DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1152 cigarette smoking has been reported to worsen both subclinical
hypothyroidism (Müller et al., 1995) and Graves’ ophthalmopathy
(Bartalena et al., 1998b). Dietary precursors of thiocyanate
may be a contributing factor in endemic goiter in certain parts of
the world, especially in Central Africa, where the intake of iodine
is very low.
Among other anions, perchlorate (ClO 4–
) is 10 times as active
as thiocyanate (Wolff, 1998). The various NIS inhibitors, perchlorate,
thiocyanate, and nitrate, are additive in inhibiting iodine uptake
(Tonacchera et al., 2004). Perchlorate blocks the entrance of iodide
into the thyroid by competitively inhibiting the NIS. Perchlorate is
transported by NIS using a different stoicheiometry, electroneutral,
compared with that seen with transport of iodine (Dohan et al.,
2007). Although perchlorate can be used to control hyperthyroidism,
it has caused fatal aplastic anemia when given in excessive amounts
(2-3 g daily). Perchlorate in doses of 750 mg daily has been used in
the treatment of Graves’ disease and amiodarone-iodine–induced
thyrotoxicosis (National Academy of Sciences/National Research
Council [NAS/NRC], 2005). Perchlorate can be used to “discharge”
inorganic iodide from the thyroid gland in a diagnostic test of iodide
organification. Other ions, selected on the basis of their size, also
have been found to be active; fluoroborate (BF 4–
) is as effective as
perchlorate.
Ammonium perchlorate is an essential oxidizer in the production
of rocket fuel, and water supplies have been contaminated
with perchlorate derived from the sites of production. A National
Academy of Sciences Committee recommended a reference dose
of perchlorate exposure of 0.0007 mg/kg per day that would produce
no adverse effect. This level of no effect is much higher than
that found in most water supplies, indicating a low risk of perchlorate
exposure influencing thyroid function (NAS/NRC, 2005). The
reference dose was primarily derived from a 2-week study in normal
volunteers that determined the daily dose of perchlorate that
produced no effect on thyroid function or 123 I uptake (Greer et al.,
2002). There remain concerns that accumulated perchlorate exposure
from multiple sources and combined exposure to other iodine
uptake inhibitors may impair thyroid function, especially as it
might affect pregnant women and young children (Miller et al.,
2009). A study in the U.S. showed a correlation between perchlorate
exposure and an increase in serum TSH (still within the normal
range), only among women with low iodine intake (Blount et
al., 2006). Men and women with adequate iodine intake did not
show any influence of perchlorate on thyroid function. Others
have argued that the risk of thyroid dysfunction from perchlorate
exposure is extremely low and there is little evidence to support
this view (Charnley, 2008). A study among pregnant women
living in areas of very high natural perchlorate contamination
showed no effect on maternal thyroid function or pregnancy outcome
for mother or infant (Tellez et al., 2006). Although reassuring,
the high iodine content in this region may limit the effects of
perchlorate. Because the primary mode of toxicity of perchlorate
is inhibition of iodine uptake, the best approach to reduce susceptibility
is to maintain adequate iodine intake, especially during
pregnancy (Becker et al., 2006).
Lithium has a multitude of effects on thyroid function; its
principal effect is decreased secretion of thyroxine and triiodothyronine
(Takami, 1994), which can cause overt hypothyroidism in some
patients taking Li + for the treatment of mania (Chapter 16).
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Iodide
Iodide is the oldest remedy for disorders of the thyroid
gland. Before the anti-thyroid drugs were used, it was
the only substance available for control of the signs and
symptoms of hyperthyroidism. Its use in this way is
indeed paradoxical, and the explanation for this paradox
is still incomplete.
Mechanism of Action. High concentrations of iodide
appear to influence almost all important aspects of
iodine metabolism by the thyroid gland. The capacity of
iodide to limit its own transport was mentioned earlier.
Acute inhibition of the synthesis of iodotyrosines and
iodothyronines by iodide also is well known (the Wolff-
Chaikoff effect). This transient 2-day inhibition is
observed only above critical concentrations of intracellular
rather than extracellular concentrations of iodide.
With time, “escape” from this inhibition is associated
with an adaptive decrease in iodide transport and a lowered
intracellular iodide concentration, associated with
a decrease in NIS mRNA and protein (Eng et al., 1999).
An important clinical effect of high [I – ] plasma
is
inhibition of the release of thyroid hormone. This action
is rapid and efficacious in severe thyrotoxicosis. The
effect is exerted directly on the thyroid gland and can be
demonstrated in the euthyroid subject as well as in the
hyperthyroid patient. Studies in a cultured thyroid cell
line suggest that some of the inhibitory effects of iodide
on thyrocyte proliferation may be mediated by actions
of iodide on crucial regulatory points in the cell cycle
(Smerdely et al., 1993).
In euthyroid individuals, the administration of doses of iodide
from 1.5-150 mg daily results in small decreases in plasma thyroxine
and triiodothyronine concentrations and small compensatory
increases in serum TSH values, with all values remaining in the normal
range. However, euthyroid patients with a history of a wide variety
of underlying thyroid disorders may develop iodine-induced
hypothyroidism when exposed to large amounts of iodine present in
many commonly prescribed drugs (Table 39–6), and these patients
do not escape from the acute Wolff-Chaikoff effect (Roti et al.,
1997). Among the disorders that predispose patients to iodine-induced
hypothyroidism are treated Graves’ disease, Hashimoto’s thyroiditis,
postpartum lymphocytic thyroiditis, subacute painful thyroiditis, and
lobectomy for benign nodules. The most commonly prescribed
iodine-containing drugs are certain expectorants (e.g., potassium
iodide), topical antiseptics (e.g., povidone iodine), and iodinated
radiological contrast agents.
Response to Iodide in Hyperthyroidism. The response to
iodides in patients with hyperthyroidism is often
striking and rapid. The effect usually is discernible
within 24 hours, and the basal metabolic rate may fall
at a rate comparable to that following thyroidectomy.