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 “antiepinephrine” agents such as phenoxybenzamine reversed the hypertension but not the tachycardia associated with epinephrine. According to Alquist’s theory, these xenobiotics acted at the α receptors. The β receptors, in his schema, mediated catecholamine-induced tachycardia. 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. Pronethalol 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 196431,235 and in the United States in 1973. Before the introduction of β-adrenergic antagonists, the management of angina was limited to xenobiotics such as nitrates, which reduced preload through dilation 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 decreased morbidity and mortality in patients with ischemic heart disease.134 New medications soon followed, and by 1979, there were 10 β-adrenergic antagonists available in the United States.74 Unfortunately, it soon became apparent that these xenobiotics were dangerous when taken in overdose, and by 1979, severe toxicity and death from β-adrenergic overdose were reported.74 There are currently 20 US Food and Drug Administration–approved β-adrenergic antagonists with additional β-adrenergic antagonists available worldwide (Table 59–1). They are commonly used in the treatment of cardiovascular disease: hypertension, coronary artery disease, and tachydysrhythmias. Other indications for β-adrenergic antagonists include congestive heart failure, migraine headaches, benign essential tremor, panic attack, stage fright, and hyperthyroidism. Ophthalmic β-adrenergic antagonists are used in the treatment of glaucoma.101 The pharmacology, toxicology, and poison management issues discussed in this chapter are applicable to all of these indications.
TABLE 59–1Pharmacologic Properties of the β-Adrenergic Antagonists ||Download (.pdf) TABLE 59–1 Pharmacologic Properties of the β-Adrenergic Antagonists
| ||Adrenergic Blocking Activity ||Partial Agonist Activity (ISA) ||Membrane-Stabilizing Activity ||Vasodilating Property ||Log Db ||Protein Binding (%) ||Oral Bioavailability (%) ||Half-Life (h) ||Metabolism ||Volume of Distribution (L/kg) |
|Acebutolol ||β1 ||Yes ||Yes ||No ||0.52 ||25 ||40 ||2–4 ||Hepatic or renal ||1.2 |
|Atenolol ||β1 ||No ||No ||No ||-2.03 ||<5 ||40–50 ||5–9 ||Renal ||1 |
|Betaxolol (tablets and ophthalmic) ||β1 ||No ||Yes ||Yes (calcium channel blockade) ||0.56 ||50 ||80–90 ||14–22 ||Hepatic or renal ||4.9–8.8 |
|Bisoprolol ||β1 ||No ||No ||No ||0.11 ||30 ||80 ||9–12 ||Hepatic or renal ||3.2 |
|Bucindolola ||β1, β2 ||β2 ||NA ||Yes (β2 agonism and α...|