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162 SECTION II Autonomic Drugs

Erectile Dysfunction Pharmacokinetic Properties of the
Sildenafil and other cGMP phosphodiesterase inhibitors are drugs Beta-Receptor Antagonists
of choice for erectile dysfunction (see Chapter 12). Other effective A. Absorption
but now largely abandoned approaches have included a combina- Most of the drugs in this class are well absorbed after oral administra-
tion of phentolamine with the nonspecific smooth muscle relax- tion; peak concentrations occur 1–3 hours after ingestion. Sustained-
ant papaverine; when injected directly into the penis, these drugs release preparations of propranolol and metoprolol are available.
may cause erections in men with sexual dysfunction. Long-term
administration may result in fibrotic reactions. Systemic absorp- B. Bioavailability
tion may also lead to orthostatic hypotension; priapism may Propranolol undergoes extensive hepatic (first-pass) metabolism;
require direct treatment with an α-adrenoceptor agonist such its bioavailability is relatively low (Table 10–2). The proportion
as phenylephrine. Alternative therapies for erectile dysfunction of drug reaching the systemic circulation increases as the dose is
include prostaglandins (see Chapter 18) and apomorphine.
increased, suggesting that hepatic extraction mechanisms may
Applications of Alpha Antagonists become saturated. A major consequence of the low bioavailability
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of propranolol is that oral administration of the drug leads to
Alpha antagonists have relatively little clinical usefulness. They much lower drug concentrations than are achieved after intra-
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have definite but limited benefit in male erectile dysfunction. venous injection of the same dose. Because the first-pass effect
There has been experimental interest in the development of highly varies among individuals, there is great individual variability in
selective antagonists for treatment of type 2 diabetes (α receptors the plasma concentrations achieved after oral propranolol. For
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inhibit insulin secretion) and for treatment of psychiatric depres- the same reason, bioavailability is limited to varying degrees for
sion. It is likely that better understanding of the subtypes of α most β antagonists with the exception of betaxolol, penbutolol,
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receptors will lead to development of clinically useful subtype- pindolol, and sotalol.
selective α antagonists.
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C. Distribution and Clearance
■ BASIC PHARMACOLOGY The β antagonists are rapidly distributed and have large volumes of
OF THE BETA-RECEPTOR distribution. Propranolol and penbutolol are quite lipophilic and
readily cross the blood-brain barrier (Table 10–2). Most β antago-
ANTAGONIST DRUGS nists have half-lives in the range of 3–10 hours. A major excep-
tion is esmolol, which is rapidly hydrolyzed and has a half-life of
Beta-receptor antagonists share the common feature of antago- approximately 10 minutes. Propranolol and metoprolol are exten-
nizing the effects of catecholamines at β adrenoceptors. Beta- sively metabolized in the liver, with little unchanged drug appear-
blocking drugs occupy β receptors and competitively reduce ing in the urine. The CYP2D6 genotype is a major determinant
receptor occupancy by catecholamines and other β agonists. Most of interindividual differences in metoprolol plasma clearance (see
β-blocking drugs in clinical use are pure antagonists; that is, the Chapters 4 and 5). Poor metabolizers exhibit threefold to tenfold
occupancy of a β receptor by such a drug causes no activation of higher plasma concentrations after administration of metoprolol
the receptor. However, some are partial agonists; that is, they cause than extensive metabolizers. Atenolol, celiprolol, and pindolol are
partial activation of the receptor, albeit less than that caused by less completely metabolized. Nadolol is excreted unchanged in the
the full agonists epinephrine and isoproterenol. As described in urine and has the longest half-life of any available β antagonist (up
Chapter 2, partial agonists inhibit the activation of β receptors to 24 hours). The half-life of nadolol is prolonged in renal failure.
in the presence of high catecholamine concentrations but moder- The elimination of drugs such as propranolol may be prolonged
ately activate the receptors in the absence of endogenous agonists. in the presence of liver disease, diminished hepatic blood flow, or
Finally, evidence suggests that some β blockers (eg, betaxolol, hepatic enzyme inhibition. It is notable that the pharmacodynamic
metoprolol) are inverse agonists—drugs that reduce constitutive effects of these drugs are sometimes prolonged well beyond the
activity of β receptors—in some tissues. The clinical significance time predicted from half-life data.
of this property is not known.
The β-receptor–blocking drugs differ in their relative affini- Pharmacodynamics of the Beta-Receptor
ties for β and β receptors (Table 10–1). Some have a higher Antagonist Drugs
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affinity for β than for β receptors, and this selectivity may have
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important clinical implications. Since none of the clinically avail- Most of the effects of these drugs are due to occupation and blockade
able β-receptor antagonists are absolutely specific for β receptors, of β receptors. However, some actions may be due to other effects,
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the selectivity is dose-related; it tends to diminish at higher drug including partial agonist activity at β receptors and local anesthetic
concentrations. Other major differences among β antagonists action, which differ among the β blockers (Table 10–2).
relate to their pharmacokinetic characteristics and local anesthetic
membrane-stabilizing effects. A. Effects on the Cardiovascular System
Chemically, most β-receptor antagonist drugs (Figure 10–5) Beta-blocking drugs given chronically lower blood pressure in
resemble isoproterenol to some degree (see Figure 9–4). patients with hypertension (see Chapter 11). The mechanisms