Pharmacologic Therapy for Erectile Dysfunction and its Interaction With the Cardiovascular System

Physiology of Erection

Erection involves sinusoidal relaxation, arterial dilatation, and venous compression in the penis. ² Because the penis is a richly vascularized organ, penile erections are, in large part, a vascular event. The endothelium of penile vasculature plays an important role in modulating vascular tone and blood flow into the penis in response to humoral, neural, and mechanical stimuli. ¹⁵ Endothelial cells lining the internal surface of penile arteries and sinusoids of the cavernosal tissue affect the tone of adjacent smooth muscle cells through the release of relaxing factors (such as NO, prostanglandin-E2, and C-type natriuretic peptide) and vasoconstrictive agents (such as endothelin-1 and angiotensin-II). ¹⁶ The NO pathway is of critical importance in the normal induction and maintenance of erections. The NO-dependent relaxation of the cavernosal smooth muscles leads to compression of the subtunical small veins, occluding local venous return, and resulting in an erection. Penile detumescence is due to a reduction in arterial blood inflow and a collapse of lacunar spaces. Decompression of the drainage venules from the cavernous bodies occurs, allowing venous drainage of the lacunar spaces and relief of the erection. ^15,16

Classification of ED

Erectile Dysfunction = Endothelial Dysfunction

Not all ED is due to endothelial dysfunction. Corporeal venous leakage, prostatectomy, and other urological as well as psychological conditions account for a significant proportion of patients with ED. ²⁰ However, in many patients vasculogenic ED may be the consequence of a derangement of the normal NO-mediated endothelial vasodilation and the complex interplay between endothelial dysfunction, subclinical inflammation, and testosterone deficiency, which often lead to the development of atherosclerotic plaque. ^16,17,21,22 In vasculogenic ED, dysfunctional endothelial cells lining the penile arterial system and the corpus cavernosum produce less NO. Hence, PDE5 isoenzyme, abundant in perivascular smooth muscle cells, degrades faster the reduced quantities of cyclic guanosine monophosphate (cGMP), thus limiting the duration of vasodilation and having negative impact on obtaining and sustaining an erection (Figure 1). ^17,21

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Figure 1.

Molecular mechanisms of smooth muscle relaxation by the cGMP pathway. Adapted with permission from Sáenz de Tejada ¹⁵ and Abrams D et al. ²⁸ cGMP indicates cyclic guanosine monophosphate; GC, guanylate cyclase; GMP, guanosine monophosphate; GTP, guanosine-5′-triphosphate; IP₃, inositol triphosphate; PKA, protein kinase A; PKG, protein kinase G; PLB, phospholipase B; PLC, phospholipase C; NO, nitric oxide.

Inflammation plays an important pathophysiological role in both ED and systemic arterial dysfunction. ²⁰ The dysfunctional endothelium sets the stage for both initiation and progression of atherosclerotic lesions in the penile and systemic vasculature by promoting inflammation within the vessel wall through enhanced production of cytokines and expression of cellular adhesion molecules. Increasing attention is focused also on the effect of testosterone on arterial function. Appropriate testosterone levels have been demonstrated to be necessary for maintenance of intrapenile NO synthase levels. Testosterone deficiency and ED appear to be interrelated at the pathophysiologic level through associations with endothelial dysfunction. ²³

