Pharmacotherapy for Erectile Dysfunction

Blackwell Science, LtdOxford, UKJSMJournal of Sexual Medicine1743-6095Journal of Sexual Medicine 1743 6095200412128140Original ArticlePharmacotherapy for Erectile DysfunctionPadma-Nathan et al.

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ORIGINAL RESEARCH—PHOSPHODIESTERASE INHIBITOR THERAPY FOR ED Pharmacotherapy for Erectile Dysfunction Harin Padma-Nathan, MD, George Christ, PhD, Ganesan Adaikan, MD, Edgardo Becher, MD, Gerald Brock, MD, Serge Carrier, MD, Culley Carson, MD, Jackie Corbin, PhD, Sharon Francis, PhD, Robert DeBusk, MD, Ian Eardley, MD, Hans Hedlund, PhD, Adolph Hutter, MD, Graham Jackson, MD, Robert Kloner, MD, PhD, Shin Lin, PhD, Kevin McVary, MD, Andrew McCullough, MD, Ajay Nehra, MD, Hartmut Porst, MD, Claude Schulman, MD, Allen Seftel, MD, Ira Sharlip, MD, Christian Stief, MD, and Claude Teloken, MD Summary of Committee. For the complete report please refer to Sexual Medicine: Sexual Dysfunctions in Men and Women, edited by T.F. Lue, R. Basson, R. Rosen, F. Giuliano, S. Khoury, F. Montorsi, Health Publications, Paris 2004. ABSTRACT

Introduction. Advances in understanding of the biochemistry and physiology of penile erection have led to breakthroughs in pharmacotherapy of erectile dysfunction. Aim. To provide recommendations/guidelines concerning state-of-the-art knowledge for the putative molecular and cellular mechanisms of action of centrally and peripherally acting drugs currently utilized in pharmacotherapy of erectile dysfunction. Methods. An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a two-year period. Concerning the Pharmacotherapy for Erectile Dysfunction Committee there were 25 experts from 10 countries. Main Outcome Measure. Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation and debate. Results. Selective and potent oral PDE5 inhibitors have significantly more affinity than cGMP and form broader molecular interactions with multiple amino acids, thereby blocking access to cGMP in the catalytic sites of the PDE5 enzyme. PDE5 inhibitors, which vary as to biochemical potency, selectivity and pharmacokinetics, lead to cGMP elevation and relaxation facilitation of penile corpus cavernosum smooth muscle cells following sexual stimulation. Various centrally acting drugs influence sexual behaviour. In particular, the dopaminergic substance apomorphine is a central enhancer that acts in the paraventricular nucleus of the hypothalamus as a dopamine (D2) receptor agonist, induces and increases penile erection responses via disinhibition, following sexual stimulation. Conclusions. There is a need for more research in the pharmacotherapeutic development of central and peripheral agents for safe and effective erectile dysfunction treatment. Key Words. Penile Erection Physiology; Biochemistry; Pharmacotherapy; Erectile Dysfunction; PDE5 Inhibitors; Apomorphine; Yohimbine

J Sex Med 2004; 1: 128–140

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Pharmacotherapy for Erectile Dysfunction Introduction

Centrally Acting Drugs

T

Apomorphine Although the mechanisms underlying erectile function are not fully understood, advances have been made regarding the interplay of central and peripheral mechanisms. It is now widely agreed that central disinhibition plays a crucial role in the induction of erectile responses and this has led to the development of the central enhancer, the dopaminergic substance apomorphine. Apomorphine acts in the paraventricular nucleus of the hypothalamus as a dopamine (D2) receptor agonist. It works as a pro-erectile conditioner at this level to increase the responses of the erectile pathway following appropriate sexual stimulation. Understanding the role of central pathways/mech-

he putative mechanism of actions of the available centrally and peripherally acting drugs are reviewed. These reviews are accompanied by summary figures (Figures 1 and 2) that provide a conceptual framework for understanding this field of medical therapy. In addition, a detailed summary table (Table 1) is given, which outlines as much as possible, the specific mechanism of action of these drugs. In the last mechanism of action section, which deals with the exciting developments in the PDE5 inhibitor field, there are three additional figures (Figures 3–5) and an additional table (Table 2), to provide detail about the currently most explosive area of drug research and development in erectile dysfunction.

