madman
Super Moderator
Pharmacotherapy for Erectile Dysfunction in 2021 and Beyond (2022)
Farnoosh Nik-Ahd, MD, Alan W. Shindel, MD, MAS*
INTRODUCTION
Erectile dysfunction (ED) is a common and vexing clinical problem that leads to the substantial disruption of quality of life and relationships.1 Interest in facilitating and restoring erections is documented in ancient texts going back to the beginnings of recorded human history and probably extends back even further than that.2 A variety of superstitions and herbal remedies have been touted; some of these ancient remedies have pharmacologic properties that are consistent with erectogenic effects and/or have been investigated in modern clinical trials.2,3
Despite millennia of interest in ED, it is only within the past 40 years that demonstrably and consistently effective pharmacologic treatments have been available for this common ailment. The arrival of effective pharmacotherapy for ED was heralded by the famous (or perhaps infamous) actions of Dr. Giles Brindley, who demonstrated his pharmacologically induced erection at a scientific session of the 1983 Annual Meeting of the American Urologic Association.4 This dramatic presentation ushered in an era of effective pharmacotherapy for ED. Approximately 10 years later the fundamental role of nitrergic neurons (formerly known as nonadrenergic-noncholinergic “NANC” neurons) in mediating vascular responses was determined.5 These discoveries paved the way for pharmacotherapies that modulated steps in the nitrergic pathway as treatments for ED, culminating in the release of the first highly effective and tolerable oral pharmacotherapy for ED in 1998.6
In this article, we review the current state of the art in pharmacotherapy for ED. An understanding of ED pharmacotherapy necessitates at least a brief review of the molecular mechanisms that mediate penile vasodilation. Our focus will be on agents currently approved for use by the United States Food and Drug Administration (US FDA) although we will also consider the commonly used (albeit not formally approved) agents used as injectable drugs for the induction of penile erection. The main classes of pharmacotherapy for ED are listed in Table 1. Brief consideration will be given to agents approved for use by regulatory bodies outside the United States. We will conclude with the consideration of directions for future research and development in medical therapy for ED.
MOLECULAR MECHANISMS OF ERECTION
A detailed discussion of the anatomic/tissue properties of the penis that allow for penile erection is beyond the scope of this article. The reader is referred to excellent historical and recent publications on this topic for more detail.7,8 However, an understanding of the pharmacology of ED treatment requires some knowledge of the molecular mechanisms that regulate penile vasodilation.
The nitric oxide (NO) pathway has emerged as a fundamental and essential element of genital vasodilation.7 NO is derived from neuronal and endothelial Nitric Oxide Synthase (nNOS and eNOS, respectively). NO is in turn responsible for activating Soluble Guanylate Cyclase, which catalyzes the conversion of Guanosine Triphosphate (GTP) to cyclic Guanosine Monophosphate (cGMP). cGMP plays a critical role in modulating a number of cellular processes via the activation of Protein Kinase G (PKG). The downstream effects of PKG in the penis include potassium sensitization, suppression of the calcium sensitizing RhoA-Rho Kinase pathway, and depletion of intracellular calcium by sequestration in the sarcoplasmic reticulum and expulsion through membrane-bound calcium channels. The net effect of all these pathways is to oppose the activation of the actin-myosin cross-bridge formation in smooth muscle cells of penile arteries and corporal erectile tissue, leading to muscular relaxation and subsequent vasodilation. With vasodilation, penile blood flow is increased and the corporal bodies become engorged with blood.
With the cessation of sexual arousal, the production of NO declines. Production of cGMP declines in turn and the processes that mediate corporal vasodilation cease. cGMP is broken down by the action of phosphodiesterases. The most clinically relevant isoform of phosphodiesterase in the penis is type 5 (PDE5). Selective inhibitors of PDE5 (PDE5i) are potent erectogenic agents that work by prolonging the vasodilatory effects of cGMP in the penis. These highly efficacious agents have been the mainstay of ED therapy for over 2 decades; their unique mechanism of action explains the important observation that these drugs are primarily useful for maintaining rather than attaining an erection. Reliance on initial NO activity for efficacy also makes clear how these agents are less effective in men with neurogenic etiologies for ED (eg, post pelvic surgery, severe diabetes).9
While the NO/cGMP/PDE5 pathway is arguably the most fundamental and clinically important molecular pathway mediating erection, a number of other vascular mechanisms are also at play and may be manipulated pharmacologically to induce erections. The sympathetic tone is dominant in the penis at baseline and limits the inflow of blood. Therefore, erections are mediated by parasympathetic neural input from the sacral (S2–S4) spinal cord.10 Cessation of sympathetic tone to the penis via cortical inhibition of sympathetic projections from the thoracic spinal cord is an important mechanism of psychogenic arousal contributing to penile erection. Sympatholytic drugs administered to the penis may also have erectogenic effects. Protein Kinase A (PKA) works in a fashion similar to PKG and can have similar vasodilatory effects mediated by many of the same mechanisms. PKA may be produced by the action of various other drugs known to be associated with the induction of erections, specifically prostaglandin E1.7
ORAL PHARMACOTHERAPY FOR ERECTILE DYSFUNCTION
Dr. Louis Ignarro, Dr. Jacob Rajfer, and colleagues at the University of California, Los Angeles reported that nitric oxide (NO) was the chemical mediator of penile erections in 1992.5 Dr. Ignarro would later be awarded the Nobel prize for his discovery of the role of NO in vasodilation. Subsequent elucidation of the presence of PDE5I in the penis and the discovery of drugs that were selective inhibitors of this enzyme led to the use of PDE5i as a mainstay of ED treatment, a development that persists to this day.5,6,11 The creation of an effective and safe oral therapy for ED had profound effects on culture and society that were out of proportion to its medical utility. The advent of PDE5 put sex and sexuality at the forefront of public consciousness and altered the way the world views and discusses sex.