Physiology of the Types of PDEs and Cross-Talk

Phosphodiesterases are a heterogenous group of hydrolytic enzymes whose principal biological activity is to modulate intracellular levels of cyclic nucleotides such as cGMP and cyclic adenosine monophosphate. ²⁴ Of the 11 families of PDEs consisting of more than 50 isoenzymes identified to date, 6 (PDE 1, 2, 3, 4, 5, and 11) have been proven to be of pharmacological importance (Table 1). ²⁵ Since the distribution and functional significance of PDE isoenzymes varies in different tissues, isoenzyme selective inhibitors have the potential to exert specific effects on the target tissue. ²⁴ Undoubtedly, the major interest of research was focused on PDE5 isoenzyme because of its specificity in catalyzing the hydrolysis of cGMP. ^24,26 Since cGMP is catabolized by the PDE5 isoenzyme, its inhibition will result in an increase in the intracellular levels of cGMP and prolong the duration of its action. Preferential expression of PDE5 in the corpus cavernosum and the cGMP-mediated relaxation of the cavernous smooth muscle during sexual stimulation have made inhibition of this enzyme by sildenafil, vardenafil, or tadalafil, a clinical benefit in the management of ED. ^15,27 Apart from corpus cavernosum, PDE5 isoform is expressed in various other tissues, such as the arterial and venous vasculature, myocardial, skeletal, visceral, and tracheobronchial muscles, brain, retina, and platelets, and there is “cross-talk” between the PDEs expressed in the heart (Figures 1 and 2). ^25,26,28

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Figure 2.

Regulatory network interconnecting cardiac phosphodiesterases. Arrows indicate activation; blunt-ends indicate inhibition or cyclic nucleotide hydrolysis. Adapted with permission from Zaccolo M, Movsesian MA. ²⁶ Ca²⁺ indicates Ca²⁺ calcium ion; CaM, calmodulin; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; PDE, phosphodiesterase; PKA, protein kinase A; PKG, protein kinase G.

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Table 1.

Tissue Distribution and Specificity of Various Isoforms of PDE.^a

Isoforms of PDE	Tissue Distribution	Specificity for
PDE 1	Vascular smooth muscle, cardiomyocytes, brain	cAMP, cGMP
PDE 2	Vascular smooth muscle, cardiomyocytes, brain, corpus cavernosum	cAMP, cGMP
PDE 3	Vascular smooth muscle, cardiomyocytes, corpus cavernosum, platelets	cAMP
PDE 4	Vascular smooth muscle, cardiomyocytes	cAMP
PDE 5	Corpus cavernosum, vascular smooth muscle, skeletal muscle, platelets	cGMP
PDE 6	Retina	cGMP
PDE 7-10	Various	cAMP or cGMP
PDE 11	Skeletal muscle, heart, vascular smooth muscle	cAMP, cGMP

Abbreviations: PDE, phosphodiesterase; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate.

^a Adapted with permission from Reffelmann and Kloner. ²⁵

Pharmacology of PDE Inhibitors

The vascular tone, systemic vasodilation, and circulation are principally regulated through the endothelial production of NO from the systemic arteries and veins. After its production, NO diffuses into the adjacent smooth muscle cells and enhances the production of cGMP, which, in turn, increases the production of NO and leads to both vascular smooth muscle relaxation and an increase in systemic vasodilation. Since cGMP is catabolized by the PDE5 enzyme, its inhibition by the PDE5 inhibitors will result in an increase in the intracellular levels of cGMP and prolongation of the duration of its action. ^15,27,29

The chemical structures of the 3 PDE5 inhibitors approved by the US Food and Drug Administration (US FDA) are depicted in Figure 3. All PDE5 inhibitors are rapidly absorbed after oral administration and are reported as effective within 30 minutes from administration. The chemical structures of sildenafil and vardenafil are very similar, their half-lives are approximately 4 hours, and their action is dissipated 24 hours later. In contrast, the chemical structure of tadalafil is different, wherein its half-life is longer (approximately 17.5 hours) and its action is dissipated 48 hours later. ^27,29,30

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Figure 3.

Molecular structures of PDE5 inhibitors sildenafil, vardenafil, and tadalafil. Adapted with permission from Rosen RC and Kostis JB. ²⁷ PDE5 indicates phosphodiesterase type 5.

The actions of PDE5 inhibitors could have clinical implications in patients with ED and CAD receiving nitrates, which are also NO donors and could lead to significant vasodilation and lowering of blood pressure. ³¹ In addition, they could have interactions with other drugs taken by patients with CAD, hypertension, heart failure, and diabetes. ^{31 –33} These drug interactions are important to be known by physicians managing these patients.