Brain

Spinal cord

Peripheral nerve

End Organ (Penis)

Smooth muscle cells Endothelial cells Figure 1

J Sex Med 2004; 1: 128–140

J Sex Med 2004; 1: 128–140 Paraventricular nucleus (PVN)

Sublingual

Subcutaneous

Topical, IU, IC Topical, IC Oral Intracavernosal

Oral

Oral Oral

Oral, IV

Oral

IC Topical Topical

Melanocortins/Melanotan II

PGE1 Papaverine Phentolamine

Yohimbine

L-Arginine Trazodone

Delequamine

Nalmafene Naltrexone

VIP Minoxidil NTG

Penis Penis Penis

CNS

CNS Penis

Penis Brain Penis

CNS Penis

Hypothalamus, spinal, penile sensory afferents Penis Penis Penis

Penis

Oral

Sildenafil Vardenafil Tadalafil Apomorphine

Site of action

Mode of administration

Mechanism of action summary

Drug

Table 1

EP2/4 receptor activation: increased intracellular CAMP levels Nonspecific PDE inhibitor: Increased cAMP and cGMP levels Blockade of postjunctional a1- and a2-adrenoceptors on corporal smooth muscle cells Increase supply of NO via nonadrenergic, noncholinergic effect on NOS Blockade of prejunctional a2-adrenoceptors in hypothalamus (MPOA) Blockade of postjunctional a2-adrenoceptors on corporal smooth muscle cells Blockade of prejunctional a2-adrenoceptors penile arteries Increased supply of nitric oxide (endothelial, neural) Serotonin reuptake inhibitor Blockade of postjunctional a1- and a2-adrenoceptors on corporal smooth muscle cells Blockade of prejunctional a2-adrenoceptors in the locus ceoruleus Blockade of postjunctional a2-adrenoceptors on corporal smooth muscle cells Opioid receptor antagonist; attenuation of altered central opioid function (e.g., LHRH, LH, testosterone) Increased intracellular cAMP levels K channel modulator: Increased K channel activity NO donor: Increased cGMP levels

Increased CSM relaxation Increased CSM relaxation Increased CSM relaxation

Conditioner

Increased CSM relaxation Prolonged erections Increased corporal smooth muscle relaxation Conditioner Increased CSM relaxation

Conditioner Increased CSM relaxation

Conditioner: increases the response to sexual stimulation Conditioner/initiator of penile erection Increased CSM relaxation Increased CSM relaxation Increased CSM relaxation

D2-like receptor activation of oxytocinergic neurons

Activation of melanocortin receptors (M4; M3?)

Increased corporal smooth muscle (CSM) relaxation

Effect

PDE V Inhibitor. Increased cGMP levels

Mechanism of action

130 Padma-Nathan et al.

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Pharmacotherapy for Erectile Dysfunction

Ionic mechanisms: convergence of diverse cellular processes

Ca-mobilization mechanisms: the key to changes in contractility

Ca-sensitization mechanisms: a key to sustained contraction

Kinase activation: PKA, PKC, PKG

Figure 2 Schematic depiction of mechanism of action of drugs acting in the penis.

anisms in the control of the erectile process is critical to elucidating the mechanism of action of this newer class of orally active erectogenic agents. Dopamine is one among a number of important central neurotransmitters involved in the initiation of erection. Dopamine is the main transmitter within the paraventricular nucleus (PVN) [1,2] that plays an important role in the central control of erection. Dopamine receptors are divided into

two main families, D1 and D2-like receptors. Apomorphine has a higher affinity for the D2-like receptors [3] that are thought to be the main site for the induction of erections in the PVN [4]. Oxytocinergic neurones in this nucleus are responsive to the administration of apomorphine via activation of both the D1-and D2-receptor subtypes, which subsequently induces a cascade of events that reach the periphery to elicit penile

