DRUGS USED IN
THE TREATMENT OF HYPERTHYROIDISM
Treatment of hyperthyroidism
is directed at reducing the excessive synthesis and secretion of thyroid
hor-mones. This may be accomplished by inhibiting thy-roidal synthesis and
secretion with antithyroid drugs, by reducing the amount of functional thyroid tissue,
or by both. Unfortunately, only a small proportion of patients treated with
antithyroid drugs obtain long-term remis-sion of their hyperthyroidism.
Ablative therapy is often necessary. Since many of the signs and symptoms of
hy-perthyroidism reflect increased cellular sensitivity to adrenergic
stimulation, a β-adrenergic antagonist is of-ten used adjunctively. Propranolol (Inderal), the most widely used β-adrenoceptor blocker, is
effective in ame-liorating many of the manifestations of thyrotoxicosis. It may
reduce thyrotoxicosis-induced tachycardia, palpita-tions, tremor, sweating,
heat intolerance, and anxiety, which are largely mediated through the
adrenergic nervous system. Propranolol may also impair the con-version of T4
to T3. The use of propranolol is contraindi-cated in thyrotoxic
patients with asthma or chronic obstructive pulmonary disease because it
impairs bron-chodilation. It is also contraindicated in patients with heart
block and those with congestive heart failure, un-less severe tachycardia is a
contributory factor.
Thionamides are the primary
drugs used to decrease thyroid hormone production. They do not inhibit
secre-tion of stored thyroid hormone, and therefore, when they are used alone,
their clinical effects are not apparent until the preexisting intrathyroidal
store of thyroid hormone is depleted. This may take several weeks.
Propylthiouracil and methylthiouracil (methimazole; Tapazole) are the most commonly used preparations in the United States.
Thionamide drugs interfere
with peroxidase-catalyzed reactions. In the thyroid gland, they inhibit the
activity of the enzyme TPO, which is required for the intrathyroidal oxidation
of I- , the incorporation of I- into Tg, and the coupling of iodotyrosyl
residues to form thyroid hormones. Thus, these drugs inhibit thy-roid hormone
synthesis and with time, also secretion. Propylthiouracil, but not methimazole,
also inhibits D1, which deiodinates T4 to T3. Because of
this additional action, propylthiouracil is often used to provide a rapid
alleviation of severe thyrotoxicosis.
In patients with autoimmune
thyroid disease, thion-amide drugs may also exert an immunosuppressive ef-fect.
As the drug is concentrated in thyroid follicular cells, the expression of
thyroid antigen and the release of prostaglandins and cytokines are decreased.
Subse-quently, the autoimmune response is impaired. Thion-amides also inhibit
the generation of oxygen radicals in T cells, B cells, and particularly the
antigen-presenting cells within the thyroid gland. Thus, thionamides may cause
a decline in thyroid autoantibody titers, although the clinical importance of
immunosuppression is un-clear.
Thionamide drugs are well
absorbed from the gas-trointestinal tract. Although they have short plasma
half-lives (propylthiouracil 1.5 hours; methimazole 6 hours), they accumulate
in the thyroid gland, and a sin-gle daily dose may exert effects for greater
than 24 hours. Thionamides undergo hepatic conjugation to form glucuronides and
are excreted in the bile and urine. Nevertheless, few glucuronide conjugates
are found in the feces because they are absorbed from the gastrointestinal
tract.
The thionamide drugs are used
in the management of hyperthyroidism and thyrotoxic crisis and in the
preparation of patients for surgical subtotal thyroidec-tomy. Although the use
of thionamides alone may re-store euthyroidism, it is difficult to adjust the
dosage in some patients. This has led to the development of block-and-replace
regimens in which a full blocking dose of thionamide plus a levothyroxine
supplement is pre-scribed. Although thionamides may be used to treat
hy-perthyroidism during pregnancy, they should be given in minimally effective
doses to avoid inducing infantile hypothyroidism and thyroid enlargement in the
devel-oping fetus.
If given in excessive amounts
over a long period, thionamides may cause hypothyroidism and enlargement of the
thyroid gland. The most serious adverse effects are granulocytopenia and
agranulocytosis, which occur in about 0.5% of patients and usually within 3
months of starting therapy. The most frequently observed adverse
effect is rash. Arthralgia,
myalgia, cholestatic jaundice, lymphadenopathy, drug fever, psychosis, and a
lupuslike syndrome have also been reported.
The effects of iodide on the
thyroid gland are complex. When administered in pharmacological amounts,
potas-sium iodide (KI) causes a transient inhibition of the up-take and
incorporation of I- into Tg (Wolff-Chaikoff ef-fect). In addition, high doses
of KI also inhibit the secretion of thyroid hormone and thyroid blood flow.
These effects make KI an ideal agent for treating severe thyrotoxicosis or
thyroid crisis when a rapid decrease in plasma T4 and T3
is desirable. As the thyroid gland es-capes from Wolff-Chaikoff effect, I- accumulates
within the gland and hormone synthesis resumes. With contin-ued treatment with
KI alone, the inhibition of thyroid secretion may also diminish. Hypersecretion
of thyroid hormone and thyrotoxicosis may return at the previous or a more
severe intensity. For this reason, iodide alone is not used for the management
of hyperthyroidism. Nevertheless, KI has long been used in combination with
propylthiouracil in the management of thyrotoxic crisis to rapidly inhibit
thyroid hormone secretion. Iodide plus a thionamide has also been used in the
im-mediate preoperative preparation of patients about to undergo total or
subtotal surgical thyroidectomy.
