Thyroid and Antithyroid Drugs Flashcards
Anatomy of the thyroid and parathyroid glands
Overview of the thyroid - histology
What are Thyroid Hormones (THs)?
- Thyroid hormone are built on a backbone of two tyrosine molecules that are iodinated and connected by an ether linkage
- Tetraiodothyronine [thyroxine] (T4)
- Triiodothyronine (T3) → active form
- Reverse T3 (rT3) → inactive form
- Number of iodine is what varies in each molecule - T4 is the major product of the thyroid gland
- T3 and rT3 are largely produced by peripheral tissues by the action of deiodinases:
- D1
- D2
- D3
What are Deiodinases and why are they important?
- Deiodinases are important in the activation and deactivation of THs
- T4 activation → T3 – removal of an iodine atom on the OUTER ring
- T4 DE-activation → rT3 – removal of an iodine atom on the INNER ring
- D1 converts to T4 to the majority of serum T3
- D2 converts T4 to T3 locally
- D3 is responsible largely for conversion of T4 to the biologically inactive rT3
Physiology Pharmacology – Hypothalamus Pituitary Thyroid Axes
Physiology Pharmacology – Synthesis and Release
Physiology Pharmacology – Pharmacokinetics of Serum T3 and T4
Serum T3 and T4 Pharmacokinetics:
- T4:T3 is released in a ~4:1 ratio by thyroid
- Circulate bound to Thyroid Binding Globulin; ~99%
- Elimination half-life: T4 (7 days) vs T3 (1 day) → therefore prefer to have T4 circulating, stays in the body longer
- Peripheral conversion T4 to T3 by 5’-deiondinase
- Type I-liver, kidney, thyroid, skeletal/cardiac muscle
- Type II-brain, pituitary gland
- T3 has 4 times the biologic potency as T4 (prohormone)
Physiology Pharmacology – Thyroid Hormone Physiologic Actions:
Physiologic Actions:
- Thyroid hormones have numerous actions, both direct actions, and many permissive effects in conjunction with other hormones
- Actions of thyroid hormones on target tissues are mediated primarily by control of transcription in the cell nucleus and hence protein synthesis
- Regulation of metabolism
- CHO’s, lipids and proteins-calorigenesis
- Cellular O2 consumption by effects on sodium pump (Na+/K+ - ATPase)
- Growth and development
- Nervous, skeletal, and reproductive tissues
- Cardiovascular; myocardial contractile proteins
Clinical Applications – Hypothyroidism - what is it? its causes? clinical signs?
- Hypothyroidism is the most common thyroid disorder
Causes: - Primary hypothyroidism is most common form
- Hypothalamus not producing TRH therefore not stimulating TSH in anterior pituitary → can’t produce enough T3/T4
- TSH insufficiency (pituitary) is much less common - Iodine deficiency-child (cretinism)/adult
- Most common cause of hypothyroid world-wide
- Cretinism is the name given to the congenital condition and it is thought to be due to maternal hypothyroidism - Congenital absence of gland or its development
- Autoimmune thyroiditis (Hashimoto’s thyroiditis)
- Most common cause in non-endemic areas
- Antibodies against thyroid peroxidase
- Thyroglobulin and TSH receptor antibodies also possible - Iatrogenic
- Surgery, radioactive I- for hyperthyroid treatment
- Chemotherapy for other cancers
- Drugs-thioamides, others
Clinical Signs: - Manifest as a slowing of bodily functions; CNS cardiovascular and energy metabolism
- Lethargy, weakness, fatigue
- Cold intolerance, decreased libido
- Weight gain, bradycardia
- Myxedema; severe, end-stage, emergency
- Water intoxication, hypothermia, hypoglycemia, hypoventilation, hyponatremia, shock, coma
Clinical Applications – Hypothyroidism - What is goiter? What is hypothyroidism diagnosis?