Table 2 Pharmacokinetic parameters of the selective PDE5 inhibitor Parameter

Tadalafil* (fasted)

Sildenafil† (fasted) 100 mg

Vardenafil‡ (fasted) 20 mg

Cmax, ng/mL tmax, hour

378 2 (0.5–12.0) 17.5 (21.6: elderly) NA NA

450 0.8

20.9 0.7–0.9

3–5

4–5

96% 40%

91% 14.5%

t1/2 hour Protein binding, % Bioavailability, %

* Patterson B. et al. 4th Congress of ESSIR, 2001, Rome, Italy. † Viagra USPI [package insert], 2000. ‡ Sasche et al., AUA, 2001.

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Padma-Nathan et al. reported to initiate penile erection in normal men as well as men with psychogenic and organic ED [9–11]. It is also noted to significantly increase sexual desire [11]. The frequent side-effects associated with melanotan II administration are nausea and stretching/yawning.

Figure 3 A number of other compounds that are also highly potent and selective for PDE5 have been developed. Two more compounds, vardenafil hydrochloride (Bay-389456, NuvivaTM, Bayer, Inc) [16–18] and tadalafil (IC351, CialisTM, Lilly/ICOS) [19,20] are being tested in clinical trials for future release and introduction to the market. The greatest information is available for sildenafil because it was the first candidate approved in the class and is the only one with extensive use outside of controlled clinical trials [26].

erection. It has been suggested that nitric oxide acts as a cofactor at the level of the PVN of the hypothalamus with regards to the activation of the oxytocinergic neurones [5]. Apomorphine is postulated to increase erectile responses by acting as a conditioner in the PVN, increasing the response to sexual stimuli resulting in enhanced erections induced in the periphery [6].

Melanocortin Agonist: Melanotan Ii and Pt-141 Melanotan II is a synthetic nonselective analogue of a-melanocyte-stimulating hormone (a-MSH). a-MSH and adrenocorticotrophin, known as the melanocortins, are derived from proteolytic cleavage of the precursor, pro-opiomelanocortin. Melanocortins are implicated in the regulation of sexual behaviour including penile erection, sexual motivation and in the female rat, the secretion of sexual attractants from the preputial gland [7,8]. Melanotan II delivered subcutaneously has been

Trazodone Trazodone, a serotonin reuptake inhibitor, is a nontricyclic antidepressant that has been associated with prolonged erection and priapism when administered orally in depressive patients. The pro-erectile action of trazodone is likely to be related to the a2-adrenoceptor blocking property of trazodone in erectile tissue. The proerectile property of m-CPP involves activation of 5-HT2C receptors localized in the lumbosacral spinal level of the rat [12,13]. The neuro-modulatory role of m-CPP on penile erectile activity contributing to pharmacological action of trazodone in human is not clear. Delequamine Delequamine is a more specific and selective a2adrenoceptor antagonist than yohimbine [14]. The central effect of a-adrenoceptor blockade by delequamine is an increased noradrenaline level at the synapse by blocking re-uptake leading to sexual arousal [15]. Low dose of the drug in normal controls produced an increase in NPT during

PDE5 inhibitor Sildenafil Vardenafil Tadalafil

cGMP Sildenafil Vardenafil Tadalafil

PDE5 inhibitor

Allosteric binding

cGMP

Neurons or endothelium PDE5

Nitric oxide

5’-GMP

cGMP Proteins

Guanylyl cyclase

PKG

Phospho-proteins

Lower Ca++

Relaxation

Figure 4

J Sex Med 2004; 1: 128–140

(P’lamban, Ca++ pumps, K+ channel & P’tase, IRAG, IP3 rec., myosin P’tase)

Figure 5 The higher the affinity of a drug for a given receptor site relative to other potential receptor sites, the greater the selectivity of the drug. For the PDE inhibitors, highly selective drugs are expected to have affinities, and therefore IC50 values, in the nanamolar (nM) range. PDE5 inhibitors are competitive inhibitors, competing with cGMP for the catalytic site of PDE5.

