Plummer originally observed that the administration of iodide to thyrotoxic patients resulted in an amelioration of their symptoms. This reaction is associated with a decreased rate of release of thyroid hormone from the gland and with a gradual increase in the quantity of stored hormone. The effect of iodide on thyroid hormone release and concentration in blood is apparent in Figure 11-6. The mechanism of action may be by inhibition of generation of cAMP, and involves inhibition of proteolysis, but is not fully understood. Therapeutic quantities of iodide also have an effect on hormone synthesis through inhibition of organification of iodide. Iodide has similar but less intense effects on the normal thyroid gland, apparently because of the adaptive mechanisms described in Chapter 5.

Figure 11-6. KI in doses over 6 mg/day dramatically inhibits release of hormone from the Graves' thyroid, as shown after treatment in this study starting during day 4. Serum hormone levels (PBI) consequently fall.

Administration of large amounts of iodide to laboratory animals or humans blocks the synthesis of thyroid hormone and results in an accumulation of trapped inorganic iodide in the thyroid gland (the Wolff-Chaikoff effect, see Ch 2). The thyrotoxic gland is especially sensitive to this action of iodide. Raising the plasma iodide concentration to a level above 5 µg/dl results in a complete temporary inhibition of iodide organification by the thyrotoxic gland. In normal persons elevation of the inorganic ¹²⁷I level results, up to a point, in a progressive increase of accumulation of iodide in the gland. When the plasma concentration is above 20 µg/dl, organification is also inhibited in the normal gland.¹⁶⁰ The sensitivity of the thyrotoxic gland, in comparison with that of the euthyroid gland, may be due to an increased ability to concentrate iodide in the thyroid, and its failure to "adapt" by decreasing the iodide concentrating mechanism.

When iodine is to be used therapeutically in Graves' disease, one usually prescribes a saturated solution of potassium iodide (which contains about 50 mg iodide per drop) or Lugol's solution (which contains about 8.3 mg iodide per drop). Thompson and co- workers¹⁶¹ found that 6 mg of I- or KI produces a maximum response. This fact was reemphasized by Friend, who pointed out that the habit of prescribing the 5 drops of Lugol's or SSKI three times daily is unnecessary.¹⁶² Two drops of Lugol's solution or 1 drop of a saturated solution of potassium iodide two times daily is more than sufficient.

The therapeutic response to iodide begins within two to seven days and is faster than can be obtained by any other methods of medical treatment. Only 3% of patients so treated fail to respond.  Men, older persons, and those with nodular goiter are in the group less likely to have a response to iodide.  Although almost all patients initially respond to iodide, about one-third respond partially and remain toxic, and another one-third initially respond but relapse after about six weeks.¹⁶⁵ The use of iodide as definitive therapy for thyrotoxicosis has been discarded in favor of the modalities previously described.

Iodides are sometimes given after ¹³¹I therapy to control hyper-thyroidism, and are usually given as part of treatment before thyroidectomy.