Although PDE5 inhibitors were initially approved as on-demand therapy, in 2008, tadalafil was also approved for everyday use in 2.5 mg or 5 mg doses.

Efficacy and Effectiveness of PDE Inhibitors in Treating ED

Clinical studies demonstrate that the 3 PDE5 inhibitors are similarly effective at improving the erectile function domain scores of patients with organic, psychogenic, and mixed etiology of ED. ^27,33 PDE5 inhibitors are the first-line therapy for ED of organic etiology unless there is a specific contraindication to their use. This class of agents is widely used because of its effectiveness and safety. The efficacy and safety of PDE5 inhibitors in improving erectile function in patients with clinical CVD or CV risk factors have been established in numerous randomized controlled clinical trials. ³⁴ As tadalafil and vardenafil were more recently licensed than sildenafil, there are fewer published clinical trials specific for tadalafil and vardenafil in patients with CVDs.

The clinical efficacy of PDE5 inhibitor therapy in the general ED population has been extensively evaluated in clinical trials and is well documented. ³⁵ Further, efficacy of the 3 currently available PDE5 inhibitors has been evaluated extensively in patients with ED and concomitant hypertension, dyslipidemia, diabetes, or known CVD. ^33,36 Overall, these studies have shown similar efficacy for the 3 agents, resulting in significant improvement of erectile function in patients with any of these comorbid conditions. However, diabetic patients are one of the most difficult to treat subgroup. ^33,36

Findings from several studies have shown that chronic or daily use of PDE5 inhibitors in ED can significantly improve endothelial dysfunction. Tadalafil 5 mg is the only PDE5 inhibitor clinically approved for daily use in the treatment of ED. Potential benefits of daily use of PDE5 inhibitors include salvage of on-demand PDE5 inhibitor nonresponders, apparent disease modification, and development of a more natural sexual function. ^{36 –38}

Sildenafil has been proven to be effective across all efficacy measures, regardless of ED duration. ³⁷ Similar data have not been published for tadalafil or vardenafil. In a study by Matic and McCabe, men who had experienced ED for different lengths of time did not differ in their preference for or satisfaction with PDE5 inhibitors with longer or shorter duration of action. ³⁹

Adverse Effects of PDE Inhibitors

Adverse events are dose related, mild in nature, and self-limited by continuous use. ³⁷ The drop-out rate due to adverse events is similar to placebo (2% for sildenafil vs 2.3% for placebo). ³³ The most common side effects are facial flushing and headache, which are mild to moderate in severity and are short lived. ^27,33 Tadalafil can cause myalgia and pain at different body sites. The PDE5 inhibitor-related priapism has been reported in a few instances. Although nonarteritic ischemic optic neuropathy has been reported after PDE5, a direct link could not be established. However, minor visual adverse effects occur in 3% to 11% of patients receiving these medications and they are transient and reversible. ⁴⁰ Patients using PDE5 inhibitors should be also warned about a possible link between PDE5 inhibitor use, especially sildenafil, and transient hearing impairment.

A strong body of clinical data shows that all 3 agents (sildenafil, tadalafil, and vardenafil) do not increase the risk of nonfatal myocardial infarction, stroke, or CV deaths. ³⁴ These drugs do not exacerbate ischemia or worsen exercise tolerance in patients with known CAD who achieve levels of exercise comparable or greater than that achieved during sexual intercourse. ^41,42 Furthermore, the safety profile of sildenafil in men with ED and diabetes mellitus, arterial hypertension, or CV conditions is similar to that in men with ED without these conditions. ³³ The safety of sildenafil has not been studied in men with recent history of stroke or myocardial infarction, and its use is therefore currently contraindicated in men with these conditions. Existing data cannot give straight answers on the safety of PDE5 inhibitors in patients with obstructive sleep apnea.

