Hypothyroidism

CLINICAL PHARMACOLOGY OF THYROID & ANTITHYROID DRUGS

HYPOTHYROIDISM

Hypothyroidism is a syndrome resulting from deficiency of thyroid hormones and is manifested largely by a reversible slowing down of all body functions (Table 38–4). In infants and children, there is striking retardation of growth and development that results in dwarfism and irreversible mental retardation.

The etiology and pathogenesis of hypothyroidism are outlined in Table 38–5. Hypothyroidism can occur with or without thyroid enlargement (goiter). The laboratory diagnosis of hypothyroidism in the adult is easily made by the combination of a low free thyroxine and elevated serum TSH (Table 38–2).

The most common cause of hypothyroidism in the USA at this time is probably Hashimoto’s thyroiditis, an immunologic disorder in genetically predisposed individuals. In this condition, there is evidence of humoral immunity in the presence of antithyroid anti-bodies and lymphocyte sensitization to thyroid antigens. Certain medications can also cause hypothyroidism (Table 38–5).

MANAGEMENT OF HYPOTHYROIDISM

Except for hypothyroidism caused by drugs, which can be treated in some cases by simply removing the depressant agent, the gen-eral strategy of replacement therapy is appropriate. The most sat-isfactory preparation is levothyroxine, administered as either a branded or generic preparation. Treatment with combination levothyroxine plus liothyronine has not been found to be superior to levothyroxine alone. Infants and children require more T₄ per kilogram of body weight than adults. The average dosage for an infant 1–6 months of age is 10–15 mcg/kg/d, whereas the average dosage for an adult is about 1.7 mcg/kg/d. Older adults (> 65 years of age) may require less thyroxine for replacement. There is some variability in the absorption of thyroxine, so this dosage will vary from patient to patient. Since interactions with certain foods (eg, bran, soy, coffee) and drugs (Table 38–3) can impair its absorption, thyroxine should be administered on an empty stom-ach (eg, 30 minutes before meals or 1 hour after meals or at bedtime). Its long half-life of 7 days permits once-daily dosing. Children should be monitored for normal growth and develop-ment. Serum TSH and free thyroxine should be measured at regu-lar intervals and TSH maintained within an optimal range of 0.5–2.5 mU/L. It takes 6–8 weeks after starting a given dose of thyroxine to reach steady-state levels in the bloodstream. Thus, dosage changes should be made slowly.

In long-standing hypothyroidism, in older patients, and in patients with underlying cardiac disease, it is imperative to start treatment with reduced dosages. In such adult patients, levothy-roxine is given in a dosage of 12.5–25 mcg/d for 2 weeks, increas-ing the daily dose by 12.5–25 mcg every 2 weeks until euthyroidism or drug toxicity is observed. In older patients, the heart is very sensitive to the level of circulating thyroxine, and if angina pectoris or cardiac arrhythmia develops, it is essential to stop or reduce the dose of thyroxine immediately. In younger patients or those with very mild disease, full replacement therapy may be started immediately.

The toxicity of thyroxine is directly related to the hormone level. In children, restlessness, insomnia, and accelerated bone maturation and growth may be signs of thyroxine toxicity. In adults, increased nervousness, heat intolerance, episodes of palpitation and tachycar-dia, or unexplained weight loss may be the presenting symptoms. If these symptoms are present, it is important to monitor serum TSH (Table 38–2), which will determine whether the symptoms are due to excess thyroxine blood levels. Chronic overtreatment with T₄, particularly in elderly patients, can increase the risk of atrial fibrilla-tion and accelerated osteoporosis.

Special Problems in Management of Hypothyroidism

A. Myxedema and Coronary Artery Disease

Since myxedema frequently occurs in older persons, it is often asso-ciated with underlying coronary artery disease. In this situation, the low levels of circulating thyroid hormone actually protect the heart against increasing demands that could result in angina pec-toris or myocardial infarction. Correction of myxedema must be done cautiously to avoid provoking arrhythmia, angina, or acute myocardial infarction. If coronary artery surgery is indicated, it should be done first, prior to correction of the myxedema by thyroxine administration.

B. Myxedema Coma

Myxedema coma is an end state of untreated hypothyroidism. It is associated with progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, water intoxication, shock, and death.

Myxedema coma is a medical emergency. The patient should be treated in the intensive care unit, since tracheal intubation and mechanical ventilation may be required. Associated illnesses such as infection or heart failure must be treated by appropriate ther-apy. It is important to give all preparations intravenously, because patients with myxedema coma absorb drugs poorly from other routes. Intravenous fluids should be administered with caution to avoid excessive water intake. These patients have large pools of empty T₃ and T₄ binding sites that must be filled before there is adequate free thyroxine to affect tissue metabolism. Accordingly, the treatment of choice in myxedema coma is to give a loading dose of levothyroxine intravenously—usually 300–400 mcg ini-tially, followed by 50–100 mcg daily. Intravenous T₃ can also be used but may be more cardiotoxic and more difficult to monitor. Intravenous hydrocortisone is indicated if the patient has associ-ated adrenal or pituitary insufficiency but is probably not neces-sary in most patients with primary myxedema. Opioids and sedatives must be used with extreme caution.

C. Hypothyroidism and Pregnancy

Hypothyroid women frequently have anovulatory cycles and are therefore relatively infertile until restoration of the euthyroid state. This has led to the widespread use of thyroid hormone for infertil-ity, although there is no evidence for its usefulness in infertile euthyroid patients. In a pregnant hypothyroid patient receiving thyroxine, it is extremely important that the daily dose of thyrox-ine be adequate because early development of the fetal brain depends on maternal thyroxine. In many hypothyroid patients, an increase in the thyroxine dose (about 30–50%) is required to nor-malize the serum TSH level during pregnancy. It is reasonable to counsel women to take an extra 25 mcg thyroxine tablet as soon as they are pregnant and to separate thyroxine from prenatal vita-mins by at least 4 hours. Because of the elevated maternal TBG levels and, therefore, elevated total T₄ levels, adequate maternal thyroxine dosages warrant maintenance of TSH between 0.5 and 3.0 mU/L and the total T ₄ at or above the upper range of normal.

D. Subclinical Hypothyroidism

Subclinical hypothyroidism, defined as an elevated TSH level and normal thyroid hormone levels, is found in 4–10% of the general population but increases to 20% in women older than age 50

The consensus of expert thyroid organizations concluded that thyroid hormone therapy should be considered for patients with TSH levels greater than 10 mIU/L while close TSH monitoring is appropriate for those with lower TSH elevations.

E. Drug-Induced Hypothyroidism

Drug-induced hypothyroidism (Table 38–3) can be satisfactorily managed with levothyroxine therapy if the offending agent cannot be stopped. In the case of amiodarone-induced hypothyroidism, levothyroxine therapy may be necessary even after discontinuance because of amiodarone’s very long half-life.