The ability of KI to block
the thyroidal uptake of I- and its incorporation into Tg would prove useful in
the event of an accident at a nuclear power plant. In such an event, large
quantities of radionuclides, including iso-topes of radioiodine, could be
released into the atmos-phere. Administration of KI (Thyro-Block) to inhibit the uptake and incorporation of radioiodine
would be the most effective means of limiting the potential dam-age to the
thyroid gland.
Adverse reactions to iodine
can be divided into in-trathyroidal and extrathyroidal reactions. Among the
intrathyroidal reactions is iodine-induced thyrotoxico-sis (Jod-Basedow’s
phenomenon), which may occur in patients with nontoxic nodular goiter given low
doses ( 25 mg/day) of potassium or sodium iodide. At higher doses (50–500
mg/day), iodide goiter or hypothyroidism or both may develop, but this usually
requires long ex-posure. Extrathyroidal adverse reactions to iodine are
relatively rare and generally not serious. These include rash, which may be
acneiform; drug fever; sialadenitis (inflammation of the salivary glands);
conjunctivitis and rhinitis; vasculitis; and a leukemoid eosinophilic
granu-locytosis.
The iodine-containing oral
cholecystographic contrast agents (OCAs) include sodium ipodate (Oragrafin), iopanoic acid (Telepaque), tyropanoic acid (Bilopaque), and iocetamic acid (Cholebrine). They all inhibit D1 and D2.
These actions make OCAs useful as adjunctive therapy with other antithyroid
drugs by promoting a rapid fall in the plasma T3 concentration of
the seriously thyrotoxic patient.
In addition, the metabolism
of OCAs results in the release of large amounts of I- into the circulation. As
described for KI, I- released from OCAs may have ef-fects at the thyroid gland
and if used alone to treat hy-perthyroidism, OCAs carry the same potential to
in-duce increased secretion of thyroid hormone and exacerbation of
thyrotoxicosis. When an OCA is used in the treatment of hyperthyroidism, large
doses of an-tithyroid agents are usually administered concomi-tantly. However,
the combination of OCAs and antithy-roid drugs may cause resistance to the
antithyroid drugs with time, presumably because of the elevation in
in-trathyroidal I- content. Thus, it is recommended that the use of OCAs be
reserved for short-term treatment of patients with severe thyrotoxicosis and
significant co-morbidity (e.g., myocardial infarction, sepsis, stroke) for
rapid control of plasma T3 concentrations.
When the OCAs are used for
these purposes, they are administered at much lower doses than when used for
cholecystography. At the higher doses, the major ad-verse effects of these
compounds are acute renal failure, thrombocytopenia, and athrombocytosis;
possible mi-nor adverse reactions include diarrhea, nausea, vomit-ing, and
dysuria.
Millicurie amounts of 131I
( Iodotope I-131) are used for
thyroid ablation in the management of hyperthy-roidism. 131I is
taken up and trapped in the same manner as I- . The ablative effect is exerted
primarily through - particle emissions, which destroy thyroid tissue. The
ma-jor disadvantage associated with this therapy is the de-velopment of
hypothyroidism after thyroid ablation. Microcurie amounts of radioiodine also
are used for the diagnostic evaluation of thyroid function.
The perchlorate ion of
potassium perchlorate, KClO4, is a competitive inhibitor of
thyroidal I- transport via the Sodium Iodide Symporter (NIS). This drug can
cause fa-tal aplastic anemia and gastric ulcers and is now rarely used. If
administered with careful supervision, in limited low doses and for only brief
periods, serious toxic effects can be avoided. The compound is especially
effective in treating iodine-induced hyperthyroidism, which may oc-cur, for
example, in patients treated with the antiar-rhythmic compound amiodarone.
Perchlorate ion can also be used in a diagnostic test of I- incorporation into
Tg, the so-called perchlorate discharge test.
Lithium inhibits thyroidal
incorporation of I- into Tg, as well as the secretion of thyroid hormones, but
it does not inhibit the activity of the NA+ –I symporter or the
accumulation of I- within the thyroid. Lithium offers no particular advantage
over drugs of the thionamide class but may be employed for temporary control of
thyro-toxicosis in patients who are allergic to both thion-amides and iodide.
As the plasma levels of T4
and T3 fall after the adminis-tration of antithyroid drugs, the
catabolism of vitamin K–dependent clotting factors decreases, thus reducing the
effectiveness of coumarin anticoagulants. During concomitant therapy, the
dosage of the anticoagulant may have to be increased. Conversely, the use of
an-tithyroid therapy in patients with diabetes mellitus may decrease the
patient’s requirement for insulin or oral hy-poglycemic agents. Similarly,
patients receiving cardiac glycosides, such as digitoxin, may require a smaller
dose.
Lithium carbonate,
administered for affective and bipolar disorders, may enhance the effects of
antithy-roid drugs. Potassium iodide, used as an expectorant, is a major
ingredient in many cough medications. Iodide derived from this source may
enhance the effects of an-tithyroid drugs and lead to iodine-induced
hypothy-roidism. Iodine in topical antiseptics and radiological contrast agents
may act in a similar manner.
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