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

Table 39–4
Anti-thyroid Compounds
PROCESS AFFECTED
Active transport
of iodide
Iodination of
thyroglobulin
Coupling reaction
Hormone release
Iodotyrosine
deiodination
Peripheral
iodothyronine
deiodination
Hormone excretion/
inactivation
Hormone action
EXAMPLES OF INHIBITORS
Complex anions: perchlorate,
fluoborate, pertechnetate,
thiocyanate
Thionamides: propylthiouracil,
methimazole, carbimazole
Thiocyanate
Aniline derivatives; sulfonamides
Iodide
Thionamides
Sulfonamides
?All other inhibitors of iodination
Lithium salts
Iodide
Nitrotyrosines
Thiouracil derivatives
Oral cholecystographic agents
Amiodarone
Inducers of hepatic
drug-metabolizing
enzymes: phenobarbital,
rifampin, carbamazepine,
phenytoin
Thyroxine analogs
Amiodarone
?Phenytoin
Binding in gut: cholestyramine
Source: Data adapted from Meier C.A., Burger A.C. Effects of drugs
and other substances on thyroid hormone synthesis and metabolism.
In: Werner and Ingbar’s The Thyroid, 9th ed. (Braverman L.E. and
Utiger R.D. eds.) Lippincott Williams & Wilkins, Philadelphia, 2005.
Anti-Thyroid Drugs
The anti-thyroid drugs that have clinical utility are the
thioureylenes, which belong to the family of thionamides.
Propylthiouracil may be considered as the
prototype.
History. Studies on the mechanism of the development of goiter
began with the observation that rabbits fed a diet composed largely
of cabbage often developed goiters. This result was probably due to
the presence of precursors of the thiocyanate ion in cabbage leaves.
Later, two pure compounds were shown to produce goiter:
sulfaguanidine, a sulfanilamide antimicrobial used to treat enteric
infections, and phenylthiourea.
Investigation of the effects of thiourea derivatives revealed
that rats became hypothyroid despite hyperplastic changes in their
thyroid glands that were characteristic of intense thyrotropic stimulation.
After treatment was begun, no new hormone was made, and
the goitrogen had no visible effect on the thyroid gland following
hypophysectomy or the administration of thyroid hormone. This suggested
that the goiter was a compensatory change resulting from the
induced state of hypothyroidism and that the primary action of the
compounds was to inhibit the formation of thyroid hormone. The
therapeutic possibilities of such agents in hyperthyroidism were evident,
and the substances so used became known as anti-thyroid drugs
(Astwood, 1945).
Structure–Activity Relationship. The two goitrogens
found in the early 1940s proved to be prototypes of two
different classes of anti-thyroid drugs. These two, with
one later addition, made up three general categories into
which most of the agents can be assigned:
• Thioureylenes include all the compounds currently
used clinically (Figure 39–9);
• Aniline derivatives, of which the sulfonamides
make up the largest number, embrace a few substances
that have been found to inhibit thyroid hormone
synthesis;
• Polyhydric phenols, such as resorcinol, which have
caused goiter in humans when applied to abraded
skin.
A few other compounds, mentioned briefly later,
do not fit into any of these categories.
Thiourea and its simpler aliphatic derivatives and heterocyclic
compounds containing a thioureylene group make up most of the
known anti-thyroid agents that are effective in humans. Although
most of them incorporate the entire thioureylene group, in some a
nitrogen atom is replaced by oxygen or sulfur so that only the
thioamide group is common to all. Among the heterocyclic compounds,
active representatives are the sulfur derivatives of imidazole,
oxazole, hydantoin, thiazole, thiadiazole, uracil, and barbituric acid.
L-5-Vinyl-2-thiooxazolidone (goitrin) is responsible for the
goiter that results from consuming turnips or the seeds or green parts
of cruciferous plants. These plants are eaten by cows, and the compound
is found in cow’s milk in areas of endemic goiter in Finland;
it is about as active as propylthiouracil in humans.
As the result of industrial exposure, toxicological studies, or
clinical trials for various purposes, several other compounds have
been noted to possess anti-thyroid activity (Miller et al., 2009).
Thiopental and oral hypoglycemic drugs of the sulfonylurea class
Propylthiouracil
Methimazole
CH 3CH 2CH 2 N S N SH
H CH 3
N
N
Carbimazole
CH 3
N S
N
COOC 2H 5
O
Figure 39–9. Anti-thyroid drugs of the thiamide type.
1147
CHAPTER 39
THYROID AND ANTI-THYROID DRUGS