solution: a mixture of iodine and potassium iodide
2. Saturated Solution of Potassium Iodide
   AE: chronic iodide intoxication (iodism), anaphylactoid reaction (angioedema, swelling of larynx, eyelids), brassy taste, burning of teeth and gums and enlargement of parotid and maxillary glands.

Question 27

Next up for hyperthyroid treatment is Radioactive Iodine (131I). What are some features of this?

Answer 27

Is taken up and sequestered by thyroid gland
—the intracellular 131-I damage the tissue through emission of toxic beta rays, no effect on other tissues
Use:
–hyperthyroidism, graves disease (That have been refractory to other antithyroid drugs and persistent symptoms even after subtotal thyroidectomy)

Question 28

131-1 (radioactive iodine) is the only medical therapy that produces permanent reduction in thyroid activity. What are some other features of this drug?

Answer 28

No evidence of causing any cancer
AE: Patient may develop hypothyroidism (dose is difficult to nail down)
Contraindicated:
–pregnant women and nursing mothers

Question 29

Next for the hyperthyroid drugs are Beta Blockers. What are they used for?

Answer 29

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

Question 30

What beta blockers are used?

Answer 30

Propranolol: non specific beta blocker prevents conversion of T4 and T3
Esmolol: short acting beta blockers can be used to control intra-operative thyroid storm
–alternatives to beta blockers in thyroid storm for patients with asthma are CCB, Diltiazem or Verapamil