Use of β-Adrenoceptor Blocking Drugs in Hyperthyroidism

Summary

There is an increasing use and variety of β-adrenoceptor blocking agents (β-blockers) available for the treatment of hyperthyroidism. Recent comparative studies suggest that atenolol (200mg daily), metoprolol (200mg daily), acebutolol (400mg daily), oxprenolol (160mg daily), nadolol (80mg daily) and timolol (20mg daily) produce a beneficial clinical response equal to that seen with propranolol (160mg daily). Most β-blockers reduce resting heart rate by approximately 25 to 30 beats/min, although a lesser reduction is seen with those possessing intrinsic sympathomimetic activity such as oxprenolol and pindolol While earlier studies employing large doses of intravenous propranolol concluded that β-blockade reduced myocardial contractility, more recent non-invasive studies suggest that the predominant cardiac effect is on heart rate. In patients with cardiac failure, β-blockers may, however, produce a profound fall in cardiac output. Nevertheless, in combination with digoxin they may be useful in controlling the atrial fibrillation of thyrocardiac disease.

β-Blockers improve nervousness and tremor (although to a lesser extent with cardioselective agents) and severe myopathy, and they also reduce the frequency of paralysis in patients with thyrotoxic periodic paralysis. There is often subjective improvement in sweating but usually no major effect on eye signs. Recent studies show a 10% reduction in oxygen consumption/basal metabolic rate with long term oral use of selective or nonselective β-blockers. In addition, many agents (propranolol, metoprolol, nadolol and sotalol but not acebutolol, atenolol or oxprenolol) reduce circulating tri-iodothyronine (T₃) concentration by between 10 and 40%, although the clinical significance of this effect (if any) is not established. β-Blockers may also have endocrinological effects on gastrin, cyclic AMP, catecholamines and other hormone levels. Given in adequate dosage, propranolol has been shown to control thyrotoxic hypercalcaemia. Minor side effects (nausea, headaches, tiredness, etc.) are quite common but overall β-blockers are well tolerated by the thyrotoxic patient.

The major use of these drugs is in symptomatic control while awaiting definitive diagnosis or treatment. As an adjunct to antithyroid drugs or radioactive iodine, β-blockers will produce a satisfactory clinical response in the weeks to months before these forms of therapy produce a euthyroid state. β-Blockers are more convenient than antithyroid drugs in the control of patients receiving therapeutic radioiodine, in that continuous therapy and assessment of biochemical response is possible. The long term use of β-blockers alone in the management of hyperthyroidism cannot be recommended except in mild and transient forms of the disorder such as postpartum thyrotoxicosis.

There is increasing use of β-blockers to prepare patients for partial thyroidectomy. Given in adequate dosage and continued postoperatively, the clinical course is similar to conventional therapy but with a major reduction in the time to prepare patients, a greater flexibility in timing of surgery, and a decreased gland vascularity. However, this regimen, even with the addition of iodide, is not suitable for the more severely toxic patient. Of almost 1000 patients studied, approximately 3% showed exaggeration of toxic symptoms postoperatively. Cases of thyroid storm (crisis) have been associated with low dosage (160 mg/day propranolol or less), omission of critical postoperative doses, and a failure to objectively assess individual patient dosage requirements. A long acting β-blocker, nadolol, appears more convenient to use than propranolol in the perioperative setting, β-Blockers are now standard therapy in the management of thyroid storm but their use in pregnancy is somewhat controversial, as occasional cases of neonatal bradycardia have been reported. They may, however, be used for short term control as adjunctive therapy to antithyroid drugs or to prepare the patient for mid-trimester thyroidectomy. Added to conventional therapy, β-blockers have proved useful in some cases of neonatal thyrotoxicosis.

The clearance of β-blockers that undergo extensive hepatic metabolism such as propranolol and metoprolol is increased in hyperthyroidism, while that of renally excreted agents such as atenolol and sotalol is unchanged. There is a wide interindividual variation in plasma concentrations in patients receiving the same dosage, particularly with propranolol where age and smoking habits are important determinants. Concentration-effect relationships for propranolol, metoprolol and nadolol are becoming apparent. Plasma propranolol concentrations are correlated with the degree of objective response (heart rate reduction, β-blockade, weight change and reduction in serum T₃ concentrations) but not with the subjective response.

Long-acting propranolol or nadolol given once daily appear to give adequate control. Where a cardioselective agent is indicated there is little to choose between atenolol and metoprolol. Otherwise, our long term experience with propranolol suggests that it is suitable for most situations. However, irrespective of which β-blocker is chosen, individualisation of dosage is necessary to produce a high degree of β-blockade.