- Goiter: enlargement of thyroid gland → inflammation and accumulation of T4/T3 cells in colloid
- Goitrous hypothyroidism; causes:
- I- def
- Neoplasms
- Autoimmune destruction - Diagnosis:
- Clinical signs
- Low circulating free T4 + elevated circulating TSH
Clinical Applications – Hypothyroidism - Therapy
Therapy:
- Levothyroxine (T4) is drug of choice for replacement therapy in clinical hypothyroidism
- Long half-life (7 days) allows for once daily dosing
- T4 is main circulating thyroid hormone vs T3
- Easily monitored in plasma
- Steady-state levels of T4 require 6-8 weeks
- Liothyronine (T3) also available as tablet and powder for injection; not as much use as T4 (longer half-life)
- Liotrix is a mixture of T4/T3 in a 4:1 ratio; expensive
- Cautions: initial low dose therapy in high risk patients due to cardiac adverse effects
- Long-standing hypothyroidism, elderly, CV disease
- Removal of culprit drugs – reversal of hypothyroidism
- Iodine in iodine deficient patients
- Myxedema: medical emergency, IV route for T4 (T3), loading dose often needed, other supportive care
- Pregnancy: monitor plasma [T4 – can lead to cretinism in fetus → mental delay] – fetal brain needs thyroid for normal development
Clinical Applications – Hyperthyroidism - What is it? What are the causes?
Hyperthyroidism: Elevated thyroid hormones (thyrotoxicosis) – too much T3/T4
Etiology (causes)
- Graves’ disease: “diffuse toxic goiter”
- Most common cause of hyperthyroidism
- Autoimmune disorder; T-suppressor defect
- IgG ab’s bind and activate TSH receptor on thyroid
- Iatrogenic
- Overzealous use of T4 supplementation
- Neoplasms (benign adenomas)
- Uninodular or multinodular toxic goiter
- Older patients more commonly
- Infection and inflammation of the thyroid
- Destruction of thyroid tissue and hormone release; usually transient; supportive therapy may be used
Clinical Applications – Hyperthyroidism - What are the clinical signs? Its diagnosis?
Clinical Signs:
- Manifest as a speeding-up of bodily functions; CNS, cardiovascular and energy metabolism
- Hyperactive to agitated; nervous, insomnia
- Heart intolerance, rapid heart rate
- Weight loss, frail (muscle wasting)
- Exophthalmos; “bug-eyed” possible
Diagnosis:
- Clinical signs
- High circulating free T4/T3 + low circulating TSH
- Radioiodine uptake scan, MRI, U/S can be helpful in identifying nodules vs whole gland as culprit
Clinical Applications – Hyperthyroidism Therapy
Therapy:
1. Antithyroid Drugs
- Most useful in young patients with mild disease
- Also used to stabilize patients for other types of hyperthyroid procedures
- Thioamides
- Methimazole (Tapazole®) and Propylthiouracil
- Both given orally; MZ 10X as potent as PTU
- Drugs inhibit TPO-organification and iodotyrosine coupling steps; block hormone synthesis only
- Iodinated Contrast Media
- Inhibit the conversion of T4 to T3
- Used when other drugs contraindicated; short-term
- Generally considered safe
- Adjunct Drugs
- Beta-blockers e.g. propranolol
- Calcium channel blockers e.g. diltiazem
2. Radioiodine Therapy
- I131 is the preferred treatment for most patients
- Antithyroid drugs may/may not be indicated before treatment to stabilize patient
- Given orally as a solution; high uptake by thyroid
- Effect due to emission of β rays and cell destruction
- A second treatment is needed in some patients
- 80% of patients become hypothyroid
- Surgery
- A near-total thyroidectomy is the treatment of choice for patients with very large glands or multinodular goiters
- Antithyroid drugs are used pre-surgery to lower T4
- Potassium Iodide is given to reduce vascularity of gland also pre-surgery; simplifies surgery
- Replacement T4 therapy will be needed in most cases following surgery