The PDE5 gene is localized to chromosome 4q26.12,13 It encodes the PDE5 enzyme, which is a homodimer that is about 200 kDa large.13 PDE5 selectively hydrolyzes only cGMP, in contrast to other PDE isoforms which may catalyze both cAMP and cGMP or just cAMP.14,15 There are 3 main components to PDE5: the N-terminal fold, the linker region, and the L-terminal helix.16,17 The N-terminal serves to regulate the catalytic domain and is activated by cGMP binding and phosphorylation. Though there are 3 unique isoforms of PDE5, the catalytic domain is conserved across isoforms. The catalytic domain of PDE5 consists of a core pocket, a lid region, a hydrophobic pocket, and a metal-binding site. The core pocket consists of 3 components: the saddle, which in PDE5I is specific to cGMP, and 2 deep pockets which serve as hydrophilic clamps that “sandwich” cGMP or PDE5i and help potentiate the activity of PDE5i.18
PDE5i are currently used on-label in the treatment of both ED and pulmonary hypertension. All currently approved oral pharmacotherapies for ED are of the PDE5i class (Table 2). These agents have revolutionized the care of men with ED and improved the quality of life for many men and their partners. All of these drugs have proven efficacy. Limited published data, typically industry-sponsored, tout the advantages or patient preferences of one drug over the others but ultimately it is not clear that anyone is superior across the board for all patients. The selection of PDE5i ultimately comes down to issues of individual patient preferences and (often) access in terms of insurance coverage and costs.
PDE5i have accrued a very favorable safety profile over the past 22+ years they have been available.19 The only class-specific medical contraindication is the use of concomitant daily dose nitrate therapy as the combination of a nitrate drug and PDE5i may lead to a precipitous drop in blood pressure.20 PDE5i may be offered to patients who have been prescribed short-acting nitrate medications (eg sublingual nitroglycerin) but it must be made clear to such patients that they should not use these drugs within 24 hours of one another (and possibly 36 in the case of long-acting PDE5i such as tadalafil). Alpha-blocker therapy is a relative contraindication due to the potential for the exacerbation of orthostatic hypotension; this effect is typically mild and can be mitigated by providing an interval between dosing.21
Common adverse reactions associated with PDE5i include headaches (12%–15%), flushing (4%–14%), indigestion (<1–10%), stuffy nose/ congestion (4%–10%), vision disturbances (0%– 5%), and myalgias (rare-4%). Serious side effects include angina, sudden decrease or loss of vision, serious skin reactions, and seizures.22 The mechanism of these adverse events and whether they are truly related to the use of the medication is somewhat unclear; the absolute incidence of these events appears to be quite rare given the long clinical history of PDE5i and the numerous prescriptions dispensed as they became commercially available.
The incidence of priapism with the use of PDE5i, while frequently mentioned in advertising, seems to be lower than for some other common medications that are not explicitly given with the intention of inducing erections (eg trazodone, second-generation antipsychotics).23 Patients should be counseled on this potential but may be reassured that the likelihood of prolonged erection is low.
A number of clinical syndromes have been reported in association with PDE5i, including NonArteric Ischemic Optic Neuropathy (NAION, a source of sudden unilateral vision loss), sensorineural hearing loss, major adverse cardiac events, and melanoma.23 Evidence in support of these syndromes being clearly linked to PDE5i as an independent risk factor is generally scant with the possible exception of NAION. However, NAION is a rare clinical entity with an estimated annual incidence of about 1 case per 10,000 person-years.24 Given very low baseline probability, even a statistically significant increase in incidence with PDE5i use translates into a very low absolute risk for this condition in PDE5i users.
Sildenafil
Sildenafil was the first PDE5i and was originally synthesized in Sandwich, UK. In 1991, the drug underwent a phase 1 clinical trial for angina. Although the drug did not have efficacy for angina, it was speculated that it may help with erectile problems. In 1992, a multi-dose phase 1 trial in healthy volunteers was conducted in Wales, and erections were noted to be a side effect. The efficacy of the medication was further demonstrated in 1993 during a pilot cross-over study of 16 men, in which “clear differences between sildenafil and placebo” were noted. Phase 2 and Phase 3 clinical trials were conducted between 1994 and 1997. Importantly, the drug demonstrated excellent tolerability, with the main adverse effects of headache, flushing, dyspepsia, and congestion. No significant differences were noted in the rate of MI, CVA, or serious cardiac events.25 In 1998, Viagra was approved as the first oral agent for the treatment of ED.6
Sildenafil consists of a pyrazolopyrimidine group (which binds to the core pocket of the catalytic domain of PDE5), an ethoxyphenyl group (which binds to the hydrophobic pocket), and methylpiperazine (which lies in the lid region). This drug has no interaction with the metal-binding site.26 Inhibition of PDE5 in this fashion leads to the diminished breakdown of cGMP.
Typical dosages of sildenafil are 25 to 100 mg taken on demand. This medication is also sold under the trade name Revatio, administered at 20 mg three times daily for the management of pulmonary hypertension.27 Sildenafil has a half-life of 3 to 5 hours and a mean apparent steady-state volume of distribution of approximately 105 L.28 This substantially exceeds the body’s total volume of water, which is approximately 42 L. The onset of action typically occurs within 60 minutes. Sildenafil is metabolized by the hepatic P450 enzymes CYP3A4 and CYP2C9. Patients using strong inhibitors of these cytochromes (eg ritonavir, erythromycin, ketoconazole) and those patients with liver failure or severe renal failure experience increased exposure to the drug at a given dose29; low starting doses should be considered in these patients. Of note, absorption of sildenafil is slowed by intake of dietary lipids. Thus, this medication should not be taken after a meal, and it is often recommended that this medication be taken preprandial.
Vardenafil
Vardenafil, approved by the FDA in 2003, has similar pharmacokinetics to those of sildenafil. The pyrazolopyrimidine structure of this drug is very similar to sildenafil. Trade names for this medication are Levitra and Staxyn. Typical dosages of vardenafil are 5 to 20 mg. Vardenafil has a half-life of 4 to 6 hours and a mean apparent steady-state volume of distribution of 208 L.28 Fifty percent of users report getting an erection within 30 minutes of oral dosing. Vardenafil is also available in a sublingually administered 10 mg formulation. Side effects are similar to those listed above.
