The pharmacology, toxicology, and poison management issues dis cussed in this chapter are applicable to all of the β-adrenergic antagonists. They are commonly used in the treatment of patients with cardiovascular disease, including hypertension, coronary artery disease, and tachydysrhythmias. Additional indications for β-adrenergic antagonists include congestive heart failure, migraine headaches, benign essential tremor, panic attack, stage fright, and hyperthyroidism. Ophthalmic preparations containing β-adrenergic antagonists are used in the treatment of glaucoma.56 The diverse indications have led to complex toxicologic emergencies from intentional and unintentional overdoses as well as adverse drug reactions and drug—drug interactions. The management of patients with β-adrenergic antagonist overdoses is complicated by the lack of a routine strategy or a simple antidote. It is for these reasons that this class of xenobiotics remains intensely under study.
In 1948, Raymond Alquist postulated that epinephrine's cardiovascular actions of hypertension and tachycardia were best explained by the existence of two distinct sets of receptors that he generically named α and β receptors. At that time, the contemporary "antiepinephrines," such as phenoxybenzamine, reversed the hypertension but not the tachycardia associated with epinephrine. According to Alquist's theory, these drugs acted at the α-adrenergic receptors. The β-adrenergic receptors, in his schema, mediated catecholamine-induced tachycardia. The British pharmacist Sir James Black was influenced by Alquist's work and recognized the potential clinical benefit of a β-adrenergic antagonist. In 1958, Black synthesized the first β-adrenergic antagonist, pronethalol. This drug was briefly marketed as Alderlin, named after Alderly Park, the research headquarters of ICI Pharmaceuticals. Pronethalol was discontinued because it produced thymic tumors in mice. Propranolol was soon developed and marketed as Inderal (an incomplete anagram of Alderlin) in the United Kingdom in 196417,146 and in the United States in 1973.
Before the introduction of β-adrenergic antagonists, the management of angina was limited to medications such as nitrates that reduced preload through dilatation of the venous capacitance vessels and increased myocardial oxygen delivery by vasodilation of the coronary arteries. Propranolol gave clinicians the ability to decrease myocardial oxygen utilization. This new approach proved to decrease morbidity and mortality in patients with ischemic heart disease.74 New drugs soon followed, and by 1979 there were ten β-adrenergic antagonists available in the United States.37 Unfortunately it soon became apparent that these medications were dangerous when taken in overdose, and by 1979 cases of severe toxicity and death from β-adrenergic overdose were reported.37 Today 19 β-adrenergic antagonists are approved by the Food and Drug Administration (FDA), and other β-adrenergic antagonists are available worldwide (Table 61–1).
Table 61–1. Pharmacologic Properties of the β-Adrenergic Antagonists38,51,109,154,101,165 |Favorite Table|Download (.pdf)
Table 61–1. Pharmacologic Properties of the β-Adrenergic Antagonists38,51,109,154,101,165
|Adrenergic Antagonist Activity||Partial Agonist Activity (ISA)||Membrane Stabilizing Activity||Vasodilating Property||Lipid Solubility||Protein ...|