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APPENDIX B. 9 PANEL ON DRUGS USED IN ENDOCRINE DISTURBANCES and PANEL ON DRUGS USED IN METABOLIC DISORDERS a. Statement on the Use of Multiple-Vitamin Preparations The Panel does not recognize the need for multi-vitamin supplementa- tion in healthy individuals who have an adequate diet. However, the Panel does recognize the need for multiple-vitamin and mineral prepara- tions in certain segments of the population. It also recognizes the lack of precise data on which rational formulation can be based. Therefore, it takes the following position toward all such preparations: 1. All should be appropriately labeled as either "supplemental" or "therapeutic." 2. The formulations of supplemental preparations should be based on dietary allowances recommended either by the Food and Nutrition Board of the National Academy of Sciences or by · an equivalent body. 3. Any preparations labeled "therapeutic" should be so for- mulated that the physician can prescribe adequate therapeutic amounts without the danger of toxicity. 4. The preparations should not contain disproportionate amounts of any nutrient that could be potentially hazardous in the rec- ommended dosage. The recommended dosage and labeling for any fat-soluble vitamin should include proper warning concerning possible toxicity. 5. The preparations should not contain non-essential materials. 6. The Panel favors the use of oral preparations when it is feasible to use such formulations. 213
b. Statement on the Use of Propylthiouracil Propylthiouracil (6-n-propyl-2-thiouracil) inhibits the synthesis of thyroid hormones by the thyroid gland, and thus it is effective in the treatment of hyperthyroidism, because it blocks excess production of these hormones. The drug does not inactivate thyroxine and triiodothyronine already made and stored in the colloid or circulating in the blood, nor does it alter thyroid hormones given by mouth or by injection. The prin- cipal application of propylthiouracil is in the therapy of hyperthyroid- ism, as follows: A. In long-term therapy leading to remission of the disease. B. In short-term therapy to ameliorate hyperthyroidism in preparation for subtotal thyroidectomy or radioactive iodine. Other, less frequent, uses of this compound include use: A. In lowering metabolism in euthyroid subjects who have severe angina pectoris. B. In increasing avidity of thyroid cells for radioactive iodine therapy. The drug is given orally. Owing to its poor solubility, no paren- teral use of propylthiouracil is feasible. Because the drug is rapidly metabolized, the total daily dose is usually administered in three equal doses at approximately 8 hour intervals. The initi~l dose is 100 mg (300 mg daily). In patients with severe hyperthyroidism, or with very large goiters, or both, the initial dosage should be 400 mg daily or more. Doses of up to 1.2 g daily have occasionally been given, but large doses increase the likelihood of toxic reactions and should be used with cau- tion. Refractoriness in response is uncommon. The length of time required to achieve euthyroidism depends largely on the severity of the initial hyperthyroidism, the size of the goiter, and the amount of drug given. Patients with mild hyperthyroidism may become euthyroid in 1 month; those with severe disease may require 3-4 months of therapy. Patients should be rendered euthyroid before being submitted to subtotal thyroidectomy. The drug is continued to the day of operation. A saturated solution of potassium iodide, 10 drops three times daily, is also given for 10-14 days preoperatively. In long-term medical treatment, dosage can be reduced to maintenance levels of about 100-150 mg daily when euthyroidism is achieved. During such therapy, concomitant administration of thyroid hormone (64-128 mg of desiccated thyroid, U.S.P., or 0.1-0.2 mg of L-thyroxine) is considered beneficial. 214
Such combined treatment may be administered for 1-5 years, and occasionally longer. Reduction in goiter size during long-term treat- ment is the most reliable index that a long-lasting remission may occur after cessation of antithyroid therapy. If the dose of the drug is ex- cessive, further enlargement of the thyroid may occur, and - indeed - hypothyroidism may ensue. Treatment with iodine before administration of propylthiouracil delays the action of the latter drug. When propyl- thiouracil is given to hyperthyroid patients pretreated with iodine, a period of 30-60 days should elapse before it is concluded that propyl- thiouracil is ineffective or before the dosage is increased. When radio- active iodine is contemplated, there should be a lapse of 3 or 4 days between termination of propylthiouracil therapy and administration of radioactive iodine. Adverse