Vardenafil is predominantly metabolized in the liver via CYP3A4 and like sildenafil, the dosing should be adjusted to lower concentrations in patients taking inhibitors of this cytochrome. Similar to sildenafil, absorption of vardenafil is slowed by dietary lipid intake, and it is recommended that vardenafil not be taken after a meal and instead be taken preprandial. Vardenafil is also contraindicated in patients with congenital QT syndrome and also patients using Type IA or III antiarrhythmics.30 The FDA also recommends against the use of vardenafil in patients on hemodialysis or with severe hepatic failure.31
Tadalafil
Tadalafil was initially approved by the FDA in November 2003 and is sold under the brand name Cialis. Its chemical composition creates a rigid structure, which improves the drug’s selectivity and at least hypothetically may reduce the likelihood of adverse reactions related to the cross-binding of this drug to other PDE isoforms in other parts of the body. Typical dosages of this medication for ED are 5 to 20 mg on-demand or 2.5 to 5 mg daily dose. Tadalafil has a half-life of 17.5 hours and a mean apparent steady-state volume of distribution of 60 to 70 L.28 Unlike sildenafil and vardenafil, the absorption of tadalafil is not affected by food intake. Tadalafil is predominantly metabolized by the hepatic enzyme CYP3A. Unique features of Tadalafil’s structure are that there is a hydrogen bond to the saddle, that methylenedioxyphenyl binds to the Q2 pocket, and that there is extensive interaction with the hydrogen pocket which leads to a rigid structure and decreased entropy with binding. Its patent protection expired from 2017 to 2020.
*Of note, tadalafil is the only PDE5i that is approved to be taken daily (the other PDE5i medications are approved for on-demand use). Daily tadalafil has also been shown to be effective for treating benign prostatic hyperplasia that causes lower urinary tract symptoms.32
Avanafil
Avanafil was approved by the FDA in 2012 after meeting primary efficacy and safety endpoints and is commercially available as Stendra. The side effect profile is consistent with other existing PDE5is and includes congestion, headache, flushing, and rhinorrhea. Typical dosages are 50 to 200 mg dosed on-demand. Of note, avanafil is purported to have a more rapid onset of action compared with other FDA-approved PDE5i; direct comparison data on the onset of action are limited. The half-life of avanafil is approximately 6 hours and a steady-state volume of distribution of 47 to 83L.22
Avanafil is unique structurally in that it contains a chloromethoxy benxylamino group, pyrimidine carboxyamide, and a pyrimidinylmethyl group. Additionally, the catalytic site binding is irrespective of the molecule’s orientation.33 The FDA recommends against the use of avanafil in patients with severe renal or hepatic impairment.34 At the time of this writing, there is no generic form of this medication available.
Other phosphodiesterase type V inhibitors
Numerous PDE5I have been developed and approved outside of the United States. Examples include mirodenafil, udenafil, and lodenafil. These agents differ in terms of absorption and half-life but estimates of overall efficacy seem similar to what is observed in studies of agents available in the United States. Mirodenafil is sold under the trade name Mvix and has a Tmax of 1.125 hours and a half-life of 2.5 hours. The typical dose is 5 to 100 mg. Udenafil is sold under the trade name Zydena. Its Tmax is 1 to 1.5 hours and its half-life is 11 to 13 hours. Typical dosages are 100 to 200 mg. Lodenafil, sold under the brand name Helleva, has a Tmax of 1.2 hours and a half-life of approximately 2 hours. Its typical dosages are 40 to 80 mg.22
INJECTION PHARMACOTHERAPY FOR ERECTILE DYSFUNCTION
Prostaglandin E1 (PgE1, also known as Alprostadil) is the only agent that has been approved by the US FDA as an intracavernosal injection for the management of ED. PgE1 acts to stimulate the production of cAMP and works to induce vasodilation, smooth muscle relaxation, and inhibit platelet aggregation.35 In studies, intracavernous Alprostadil was either significantly more efficacious or comparable to comparative medications.
Although not formally approved as treatments for ED, a number of other vasodilatory agents have been widely used with good efficacy and safety for the management of ED. The alphaantagonist phentolamine opposes sympathetic tone to the penis; when administered as an injection this drug has the effect of “removing the brakes” of sympathetic induced vasoconstriction and inducing erection response. The nonspecific PDE inhibitor papaverine is also widely used as an injectable medication for ED; inhibition of PDE in the penis has the net effect of helping to maintain the presence of cGMP and cAMP in the corporal bodies, leading to the preservation of vasodilation by mechanisms addressed in the above section on selective PDE5i. These injectable medications are most commonly used as compounded mixtures combining 2 or 3 agents (known as bimix and trimix, respectively). The cholinergic drug atropine is sometimes added to produce the so-called “quadmix.” The clinical utility of atropine for the potentiation of penile erection is ambiguous and has not been supported in clinical trials.36
To determine the pharmacodynamic profile of intracavernous prostaglandin E1, one study randomized patients to 1 of 5 dose groups (placebo, 2.5 mg, 5 mg, 10 mg, or 20 mg).37 Interestingly, no significant differences were identified among the various formulations and there was little or no intrapatient variation in dose-response. To determine whether “slow” versus “bolus” injection is superior, an open clinical study of 52 patients was performed using the same dosage.38 This study found that 28 of the 52 patients reported improved penile rigidity with bolus injection rather than a slow injection, while 24 patients reported no difference. There seems to be no particular utility to slow administration although the authors of this article did not clarify the functional parameters of a “slow” versus bolus injection.
One study measuring the local intracavernous and peripheral venous concentration curves of papaverine and prostaglandin E1 found that papaverine slowly drains into the systemic circulation and shows a slightly higher level in the peripheral blood approximately 30 to 60 minutes after injection.39 Prostaglandin E1 shows a much more rapid decrease in the local concentration with no measurable increase in the peripheral concentration, which is presumably due to the short halftime of the drug after it passes the lungs.
*Corporal fibrosis/Peyronie’s Disease and priapism are the 2 most common serious adverse effects that have been reported in the context of intracavernous injections for ED.
