L17 – Pharmacological Agents in the Treatment of Thyroid Disorders

Question 1

Function of thyroid peroxidase?

Answer 1

Oxidizes I- into I2

Organification: I2 reacts with tyrosine residue in thyroglobulin&raquo_space; form T3, T4, store in colloid

Question 2

Describe the action of the hypothalamus - anterior pituitary - thyroid axis to release T3, T4??

Answer 2

Cold, trauma, stress stimulate hypothalamus

> > Thyrotrophin-releasing hormone (TRH) (+) to Anterior pituitary

> > thyroid-stimulating hormone (thyrotropin, TSH)

> > proteolysis of T3, T4 from thyroglobulin by proteases for release

Question 3

Compare the abundance and distribution of T3 and T4?

Answer 3

T3:
Small pool, intracellular, fast onset and turnover

T4:
Large pool, in circulation , Slow onset, slow turnover

Question 4

MoA of T4, T3 at target cells?

Answer 4

1) Enter cell via channel
2) T4 converted to T3
3) T3 binds to receptor, displaces co-repressor, recruits co-activator
4) Transcription of mRNA&raquo_space; protein&raquo_space; response

Question 5

Metabolic effects of thyroid hormones?

Answer 5

Increase metabolism of carbs, fats, proteins

Calorigenic action: increase O2 consumption, heat production

Question 6

Effects of thyroid hormones on growth and development?

Answer 6

1. Directly stimulates cell growth
2. Increase growth hormone secretion =
   growth of body, maturation of CNS
3. Normal response to parathormone (PTH), calcitonin for skeletal development

Question 7

5 causes of hypothyroidism?

Answer 7

Hashimoto’s thyroiditis (CMI against follicles)

Hypopituitarism (decrease secretion of TSH)

Goitogens (e.g. cabbage) – inhibit thyroid hormone secretion

Drugs (lithium)

Dietary def. of Iodine

Question 8

Symptoms of hypothyroidism?

Answer 8

• Myxedema
• cannot meta. carbs = tiredness, no thermogenesis, intolerance to cold
• decrease appetite
• Dry skin (inactive sebaceous gland)
• Decrease cardiac output and BP (permissive effect of Adrenaline)
• Dwarfism, mental retardation

Question 9

List 2 treatment options for hypothyroidism?

Answer 9

Severe, acute (e.g. hypothyroid coma): liothyronine (T3)

Routine replacement therapy: thyroxine (T4)

Question 10

ADR of Liothyronine and Thyroxine?

Answer 10

Thyrotoxicosis (i.e. hyperthyroidism)

Headache, dizziness, weakness, abdominal pain

Risk of worsening ischemic, CVD symptoms

Risk of acute adrenal crisis

Question 11

Explain why thyroxine and liothyronine is C/O in CVD?

Answer 11

Increase catecholamine/ sympathetic effects

> > Increase vasoconstriction and HR, BP

> > Worsen ischemic symptoms e.g. angina, HF

Question 12

Explain how liothyronine and thyroxine causes acute adrenal crisis?

Answer 12

Thyroxine increase metabolic clearance of adrenocortical hormones

> > (very low aldosterone, cortisol

Question 13

3 causes of hyperthyroidism?

Answer 13

1) Graves’ disease (antibody on TSH receptors on thyroid cells)
2) Adenoma of thyroid gland
3) Drugs (e.g. amiodarone for arrhythmia: contains iodine)

Question 14

Symptoms of hyperthyroidism?

Answer 14

Increase BMR, increase appetite

Increase thermogenesis: heat intolerance, sweating , warm, moist skin

Stronger catecholamine effect

Exophthalmia

Question 15

Explain why hyperthyroidism impacts catecholamine effects?

Answer 15

Increase expression of β1 and β2 adrenergic receptors in target tissue:

 Tachycardia, angina, high-output heart failure

 β2 receptors in muscle: tremor

 β1 receptor in brain: nervousness

Question 16

Treatment for thyrotoxic crisis/ before thyroidectomy surgery?

Answer 16

β blockers: nonselective (propranolol)

+/- Lugol’s solution (5%
iodine + 10% potassium iodide)

Question 17

Initial and sustained therapy for hyperthyroidism?

Answer 17

Initial = Propranolol + Lugol’s solution

Sustained = thionamides and I-131

Question 18

MoA of propranolol?

Answer 18

 blocks both β1, β2 to relieve thyrotoxic symptoms:

 β1 in heart: palpitation
 β1 in brain: nervousness
 β2 in skeletal muscle: tremor

Question 19

Explain the effects of iodine on production of T3 and T4?

Answer 19

Normal to high levels of iodine = Increase T3,T4 production

Very high levels = Inhibit T3,T4 production:
- Inhibit peroxidase and organogenesis of T3 T4

Question 20

MoA of Lugol’s solution? (3)

Answer 20

(5% iodine + 10% potassium iodide)

1. Inhibits generation of H2O2 by peroxidase&raquo_space; cannot incorporate I- into tyrosine
2. Vasoconstriction, reduce blood flow, vascularity in thyroid gland = decrease production of T3, T4
3. Inhibits release of T3, T4

Question 21

Indication and administration duration of Lugol’s solution?

Answer 21

pre-operatively before thyroidectomy: reduce the risk of bleeding

10-14 days admin, 3 times daily well diluted with milk or water

desensitization = not for long term

Question 22

ADR of Lugol’s solution?

Answer 22

 Rash, Fever

 Angioedema (swelling of lips, tongue, deep tissues under skin)

 Conjunctivitis

 Bronchitis

 Pain in salivary gland

Question 23

C/O of Lugol’s solution?

Answer 23

No breast feeding

Iodine secreted in breast milk&raquo_space; Enlargement of thyroid gland in infants + Suppresses T3, T4 production (development)

Question 24

Long- term treatment for hyperthyroidism?

Answer 24

Thionamides (aka thioamides, thioureylenes):

• Methimazole (active)
• Carbimazole (inactive)
• Propylthiouracil

Radioiodine: Sodium Iodide-131

Question 25

MoA of thionamides?

Answer 25

contains thiocarbamide group (S=C-N): antithyroid activity: - inhibits peroxidase = cannot incorporate I- into tyrosine = decrease T3, T4 production - Propylthiouracil also inhibits peripheral conversion of T4 to T3 (e.g. liver)

Question 26

Onset time, admin duration of thionamides

Answer 26

Slow onset 18 months High initial dose to achieve euthyroid, reduced dose after

Question 27

Indication for propylthiouracil?

Answer 27

patients who suffer sensitivity reactions to carbimazole

Question 28

ADR of thionamides?

Answer 28

- Common allergic reaction: skin rash, pruritus (add anihistamines) - Rare, severe Bone marrow depression (e.g. thrombocytopenia, agranulocytosis) - Cross placenta, breast milk: use lowest effective dose + monitor

Question 29

MoA of Radioiodide?

Answer 29

peroxidase incorporates 131-I into tyrosine >> β radiation damages thyroid >> number of thyroid cells decrease, suppress T3, T4 levels

Question 30

Indication of radioiodide?

Answer 30

relapse of hyperthyroidism after thionamide therapy ablate residual tumor tissue after surgery

Question 31

Admin and ADR of radioiodide?

Answer 31

Single dose with delayed cytotoxic effect ADR: - Hypothyroidism (add thyroxine) - Thyroid damage to fetus and infants: C/O pregnant or breastfeeding women - Potential cancer, infertility risk

Question 32

Which treatment for hyperthyroidism is indicated for pregnant women?

Answer 32

Propanolol Thionamides