reactions are infrequent, probably less than 3%. The minor reactions include urticaria, maculopapular rash, falling out of hair, and loss of taste. Ma1or reactions are much less common and include inhibition of myelopoiesis (agranulocytosis, granulopenia, and thrombo- cytopenia), drug fever, a lupus-like syndrome, and hepatitis. Patients should be advised to report sore throat, rash, fever, or other unusual symptoms promptly. Withdrawal of medication is usually sufficient to correct an adverse response. Antibiotics and adrenal steroids have been reported to be helpful in agranulocytosis. In severe cases, "reverse isolation" and measures directed to prevention of sepsis are important. Physicians should note that about 10% of patients with untreated hyper- thyroidism have leukopenia, i.e., counts of white blood cells of less than 4000 mm3, often with relative granulopenia. Propylthiouracil, used judiciously, is an effective drug in hyper· thyroidism complicated by pregnancy. Because propylthiouracil readily crosses placental membranes and can induce goiter in the developing fetus, it is important that a sufficient, but not excessive, dose be given to control the maternal hyperthyroidism. Moreover, in many preg- nant women with coexisting hyperthyroidism, the thyroid dysfunction diminishes as the pregnancy proceeds and this phenomenon often makes reduction of the dose possible during the latter half of pregnancy. Following initial control of hyperthyroidism, the dose of propylthiouracil required for maintenance is often as little as 100 mg daily. In some instances, propylthiouracil can be withdrawn 2 or 3 weeks before delivery. The concomitant administration of thyroid (64-128 mg of desiccated thyroid or 0.1-0.2 mg of L-thyroxine daily) during propylthiouracil therapy of the pregnant hyperthyroid woman is also recommended. This hormone prevents hypothyroidism in the mother and her fetus, a condition that might result from inadvertent overdosage of the antithyroid drug. Administration should be continued through and beyond delivery. Lugol's solution or saturated solution of potassium iodide is contraindicated inasmuch as iodine may produce goiter in the developing fetus. The physician should keep in mind the physiologic changes of healthy preg- nancy and not confuse them with hyperthyroidism. Diffused enlargement of the thyroid, increased body warmth, and increased pulse rate may 215
occur. Also during normal pregnancy, the BMR increases; and the level of thyroxine in serum, as measured by PBI or thyroxine by column, rieee above normal levels. Neither change indicates hyperthyroidism; the in- creased BMR is due to the metabolism of the fetus, and the high thyroxine level is due to increased binding of thyroxine to the proteins of serum. Thus, when true hyperthyroidism complicates pregnancy, the physician should keep these changes in mind to avoid overdosage with antithyroid drug. Following delivery, many hyperthyroid mothers experience a con- tinued remission of symptoms that lasts several months. Periodic ob- servation is necessary along with prompt reinstitution of antithyroid therapy if hyperthyroidism recurs. Propylthiouracil appears in the milk if administered during lactation. Accordingly, the drug is usually not recommended for use in mothers who breast-feed their babies. The amount of the drug that appears in the milk is small, however, and the contraindication is not mandatory. 216
c. Statement on the Use of Single Vitamin Preparations The Panel does not recognize the need for vitamin supplementation in healthy individuals who have an adequate diet. However, the Panel does recognize the need for supplementation with single vitamin prepara- tions in certain segments of the population. The Panel also recognizes the need for single vitamin preparations in the therapy of vitamin defi- ciency states. Therefore, the Panel takes the following pbsitions with respect to all single vitamin preparations: 1. All preparations in this category should be appropriately la- beled as either "supplemental" or "therapeutic". 2. The recommended dosage as stated on the label of each supple- mental vitamin should stipulate an amount of the vitamin that is at least equivalent to the dietary allowances recommended by the Food and Nutrition Board of the National Academy of Sciences or by an equivalent body. 3. A:ny preparation that is labeled "therapeutic" should be so for- mulated that the physician, acting on the basis of this labeling, can prescribe adequate therapeutic amounts of the vitamin without the danger of toxicity. 4. The labeling for any fat-soluble vitamin should incorporate proper warnings concerning possible toxicity at the recommended dosages. 5. The Panel favors the use of oral preparations when feasible. 217
