THYROID HORMONES, ANTITHYROID DRUGS
[Legend of the handout:
• the drug
• indication(s)]
Thyroid gland synthesizes and releases hormones: T4, T3
Synthesis:
1.accumulation of iodide into gland→
2. oxidation of iodide to iodine by peroxidase→
3. iodination of tyrosyl residues on thyroglobulin→ MIT, DIT formation→
4. coupling of MIT and DIT→ T4 (80%), T3 (20%) formation→
5. proteolytic release of T4,T3 from thyroglobulin→
6. T4 (80%) to T3 conversion in peripheral tissues (5’deiodinase; liver, kidney, spleen)
- food and iodide supplements are source of the iodine for the synthesis of T4 and T3
(doses of many grams→symptoms of acute iodine poisoning: burning of the mouth, throat,
and stomach, fever, nausea, vomiting, diarrhea, a weak pulse, coma)
- receptor (intracellular) affinity in target organs is 10-fold higher for T3
- the effect of T3 develops more rapidly and has a shorter duration than does that of T4
- TSH: stimulates the uptake of iodide, stimulates the synthesis and release of thyroid
hormones, exerts growth-promoting effect that causes thyroid cell hyperplasia and an
enlarged gland (GOITER)
- effects of thyroid hormones: proper growth and development of the nervous, reproductive,
skeletal systems, control of metabolism of fats, carbohydrates, proteins, vitamins
- toxicity of thyroid hormones used in clinic: moist, warm skin, heat intolerance, sweating,
dyspnea, exophtalmos, nervousness, weight loss, hyperkinesia, tremor, increased deep tendon
reflexes, weakness, menstrual irregularity, decreased fertility, tachycardia, increased stroke
volume, cardiac outpute and pulse pressure (older patients and patients with co-existed
cardiovascular disease, and those with long-standing hypothyroidism are especially sensitive
to T4 stimulatory effect on the heart- lower initial doses of T4!)
t½ for T4 = 7 days
t½ for T3 = 1,5 days
- for therapeutic purposes, T4 (levothyroxine) is choosen (primary, i.e., caused by thyroid
disease, or secondary, i.e., resulting from TSH deficiency,
- hypothyroidism is treated by oral administration of T4 in gradually increased doses to
avoid the risk of cardiac overload, exeption: pregnancy- starting dose is target dosecretinism prevention)
- T3 (liothyronine) is the active form and better absorbed from the gut; faster acting;
shorter half-life; more expensive
- with T4 administration, more constant blood levels can be achieved because T4
degradation is so slow
- T4 absorption is maximal from an empty stomach, so T4 is taken about half an hour
before breakfast
- the final maintenance dose required to restore a euthyroid state depends on individual
needs (about 150 mcg/day)
III. Drugs related to thyroid gland hormones:
1. Thyroid hormones: biological activity: 25 μg T3 = 100 μg T4
Levothyroxine (T4), p.o. (tabl.), parental, L-thyroxine Serb (T4), p.o. (gtt.)
Liothyronine (T3), p.o., parental, Loitrix (T4:T3=4:1), p.o.
Novothyral (T4:T3=5:1), p.o., Euthyral (T4:T3= 5:1), p.o.
Thyroid desiccated (Armour thyroid), p.o.-variables in biologic activity
Thyreocomb (T4+KJ-150 μg), p.o.
→ hypothyroidism, nontoxic goiter (the release of thyroid hormones is not disturbed to the
lafge extend; to inhibit the TSH release), chronic and subacute inflammatory disease of
thyroid gland, after surgery thyroid gland removal, neonatal hypothyroidism
2. Antithyroid drugs:
A. I131 (radioactive iodine parenterally) →block phase 1 (destructions of cells by β decay)→
thyrotoxicosis
- side effects: permanent hypothyroidism, worsening of the Graves’ ophtalmopathy,
particularly if the patient is allowed to become hypothyroid, thyroid storm (rarely), fetal
thyroid after the first trymester can concentrate the isotope→ damage, colorectal cancer?
B. Thioamides (methimazole, propylthiouracil- the drug of choice in pregnancy)→ block
phase 2, 3, 4→ hyperthyroidism (uncomplicated)
thioamides do not inhibit the release of preformed thyroid hormones→ their onset of
activity is usually slow (3-4 weeks for full effect!
- toxic effects: urticarial skin rash (treated with antihistaminics, GCs), vasculitis, arthralgias,
paresthesias, agranulocytosis (developed gradually, sudden (hypersensitivity)
- methimazole starting dose 20-40 mg in 2-3 divided doses, after 3- 6 weeks- lowering of the
dose, the time to achieve an euthyreosis ± 6 weeks, maintenance dose: 2,5- 10 mg/24h once
daily, not contraindicated in pregnancy but crosses the placenta- should be used in the
minimimal- possible doses: starting dose 10- 15 mg/24h
- propylothiouracil starting dose 100- 150 mg every 8h (pregnancy 100 mg/24h), lowering
the dose→ after 4- 8 weeks, the time to achieve an euthyreosis ± 10-17 weeks, maintenance
dose 50- 150 mg/24h, in pregnant women- lower the dose when Ft4 is 10% above the upper
normal value , is less likely than methimazole to cross the placenta and enter breast milk
C. high doses of iodide (Lugol’s solution=potassium iodide+iodine solution p.o., iodinated
contrast media: ipodate p.o. or triazoate sodium parenterally)→
block phase 5 (up to 10 days, then “escape phenomenon”= thyroid gland escapes from phase
5 inhibition) → thyrotoxicosis- before the surgery to decrease gland size, its vascularity and
fragility
- side effects: rash (calcium, antihistaminics, promethazine), drug fever, acne iodica
(hydrocortisone), metallic taste, bleeding disorders, anaphylactic reactions (hydrocortisone)
D. propylothiouracil, propranolol, GCs, iodinated contrast media, amiodarone→ block
phase 6→ thyrotoxicosis, hyperthyroidic storm