Fibrosis is thought to occur after multiple intracavernosal injections and led to plaques similar to those seen in Peyronie’s disease, which may lead to penile curvature and/or worsening ED. One study of 92 patients found that fibrosis occurred in 12% of men after a mean of 10 months of use. Interestingly, this study did not find that fibrosis incidence was associated with the number of injections, but rather, that it is associated with inadequate compression of injection sites after intracavernosal injections.40 Onset of fibrosis has also been reported after relatively low numbers of injections, in particular when there are complications of injection technique such as subcutaneous injections or hematoma formation.41 For these reasons it is deemed essential to instruct patients to hold pressure on the injection site as a routine recommendation. Interpretation of the incidence of penile fibrosis/Peyronie’s Disease in the context of penile injections is complicated in that many men who use injections have not had a full/rigid penile erection for years before the treatment. For this reason, clinically occult scars/fibrosis may become clinically apparent only after the injection is administered, in which case the injection itself may be falsely implicated as the cause.
Priapism is the most serious common adverse reaction clearly linkable to penile injection therapy. This form of priapism is generally amenable to the irrigation/aspiration of the corporal bodies. It is common practice to also include intracorporal injection of the sympathomimetic agent, preferably phenylephrine due to its selective binding to alpha-1-receptors.42,43 The efficacy of this therapy for the resolution of priapism declines with the duration of erection so patients should be advised to not delay presentation for therapy in the context of injection-induced priapism. Prevention of priapism in the first place is preferred; for this reason, it is typical to start injection therapy for ED at a very low dose under the direct supervision of a clinician. Dose escalation may be considered under the guidance of the prescribing physician.1
INTRAURETHRAL PHARMACOTHERAPY FOR ERECTILE DYSFUNCTION
The mucosal lining of the urethra is permeable to prostaglandin. This property permitted the development of a urethral suppository that delivers concentrated prostaglandin to facilitate erection. The cleverly named Medicated Urethral Suppository for Erections (MUSE) is available in concentrations of 125, 250, 500, and 1000 mcg. The half-life is approximately 5 to 10 minutes, with the onset of action within 30 to 60 minutes.44
The most common side effects are urethral burning and pain, reported in 12% of patients. Less common side effects include urethral bleeding (5%), and even less frequently, blurred vision, confusion, dizziness, sweating, and fatigue. Rarely, this medication can cause fainting. MUSE is contraindicated in patients with PGE1 hypersensitivity, and it is recommended to use only with caution in patients with a known urethral stricture, balanitis, severe hypospadias, and curvature, and in patients with acute or chronic urethritis. MUSE should not be used if the man is engaging in vaginal intercourse with a pregnant partner unless a condom is used to mitigate the possible transfer of prostaglandin and subsequent induction of labor.
COMBINATION THERAPY
Combination therapy (most commonly an oral PDE5i and an intracavernosal injection agent) has been suggested as a potential treatment modality for some men who do not have success with a single therapy. This approach is associated with an increased risk of adverse events, in particular priapism. Combination therapy is currently considered off-label use and should be conducted with caution and careful patient selection.
One study of 34 men postradical prostatectomy demonstrated that two-thirds had increased response after combining ICI with a PGE1 with a maximum dose of PDE5i.45 This was also demonstrated in a larger study of 93 men, though this study also demonstrated a higher side effect rate when compared with PDE5i use alone.46 MUSE combined with PDE5i has also been demonstrated to result in improved erections. In a study of 23 men who had undergone prostatectomy and had failed the maximum dose of sildenafil, 83% reported enhanced erections using combination therapy and reported that approximately 80% of the time they were able to achieve an erection that was sufficient for penetrative intercourse.22
FUTURE DIRECTIONS
The efficacy and safety of PDE5i for ED have dampened enthusiasm for the investment required to develop truly novel pharmacotherapies for ED. That said, a number of compounds have been developed to modulate other molecular pathways and/or steps in the NO-cGMP pathway.
Tissue and receptor selectivity is a major roadblock in the development of novel ED pharmacotherapies. The predominance of a specific PDE isoform (PDE5) in the penis makes targeting with a selective inhibitor feasible. Other molecular messengers are more widely expressed in the body, increasing the odds of undesirable side effects, particularly for medications that are dosed orally and subsequently have the potential to be distributed to other body regions.
Soluble guanylate cyclase activators are a promising class of agents for ED that work to stimulate the production of cGMP without reliance on nitric oxide. The promise of these agents largely revolves around use in men who have neurogenic ED (eg related to pelvic surgery or diabetic neuropathy) and hence the absence of the nNOS required for initiating erectile processes. These agents may be beneficial as monotherapy or as an adjunct to PDE5i. Both soluble and insoluble forms are under investigation. Preliminary evidence has been promising.47 However, none of these agents have at this time achieved approval by a regulatory body and the potential clinical utility of such agents remains ambiguous based on the absence of recent peer-reviewed published data.48
The RhoA/Rho Kinase pathway has been of considerable interest as a management strategy for ED for some time. Rho Kinase enhances calcium activity/sensitivity in corporal smooth muscle, leading to increased muscle tone and vasoconstriction.7,8 Animal studies have suggested a beneficial effect of Rho Kinase Inhibitors (RKI) in the induction of penile erection.49 In vitro studies of human corporal tissues have demonstrated that a specific RKI can induce smooth muscle relaxation and an effect that is potentiated by the addition of a PDE55i.50 Whether these encouraging findings can be translated into a clinical application remains uncertain.
At the time of this writing, there is no pharmacotherapy approved specifically for the management of hypoactive sexual desire disorder in men. Testosterone supplementation is an approved treatment of testosterone deficiency syndrome (TDS) with improvements in a libido a commonly sought beneficial effect of therapy.51 A discussion of testosterone merits much more consideration than can be incorporated into a review of this nature.
Flibanserin is a novel multifunctional serotonin agonist and antagonist that has been approved as an oral formulation for the management of HSDD in women. This medication acts as a full agonist at postsynaptic 5HT1A receptors and as an antagonist at postsynaptic 5HT2A receptors.52,53 This medication acts selectively on pyramidal neurons to release dopamine and norepinephrine and reduce serotonin. Bremelanotide is a melanocortin analog that has been approved as a dopamine receptor agonist for the management of the same condition. A limited body of evidence supports the use of these agents for men with HSDD but neither has been submitted for FDA approval in men.54
SUMMARY
A wide variety of pharmacotherapies are available for men with ED. The appropriate treatment of a given man depends on the severity of his ED, his comorbid risk factors, and his tolerance for treatment-related adverse events.
