Clinical Toxicity Of The Beta-Receptor Antagonist Drugs

CLINICAL TOXICITY OF THE BETA-RECEPTOR ANTAGONIST DRUGS

Many adverse effects have been reported for propranolol but most are minor. Bradycardia is the most common adverse cardiac effect of β-blocking drugs. Sometimes patients note coolness of hands and feet in winter. Central nervous system effects include mild sedation, vivid dreams, and rarely, depression. Discontinuing the use of β blockers in any patient who develops psychiatric depression should be seriously considered if clinically feasible. It has been claimed that β-receptor antagonist drugs with low lipid solubility are associated with a lower incidence of central nervous system adverse effects than compounds with higher lipid solubil-ity (Table 10–2). Further studies designed to compare the central nervous system adverse effects of various drugs are required before specific recommendations can be made, though it seems reason-able to try the hydrophilic drugs nadolol or atenolol in a patient who experiences unpleasant central nervous system effects with other β blockers.

The major adverse effects of β-receptor antagonist drugs relate to the predictable consequences of β blockade. Beta₂-receptor blockade associated with the use of nonselective agents commonly causes worsening of preexisting asthma and other forms of airway obstruction without having these consequences in normal indi-viduals. Indeed, relatively trivial asthma may become severe afterblockade. However, because of their lifesaving potential in car-diovascular disease, strong consideration should be given to indi-vidualized therapeutic trials in some classes of patients, eg, thosewith chronic obstructive pulmonary disease who have appropriate indications for β blockers. While β₁-selective drugs may have less effect on airways than nonselective β antagonists, they must be used very cautiously in patients with reactive airway disease. Beta₁-selective antagonists are generally well tolerated in patients with mild to moderate peripheral vascular disease, but caution is required in patients with severe peripheral vascular disease or vasospastic disorders.

Beta-receptor blockade depresses myocardial contractility and excitability. In patients with abnormal myocardial function, cardiac output may be dependent on sympathetic drive. If this stimulus is removed by β blockade, cardiac decompensation may ensue. Thus, caution must be exercised in starting a β-receptor antagonist in patients with compensated heart failure even though long-term use of these drugs in these patients may prolong life. A life-threatening adverse cardiac effect of a β antagonist may be overcome directly with isoproterenol or with glucagon (glucagon stimulates the heart via glucagon receptors, which are not blocked by β antagonists), but neither of these methods is without hazard. A very small dose of a β antagonist (eg, 10 mg of propranolol) may provoke severe cardiac failure in a susceptible individual. Beta blockers may interact with the calcium antagonist verapamil; severe hypotension, bradycardia, heart failure, and cardiac con-duction abnormalities have all been described. These adverse effects may even arise in susceptible patients taking a topical (oph-thalmic) β blocker and oral verapamil.

Patients with ischemic heart disease or renovascular hyperten-sion may be at increased risk if β blockade is suddenly interrupted. The mechanism of this effect might involve up-regulation of the number of β receptors. Until better evidence is available regarding the magnitude of the risk, prudence dictates the gradual tapering rather than abrupt cessation of dosage when these drugs are dis-continued, especially drugs with short half-lives, such as propra-nolol and metoprolol.

The incidence of hypoglycemic episodes exacerbated by β-blocking agents in diabetics is unknown. Nevertheless, it isinadvisable to use β antagonists in insulin-dependent diabetic patients who are subject to frequent hypoglycemic reactions if alternative therapies are available. Beta₁-selective antagonists offer some advantage in these patients, since the rate of recovery from hypoglycemia may be faster compared with that in diabetics receiving nonselective β-adrenoceptor antagonists. There is con-siderable potential benefit from these drugs in diabetics after a myocardial infarction, so the balance of risk versus benefit must be evaluated in individual patients.