Propranolol withdrawal syndrome - why?

FEW WHO HAVE WITNESSED the propranolol withdrawal phenomenon would deny its existence. The syndrome, which comprises the development of ventricular arrhythmias, severe angina, myocardial infarction and even death soon after sudden cessation of propranolol therapy, was first described in a series of case reports.' Perhaps the most convincing evidence was obtained by Miller et al.,6 who noted a 50% incidence of the withdrawal syndrome after cross-over to placebo during a double-blind trial of propranolol in the treatment of angina pectoris. While this dramatic result was convincing evidence of the syndrome, it clearly over-estimated its true incidence, which is probably about 5%. It is also generally agreed that the problems of propranolol withdrawal occur more often in patients who maintain normal activity than those in the hospital. For example, Shiroff et al.7 could find evidence of the phenomenon in only one of 55 patients hospitalized before cardiac catheterization. The time at which adverse events occur seems to vary widely, from one to 14,6' 6 or even 21 days.3 This would seem to represent a balance between the time taken for the drug to dissipate and the onset of the precipitating event. Although propranolol has a relatively short half-life (about 3-6 hours in patients with normal liver function), its duration of action depends just as much on the initial plasma concentrations,8 with higher levels associated with more prolonged action. With the usual doses of about 160-320 mg daily,. negligible drug levels are seen between 16-48 hours after sudden withdrawal.9"10 Thereafter, the time at which the withdrawal syndrome occurs depends on the mechanism responsible and on the nature of the precipitating event. While reactivation of the beta-adrenergic nervous system is clearly involved, it is not clear why this causes tachycardia and tremulousness, or why it precipitates arrhythmias and coronary events. One of the earliest suggestions was that the disease process had progressed, or that the patients continued to attempt the more strenuous activity that propranolol treatment had allowed. Disease progression seems less likely to account for the syndrome observed in patients after only six weeks of treatment given in the controlled trials,5 6 but increased activity could well account for the great incidence or severity in ambulant compared with hospitalized patients. The area of greatest interest has been whether there is a true rebound "hyperadrenergic" state, and, if so, of