Farnoosh Nik-Ahd, MD, Alan W. Shindel, MD, MAS*
INTRODUCTION
Erectile dysfunction (ED) is a common and vexing clinical problem that leads to the substantial disruption of quality of life and relationships.1 Interest in facilitating and restoring erections is documented in ancient texts going back to the beginnings of recorded human history and probably extends back even further than that.2 A variety of superstitions and herbal remedies have been touted; some of these ancient remedies have pharmacologic properties that are consistent with erectogenic effects and/or have been investigated in modern clinical trials.2,3
Despite millennia of interest in ED, it is only within the past 40 years that demonstrably and consistently effective pharmacologic treatments have been available for this common ailment. The arrival of effective pharmacotherapy for ED was heralded by the famous (or perhaps infamous) actions of Dr. Giles Brindley, who demonstrated his pharmacologically induced erection at a scientific session of the 1983 Annual Meeting of the American Urologic Association.4 This dramatic presentation ushered in an era of effective pharmacotherapy for ED. Approximately 10 years later the fundamental role of nitrergic neurons (formerly known as nonadrenergic-noncholinergic “NANC” neurons) in mediating vascular responses was determined.5 These discoveries paved the way for pharmacotherapies that modulated steps in the nitrergic pathway as treatments for ED, culminating in the release of the first highly effective and tolerable oral pharmacotherapy for ED in 1998.6
In this article, we review the current state of the art in pharmacotherapy for ED. An understanding of ED pharmacotherapy necessitates at least a brief review of the molecular mechanisms that mediate penile vasodilation. Our focus will be on agents currently approved for use by the United States Food and Drug Administration (US FDA) although we will also consider the commonly used (albeit not formally approved) agents used as injectable drugs for the induction of penile erection. The main classes of pharmacotherapy for ED are listed in Table 1. Brief consideration will be given to agents approved for use by regulatory bodies outside the United States. We will conclude with the consideration of directions for future research and development in medical therapy for ED.
MOLECULAR MECHANISMS OF ERECTION
A detailed discussion of the anatomic/tissue properties of the penis that allow for penile erection is beyond the scope of this article. The reader is referred to excellent historical and recent publications on this topic for more detail.7,8 However, an understanding of the pharmacology of ED treatment requires some knowledge of the molecular mechanisms that regulate penile vasodilation.
The nitric oxide (NO) pathway has emerged as a fundamental and essential element of genital vasodilation.7 NO is derived from neuronal and endothelial Nitric Oxide Synthase (nNOS and eNOS, respectively). NO is in turn responsible for activating Soluble Guanylate Cyclase, which catalyzes the conversion of Guanosine Triphosphate (GTP) to cyclic Guanosine Monophosphate (cGMP). cGMP plays a critical role in modulating a number of cellular processes via the activation of Protein Kinase G (PKG). The downstream effects of PKG in the penis include potassium sensitization, suppression of the calcium sensitizing RhoA-Rho Kinase pathway, and depletion of intracellular calcium by sequestration in the sarcoplasmic reticulum and expulsion through membrane-bound calcium channels. The net effect of all these pathways is to oppose the activation of the actin-myosin cross-bridge formation in smooth muscle cells of penile arteries and corporal erectile tissue, leading to muscular relaxation and subsequent vasodilation. With vasodilation, penile blood flow is increased and the corporal bodies become engorged with blood.
With the cessation of sexual arousal, the production of NO declines. Production of cGMP declines in turn and the processes that mediate corporal vasodilation cease. cGMP is broken down by the action of phosphodiesterases. The most clinically relevant isoform of phosphodiesterase in the penis is type 5 (PDE5). Selective inhibitors of PDE5 (PDE5i) are potent erectogenic agents that work by prolonging the vasodilatory effects of cGMP in the penis. These highly efficacious agents have been the mainstay of ED therapy for over 2 decades; their unique mechanism of action explains the important observation that these drugs are primarily useful for maintaining rather than attaining an erection. Reliance on initial NO activity for efficacy also makes clear how these agents are less effective in men with neurogenic etiologies for ED (eg, post pelvic surgery, severe diabetes).9
While the NO/cGMP/PDE5 pathway is arguably the most fundamental and clinically important molecular pathway mediating erection, a number of other vascular mechanisms are also at play and may be manipulated pharmacologically to induce erections. The sympathetic tone is dominant in the penis at baseline and limits the inflow of blood. Therefore, erections are mediated by parasympathetic neural input from the sacral (S2–S4) spinal cord.10 Cessation of sympathetic tone to the penis via cortical inhibition of sympathetic projections from the thoracic spinal cord is an important mechanism of psychogenic arousal contributing to penile erection. Sympatholytic drugs administered to the penis may also have erectogenic effects. Protein Kinase A (PKA) works in a fashion similar to PKG and can have similar vasodilatory effects mediated by many of the same mechanisms. PKA may be produced by the action of various other drugs known to be associated with the induction of erections, specifically prostaglandin E1.7
ORAL PHARMACOTHERAPY FOR ERECTILE DYSFUNCTION
Dr. Louis Ignarro, Dr. Jacob Rajfer, and colleagues at the University of California, Los Angeles reported that nitric oxide (NO) was the chemical mediator of penile erections in 1992.5 Dr. Ignarro would later be awarded the Nobel prize for his discovery of the role of NO in vasodilation. Subsequent elucidation of the presence of PDE5I in the penis and the discovery of drugs that were selective inhibitors of this enzyme led to the use of PDE5i as a mainstay of ED treatment, a development that persists to this day.5,6,11 The creation of an effective and safe oral therapy for ED had profound effects on culture and society that were out of proportion to its medical utility. The advent of PDE5 put sex and sexuality at the forefront of public consciousness and altered the way the world views and discusses sex.
