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

1148 have weak anti-thyroid action in experimental animals. This is not
significant at usual doses in humans. However, anti-thyroid effects
in humans have been observed from dimercaprol and lithium salts.
Polychlorinated biphenyls bear a striking structural resemblance to
the thyroid hormones and may function as either agonists or antagonists
of thyroid hormone action (Zoeller et al., 2000). Amiodarone,
the iodine-rich drug used in the management of cardiac arrhythmias,
has complex effects on thyroid function (Basaria and Cooper,
2005). In areas of iodine sufficiency, amiodarone-induced hypothyroidism
due to the excess iodine is not uncommon, whereas in
iodine-deficient regions, amiodarone-induced thyrotoxicosis predominates,
whether because of the excess iodine or the thyroiditis
induced by the drug. Amiodarone and its major metabolite,
desethylamiodarone, are potent inhibitors of iodothyronine deiodination,
resulting in decreased conversion of thyroxine to triiodothyronine.
In addition, desethylamiodarone decreases binding
of triiodothyronine to its nuclear receptors. Recommendations have
been made as to screening methods to identify chemicals that may
alter thyroid hormone action or homeostasis (Diamanti-Kandarakis
et al., 2009).
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Mechanism of Action. The mechanism of action of the
thioureylene drugs has been thoroughly reviewed
(Cooper, 2005). Anti-thyroid drugs inhibit the formation
of thyroid hormones by interfering with the incorporation
of iodine into tyrosyl residues of
thyroglobulin; they also inhibit the coupling of these
iodotyrosyl residues to form iodothyronines. This
implies that they interfere with the oxidation of iodide
ion and iodotyrosyl groups. The drugs are thought to
inhibit the peroxidase enzyme, thereby preventing oxidation
of iodide or iodotyrosyl groups to the required
active state (Taurog et al., 1996). The anti-thyroid drugs
bind to and inactivate the peroxidase only when the
heme of the enzyme is in the oxidized state. Over a
period of time, the inhibition of hormone synthesis
results in the depletion of stores of iodinated thyroglobulin
as the protein is hydrolyzed and the hormones are
released into the circulation. Only when the preformed
hormone is depleted and the concentrations of circulating
thyroid hormones begin to decline do clinical
effects become noticeable.
There is some evidence that the coupling reaction
may be more sensitive to an anti-thyroid drug, such as
propylthiouracil, than is the iodination reaction. This
may explain why patients with hyperthyroidism
respond well to doses of the drug that only partially
suppress organification.
When Graves’ disease is treated with anti-thyroid
drugs, the concentration of thyroid-stimulating
immunoglobulins in the circulation often decreases,
prompting some to propose that these agents act as
immunosuppressants. Perchlorate, which acts by an
entirely different mechanism, also decreases thyroidstimulating
immunoglobulins, suggesting that
improvement in hyperthyroidism may reduce thyroid
antibodies.
In addition to blocking hormone synthesis, propylthiouracil
partially inhibits the peripheral deiodination
of T 4
to T 3
. Methimazole does not have this effect;
although the quantitative significance of this inhibition
has not been established, it provides a rationale for the
choice of propylthiouracil over other anti-thyroid drugs
in the treatment of severe hyperthyroid states or of thyroid
storm, where a decreased rate of T 4
→T 3
conversion
would be beneficial.
Absorption, Metabolism, and Excretion. The anti-thyroid
compounds currently used in the U.S. are propylthiouracil
(6-n-propylthiouracil) and methimazole
(1-methyl-2-mercaptoimidazole; TAPAZOLE, others).
In Great Britain and Europe, carbimazole (NEO-
MERCAZOLE), a carbethoxy derivative of methimazole,
is available, and its anti-thyroid action is due to its conversion
to methimazole after absorption. Pharmacological
properties of propylthiouracil and methimazole are
shown in Table 39–5.
Table 39–5
Selected Pharmacokinetic Features of Anti-thyroid
Drugs
PROPYLTHIOURACIL METHIMAZOLE
Plasma protein ~75% Nil
binding
Plasma t 1/2
75 minutes ~4-6 hours
Volume of ~20 liters ~40 liters
distribution
Concentrated in Yes Yes
thyroid
Metabolism of
drug during
illness
Severe liver Normal Decreased
disease
Severe kidney Normal Normal
disease
Dosing frequency 1-4 times Once or twice
daily
daily
Transplacental Low Low
passage
Levels in breast Low Low
milk