Interactions with CV drugs have been minimal with the exception of nitrates and other NO donors (such as nicorandil), where coadministration may result in severe vasodilation and hypotension. ³¹ Since nitrates are often overused in clinical practice, the option of their discontinuation should be considered in order to allow PDE5 therapy. Treatment-emergent adverse events have been shown to be similar in patients who are taking antihypertensive agents and those who are not, and no clinically relevant changes in blood pressure were observed even in patients taking 2 or more antihypertensive agents. ³² To avoid hypotension, low starting doses of PDE5 inhibitors are preferred in patients on α-blocker treatment, and likewise, low starting doses of α-blockers are encouraged in patients taking PDE5 inhibitors. ³² No direct effect of PDE5 inhibitors on cardiac repolarization (QT interval or dispersion) is reported. However, precautions may be warranted when using these drugs in patients with congenital QT prolongation, class Ia, III antiarrhythmics (vardenafil), and in patients with heart failure. ⁴³

Effects of PDE Inhibitors on the CV System

Although currently their only additional indication, beyond ED, is idiopathic pulmonary hypertension (PAH; for sildenafil and tadalafil), PDE5 show potential to be of benefit in several other conditions, such as CAD and heart failure with left ventricular systolic function. ^43,44 The PDE5 inhibitors are an exciting class of drugs with pleiotropic effects since PDE5 isoenzymes are expressed throughout the human body, including the pulmonary and systemic vasculature and hypertrophied myocardium. ^25,26,28 Indeed, accumulating data show that the therapeutic potential extends to the myocardium, the coronary and peripheral arteries, subclinical inflammation, oxidative stress, thrombosis, neurological recovery, and pathways of fibrosis (Table 2). Mechanisms of benefit of PDE5 inhibitors include pulmonary and systemic vasodilation, increased myocardial contractility, reduced large artery stiffness and wave reflections, improved endothelial function and reduced apoptosis, fibrosis, and hypertrophy through mechanisms involving NO, cGMP, protein kinase G, and ρ-kinase inhibition. ^43,44 It should be stressed that although the currently available agents show many similar modes of action, an effect proven for an agent does not necessarily apply to the others. Furthermore, extrapolations of experimental evidence to clinical settings should be made with caution. A very important issue is whether treatment of ED per se (and not of its risk factors and comorbidities) will have an impact on CV risk. Although this applies to all therapeutic modalities of ED, it is particularly pertinent for PDE5 inhibitors, since they represent the mainstay of ED therapy. Data are limited to date. Gazzaruso et al ¹² showed a trend of PDE5 inhibitors to reduce CV morbidity and mortality in diabetic patients with silent CAD and ED, while Frantzen et al showed that 2 years after the introduction of sildenafil, the relative risk of the incidence of CVD among men with ED compared with healthy men significantly decreased from 1.7 to 1.1. ⁵⁰

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Table 2.

Effects and Clinical Significance of PDE5 Inhibition on the Cardiovascular System.

