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

Measurements of the course of organification of radioactive
iodine by the thyroid show that absorption of effective amounts of
propylthiouracil follows within 20-30 minutes of an oral dose and
that the duration of action of the compounds used clinically is brief.
The effect of a dose of 100 mg of propylthiouracil begins to wane in
2-3 hours, and even a 500-mg dose is completely inhibitory for only
6-8 hours. As little as 0.5 mg of methimazole similarly decreases the
organification of radioactive iodine in the thyroid gland, but a single
dose of 10-25 mg is needed to extend the inhibition to 24 hours.
The t 1/2
of propylthiouracil in plasma is ~75 minutes, whereas
that of methimazole is 4-6 hours. The drugs are concentrated in
the thyroid, and methimazole, derived from the metabolism of
carbimazole, accumulates after carbimazole is administered. Drugs
and metabolites appear largely in the urine.
Propylthiouracil and methimazole cross the placenta equally
(Mortimer et al., 1997) and also can be found in milk. The use of
these drugs during pregnancy is discussed later.
Untoward Reactions. The incidence of side effects from
propylthiouracil and methimazole as currently used is
relatively low. The overall incidence as compiled from
published cases by early investigators was 3% for
propylthiouracil and 7% for methimazole, with 0.44%
and 0.12% of cases, respectively, developing the most
serious reaction, agranulocytosis.
Agranulocytosis usually occurs during the first few weeks or
months of therapy but may occur later. Because agranulocytosis can
develop rapidly, periodic white cell counts usually are of little help,
although a baseline white blood cell count and differential should
be obtained before anti-thyroid drug treatment is initiated. Patients
should be instructed to immediately report the development of sore
throat or fever, which are often signs of the presence of leukopenia.
If these signs or symptoms occur, patients should discontinue their
anti-thyroid drug and obtain a granuloctye count. Agranulocytosis
is reversible upon discontinuation of the offending drug, and the
administration of recombinant human granulocyte colony-stimulating
factor may hasten recovery (Magner and Snyder, 1994). Mild
granulocytopenia, if noted, may be due to thyrotoxicosis or may be
the first sign of this dangerous drug reaction. Caution and frequent
leukocyte counts are then required.
The most common reaction is a mild, occasionally purpuric,
urticarial papular rash. It often subsides spontaneously without interrupting
treatment, but it sometimes calls for the administration of an
antihistamine, corticosteroids, and changing to another drug (crosssensitivity
between propylthiouracil and methimazole is uncommon).
Other less frequent complications are pain and stiffness in the joints,
paresthesias, headache, nausea, skin pigmentation, and loss of hair.
Drug fever, hepatitis, and nephritis are rare, although abnormal liver
function tests are not infrequent with higher doses of propylthiouracil.
Although vasculitis was previously thought to be a rare complication,
antineutrophilic cytoplasmic antibodies (ANCAs) have been reported
to occur in ~50% of patients receiving propylthiouracil and rarely
with methimazole (Sato et al., 2000; Sera et al., 2000).
Propylthiouracil-associated hepatic failure has been increasingly
recognized, especially in children and pregnant women
(Cooper and Rivkees, 2009). There are 47 published reports of
propylthiouracil-associated liver failure in adults and children, and
23 liver transplants between 1990 and 2007 due to propylthiouracilassociated
liver failure. Methimazole may cause cholestatic dysfunction,
but it is not associated with hepatocellular necrosis, and there
are no reports of liver transplants due to methimazole-associated
liver toxicity. There is increasing concern about using propylthiouracil
as a first-line treatment, except in severe thyrotoxicosis when
the inhibition of T 4
to T 3
is desired, and possibly in the first trimester
of pregnancy. The FDA has added a “black box” warning to propylthiouracil
because of liver failure, recommending close monitoring
of liver function during its use. Propylthiouracil should not be used
in children except in the case of methimazole allergy.
Therapeutic Uses. The anti-thyroid drugs are used in
the treatment of hyperthyroidism in the following three
ways:
• as definitive treatment, to control the disorder in
anticipation of a spontaneous remission in Graves’
disease
• in conjunction with radioactive iodine, to hasten
recovery while awaiting the effects of radiation
• to control the disorder in preparation for surgical
treatment (Cooper, 2003)
Methimazole is the drug of choice for Graves’ disease; it is
effective when given as a single daily dose, has improved adherence,
and is less toxic than propylthiouracil. Methimazole has a relatively
long plasma and intrathyroidal t 1/2
, as well as a long duration of
action. The usual starting dose for methimazole is 15–40 mg per day.
The usual starting dose of propylthiouracil is 100 mg every 8 hours.
When doses >300 mg daily are needed, further subdivision of the
time of administration to every 4-6 hours is occasionally helpful.
Failures of response to daily treatment with 300-400 mg of propylthiouracil
or 30-40 mg of methimazole are most commonly due to
nonadherence but can be seen with very severe disease. Delayed
responses also are noted in patients with very large goiters or those
in whom iodine in any form has been given beforehand. Once euthyroidism
is achieved, usually within 12 weeks, the dose of anti-thyroid
drug can be reduced, but not stopped, lest an exacerbation of
Graves’ disease occur (see later section on remissions).
Response to Treatment. The thyrotoxic state usually
improves within 3-6 weeks after the initiation of
anti-thyroid drugs. The clinical response is related to
the dose of anti-thyroid drug, the size of the goiter, and
pretreatment serum T 3
concentrations. The rate of
response is determined by the quantity of stored hormone,
the rate of turnover of hormone in the thyroid, the
t 1/2
of the hormone in the periphery, and the completeness
of the block in synthesis imposed by the dosage
given. When large doses are continued, and sometimes
with the usual dose, hypothyroidism may develop as a
result of overtreatment. The earliest signs of hypothyroidism
call for a reduction in dose; if they have
advanced to the point of discomfort, thyroid hormone in
full replacement doses can be given to hasten recovery;
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CHAPTER 39
THYROID AND ANTI-THYROID DRUGS