The PDE5 gene is localized to chromosome 4q26.12,13 It encodes the PDE5 enzyme, which is a homodimer that is about 200 kDa large.13 PDE5 selectively hydrolyzes only cGMP, in contrast to other PDE isoforms which may catalyze both cAMP and cGMP or just cAMP.14,15 There are 3 main components to PDE5: the N-terminal fold, the linker region, and the L-terminal helix.16,17 The N-terminal serves to regulate the catalytic domain and is activated by cGMP binding and phosphorylation. Though there are 3 unique isoforms of PDE5, the catalytic domain is conserved across isoforms. The catalytic domain of PDE5 consists of a core pocket, a lid region, a hydrophobic pocket, and a metal-binding site. The core pocket consists of 3 components: the saddle, which in PDE5I is specific to cGMP, and 2 deep pockets which serve as hydrophilic clamps that “sandwich” cGMP or PDE5i and help potentiate the activity of PDE5i.18
PDE5i are currently used on-label in the treatment of both ED and pulmonary hypertension. All currently approved oral pharmacotherapies for ED are of the PDE5i class (Table 2). These agents have revolutionized the care of men with ED and improved the quality of life for many men and their partners. All of these drugs have proven efficacy. Limited published data, typically industry-sponsored, tout the advantages or patient preferences of one drug over the others but ultimately it is not clear that anyone is superior across the board for all patients. The selection of PDE5i ultimately comes down to issues of individual patient preferences and (often) access in terms of insurance coverage and costs.
PDE5i have accrued a very favorable safety profile over the past 22+ years they have been available.19 The only class-specific medical contraindication is the use of concomitant daily dose nitrate therapy as the combination of a nitrate drug and PDE5i may lead to a precipitous drop in blood pressure.20 PDE5i may be offered to patients who have been prescribed short-acting nitrate medications (eg sublingual nitroglycerin) but it must be made clear to such patients that they should not use these drugs within 24 hours of one another (and possibly 36 in the case of long-acting PDE5i such as tadalafil). Alpha-blocker therapy is a relative contraindication due to the potential for the exacerbation of orthostatic hypotension; this effect is typically mild and can be mitigated by providing an interval between dosing.21
Common adverse reactions associated with PDE5i include headaches (12%–15%), flushing (4%–14%), indigestion (<1–10%), stuffy nose/ congestion (4%–10%), vision disturbances (0%– 5%), and myalgias (rare-4%). Serious side effects include angina, sudden decrease or loss of vision, serious skin reactions, and seizures.22 The mechanism of these adverse events and whether they are truly related to the use of the medication is somewhat unclear; the absolute incidence of these events appears to be quite rare given the long clinical history of PDE5i and the numerous prescriptions dispensed as they became commercially available.
The incidence of priapism with the use of PDE5i, while frequently mentioned in advertising, seems to be lower than for some other common medications that are not explicitly given with the intention of inducing erections (eg trazodone, second-generation antipsychotics).23 Patients should be counseled on this potential but may be reassured that the likelihood of prolonged erection is low.
A number of clinical syndromes have been reported in association with PDE5i, including NonArteric Ischemic Optic Neuropathy (NAION, a source of sudden unilateral vision loss), sensorineural hearing loss, major adverse cardiac events, and melanoma.23 Evidence in support of these syndromes being clearly linked to PDE5i as an independent risk factor is generally scant with the possible exception of NAION. However, NAION is a rare clinical entity with an estimated annual incidence of about 1 case per 10,000 person-years.24 Given very low baseline probability, even a statistically significant increase in incidence with PDE5i use translates into a very low absolute risk for this condition in PDE5i users.
Sildenafil
Sildenafil was the first PDE5i and was originally synthesized in Sandwich, UK. In 1991, the drug underwent a phase 1 clinical trial for angina. Although the drug did not have efficacy for angina, it was speculated that it may help with erectile problems. In 1992, a multi-dose phase 1 trial in healthy volunteers was conducted in Wales, and erections were noted to be a side effect. The efficacy of the medication was further demonstrated in 1993 during a pilot cross-over study of 16 men, in which “clear differences between sildenafil and placebo” were noted. Phase 2 and Phase 3 clinical trials were conducted between 1994 and 1997. Importantly, the drug demonstrated excellent tolerability, with the main adverse effects of headache, flushing, dyspepsia, and congestion. No significant differences were noted in the rate of MI, CVA, or serious cardiac events.25 In 1998, Viagra was approved as the first oral agent for the treatment of ED.6
Sildenafil consists of a pyrazolopyrimidine group (which binds to the core pocket of the catalytic domain of PDE5), an ethoxyphenyl group (which binds to the hydrophobic pocket), and methylpiperazine (which lies in the lid region). This drug has no interaction with the metal-binding site.26 Inhibition of PDE5 in this fashion leads to the diminished breakdown of cGMP.
Typical dosages of sildenafil are 25 to 100 mg taken on demand. This medication is also sold under the trade name Revatio, administered at 20 mg three times daily for the management of pulmonary hypertension.27 Sildenafil has a half-life of 3 to 5 hours and a mean apparent steady-state volume of distribution of approximately 105 L.28 This substantially exceeds the body’s total volume of water, which is approximately 42 L. The onset of action typically occurs within 60 minutes. Sildenafil is metabolized by the hepatic P450 enzymes CYP3A4 and CYP2C9. Patients using strong inhibitors of these cytochromes (eg ritonavir, erythromycin, ketoconazole) and those patients with liver failure or severe renal failure experience increased exposure to the drug at a given dose29; low starting doses should be considered in these patients. Of note, absorption of sildenafil is slowed by intake of dietary lipids. Thus, this medication should not be taken after a meal, and it is often recommended that this medication be taken preprandial.
Vardenafil
Vardenafil, approved by the FDA in 2003, has similar pharmacokinetics to those of sildenafil. The pyrazolopyrimidine structure of this drug is very similar to sildenafil. Trade names for this medication are Levitra and Staxyn. Typical dosages of vardenafil are 5 to 20 mg. Vardenafil has a half-life of 4 to 6 hours and a mean apparent steady-state volume of distribution of 208 L.28 Fifty percent of users report getting an erection within 30 minutes of oral dosing. Vardenafil is also available in a sublingually administered 10 mg formulation. Side effects are similar to those listed above.