Variable	Potential Mechanisms	Clinical Implications/Potential Therapeutic Applications
1. Cardiac function
Cardiac contraction 43 –49	Inhibition of acute β-adrenergic stimulation. Suppression and reversal of pressure overload-induced ventricular hypertrophy	Potential benefits for disorders which are complicated by hypertrophy (eg, essential hypertension), or in which neurohormonal activation is enhanced (eg, heart failure)
Cardioprotection 12,25,26,28,43,44,50	Mainly increase in cGMP levels (with activation of PKG and subsequent opening of the mitochondrial KATP channels); increased expression of eNOS, iNOS, activation of ERK, PKC, and opening of the mitochondrial KATP channels	Preconditioning-like cardioprotective effect against ischemia/reperfusion injury, potential use in acute ischemic events, coronary artery bypass surgery
2. Arteries
Coronary vasculature 43,51	Vasodilation, increase in coronary blood supply	Potential benefit in patients with diffuse coronary microvessel disease and vasospastic angina
Blood Pressure 32,35,52,53,54	Mild blood pressure lowering effect and clinically insignificant heart rate changes	Potential benefits in essential hypertension
Pulmonary vasculature 48,55,56	Enhancement of vasodilatory and antiproliferative cGMP-mediated effects; reduction of plasma levels in endothelin-1; inhibition (tadalafil) of the hypoxia-induced cytokine expression (TNF-α, IL-1β)	Improvement in hemodynamic parameters and clinical variables in patients with pulmonary arterial hypertension, either idiopathic or secondary; indication for sildenafil for the treatment of the first, potential for the second.
Peripheral vasculature 53,48	Reversal of endothelial dysfunction; increase in the number of circulating endothelial progenitor cells; decrease in large artery stiffness and wave reflections from peripheral sites	Favorable effects in patients with heart failure, coronary artery disease, and in patients with increased cardiovascular risk; reduction of microalbuminuria in patients with type 2 diabetes
3. Subclinical inflammation 20,43,57	Reduction of markers/mediators in increased inflammatory activation	Beneficial effects in patients with risk factors and increased subclinical inflammatory state
4. Oxidative stress 43	Inhibition of superoxide formation	Beneficial effects in conditions with increased vascular oxidative stress
5. Platelets 58,59	Biphasic effect on platelet response; increase in the threshold for activation of the platelet glycoprotein IIb/IIIa receptor; inhibition of aggregation	Adjunctive use as antiplatelets agents in patients with coronary artery disease
6. Angiogenesis 60,61	Via protein kinase G-dependent pathway	Angiogenesis in peripheral arterial disease

Abbreviations: PDE5, phosphodiesterase type 5; cGMP, cyclic guanosine monophosphate; PKG, protein kinase G; K_ATP, adenosine triphosphate-sensitive potassium; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; ERK, extracellular signal-regulated kinase; PKC, protein kinase C; TNF-α, tumor necrosis factor α; IL-1β, interleukin 1β.

Use of ED in the Early Identification of Men at Risk of CV Events

Erectile dysfunction carries an independent risk of CV events. A considerable number of studies has examined the ability of ED to predict the risk of future fatal and nonfatal CV events (myocardial infarction, stroke, and revascularization) and total mortality in the general population and in patients with high CV risk, in diabetic patients, and in patients with heart failure. ^{10 –13} In a meta-analysis of 14 prospective cohort studies involving 92 757 men followed for a mean period of 6.1 years, ED increased significantly and independent of traditional risk factors such as the risk of CV events, CV mortality, myocardial infarction, cerebrovascular events, and all-cause mortality by 44%, 19%, 62%, 39%, and 25%, respectively. ¹⁴ This predictive capability also extends in men with known CVD: ED increased the risk of all-cause mortality by 90%. Of importance, the predictive ability of ED is higher in younger patients with ED despite the fact that probability of ED increases with age, most likely identifying a group of patients with early and aggressive vascular disease. ¹⁴ Clinical implementation of ED as a biomarker relies on whether its addition on classical risk scores such as the Systematic COronary Risk Evaluation (SCORE) or the Framingham Risk Score (FRS) correctly reclassifies a meaningful percentage of patients into a higher or lower risk category. To this end, data are limited. Yet, in a population-based study of men 40 to 70 years of age, addition of ED status to FRS resulted in a reclassification of 6.2%, 95% confidence interval (CI) 4.6-7.8, of the men. ¹⁰

The third Princeton Consensus panel defines CV risk as the risk of morbid events during a 3- to 5-year interval from the onset of ED. ⁶² A man with organic ED should be considered at increased risk of CVD until recommended checks suggest otherwise. Office-based assessment of CV risk using conventional risk factor algorithms, such as FRS and SCORE, includes few data from patients younger than 40 years. These algorithms also lack some important risk factors (eg, family history, fasting glucose level, serum creatinine level [estimated glomerular filtration rate], urinary albumin to creatinine ratio, and, potentially, testosterone level) that should be considered when estimating CV risk in patients with ED. Therefore, although the consensus panel recommends the FRS as a starting point for estimating the likelihood of subclinical atherosclerosis in men with ED, the presence of ED per se, especially in men aged 30 to 60 years, should alert the physician to the possibility of increased CV risk independent of the FRS. ⁶²

