In 1948, Raymond Alquist postulated that the cardiovascular actions of epinephrine, 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” xenobiotics 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. 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 1964.22,199 and in the United States in 1973. Prior to the introduction of β-adrenergic antagonists, the management of angina was limited to medications 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 proved to decrease morbidity and mortality in patients with ischemic heart disease.112 New drugs soon followed and by 1979 there were ten β-adrenergic antagonists available in the United States.54 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.54 Today there are nineteen β-adrenergic antagonists approved by the US Food and Drug Administration, and other β-adrenergic antagonists are available worldwide (Table 62–1). The pharmacology, toxicology, and poison management issues discussed in this chapter are applicable to all of these drugs. They are commonly used in the treatment of cardiovascular disease: 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.80
TABLE 62–1.Pharmacologic Properties of the β-Adrenergic Antagonists |Favorite Table|Download (.pdf) TABLE 62–1. Pharmacologic Properties of the β-Adrenergic Antagonists
| ||Adrenergic Blocking Activity ||Partial Agonist Activity (ISA) ||Membrane Stabilizing Activity ||Vasodilating Property ||Log Da ||Protein Binding (%) ||Oral Bioavailability (%) ||Half-Life (hours) ||Metabolism ||Volume of Distribution (L/kg) |
|Acebutolol ||β1 ||Yes ||Yes ||No ||0.52 ||25 ||40 ||2–4 ||Hepatic/renal ||1.2 |
|Atenolol ||β1 ||No ||No ||No ||–2.03 ||< 5 ||40–50 ||5–9 ||Renal ||1 |
|Betaxolol (tablets and ocular drops) ||β1 ||No ||Yes ||Yes (calcium channel blockade) ||0.56 ||50 ||80–90 ||14–22 ||Hepatic/renal ||4.9–8.8 |
|Bisoprolol ||β1 ||No ||No ||No ||0.11 ||30 ||80 ||9–12 ||Hepatic/renal ||3.2 |
|Bucindolol ||α, β1, β2 ||β2 agonism || ||Yes (β...|
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