Vardenafil is predominantly metabolized in the liver via CYP3A4 and like sildenafil, the dosing should be adjusted to lower concentrations in patients taking inhibitors of this cytochrome. Similar to sildenafil, absorption of vardenafil is slowed by dietary lipid intake, and it is recommended that vardenafil not be taken after a meal and instead be taken preprandial. Vardenafil is also contraindicated in patients with congenital QT syndrome and also patients using Type IA or III antiarrhythmics.30 The FDA also recommends against the use of vardenafil in patients on hemodialysis or with severe hepatic failure.31
Tadalafil
Tadalafil was initially approved by the FDA in November 2003 and is sold under the brand name Cialis. Its chemical composition creates a rigid structure, which improves the drug’s selectivity and at least hypothetically may reduce the likelihood of adverse reactions related to the cross-binding of this drug to other PDE isoforms in other parts of the body. Typical dosages of this medication for ED are 5 to 20 mg on-demand or 2.5 to 5 mg daily dose. Tadalafil has a half-life of 17.5 hours and a mean apparent steady-state volume of distribution of 60 to 70 L.28 Unlike sildenafil and vardenafil, the absorption of tadalafil is not affected by food intake. Tadalafil is predominantly metabolized by the hepatic enzyme CYP3A. Unique features of Tadalafil’s structure are that there is a hydrogen bond to the saddle, that methylenedioxyphenyl binds to the Q2 pocket, and that there is extensive interaction with the hydrogen pocket which leads to a rigid structure and decreased entropy with binding. Its patent protection expired from 2017 to 2020.
*Of note, tadalafil is the only PDE5i that is approved to be taken daily (the other PDE5i medications are approved for on-demand use). Daily tadalafil has also been shown to be effective for treating benign prostatic hyperplasia that causes lower urinary tract symptoms.32
Avanafil
Avanafil was approved by the FDA in 2012 after meeting primary efficacy and safety endpoints and is commercially available as Stendra. The side effect profile is consistent with other existing PDE5is and includes congestion, headache, flushing, and rhinorrhea. Typical dosages are 50 to 200 mg dosed on-demand. Of note, avanafil is purported to have a more rapid onset of action compared with other FDA-approved PDE5i; direct comparison data on the onset of action are limited. The half-life of avanafil is approximately 6 hours and a steady-state volume of distribution of 47 to 83L.22
Avanafil is unique structurally in that it contains a chloromethoxy benxylamino group, pyrimidine carboxyamide, and a pyrimidinylmethyl group. Additionally, the catalytic site binding is irrespective of the molecule’s orientation.33 The FDA recommends against the use of avanafil in patients with severe renal or hepatic impairment.34 At the time of this writing, there is no generic form of this medication available.
Other phosphodiesterase type V inhibitors
Numerous PDE5I have been developed and approved outside of the United States. Examples include mirodenafil, udenafil, and lodenafil. These agents differ in terms of absorption and half-life but estimates of overall efficacy seem similar to what is observed in studies of agents available in the United States. Mirodenafil is sold under the trade name Mvix and has a Tmax of 1.125 hours and a half-life of 2.5 hours. The typical dose is 5 to 100 mg. Udenafil is sold under the trade name Zydena. Its Tmax is 1 to 1.5 hours and its half-life is 11 to 13 hours. Typical dosages are 100 to 200 mg. Lodenafil, sold under the brand name Helleva, has a Tmax of 1.2 hours and a half-life of approximately 2 hours. Its typical dosages are 40 to 80 mg.22
INJECTION PHARMACOTHERAPY FOR ERECTILE DYSFUNCTION
Prostaglandin E1 (PgE1, also known as Alprostadil) is the only agent that has been approved by the US FDA as an intracavernosal injection for the management of ED. PgE1 acts to stimulate the production of cAMP and works to induce vasodilation, smooth muscle relaxation, and inhibit platelet aggregation.35 In studies, intracavernous Alprostadil was either significantly more efficacious or comparable to comparative medications.
Although not formally approved as treatments for ED, a number of other vasodilatory agents have been widely used with good efficacy and safety for the management of ED. The alphaantagonist phentolamine opposes sympathetic tone to the penis; when administered as an injection this drug has the effect of “removing the brakes” of sympathetic induced vasoconstriction and inducing erection response. The nonspecific PDE inhibitor papaverine is also widely used as an injectable medication for ED; inhibition of PDE in the penis has the net effect of helping to maintain the presence of cGMP and cAMP in the corporal bodies, leading to the preservation of vasodilation by mechanisms addressed in the above section on selective PDE5i. These injectable medications are most commonly used as compounded mixtures combining 2 or 3 agents (known as bimix and trimix, respectively). The cholinergic drug atropine is sometimes added to produce the so-called “quadmix.” The clinical utility of atropine for the potentiation of penile erection is ambiguous and has not been supported in clinical trials.36
To determine the pharmacodynamic profile of intracavernous prostaglandin E1, one study randomized patients to 1 of 5 dose groups (placebo, 2.5 mg, 5 mg, 10 mg, or 20 mg).37 Interestingly, no significant differences were identified among the various formulations and there was little or no intrapatient variation in dose-response. To determine whether “slow” versus “bolus” injection is superior, an open clinical study of 52 patients was performed using the same dosage.38 This study found that 28 of the 52 patients reported improved penile rigidity with bolus injection rather than a slow injection, while 24 patients reported no difference. There seems to be no particular utility to slow administration although the authors of this article did not clarify the functional parameters of a “slow” versus bolus injection.
One study measuring the local intracavernous and peripheral venous concentration curves of papaverine and prostaglandin E1 found that papaverine slowly drains into the systemic circulation and shows a slightly higher level in the peripheral blood approximately 30 to 60 minutes after injection.39 Prostaglandin E1 shows a much more rapid decrease in the local concentration with no measurable increase in the peripheral concentration, which is presumably due to the short halftime of the drug after it passes the lungs.
*Corporal fibrosis/Peyronie’s Disease and priapism are the 2 most common serious adverse effects that have been reported in the context of intracavernous injections for ED.
