Thyroid and Antithyroid Drugs Flashcards
BIOSYNTHESIS OF THYROID HORMONES?
The major steps in the synthesis, storage, and release of thyroid
hormones are :
1. Uptake of iodide ion (I–
) by the thyroid gland.
2. Oxidation of iodide to iodine.
3. Iodination of tyrosyl groups of thyroglobulin.
4. Coupling of iodotyrosine residues to generate the thyroid
hormones.
5. Resorption of the thyroglobulin colloid from the lumen into
the cell.
6. Proteolysis of thyroglobulin and the release of thyroxine and
triiodothyronine into the blood.
THYROID HORMONES - MOA?
Thyroid hormones enter cells and bind to thyroid hormone
receptor (TR) in the nuclei.
The hormone–receptor complex then binds to DNA and increases or decreases the expression of a variety of different genes that code for proteins that regulate cell function.
T3 acts more rapidly and is more potent than T4. This is
because T3 is less tightly bound to plasma proteins than is T4, but binds more avidly to thyroid hormone receptors.
PHYSIOLOGICAL EFFECTS OF THYROID HORMONES?
↑Metabolic Rate
Synergism with Catecholamines
Normal Growth
and Development
METABOLISM OF THYROID HORMONES?
Thyroid hormones are metabolized by the following
mechanism:
Deiodination (the most important mechanism).
Glucuronidation.
Sulfation.
Describe Deiodination?
Deiodination of T4 by 5′deiodinase enzymes results in the production of either T3 which is more potent than T4 or reverse
T3 [rT3] which is metabolically inactive.
Inhibition the 5′-deiodinase results in low T3 levels in the serum.
5′deiodinase enzymes are inhibited by:
1. Drugs such as propylthiouracil, propranolol,
corticosteroids, and amiodarone.
2. Severe illness and starvation.
3. Iodinated compounds such as the radiographic agents iopanoic acid and ipodate.
Describe T4 and T3 role in the GIT?
T4 and T3 are also conjugated in the liver to form sulfates
and glucuronides.
These conjugates enter the bile and pass into the intestine where they are hydrolyzed, and some are thereafter reabsorbed (enterohepatic circulation), but others are excreted in the stool.
In the intestine, Bile acid sequestrants (e.g. cholestyramine)
bind to and prevent the enterohepatic cycling of thyroid hormones.
Describe the consequences of induction in relation to Thyroid enzyme metabolism?
Deiodinase and UDP-glucuronosyltransferase enzymes are
inducible enzymes.
Enzyme inducers (e.g. rifampin) increase the metabolism of
both T3 and T4.
Patients dependent on T4 replacement medication may
require increased dosages to maintain clinical effectiveness if they are also on an enzyme inducer.
MANIFESTATIONS OF HYPOTHYROIDISM?
Clinical manifestations of hypothyroidism include goiter, muscle weakness, dry coarse skin, lethargy, cold intolerance, decreased sweating, cold skin, thick tongue, coarse hair, yellowish tint of the
skin, and delayed DTRs.
CAUSES OF HYPOTHYROIDISM?
Hashimoto’s thyroiditis the most common cause of
hypothyroidism in the USA while iodine deficiency is the most common cause worldwide.
Other causes of hypothyroidism include thyroidectomy, external neck irradiation, radioactive iodine therapy and
drug induced.
Drugs that may cause hypothyroidism?
Drugs that may cause hypothyroidism include thioamides,
iodides, amiodarone, lithium, aminoglutethimide, rifampin,
tyrosine kinase inhibitors (e.g., imatinib, sunitinib, sorafenib),
interleukin 2, interferon-α, and sulfonylureas.
General management of hypothyroidism?
Hypothyroidism is treated by thyroid hormone replacement.
Available thyroid preparations are classified into:
A. Synthetic preparations including:
1. Levothyroxine (T4).
2. Liothyronine (T3).
3. Liotrix (mixture of T4 and T3).
B. Natural preparations of animal origin (desiccated
thyroid).
LEVOTHYROXINE VS. LIOTRIX?
The use of the more expensive thyroxine and liothyronine
fixed-dose combination (liotrix) has not been shown to be more effective than T4 administration alone.
Synthetic levothyroxine (T4) is the preparation of choice for thyroid hormone replacement therapy
AE of thyroid replacement therapy?
Thyroid replacement therapy may result in hyperthyroidism like
manifestation.
Thyroid hormones can increase the risk of atrial fibrillation and osteoporosis.
MANAGEMENT OF MYXEDEMA COMA?
Myxedema coma is a severe and long-standing form of hypothyroidism.
Cardinal features of myxedema coma are hypothermia, respiratory depression, and decreased consciousness.
Management includes supportive measures and IV
levothyroxine. Liothyronine may be added until the patient is stable and conscious.
MANAGEMENT OF HYPOTHYROIDISM
DURING PREGNANCY?
During pregnancy, adequate dose of levothyroxine is important
as early development of the fetal brain depends on maternal thyroxine.
A higher dose of levothyroxine is usually required in pregnant
patients. This is because of :
1. Increased serum concentration of Thyroxine-binding globulin (TBG) induced by estrogen.
2. Expression of 5′deiodinase 3 (D3) by the placenta.
3. Small amount of transplacental passage of
levothyroxine from mother to fetus.