Sildenafil and other cGMP phosphodiesterase inhibitors are drugs of choice for erectile dysfunction (see Chapter 12). Other effective but now largely abandoned approaches have included a combination of phentolamine with the nonspecific smooth muscle relaxant papaverine; when injected directly into the penis, these drugs may cause erections in men with sexual dysfunction. Long-term administration may result in fibrotic reactions. Systemic absorption may also lead to orthostatic hypotension; priapism may require direct treatment with an α-adrenoceptor agonist such as phenylephrine. Alternative therapies for erectile dysfunction include prostaglandins (see Chapter 18) and apomorphine.
Applications of Alpha2 Antagonists
Alpha2 antagonists have relatively little clinical usefulness. They have definite but limited benefit in male erectile dysfunction. There has been experimental interest in the development of highly selective antagonists for treatment of type 2 diabetes (α2 receptors inhibit insulin secretion) and for treatment of psychiatric depression. It is likely that better understanding of the subtypes of α2 receptors will lead to development of clinically useful subtype-selective α2 antagonists.
Beta-receptor antagonists share the common feature of antagonizing the effects of catecholamines at β adrenoceptors. Beta-blocking drugs occupy β receptors and competitively reduce receptor occupancy by catecholamines and other β agonists. Most β-blocking drugs in clinical use are pure antagonists; that is, the occupancy of a β receptor by such a drug causes no activation of the receptor. However, some are partial agonists; that is, they cause partial activation of the receptor, albeit less than that caused by the full agonists epinephrine and isoproterenol. As described in Chapter 2, partial agonists inhibit the activation of β receptors in the presence of high catecholamine concentrations but moderately activate the receptors in the absence of endogenous agonists. Finally, evidence suggests that some β blockers (eg, betaxolol, metoprolol) are inverse agonists—drugs that reduce constitutive activity of β receptors—in some tissues. The clinical significance of this property is not known.
The β-receptor–blocking drugs differ in their relative affinities for β1 and β2 receptors (Table 10–1). Some have a higher affinity for β1 than for β2 receptors, and this selectivity may have important clinical implications. Since none of the clinically available β-receptor antagonists are absolutely specific for β1 receptors, the selectivity is dose-related; it tends to diminish at higher drug concentrations. Other major differences among β antagonists relate to their pharmacokinetic characteristics and local anesthetic membrane-stabilizing effects.
Chemically, most β-receptor antagonist drugs (Figure 10–5) resemble isoproterenol to some degree (see Figure 9–4).
Pharmacokinetic Properties of the Beta-Receptor Antagonists
A. Absorption
Most of the drugs in this class are well absorbed after oral administration; peak concentrations occur 1–3 hours after ingestion. Sustained-release preparations of propranolol and metoprolol are available.
B. Bioavailability