133

Pharmacotherapy for Erectile Dysfunction non-REM sleep, and with the high dose, spontaneous erections occurred just before sleep onset [16]. During the waking state, normal controls reported significantly higher subjective ratings of sexual arousal before erotic stimulation and increased likelihood of spontaneous erections or significant prolongation of erectile response to visual erotic stimuli following high dose of delequamine [17].

Nalmefene Nalmefene, derived from naltrexone, is a longacting opioid receptor antagonist. Nalmefene treatment in older impotent men increases the activity of the hypothalamic-pituitarygonadal axis, which manifests as a significant increase in serum testosterone, LH and FSH, but no change in NPT [18]. Naltrexone In addition to exerting inhibitory effects on male sexual drive and performance, endogenous and exogenous opioids exert an inhibitory influence on hypothalamic LH releasing hormone (LHRH), which stimulates the pulsatile release of LH from pituitary gonadotropes [19–22]. In clinical trials Naltrexone consistently increased the incidence of spontaneous early morning erections without significant modification of plasma gonadotrophin levels [23,24]. Naltrexone therapy may be beneficial in ED patients with altered central opioid tone. Centrally and Peripherally Active

Yohimbine Yohimbine is an indole alkaloid from the cortex of the Coryanthe yohimbe tree, which is purported to have aphrodisiac activity. The principal pharmacological action of yohimbine is as an a2adrenoceptor antagonist. Alpha 2-adrenoceptors are located both peripherally and centrally (especially in the locus coeruleus neurones), which are associated with sexual arousal and response. Peripherally, pre- and post-junctional a2adrenoceptors are present in the human penile erectile tissues [25,26]. Activation of presynaptic alpha 2-adrenoceptors in erectile tissue inhibits the release of noradrenaline at the sympathetic nerve endings, hence reducing the sympathetic transmission [25]. Yohimbine, by blocking prejunctional a2-adrenoceptors, may also mediate relaxation of human and rabbit corpus cavernosum by effectively enhancing NO release from endo-

thelium, which is androgen dependent [27]. This might be a second peripheral mechanism by which yohimbine induces penile arterial relaxation. Yohimbine has also been demonstrated to increase sexual motivation in sexually experienced male rats and induce sexual activity in sexually naïve or previously inactive rats [28,29]. In sexually exhausted intact rats, yohimbine is able to reestablish copulatory behaviour whereas in rats administered a neurotoxin (DSP4, to cause a lesion in the central noradrenergic system), yohimbine, but not naloxone (opioid antagonist) or 8-OH-DPAT (5HT1A agonist) restored partially sexual performance. These findings indicate that the integrity of the central noradrenergic system is essential for sexual behaviour [30]. Yohimbine may presumably act also through central a2-adrenoceptor, increasing noradrenergic transmission to enhance sexual function in humans.

Phentolamine Phentolamine is a nonselective a-adrenoceptor antagonist with similar affinity for a1- and a2adrenoceptors. Phentolamine mesylate induced relaxation of corpus cavernosum erectile tissue is thought to occur by direct antagonism of a1- and a2-adrenoceptors, as well as by indirect functional antagonism via a nonadrenergic, endotheliummediated mechanism, suggesting nitric oxide synthase activation [31,32]. The clinical utility of phentolamine is presumably a reflection of the contribution of adrenergic neurotransmission to the maintained flaccidity of the penis, and thus, inhibition of a-adrenoceptor activity alone may be sufficient for erection to commence [33,34]. Oral/ intracavernosal phentolamine therefore may facilitate penile erection by inhibiting the functional predominance of a1-adrenoceptor activity that maintains erectile tissues in a nonerect state. Attenuation of the opposing adrenergic contractile response enhances NO-mediated corpus cavernosum relaxation. Furthermore, phentolamine may delay detumescence, which is mediated by noradrenaline, contributing to the maintenance of penile erection. Peripherally Active

PDE5 Inhibitors Major research efforts have led to the production and development of compounds that are selective and potent in inhibiting particular PDEs [35–44]. J Sex Med 2004; 1: 128–140

