Page 705 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 38 Thyroid & Antithyroid Drugs 691

Thyroid hormone is critical for the development and func-
Acute Circadian and tioning of nervous, skeletal, and reproductive tissues. Its effects
psychosis pulsatile rhythms depend on protein synthesis as well as potentiation of the secretion
+ + Severe and action of growth hormone. Thyroid deprivation in early life
Cold stress results in irreversible mental retardation and dwarfism—typical of
+ – congenital cretinism.
Effects on growth and calorigenesis are accompanied by a per-
H vasive influence on metabolism of drugs as well as carbohydrates,
Hypothalamus
fats, proteins, and vitamins. Many of these changes are dependent
Somato- upon or modified by activity of other hormones. Conversely, the
+ – statin Corticoids secretion and degradation rates of virtually all other hormones,
– or
TRH including catecholamines, cortisol, estrogens, testosterone, and
dopamine
insulin, are affected by thyroid status.
– Many of the manifestations of thyroid hyperactivity resemble
AP sympathetic nervous system overactivity (especially in the cardio-
T 4 ,T 3 vascular system), although catecholamine levels are not increased.
–
Changes in catecholamine-stimulated adenylyl cyclase activity
as measured by cAMP are found with changes in thyroid activ-
TSH + ity. Thyroid hormone increases the numbers of β receptors and
enhances amplification of the β-receptor signal. Other clinical
symptoms reminiscent of excessive epinephrine activity (and par-
tially alleviated by adrenoceptor antagonists) include lid lag and
Thyroid + I – retraction, tremor, excessive sweating, anxiety, and nervousness.
– The opposite constellation of effects is seen in hypothyroidism
(Table 38–4).

FIGURE 38–3 The hypothalamic-pituitary-thyroid axis. Acute Thyroid Preparations
psychosis or prolonged exposure to cold may activate the axis.
Hypothalamic thyroid-releasing hormone (TRH) stimulates pituitary See the Preparations Available section at the end of this chapter
thyroid-stimulating hormone (TSH) release, while somatostatin and for a list of available preparations. These preparations may be
dopamine inhibit it. TSH stimulates T 4 and T 3 synthesis and release synthetic (levothyroxine, liothyronine, liotrix) or of animal origin
from the thyroid, and they in turn inhibit both TRH and TSH synthesis (desiccated thyroid).
and release. Small amounts of iodide are necessary for hormone Thyroid hormones are not effective and can be detrimental in
production, but large amounts inhibit T 3 and T 4 production and the management of obesity, abnormal vaginal bleeding, or depres-
release. Solid arrows, stimulatory influence; dashed arrows, sion if thyroid hormone levels are normal. Recent meta-analysis of
inhibitory influence. H, hypothalamus; AP, anterior pituitary. T co-administered with antidepressants showed some depression
3
benefits, but the results were inconclusive and further confirma-
tion for its optimal use is required.
Large numbers of thyroid hormone receptors are found in the
most hormone-responsive tissues (pituitary, liver, kidney, heart, Synthetic levothyroxine is the preparation of choice for thyroid
skeletal muscle, lung, and intestine), while few receptor sites occur replacement and suppression therapy because of its stability,
in hormone-unresponsive tissues (spleen, testes). The brain, which content uniformity, low cost, lack of allergenic foreign protein,
lacks an anabolic response to T , contains an intermediate number easy laboratory measurement of serum levels, and long half-life
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of receptors. In congruence with their biologic potencies, the affin- (7 days), which permits once-daily to weekly administration.
ity of the receptor site for T is about ten times lower than that for In addition, T 4 is converted to T intracellularly; thus, admin-
3
4
T . Under some conditions, the number of nuclear receptors may istration of T produces both hormones and T administra-
3
4
3
be altered to preserve body homeostasis. For example, starvation tion is unnecessary. Generic levothyroxine preparations provide
lowers both circulating T hormone and cellular T receptors. comparable efficacy and are more cost-effective than branded
3
3
preparations, It is preferable that patients remain on a consistent
Effects of Thyroid Hormones levothyroxine preparation between refills to avoid changes in bio-
availability. A branded soft gel capsule (Tirosint) had faster, more
The thyroid hormones are responsible for optimal growth, devel- complete dissolution and was less affected by gastric pH or coffee
opment, function, and maintenance of all body tissues. Excess or than a tablet formulation.
inadequate amounts result in the signs and symptoms of hyper- Although liothyronine (T ) is three to four times more potent
3
thyroidism or hypothyroidism, respectively (Table 38–4). Since than levothyroxine, it is not recommended for routine replace-
T and T are qualitatively similar, they may be considered as one ment therapy because of its shorter half-life (24 hours), requiring
3
4
hormone in the discussion that follows. multiple daily doses, and difficulty in monitoring its adequacy of