Thyroid Hormones

Pharmacology Dr. Dalia A.
Muhsin
Thyroid Hormones
The endocrine system releases hormones into the bloodstream, which carries chemical
messengers to target cells throughout the body. Hormones have a much broader range of response
time than do nerve impulses, requiring from seconds to days, or longer, to cause a response that may
last for weeks or months. [Note: Nerve impulses generally act within milliseconds.] An important
function of the hypothalamus is to connect the nervous system with the endocrine system via the
pituitary gland.
Hypothalamic and Anterior Pituitary Hormones
 The hormones secreted by the hypothalamus and the pituitary are peptides or glycoproteins
that act by binding to specific receptor sites on target tissues.
 The hormones of the anterior pituitary are regulated by neuropeptides that are called either
“releasing” or “inhibiting” factors or hormones. These are produced in the hypothalamus,
and they reach the pituitary by the hypophyseal portal system .
 The interaction of the releasing hormones with receptors results in the activation of genes
that promote the synthesis of protein precursors. The protein precursors then undergo
posttranslational modification to produce hormones, which are released into the circulation.
 Each hypothalamic regulatory hormone controls the release of a specific hormone from the
anterior pituitary.
Thyroid Hormones
 The thyroid gland facilitates normal growth and maturation by maintaining a level of
metabolism in the tissues that is optimal for normal function.
 The two major thyroid hormones are triiodothyronine (T3; the most active form) and
thyroxine (T4).
 Inadequate secretion of thyroid hormone (hypothyroidism) results in bradycardia, cold
intolerance, and mental and physical slowing. In children, this can cause mental retardation
and dwarfism.
 By contrast, excess secretion of thyroid hormones (hyperthyroidism) can cause tachycardia
and cardiac arrhythmias, body wasting, nervousness, tremor, and heat intolerance.
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Thyroid hormone synthesis and secretion
 The thyroid gland is made up of multiple follicles that consist of a single layer of epithelial
cells surrounding a lumen filled with thyroglobulin (the storage form of thyroid hormone).
 Thyroid function is controlled by TSH (thyrotropin), which is synthesized by the anterior
pituitary .
 TSH action is mediated by cAMP and leads to stimulation of iodide (I) uptake by the thyroid
gland.
 Oxidation to iodine (I2) by a peroxidase is followed by iodination of tyrosines on
thyroglobulin.
 Condensation of two diiodotyrosine residues gives rise to T4, whereas condensation of a
monoiodotyrosine residue with a diiodotyrosine residue generates T3. The hormones are
released following proteolytic cleavage of the thyroglobulin. (A summary of the steps in
thyroid hormone synthesis and secretion is shown in Figure 1).
1:
 :
2
(Figure:2) : Feedback regulation of thyroid hormone release.
SS = somatostatin;T3 =triiodothyronine; T4 = thyroxine; TRH = thyrotropin-releasing hormone;

TSH = thyroid stimulating hormone.
Mechanism of action
Most circulating T3 and T4 is bound to thyroxine-binding globulin in the plasma. The hormones
must dissociate from thyroxine-binding globulin prior to entry into cells. In the cell, T4 is
enzymatically deiodinated to T3, which enters the nucleus and attaches to specific receptors. The
activation of these receptors promotes the formation of RNA and subsequent protein synthesis,
which is responsible for the effects of T4 .
Pharmacokinetics
 Both T4 and T3 are absorbed after oral administration. Food, calcium preparations, iron salts,
and aluminum containing antacids can decrease the absorption of T4.
 Deiodination is the major route of metabolism of T4.
3
 T3 also undergoes sequential deiodination. The hormones are also metabolized via
conjugation with glucuronides and sulfates and excreted into bile.
Treatment of hypothyroidism:
 Hypothyroidism usually results from autoimmune destruction of the gland and is diagnosed
by elevated TSH.
 Levothyroxine (T4) is preferred over T3 (liothyronine) or T3/T4 combination products
(liotrix) for the treatment of hypothyroidism.
 Levothyroxine is better tolerated than T3 preparations and has a longer half-life. It is dosed
once daily, and steady state is achieved in 6 to 8 weeks.
Toxicity is directly related to T4 levels and manifests as :
 nervousness,
 palpitations and tachycardia,
 heat intolerance, and
 unexplained weight loss.
Treatment of hyperthyroidism (thyrotoxicosis)
 Graves disease, an autoimmune disease that affects the thyroid, is the most common cause of
hyperthyroidism. In these situations, TSH levels are low due to negative feedback.
 [Note: Feedback inhibition of TRH occurs with high levels of circulating thyroid hormone,
which, in turn, decreases secretion of TSH.]
 The goal of therapy is to decrease synthesis and/or release of additional hormone.
 This can be accomplished by:
removing part or all of the thyroid gland,
by inhibiting synthesis of the hormones, or
by blocking release of hormones from the follicle.
4
1. Removal of the thyroid
This can be accomplished surgically or by destruction of the gland with radioactive iodine (I),
which is selectively taken up by the thyroid follicular cells. Most patients become hypothyroid after
radioactive iodine and require treatment with levothyroxine.
2. Inhibition of thyroid hormone synthesis
The thioamides, propylthiouracil (PTU) and methimazole , are concentrated in the

thyroid, where they inhibit both the oxidative processes required for iodination of tyrosyl
groups and the condensation (coupling) of iodotyrosines to form T3 and T4 (Figure 1).
PTU also blocks the peripheral conversion of T4 to T3.
Methimazole is preferred over PTU because it has a longer half-life, allowing for once-
daily dosing, and a lower incidence of adverse effects.
However, PTU is recommended during the first trimester of pregnancy due to a greater risk
of teratogenic effects with methimazole. PTU has been associated with hepatotoxicity and,
rarely, agranulocytosis.
3. Blockade of hormone release
A pharmacologic dose of iodide inhibits the iodination of tyrosines (“Wolff-Chaikoff

effect”), but this effect lasts only a few days.
More importantly, iodide inhibits the release of thyroid hormones from thyroglobulin by
mechanisms not yet understood. Iodide is employed to treat thyroid storm or prior to
surgery, because it decreases the vascularity of the thyroid gland.
Iodide, administered orally, is not useful for long-term therapy; the thyroid ceases to
respond to the drug after a few weeks. Adverse effects include sore mouth and throat,
swelling of the tongue or larynx, rashes, ulcerations of mucous membranes, and metallic
taste.
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Thyroid storm
 Thyroid storm presents with extreme symptoms of hyperthyroidism.

 The treatment of thyroid storm is the same as for hyperthyroidism, except that the drugs are
given in higher doses and more frequently.
 β-Blockers, such as metoprolol or propranolol, are effective in blunting the widespread
sympathetic stimulation that occurs in hyperthyroidism.

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Pharmacology Dr. Dalia A.

Hypothalamic and Anterior Pituitary Hormones

SS = somatostatin;T3 =triiodothyronine; T4 = thyroxine; TRH = thyrotropin-releasing hormone;

Treatment of hyperthyroidism (thyrotoxicosis)

2. Inhibition of thyroid hormone synthesis

The thioamides, propylthiouracil (PTU) and methimazole , are concentrated in the

3. Blockade of hormone release

A pharmacologic dose of iodide inhibits the iodination of tyrosines (“Wolff-Chaikoff

 Thyroid storm presents with extreme symptoms of hyperthyroidism.

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