Lecture 31: Thyroid Gland Pharmacology Flashcards
What is the thyroid gland?
“butterfly” shaped gland at the base of the neck
What are the two classes of hormones that the thyroid gland releases?
T3 (triiodothyronine - MOST ACTIVE) and T4 (thyroxine) thyroid hormones
Calcitonin
What are the multiple levels of hormonal control of thyroid hormone production?
TRH (Thyrotropin releasing hormone, hypothalamus)
TSH (thyroid stimulating hormone, anterior pituitary)
T3 and T4 exert negative feedback on both upstream glands
What are the powerful physiological effects of thyroid hormone?
increased basal metabolic rate
sensitization to catecholamines (increased cardiac output, heart rate, breathing rate)
important role in growth and development
What are thyroid hormones made up of?
thyroid hormones are made up of 2 modified tyrosine molecules
the precursor protein (thyroglobulin) is tyrosine rich
the tyrosines are enzymatically iodinated (iodine atoms added to the aromatic ring), 1 or 2 iodines per tyrosine ring
iodinated tyrosines are enzymatically coupled (2 linked rings)
TSH stimulation causes this precursor protein to be endocytosed and processed, followed by release of T4 and T3 (T4 is the predominant form that is released)
What is the “apical” side (follicle lumen)?
iodination and coupling of thyroglobulin happen here
What is the intracellular?
processing of thyroglobulin after it has been iodinated and coupled
What is the “basolateral” side (bloodstream)?
T4 and T3 are released here after being generated from thyroglobulin
What the accumulation of iodine in thyroid?
the thyroid gland concentrates iodide from the bloodstream (Na+/I- co-transporter)
iodine is transported into the folic lumen, and eventually added to thyroglobulin tyrosines during the iodination step
What is the thyroid hormone receptor?
thyroid hormones “break the rules” from what we have learned so far
the thyroid hormone receptor is an intracellular type receptor - acts as a transcription factor after binding of thyroid hormone
however, T3 and T4 are not very lipid soluble and need to be taken up into cells by a transporter protein (many different types) in order to reach their receptors
What is the mechanism of action of thyroid hormone?
at rest, unbound thyroid hormone receptors can associate with response elements (TRE) and recruit co-repressors (weakens gene transcription)
T4 and T3 are taken up via a transmembrane receptor, and T4 is typically de-iodinated to form T3
T3 binding in the nucleus causes recruitment of RXR (retinoic acid receptor) to form a heterodimer with the thyroid hormone receptor
recruitment of co-activators leads to enhanced transcription of target genes
What is hypothyroidism?
deficient thyroid function
not enough release of thyroid hormone
What are the most common causes of hypothyroidism?
iodine deficiency (dietary)
autoimmunity towards thyroid (Hashimoto’s thyroiditis)
congenital defect
inappropriate hormonal regulation (insufficient TSH or TRH)
What are the symptoms of hypothyroidism?
fatigue
weight gain
hypersensitivity to cold
bradycardia
What is the diagnosis of thpothyroidism?
measurement of TSH is helpful to know whether hypothyroidism is primary vs. seocndary
What is primary hypothyroidism?
cause: defect in thyroid function
features: low T4 and T3, high TSH
What is secondary hypothyroidism?
cause: central defect (poor function of anterior pituitary or hypothalamus)
features: low T4 and T3, low TSH
What is the treatment of hypothyroidism?
hormone replacement, most commonly with synthetic thyroxine (T4) (levothyroxine) extremely commonly prescribed
What is hyperthyroidism?
overactive thyroid function
excessive production of thyroid hormone
What are the most common causes of hyperthyroidism?
Graves’ disease (stimulatory auto-antibodies against TSH receptor, these activate the receptor leading to excess thyroid hormone release
hyperplasia of the thyroid leading to excess thyroid hormone release (thyroid adenoma, goiter)
What are the symptoms of hyperthyroidism?
sleep difficulty
heat (temperature) intolerance
tachycardia
weight loss
tremor
What is the diagnosis of hyperthyroidism?
similar to hypothyroidism, measurement of TSH is helpful to determine underlying cause
also, detection of anti-TSH receptor antibodies
What is Graves’ disease?
cause: stimulation of thyroid by anti-TSH receptor antibodies (stimulatory)
features: high T4 and T3, low TSH, detection of anti-TSH receptor antibodies “bulging eyes”, exopthalmos
What is thyroid hyperplasia?
cause: thyroid adenoma, goiter
features: high T4 and T3, low TSH
What is secondary hyperthyroidism?
uncommon
cause: central defect (excessive production of TSH by anterior pituitary)
features: high T4 and T3, high TSH
How are both Graves’ disease and Hashimoto’s thyroiditis are auto-immune diseases?
in Graves’ disease, the antibodies cause stimulation of the TSH receptor
in Hashimoto’s thyroiditis, antibodies recognize other thyroid-specific proteins and lead to damage of the thyroid
What is exophthalmos?
“bulging eyes”
primarily due to autoimmune damage of muscle/fibroblasts in the eye
What is a goiter?
swelling in the neck
in Graves’ disease this is due to overactivation of thyroid tissue (by stimulatory antibodies)
but goiter may also arise in cases of hypothyroidism (such as iodine deficiency) due to increased TSH levels
What is surgery as treatment for hyperthyroidism?
resection of part or all of thyroid, followed by hormone replacement
What are the drawbacks to surgery as treatment for hyperthyroidism?
danger of disrupting parathyroid glands (Ca2+ disturbances), needs management for hypothyroidism (and possibly hypoparathyroidism)
What is radioactive iodine treatment as treatment for hyperthyroidism?
iodine is concentrated within the thyroid, radiation leads to destruction of the thyroid
What are the drawbacks to radioactive iodine treatment as treatment for hyperthyroidism?
should not be used in pregnancy, nursing (irreversible destruction of thyroid in the infant)
What is anti-thyroid drugs (methimazole) as treatment for hyperthyroidism?
prevents several steps in T4/T3 synthesis
What are the drawbacks to anti-thyroid drugs (methimazole) as treatment for hyperthyroidism?
diverse side effects
What is symptomatic treatment with beta-blockers as treatment for hyperthyroidism?
may help with issues such as tachycardia
What are the drawbacks to symptomatic treatment with beta-blockers as treatment for hyperthyroidism?
does not influence underlying cause of the disease
What are thioamides?
e.g. Methimazole
prevent iodination and coupling steps (mediated by thyroperoxidase enzyme)
