Abstract
Clinical evidence in men with erectile dysfunction (ED) shows that the phosphodiesterase type 5 (PDE5) inhibitors sildenafil citrate, tadalafil, and vardenafil hydrochloride have favorable safety and efficacy profiles. However, as mild vasodilators, the PDE5 inhibitors are also associated with hemodynamic effects that may be clinically significant, especially when treating men with ED who have comorbid cardiovascular disease. Hemodynamic studies have shown that therapeutic dosages of the PDE5 inhibitors produce only mild and transient changes in mean systolic and diastolic blood pressure and heart rate in healthy men as well as those with ischemic heart disease or chronic stable angina. Overall, PDE5 inhibitors are safe and effective in most patient populations, including men with ischemic cardiovascular disease or those receiving antihypertensive agents, and men with diabetes or those who have undergone nerve-sparing retropubic radical prostatectomy. With the entry of three novel PDE5 inhibitors into the therapeutic armamentarium for ED, differentiating properties of the new agents may confer clinical benefits that physicians as well as patients and their partners should consider when selecting a PDE5 inhibitor.
According to the Massachusetts Male Aging Study (MMAS), the estimated prevalence of erectile dysfunction (ED) of any degree in men 40 to 70 years of age is 52%, with 25% having moderate dysfunction and almost 10% of this age group unable to achieve erections at all.
1,2 Data from a wide range of clinical trials demonstrate that the oral phosphodiesterase type 5 (PDE5) inhibitors offer efficacy in the treatment of this disorder. Further, as each of these agents—shorter-acting sildenafil citrate and vardenafil hydrochloride, and longer-acting tadalafil—was developed, it proved to confer benefits over placebo in healthy men, in men with comorbidities such as diabetes and cardiovascular disease (CVD), and in men with surgically induced ED. All the PDE5 inhibitors are generally safe and well tolerated, a finding that greatly enhances any and all efficacy benefits.
Sildenafil, the first of these agents, offered early onset of action, a favorable side effect profile, efficacy in men with diabetes, and the return, in some men, of spontaneous erections after nerve-sparing retropubic radical prostatectomy (NSRRP); the development of vardenafil brought these features plus efficacy in men previously nonresponsive to sildenafil. Tadalafil, with its extended duration of activity, then built on the established foundation of benefits by expanding the window of time in which couples could attempt and complete successful intercourse.
PDE5 Inhibitors in the Treatment of Patients With Surgically Induced Erectile Dysfunction
Men with CVD are more likely to have ED than the general male population because both conditions share risk factors (eg, age, hypertension, diabetes mellitus, obesity, smoking, hyperlipidemia, physical inactivity) and because some drugs used to treat CVD may induce E D,
22,23 which may be a marker for CVD.
23 One of the positive side effects of this drug class is that PDE5 inhibition has been shown to dilate epicardial coronary arteries, improve endothelial dysfunction, and inhibit platelet activation in patients with coronary artery disease. This activity also has an intermediate effect on myocardial ischemia compared with isosorbide dinitrate and placebo.
24
Another positive side effect of PDE5 inhibition can be seen in the brachial artery flow–mediated dilation that results from short-term and prolonged PDE5 inhibitor therapy. This activity is of particular benefit to men with diabetes who have the endothelial abnormalities that contribute to ED and vascular disease.
25
Overall, PDE5 inhibitors are safe in most male patient populations, including men with ischemic CVD or those receiving antihypertensive agents. They are not associated with increases in myocardial infarction (MI) or death rates in controlled clinical trials. In treating patients with concomitant ED and CVD, it is important to first remember that sexual activity, with or without the use of a PDE5 inhibitor, may carry a potential cardiac risk for patients with CVD.
15,17,19
As part of patient assessment, use of the Princeton Consensus Panel's classification system
26 is helpful in determining the level of cardiac risk in patients with cardiovascular risk factors or established disease. Based on these guidelines, risk is stratified as follows:
Treatment for ED—including but not limited to prescription of a PDE5 inhibitor—should be delayed until the cardiac condition stabilizes and the patient's cardiovascular specialist approves of the initiation of treatment.
22,26
Patients at indeterminate risk should undergo specialized testing and be restratified. Most men, after restratification, fall into the low-risk category and can safely resume sexual activity and receive therapy with PDE5 inhibitors if needed.
In patients at low or indeterminate risk, prescription of a PDE5 inhibitor must always be viewed in the context of any other medications the patient is taking. It is with regard to potential drug-drug interactions that the PDE5 inhibitors exhibit more similarities than dramatic differences.
