A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

294 THYROID
and interferes with the generation of oxygen radicals by
macrophages, thereby interfering with the presentation of antigen
to lymphocytes. Methimazole does not affect hormone
secretion directly. Thus hormone release decreases after a
latent period, during which time the thyroid becomes depleted
of hormone.
Adverse effects
Carbimazole is usually well tolerated, although pruritus and
rashes are fairly common. These usually respond to switching
to propylthiouracil (see below). Neutropenia is a rare but
potentially fatal adverse effect. Patients must be warned to
report sore throat or other evidence of infection immediately,
an urgent white cell count must be obtained and the drug
should be stopped if there is neutropenia. Nausea, hair loss,
drug fever, leukopenia and arthralgia are rare, but recognized
adverse effects. Use of carbimazole during pregnancy has
rarely been associated with aplasia cutis in the newborn.
Pharmacokinetics
Carbimazole is rapidly absorbed after oral administration
and hydrolysed to methimazole, which is concentrated in the
thyroid within minutes of administration. Methimazole has
an apparent volume of distribution equivalent to body water
and the t 1/2 varies according to thyroid status, being approximately
seven, nine and 14 hours in hyperthyroid, euthyroid
and hypothyroid patients, respectively. It is metabolized in the
liver and thyroid.
• in neonatal hyperthyroidism due to thyroid-stimulating
immunoglobulin from the mother – this remits within
about six weeks as maternal-derived immunoglobulin is
cleared by the infant.
Hyperthyroid patients treated with beta-blockers are not
biochemically euthyroid, even if they appear clinically euthyroid,
and thyroid crisis (‘storm’) can supervene if treatment is
discontinued.
RADIOACTIVE IODINE
Radioactive iodine is an effective oral treatment for thyrotoxicosis
caused by Graves’ disease or by toxic nodular goitre. It is
safe, causes no discomfort to the patient and has largely
replaced surgery, except when there are local mechanical problems,
such as tracheal compression. It is contraindicated in
pregnancy. Dosing has been the subject of controversy. It is
now standard practice in many units to give an ablative dose
followed by replacement therapy with thyroxine, so late-onset
undiagnosed hypothyroidism is avoided. The isotope usually
employed is 131 I with a t 1/2 of eight days. Thyroxine replacement
is started after four to six weeks and continued for life.
There is no increased incidence of leukemia, thyroid or other
malignancy after therapeutic use of 131 I, but concern remains
regarding its use in children or young women. However, the
dose of radiation to the gonads is less than that in many radiological
procedures and there is no evidence that therapeutic
doses of radioactive iodine damage the germ cells or reduce
PROPYLTHIOURACIL
Use
Propylthiouracil has similar actions, uses and toxic effects to
carbimazole, but in addition inhibits the peripheral conversion
of T 4 to active T 3 . As with carbimazole, dangerous
leukopenia may develop, but is very rare. The scheme of
attaining a euthyroid state with a large initial dose which is
then reduced is as for carbimazole. Propylthiouracil is rapidly
absorbed from the intestine. The plasma t 1/2 is short, but
the duration of action within the thyroid is prolonged and, as
with carbimazole, propylthiouracil can be given once daily. It
is used (by specialists) in pregnancy (see below) and has some
advantages over carbimazole in this setting.
β-ADRENOCEPTOR ANTAGONISTS
Beta-blockers improve symptoms of hyperthyroidism, including
anxiety, tachycardia and tremor. They inhibit the conversion
of T 4 to T 3 in the tissues. They are useful:
• while awaiting laboratory confirmation, if the diagnosis is
in doubt;
• during initiation of therapy with antithyroid drugs;
• before treatment with radio-iodine, because they do not
interfere with the uptake of iodine by the gland;
• in thyroid crisis;
• with iodine, as a rapid preparation for surgery on a
hyperactive thyroid goitre;
Key points
Antithyroid drugs
• Carbimazole works via its active metabolite,
methimazole. This is concentrated in cells that contain
peroxidase, including neutrophils as well as thyroid
epithelium. It is iodinated in the thyroid, diverting
iodine from the synthesis of T 3 and T 4 and depleting
the gland of hormone. It does not inhibit secretion of
preformed thyroid hormones, so there is a latent period
before its effect is evident after starting treatment.
• Neutropenia is an uncommon but potentially fatal
adverse effect. Patients who develop sore throat or
other symptoms of infection need to report for an
urgent white blood count. Pruritus and rash are more
common but less severe.
• Propylthiouracil is similar in its effects and adverse
effects to carbimazole/methimazole, but in addition it
inhibits peripheral conversion of T 4 to the more active
T 3 , and is therefore preferred in thyroid storm.
• β-Adrenoceptor antagonists suppress manifestations of
hyperthyroidism and are used when starting treatment
with specific antithyroid drugs, and in treating thyroid
storm (together with propylthiouracil and glucocorticoids,
which also suppress the conversion of T 4 to T 3 ).
• Radioactive iodine ( 131 I) is safe in non-pregnant adults
and has largely replaced surgery in the treatment of
hyperthyroidism, except when there are local
mechanical complications, such as tracheal obstruction.
Replacement therapy with T 4 is required after
functional ablation.