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

1150 then the lower maintenance dose of anti-thyroid drug as
discussed earlier is instituted for continued therapy.
Despite initial suggestions to the contrary, there is no
demonstrated benefit of combination levothyroxine
and methimazole therapy on either remission rates
(Rittmaster et al., 1998) or on changes in serum concentrations
of thyroid-stimulating immunoglobulins.
After treatment is initiated, patients should be examined and
thyroid function tests (serum FT 4
and total or free triiodothyronine
concentrations) measured every 2-4 months. Serum TSH will often
remain suppressed for several months after a patient has been hyperthyroid,
so the circulating thyroxine and triiodothyronine concentrations
are the most reliable assessment of thyroid status (Uy et al.,
1995). Once euthyroidism is established, follow-up every 4-6 months
is reasonable.
Control of the hyperthyroidism usually is associated with a
decrease in goiter size. When this occurs, the dose of the anti-thyroid
drug should be significantly decreased and/or levothyroxine can be
added once hypothyroidism is confirmed by laboratory testing.
Remissions. There is no highly reliable way of predicting
before treatment which patients will eventually achieve
a lasting remission and which will relapse. A favorable
outcome is unlikely when the disorder is of long standing,
the thyroid is quite large, serum T 3
concentration is
high relative to serum T 4
concentration, or various forms
of treatment have failed. To complicate the issue further,
remission and eventual hypothyroidism may represent
the natural history of Graves’ disease.
During treatment, a positive sign that a remission
may have taken place is reduced size of the goiter. The
persistence of goiter often indicates failure, unless the
patient becomes hypothyroid. Another favorable indication
is continued freedom from all signs of hyperthyroidism
when the maintenance dose is small. Finally, a
decrease in thyroid-stimulating immunoglobulins is
associated with remission, although the clinical features
and improvement in thyroid function tests are usually
sufficient to make this assessment.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
The Therapeutic Choice. Because anti-thyroid drug therapy,
radioactive iodine, and subtotal thyroidectomy all
are effective treatments for Graves’ disease, there is no
worldwide consensus among endocrinologists about the
best therapeutic approach. Prolonged drug therapy of
Graves’ disease in anticipation of a remission is most
successful in patients with small goiters or mild hyperthyroidism.
Those with large goiters or severe disease
usually require definitive therapy with either surgery or
radioactive iodine ( 131 I). Radioactive iodine remains the
treatment of choice of many endocrinologists in the U.S.
Many investigators consider coexisting ophthalmopathy to
be a relative contraindication for radioactive iodine therapy
because worsening of ophthalmopathy has been reported after
radioactive iodine (Bartalena et al., 1998a), although this remains
controversial. Others suggest that development of hypothyroidism,
regardless of the treatment, is the strongest risk factor for progression
of ophthalmopathy. Smoking is a risk factor for worsening
ophthalmopathy (Bartelena et al., 1998b). In older patients,
depleting the thyroid gland of preformed hormone by treatment
with anti-thyroid drugs is advisable before therapy with radioactive
iodine, thus preventing a severe exacerbation of the hyperthyroid
state during the subsequent development of radiation
thyroiditis. Subtotal thyroidectomy is advocated for Graves’ disease
in young patients with large goiters, children who are allergic
to anti-thyroid drugs, pregnant women (usually in the second
trimester) who are allergic to anti-thyroid drugs, and patients who
prefer surgery over anti-thyroid drugs or radioactive iodine.
Radioactive iodine or surgery is indicated for definitive therapy in
toxic nodular goiter.
Thyrotoxicosis in Pregnancy. Thyrotoxicosis occurs in
~0.2% of pregnancies and is caused most frequently by
Graves’ disease (Chan and Mandel, 2007). Anti-thyroid
drugs are the treatment of choice; radioactive iodine is
clearly contraindicated. Historically, propylthiouracil has
been preferred over methimazole because transplacental
passage was thought to be lower; however, as noted earlier,
both propylthiouracil and methimazole cross the placenta
equally (Mortimer et al., 1997). Methimazole is
also very rarely associated with aplasia cutis and an
embryopathy that can include choanal atresia and other
anomalies (Diav-Citrin and Ornoy, 2002). Current data
suggest that either may be used safely in the pregnant
patient (Momotani et al., 1997; Mortimer et al., 1997),
although the concern for propylthiouracil-associated liver
failure in pregnancy may favor the use of methimazole,
especially after organogenesis in the first trimester
(Cooper and Rivkees, 2009). Carbimazole is used in the
EU during pregnancy and is rarely associated with congenital
gut abnormalities (Barwell et al., 2002).
The anti-thyroid drug dosage should be minimized to keep
the serum FT 4
index in the upper half of the normal range or slightly
elevated. As pregnancy progresses, Graves’ disease often improves,
and it is not uncommon for patients either to be on very low doses
or off anti-thyroid drugs completely by the end of pregnancy.
Therefore the anti-thyroid drug dose should be reduced, and maternal
thyroid function should be frequently monitored to decrease
chances of fetal hypothyroidism. Relapse or worsening of Graves’
disease is common after delivery, and patients should be monitored
closely. Methimazole up to 20 mg daily in nursing mothers reportedly
has no effect on thyroid function in the infant (Azizi et al.,
2003), and propylthiouracil is thought to cross into breast milk even
less than methimazole.
Adjuvant Therapy. Several drugs that have no intrinsic
anti-thyroid activity are useful in the symptomatic treatment
of thyrotoxicosis.