Use of PDE Inhibitors in Patients With CVD

Use of PDE Inhibitors in CVDs (In The Absence of ED)

Individualized Global Risk and Global Management of Each Patient

The first and extremely important objective of the most recent, third Princeton Consensus recommendations focuses on the evaluation and management of CV risk in men with ED and no known CVD. ⁶² For patients with ED with no known CVD, the panel recommends at first evaluation of (1) patient history, including age and CV risk factors, (2) physical examination noting blood pressure, waist circumference, body mass index (BMI), cardiac auscultation, and evaluation of peripheral vascular function including fundal arterial changes, carotid bruits, and palpation of femoral and pedal pulses, (3) ED severity and duration, (4) resting electrocardiogram, (5) fasting plasma glucose level, (6) serum creatinine level (estimated glomerular filtration rate) and albumin-to-creatinine ratio, and (7) lipid profile.

After the initial evaluation, the next step to estimate CV risk associated with sexual activity is to evaluate exercise ability. ^62,77,78 Sexual activity is equivalent to walking 1 mile on the flat in 20 minutes or briskly climbing 2 flights of stairs in 10 seconds. Patients who can generally perform exercise of modest intensity without symptoms are classified as low risk, while patients unable to perform this level of exercise (such as patients with uncontrolled hypertension) are classified as high risk. Further evaluation using exercise stress test is required for patients at indeterminate risk. These patients are restratified to low or high risk based on the results of stress test (4 minutes of the standard Bruce treadmill protocol = 5-6 METs) without symptoms.

The documented interval between the onset of ED and symptomatic CAD allows for timely risk factor intervention. ⁷⁹ Modification of lifestyle factors in men with ED is the first step in preventing future CV events. In obese men (BMI > 30 kg/m²) with ED, reduced calorie intake and increased physical activity can significantly reduce weight, decrease the concentrations of inflammatory markers (eg, C-reactive protein), and improve erectile function. Similar results have been observed in men with the metabolic syndrome and comorbid ED. ⁸⁰ In men undertaking or maintaining an active lifestyle, the incidence of ED is significantly lower than in men with a sedentary lifestyle. Unfortunately, there is limited evidence that once ED has occurred, it can be reversed by initiation of an active lifestyle, although for overall health benefit this is recommended. ^80,81 Established CV risk factors such as hypertension, diabetes, and hyperlipidemia should be managed with appropriate medical therapy. However, treatment should be tailored to the individual patient, as certain drugs used in the treatment of CVD may be associated with the development of ED or exacerbation of existing ED. ³⁰ In general, unless ED developed within 4 weeks of initiating drug therapy, there is little evidence to support switching the suspect drug to alleviate the symptoms of ED. Furthermore, ED may be a result of the underlying CV pathology rather than the drugs used for its treatment. Conversely, in men with ED and hypertension, angiotensin II receptor blockers may improve sexual function and may be the drug of first choice in sexually active men, especially as the potential for adverse effects is low. ^31,32 In a number of studies involving men with ED and hypercholesterolemia, treatment with a statin has been reported to significantly reduce low-density lipoprotein cholesterol concentrations and also to improve erectile function. ²² Among men with type 2 diabetes, ED, and silent CAD, treatment with statins and PDE inhibitors has been reported to be associated with a significant reduction in major adverse cardiac events. ¹² We recommend the treatment to a target LDL cholesterol of 2 mmol/L (80 mg/dL) or less. Testosterone therapy should be reserved for patients who (1) are symptomatic (ED or reduced libido) from testosterone deficiency and (2) have biochemical evidence of low testosterone defined as total testosterone <350 ng/dL (<12 nmol/L or 3.5 ng/mL) as recommended by Buvat et al or 300 ng/dL recommended by the Endocrine Society Guidelines. ^23,82 Despite evidence of benefit in patients with preexisting CV conditions (angina or heart failure), it should be emphasized that testosterone therapy is not a medication with CV indications. ⁶³