Fibrosis is thought to occur after multiple intracavernosal injections and led to plaques similar to those seen in Peyronie’s disease, which may lead to penile curvature and/or worsening ED. One study of 92 patients found that fibrosis occurred in 12% of men after a mean of 10 months of use. Interestingly, this study did not find that fibrosis incidence was associated with the number of injections, but rather, that it is associated with inadequate compression of injection sites after intracavernosal injections.40 Onset of fibrosis has also been reported after relatively low numbers of injections, in particular when there are complications of injection technique such as subcutaneous injections or hematoma formation.41 For these reasons it is deemed essential to instruct patients to hold pressure on the injection site as a routine recommendation. Interpretation of the incidence of penile fibrosis/Peyronie’s Disease in the context of penile injections is complicated in that many men who use injections have not had a full/rigid penile erection for years before the treatment. For this reason, clinically occult scars/fibrosis may become clinically apparent only after the injection is administered, in which case the injection itself may be falsely implicated as the cause.
Priapism is the most serious common adverse reaction clearly linkable to penile injection therapy. This form of priapism is generally amenable to the irrigation/aspiration of the corporal bodies. It is common practice to also include intracorporal injection of the sympathomimetic agent, preferably phenylephrine due to its selective binding to alpha-1-receptors.42,43 The efficacy of this therapy for the resolution of priapism declines with the duration of erection so patients should be advised to not delay presentation for therapy in the context of injection-induced priapism. Prevention of priapism in the first place is preferred; for this reason, it is typical to start injection therapy for ED at a very low dose under the direct supervision of a clinician. Dose escalation may be considered under the guidance of the prescribing physician.1
INTRAURETHRAL PHARMACOTHERAPY FOR ERECTILE DYSFUNCTION
The mucosal lining of the urethra is permeable to prostaglandin. This property permitted the development of a urethral suppository that delivers concentrated prostaglandin to facilitate erection. The cleverly named Medicated Urethral Suppository for Erections (MUSE) is available in concentrations of 125, 250, 500, and 1000 mcg. The half-life is approximately 5 to 10 minutes, with the onset of action within 30 to 60 minutes.44
The most common side effects are urethral burning and pain, reported in 12% of patients. Less common side effects include urethral bleeding (5%), and even less frequently, blurred vision, confusion, dizziness, sweating, and fatigue. Rarely, this medication can cause fainting. MUSE is contraindicated in patients with PGE1 hypersensitivity, and it is recommended to use only with caution in patients with a known urethral stricture, balanitis, severe hypospadias, and curvature, and in patients with acute or chronic urethritis. MUSE should not be used if the man is engaging in vaginal intercourse with a pregnant partner unless a condom is used to mitigate the possible transfer of prostaglandin and subsequent induction of labor.
COMBINATION THERAPY
Combination therapy (most commonly an oral PDE5i and an intracavernosal injection agent) has been suggested as a potential treatment modality for some men who do not have success with a single therapy. This approach is associated with an increased risk of adverse events, in particular priapism. Combination therapy is currently considered off-label use and should be conducted with caution and careful patient selection.
One study of 34 men postradical prostatectomy demonstrated that two-thirds had increased response after combining ICI with a PGE1 with a maximum dose of PDE5i.45 This was also demonstrated in a larger study of 93 men, though this study also demonstrated a higher side effect rate when compared with PDE5i use alone.46 MUSE combined with PDE5i has also been demonstrated to result in improved erections. In a study of 23 men who had undergone prostatectomy and had failed the maximum dose of sildenafil, 83% reported enhanced erections using combination therapy and reported that approximately 80% of the time they were able to achieve an erection that was sufficient for penetrative intercourse.22
FUTURE DIRECTIONS
The efficacy and safety of PDE5i for ED have dampened enthusiasm for the investment required to develop truly novel pharmacotherapies for ED. That said, a number of compounds have been developed to modulate other molecular pathways and/or steps in the NO-cGMP pathway.
Tissue and receptor selectivity is a major roadblock in the development of novel ED pharmacotherapies. The predominance of a specific PDE isoform (PDE5) in the penis makes targeting with a selective inhibitor feasible. Other molecular messengers are more widely expressed in the body, increasing the odds of undesirable side effects, particularly for medications that are dosed orally and subsequently have the potential to be distributed to other body regions.
Soluble guanylate cyclase activators are a promising class of agents for ED that work to stimulate the production of cGMP without reliance on nitric oxide. The promise of these agents largely revolves around use in men who have neurogenic ED (eg related to pelvic surgery or diabetic neuropathy) and hence the absence of the nNOS required for initiating erectile processes. These agents may be beneficial as monotherapy or as an adjunct to PDE5i. Both soluble and insoluble forms are under investigation. Preliminary evidence has been promising.47 However, none of these agents have at this time achieved approval by a regulatory body and the potential clinical utility of such agents remains ambiguous based on the absence of recent peer-reviewed published data.48
The RhoA/Rho Kinase pathway has been of considerable interest as a management strategy for ED for some time. Rho Kinase enhances calcium activity/sensitivity in corporal smooth muscle, leading to increased muscle tone and vasoconstriction.7,8 Animal studies have suggested a beneficial effect of Rho Kinase Inhibitors (RKI) in the induction of penile erection.49 In vitro studies of human corporal tissues have demonstrated that a specific RKI can induce smooth muscle relaxation and an effect that is potentiated by the addition of a PDE55i.50 Whether these encouraging findings can be translated into a clinical application remains uncertain.
At the time of this writing, there is no pharmacotherapy approved specifically for the management of hypoactive sexual desire disorder in men. Testosterone supplementation is an approved treatment of testosterone deficiency syndrome (TDS) with improvements in a libido a commonly sought beneficial effect of therapy.51 A discussion of testosterone merits much more consideration than can be incorporated into a review of this nature.
Flibanserin is a novel multifunctional serotonin agonist and antagonist that has been approved as an oral formulation for the management of HSDD in women. This medication acts as a full agonist at postsynaptic 5HT1A receptors and as an antagonist at postsynaptic 5HT2A receptors.52,53 This medication acts selectively on pyramidal neurons to release dopamine and norepinephrine and reduce serotonin. Bremelanotide is a melanocortin analog that has been approved as a dopamine receptor agonist for the management of the same condition. A limited body of evidence supports the use of these agents for men with HSDD but neither has been submitted for FDA approval in men.54
SUMMARY
A wide variety of pharmacotherapies are available for men with ED. The appropriate treatment of a given man depends on the severity of his ED, his comorbid risk factors, and his tolerance for treatment-related adverse events.