Propranolol, metopranol, atenolol

Beta-adrenergic blocking agents have won a prominent position in the treatment of thyrotoxicosis. Although they alleviate many of the signs and symptoms, they have little effect on the fundamental disease process.^166,167 Palpitations, excessive sweating, and nervousness improve, and tremor and tachycardia are controlled. Many patients feel much improved, but others are depressed by the drug and prefer not to take it. Improvement in myocardial efficiency and reduction in the exaggerated myocardial oxygen consumption have been demonstrated.¹⁶⁸ Propranolol lowers oxygen consumption¹⁶⁹ and reverses the nitrogen wasting of thyrotoxicosis, although it does not inhibit excess urinary calcium and hydroxyproline loss.¹²⁴ Propranolol is useful in symptomatic treatment while physician and patient are awaiting the improvement from antithyroid drug or ¹³¹I therapy. ¹⁷¹ Some patients appear to enter remission after using this drug alone for six months or so of therapy.^169,172 It has been useful in neonatal thyrotoxicosis¹⁷³ and in thyroid storm.¹⁷⁴  
    The drug must be used cautiously when there is evidence of severe thyrotoxicosis, or heart failure, but often control of tachycardia permits improved circulation. Beta blockade  can induce cardiovascular collapse in patients with or without heart failure, and asystolic arrest (174a,b). Administration of beta blocker  was shown by Ikram to reduce CO by 13% in patients with uncontrolled CHF, and apparently this reduction in CO can be near fatal in rare patients.
    Some surgical groups routinely prepare patients for thyroidectomy with propranolol for 20 - 40 days and add potassium iodide during the last week.¹⁷⁵ The BMR and thyroid hormone level remain elevated at the time of operation, but the patient experiences no problems. We prefer conventional preoperative preparation with thio-carbamides, with or without iodide, and would use propranolol as an adjunct, or if the patient is allergic to the usual drugs.

Propranolol is usually given orally as 20 - 40 mg every four to six hours, but up to 200 mg every six hours may be needed. In emergency management of thyroid storm (see also Chapter 12) or tachycardia, it may be given intravenously (1 - 3 mg, rarely up to 6 mg) over 3 - 10 minutes and repeated every four to six hours under electrocardiographic control. Atropine (0.5 - 1.0 mg) is the appropriate antidote if severe brachycardia is produced.

Reserpine and Guanethidine

Drugs such as reserpine¹⁷⁷ and guanethidine¹⁷⁸ that deplete tissue catecholamines were used extensively in the past as adjuncts in the therapy for thyrotoxicosis, but fell into disuse as the value of beta -sympathetic blockade with propranolol became recognized.

Glucocorticoids, Ipodate, and Other Treatments

As described elsewhere, potassium iodide acts promptly to inhibit thyroid hormone secretion from the Graves' disease thyroid gland. PTU, propranolol, glucocorticoids,¹⁸¹ amiodarone, and sodium ipodate (Oragrafin Sodium) inhibit peripheral T₄ to T₃ conversion, and glucocorticoids may have a more prolonged suppressive effect on thyrotoxicosis.¹⁸² Orally administered resins bind T₄ in the intestine and prevent recirculation.¹⁸³ All of these agents have been used for control of thyrotoxicosis.^184,185 Combined dexamethasone, potassium iodide, and PTU can lower the serum T₃ level to normal in 24 hours, which is useful in severe thyrotoxicosis. Prednisone has been reported to induce remission of Graves' disease, but at the expense of causing Cushing's syndrome.¹⁸⁷ Ipodate (0.5 - 1 g orally per day) acts to inhibit hormone release because of its iodine content, in addition to its action to inhibit T₄ to T₃ conversion. This dose of ipodate given to patients with Graves' disease reduced the serum T₃ level by 58% and the T₄ level by 20% within 24 hours, and the effect persisted for three weeks.^188,189 This dose of ipodate was more effective than 600 mg of PTU, which decreased the T₃ level by only 23% during the first 24 hours, whereas the T₄ level did not drop. Ipodate may prove to be a useful adjunct in the early therapy of hyperthyroidism, but will increase total body and thyroidal iodine. However, when the drug is stopped, the RAIU in Graves' patients usually returns to pre- treatment levels within a week.¹⁸⁹ Because it is the most effective agent available in preventing conversion of T₄ to T₃, it has a useful role in managing thyroid storm (Chapter 12).

Lithium Chloride-The use of lithium as an adjunct to therapy with radioiodine in treatment of hyperthyroidism was compared in a randomized prospective study.  The lithium group received lithium carbonate 300 mg three times a day, for three weeks starting on the day of radioiodine administration.   Patients had been made euthyroid with antithyroid drugs prior to RAI treatment.  There was no effect on the percentage of patients cured.  Ten percent of patients complained of side effects of the lithium(189.1).