▪ Contraindication With Nitrates— Nitrates have a hypotensive effect. The combined effects of nitrates and PDE5 inhibitors on the nitric oxide/cyclic guanosine monophosphate pathway may augment this effect. As such, even though controlled clinical trials coad-ministering PDE5 inhibitors and nitrates have not been associated with increased rates of MI or death, both sildenafil and vardenafil are contraindicated in patients receiving nitrates. It is important to note that sildenafil has hemodynamic effects resembling those of modest nitrates (it has modest effects on blood pressure in healthy subjects—a decrease of approximately 10 mm Hg after a single 100-mg dose).
Vardenafil, which is associated with slight decreases in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (although it is associated also with a minor compensatory increase in heart rate),
27-29 is contraindicated in patients receiving organic nitrates. The prescribing information for tadalafil states that its use in patients taking any form of nitrates is contraindicated. In a patient who has taken tadalafil, and in whom nitrate administration is deemed necessary in a life-threatening situation, a minimum of 48 hours should pass between dosing with tadalafil and administration of nitrates, and then be commenced only under close medical supervision and with appropriate hemodynamic monitoring.
15,17,19,22,27
▪
Patients Taking Antihypertensives— Hypertension is also an important risk factor for ED, and the drugs used to treat hypertension may further exacerbate the condition.
30,31 Because of the systemic vasodilatory effects of PDE5 inhibitors, coadministration of some of these drugs and some antihypertensive medications, specifically α-blockers, may cause additive but not necessarily potentiating decreases in blood pressure. Vardenafil use has resulted in transient decreases in SBP in healthy volunteers (mean maximum decrease of 7 mm Hg SBP and 8 mm Hg DBP). Tadalafil at a 10-mg dose is associated with mean decreases in SBP of 4.5 mm Hg and DBP of 2.5 mm H g (measured with the subject standing).
15,17
An early placebo-controlled, double-blind, crossover study (N=16) that assessed the potential for interaction of sildenafil and the antihypertensive amlodipine. The study found a significant decrease 4 hours postdose in the mean maximum blood pressure with subjects in the supine and standing positions (8 mm Hg and 7 mm Hg, respectively), when compared with subjects receiving the amlodipine-placebo combination.
32 Although prescribing information for sildenafil does not recommend a waiting period after ingestion of all antihypertensives, it does state that patients should wait to take sildenafil for at least 4 hours after taking an α-blocker.
19 Similarly, although concomitant use of vardenafil and most antihypertensives (eg, the calcium channel blocker nifedipine) have not been found to lead to serious hemodynamic events, use of vardenafil is contraindicated in patients taking α-blockers.
15,33
With regard to tadalafil, its use is contraindicated with α-blockers, except tamsulosin, 0.4 mg once daily. A study of the potential for a hemodynamic interaction between tadalafil and doxazosin showed that tadalafil at a dose of 20 mg produced mean maximal postbaseline reductions in SBP and DBP measured with the subject supine and standing significantly greater than those with placebo during treatment with doxazosin mesylate, 8 mg.
17
In a clinical pharmacology study, a single dose of tadalafil, 20 mg, administered to healthy subjects taking the α
1 A-adrenergic receptor blocker tamsulosin, 0.4 mg once daily, resulted in no significant decreases in blood pressure.
17
The difference between the hypotensive effects observed after concomitant administration of tadalafil and doxazosin compared with that of tadalafil and tamsulosin are notable. One explanation may be the greater selectivity of tamsulosin. The α1 A-adrenergic receptors inhibited by tamsulosin are located mainly in nonvascular smooth muscle, such as the prostate.
Based on their efficacy profile, the novel PDE5 inhibitors tadalafil and vardenafil are a bit more highly selective than sildenafil. Tadalafil, with its 36-hour duration, offers increased dosing flexibility over sildenafil and vardenafil, both of which last for about 4 hours. The results of noncomparative studies suggest that tadalafil and vardenafil improve erections in the general population as well as in men with diabetes and men with hypertension. Adverse events are mild to moderate and transient, and they generally dissipate as treatment continues.
In the evolution of PDE5 inhibitors, as in most scientific and historic endeavors, the past is prologue. Clearly, the development of this drug class has followed a logical progression of continued discovery and improvement. The result is that patients with ED can now select from among several agents in the class of PDE5 inhibitors for ease of administration and optimal outcomes.
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