Page 709 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 38 Thyroid & Antithyroid Drugs 695

data from investigational or marketing experience, see Chapter 59). The major clinical use for potassium perchlorate is to block
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Of the two, propylthiouracil is preferable during the first trimester thyroidal reuptake of I in patients with iodide-induced hyper-
of pregnancy because it is more strongly protein-bound and, there- thyroidism (eg, amiodarone-induced hyperthyroidism). How-
fore, crosses the placenta less readily. In addition, methimazole has ever, potassium perchlorate is rarely used clinically because it is
been, albeit rarely, associated with congenital malformations. Both associated with aplastic anemia.
thioamides are secreted in low concentrations in breast milk but
are considered safe for the nursing infant.
IODIDES
Pharmacodynamics Prior to the introduction of the thioamides in the 1940s, iodides
The thioamides act by multiple mechanisms. The major action were the major antithyroid agents; today they are rarely used as
is to prevent hormone synthesis by inhibiting the thyroid sole therapy.
peroxidase-catalyzed reactions and blocking iodine organifica-
tion. In addition, they block coupling of the iodotyrosines. They Pharmacodynamics
do not block uptake of iodide by the gland. Propylthiouracil but
not methimazole also inhibits the peripheral deiodination of T Iodides have several actions on the thyroid. They inhibit organifi-
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and T (Figure 38–1). Since the synthesis rather than the release cation and hormone release and decrease the size and vascularity
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of hormones is affected, the onset of these agents is slow, often of the hyperplastic gland. In susceptible individuals, iodides can
requiring 3–4 weeks before stores of T are depleted. induce hyperthyroidism (Jod-Basedow phenomenon) or precipi-
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tate hypothyroidism.
In pharmacologic doses (>6 mg/d), the major action of iodides
Toxicity is to inhibit hormone release, possibly through inhibition of
Adverse reactions to the thioamides occur in 3–12% of treated thyroglobulin proteolysis. Improvement in thyrotoxic symptoms
patients. Most reactions occur early, especially nausea and gas- occurs rapidly—within 2–7 days—hence the value of iodide
trointestinal distress. An altered sense of taste or smell may therapy in thyroid storm. In addition, iodides decrease the vascu-
occur with methimazole. The most common adverse effect is larity, size, and fragility of a hyperplastic gland, making the drugs
a maculopapular pruritic rash (4–6%), at times accompanied valuable as preoperative preparation for surgery.
by systemic signs such as fever. Rare adverse effects include an
urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy, Clinical Use of Iodide
hypoprothrombinemia, exfoliative dermatitis, polyserositis, and
acute arthralgia. An increased risk of severe hepatitis, sometimes Disadvantages of iodide therapy include an increase in intraglandu-
resulting in death, has been reported with propylthiouracil (black lar stores of iodine, which may delay onset of thioamide therapy or
box warning), so it should be avoided in children and adults prevent use of radioactive iodine therapy for several weeks. Thus,
unless no other options are available. Cholestatic jaundice is more iodides should be initiated after onset of thioamide therapy and
common with methimazole than propylthiouracil. Asymptomatic avoided if treatment with radioactive iodine seems likely. Iodide
elevations in transaminase levels can also occur. should not be used alone, because the gland will escape from the
The most dangerous complication is agranulocytosis (granulo- iodide block in 2–8 weeks, and its withdrawal may produce severe
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cyte count < 500 cells/mm ), an infrequent but potentially fatal exacerbation of thyrotoxicosis in an iodine-enriched gland. Chronic
adverse reaction. It occurs in 0.1–0.5% of patients taking thio- use of iodides in pregnancy should be avoided, since they cross
amides, but the risk may be increased in older patients and usually the placenta and can cause fetal goiter. In radiation emergencies
within the first 90 days in those receiving more than 40 mg/d involving release of radioactive iodine isotopes, the thyroid-blocking
of methimazole. The reaction is usually rapidly reversible when effects of potassium iodide can protect the gland from subsequent
the drug is discontinued, but broad-spectrum antibiotic therapy damage if administered before radiation exposure.
may be necessary for complicating infections. Colony-stimulating
factors (eg, G-CSF; see Chapter 33) may hasten recovery of the Toxicity
granulocytes. The cross-sensitivity between propylthiouracil and Adverse reactions to iodine (iodism) are uncommon and in most
methimazole is about 50%; therefore, switching drugs in patients cases reversible upon discontinuance. They include acneiform rash
with severe reactions is not recommended. (similar to that of bromism), swollen salivary glands, mucous mem-
brane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic
ANION INHIBITORS taste, bleeding disorders, and rarely, anaphylactoid reactions.

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Monovalent anions such as perchlorate (ClO ), pertechnetate RADIOACTIVE IODINE
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(TcO 4 ), and thiocyanate (SCN ) can block uptake of iodide by
the gland through competitive inhibition of the iodide transport 131 I is the only isotope used for treatment of thyrotoxicosis.
mechanism. Since these effects can be overcome by large doses of (Others are used in diagnosis.) Administered orally in solution as
iodides, their effectiveness is somewhat unpredictable. sodium 131 I, it is rapidly absorbed, concentrated by the thyroid,