Flashcards in Thyroid Pharmacology Deck (27)
How are thyroid hormones formed?
1) The thyroid hormones are formed from two tyrosine residues that are iodinated and coupled together.
2) T3 can also be formed by deiodination of T4, specifically deiodination of the outer ring. Inactive reverse T3 is formed upon deiondination of the inner ring.
What hormones does TSH stimulate?
Thyroid Stimulating Hormone stimulates the secretion of the thyroid hormones, T3 and T4, from the thyroid gland.
Describe the hormone synthesis thyroid hormone (7).
1) Active uptake of iodide by the thyroid follicular cells
2) Diffusion of iodide across the cells
3) Transport of iodide into the colloid
4) Activation and incorporation of iodine into tyrosine residues within thyroglobulin molecules.
- This step is carried out by the thyroid peroxidase enzyme
5) Joining of diiodotyrosines (DIT) to form tetraiodothyronine (thyroxine, T4), or of DIT and monoiodotyrosine (MIT) to form triiodothyronine (T3), steps that are also carried out by the thyroid peroxidase enzyme
6) Uptake of thyroglobulin from the colloid into the follicular cell by endocytosis, fusion with lysosomes, and proteolysis to yield T4 and T3
7) Release of T4 and T3 into the circulation
Which molecules a part of thyroid synthesis can be deiodinated and recycled?
DIT and MIT can be deiodinated and recycled.
What is another way T3 can be formed?
T3 can also be formed by deiodination of T4.
Which has the longer biological half life, T3 or T4?
T4 Has a Much Longer Biological Half-life than T3
- ~ 1 week for T4
- ~ 1/2 a day for T3
What is the principle function of T4?
- T4 serves as a reservoir for the more active T3 molecule.
What is the primary hormone released by the thyroid?
Most of the hormone released by the thyroid is T4.
- This can be converted to T3 in peripheral tissues by 5’-deiodinase enzymes.
Which hormone has a higher plasma concentration, T3 or T4?
The total plasma concentration of T4 is higher than that of T3.
- However, T3 has a higher affinity for the receptor and T3 is largely responsible for effects on target tissues.
What is the drug of choice for maintenance therapy in hypothyroidism?
Levothyroxine (T4) is the drug of choice for maintenance therapy in hypothyroidism because it has a long half-life, which results in a lower potential for large fluctuations in blood levels.
Why is T3 not used for hypothyroid maintenance?
T3 is less useful for maintenance because of its shorter half-life and thus shorter duration of action.
- Although used infrequently, T3 may be useful when rapid effects are required (e.g., in myxedema coma).
What is the downside to the long half life of Levothyroxine?
Because of its long half-life, Levothyroxine does not reach steady state levels for many weeks
- Patients initiating treatment are frequently examined after ~6 weeks.
-In hypothyroidism, the half-life of Levothyroxine can be even longer in patients than in normal individuals.
What is the approach to prescribing thyroid maintenance treatment?
- The dose of thyroid hormones should be determined for each patient individually,
- Some patients require >100 µg/day.
- Therapy should begin with low doses to avoid adverse cardiovascular effects.
Which hormone binds to thyroid hormone receptors and what is the effect?
T3 ninds to thyroid hormone receptors, which have both ligand binding and DNA binding domains
How does T3 affect gene expression?
Binding of T3 disrupts binding of co-repressor to the thyroid hormone receptor and retinoid X receptor heterodimer
- T3 also promotes binding of co-activoator and increases mRNA expression
What are the adverse drug effects of thyroxine?
- Cardiac symptoms such as tachycardia, arrhythmias, angina, or infarction.
What is the aim of HYPERthyroidism treatment?
The aim of therapy is to inhibit thyroid hormone secretion or reduce the amount of functional thyroid tissue.
What is the mechanism of radioactive iodide?
Radioactive iodide is concentrated in the thyroid gland and incorporated through the normal mechanism
- it then destroys thyroid cells by emitting ionizing beta particles.
What are the indications for radioactive iodide?
- This therapy is used to destroy functional thyroid tissue in hyperthyroid patients.
- Symptoms of hyperthyroidism abate over 2-3 months.
What are the adverse side effects of radioactive iodide?
- Note that conversion of hyperthyroidism to hypothyroidism is frequently the desired effect, as hypothyroidism can be treated with Levothyroxine
- Ablation of the fetal thyroid gland if given in pregnancy.
What is the mechanism of the Thioureas, Methimazole and Propylthiouracil (PTU)?
1) These drugs prevent thyroid hormone synthesis by inhibiting thyroid peroxidase, thus inhibiting the iodination of tyrosine residues in thyroglobulin.
- The effects of the drugs do not become fully manifest for several weeks (due to pre-existing TH).
2) PTU also inhibits the peripheral deiodination of T4 to T3
What are the indications for the thioureas?
1) These drugs can be used on a short-term basis to reduce hyperthyroid symptoms before or after ablation with radioactive iodide
- Note that the drug must be discontinued several days before radioactive iodide treatment.
2) Can be used on a longer-term basis for patients with mild Grave’s disease
- Some patients undergo spontaneous remission during drug therapy. However, the majority of patients require ablation therapy.
3) PTU can also be used on emergency basis, in cases of thyrotoxic crisis.
- In this case, the drug is used for its effects on the deiodination of T4.
What adverse side effects are associated with PTU?
- Agranulocytosis (may present as a fever or sore throat)
- Hepatitis, jaundice, pruritis and rash.
* Severe liver injury and liver failure may occur rapidly in some patients
What side effects are less likely in methimazole?
The serious side effects of AGRANULOCYTOSIS and HEPATOTOXICITY are less likely with Methimazole.
What benefit does methimazole have over PTU?
Methimazole has a longer half-life than propylthiouracil and can be given once a day.
Which drug, PTU or Methimazole can be used during the 1st trimester of pregnancy?
Propylthiouracil is preferred in the first trimester of pregnancy because there have been rare cases of fetal malformations with Methimazole.