134 Sildenafil (Viagra™) is the first commercialized compound in this class, recently joined by vardenafil (Levitra™) and tadalafil (Cialis™). Vardenafil has a similar structure to sildenafil with a nitrogen shift in the bicyclic ring but the structure of tadalafil is significantly different (Figure 3). Vardenafil is more potent than sildenafil in vitro to inhibit PDE5, and this difference is explained by differences (see arrows) in molecular structures of these two compounds. Potency is an in vitro measure of a drug concentration that elicits an action. It is not a direct measure of clinical efficacy. Part of the ring structure of sildenafil or vardenafil is similar to a ring structure in cGMP, important since these drugs are competitive inhibitors of cGMP for PDE5, and they presumably form some of the same molecular interactions (hydrogen bonds, hydrophobic stacking interactions, van der Waals contact, ionic interactions, etc.) as cGMP with multiple amino acids in the catalytic and allosteric (regulatory) sites in PDE5. Even though the tadalafil structure differs significantly from those of the other two inhibitors, its molecular mechanism of action is believed to be similar. Because they have similar structures as cGMP, PDE5 inhibitors can occupy the catalytic site, blocking access to cGMP, but without catalysis occurring. Thus cGMP breakdown is inhibited, leading to elevation of cGMP in smooth muscle cells of the penile corpus cavernosum, relaxation of the muscle and penile erection. PDE5 inhibitors do not increase the nitric oxide level, but they potentiate the nitric oxide effect to stimulate erection. Without sexual arousal, which triggers the nerve-nitric oxide pathway and subsequently the blood flow-endothelial shear stress-nitric oxide pathway, these inhibitors are ineffective. PDE5 was discovered by Corbin and colleagues [45,46]. A cartoon of the enzyme structure is shown in Figure 5. Each of the two subunits of PDE5 has a catalytic domain and a regulatory domain. Although the catalytic domain of PDE5 is the direct target of PDE5 inhibitors, certain features of the regulatory domain impact the PDE5 inhibitor actions on the enzyme [47,48]. This domain contains allosteric cGMP-binding sites (one or two per subunit) as well as a phosphorylation site for negative feedback regulation of the enzyme. When cGMP binds to the allosteric sites, cGMP is not degraded as it is in the catalytic site, but PDE5 enzyme functions are activated by the binding reaction. That is, the PDE5 inhibitor stimulates its own efficacy. J Sex Med 2004; 1: 128–140

Padma-Nathan et al. Assuming all other factors are equal, the higher the affinity (potency) of a PDE5 inhibitor for PDE5, the lower the expected dose of the inhibitor that will be needed [35]. However, factors such as pharmacokinetics have strong impact on the dose required. Higher potency means that less concentration of the inhibitor is needed for the desired inhibition effect. For the PDE5 inhibitors, in head-to-head biochemical studies using IC 50, EC 50, Kd, infinite dilution experiments, and competition assays, vardenafil is more biochemically potent than are sildenafil and tadalafil [35]. The in vitro potency of a PDE5 inhibitor is not the same as clinical efficacy, which is based on the actual in vivo (clinical) effects of the inhibitor. Multiple head-to-head trials have been performed but not published and are therefore not reviewed in this paper. The biochemical selectivity of an inhibitor for PDE5 is a key factor in determining its side-effect profile [35]. For PDE5 inhibitors, selectivity is usually expressed in terms of potency (IC50) to inhibit PDE5 as opposed to inhibiting any others in the PDE family (PDE1 to PDE11). The selectivity is computed by dividing the IC50s of the two compounds that are compared. Sildenafil and vardenafil cross-react slightly with PDE6, which is expressed in the retina. This may explain the complaint of some patients that sildenafil causes visual disturbances. Tadalafil cross reacts with PDE11 but the consequences of this effect are unknown. PDE11 is expressed in testicular cells, cardiac muscle, smooth muscle and the pituitary and inhibition of PDE11A appears to be the mechanism of myalgia associated with tadalafil (Cialis USPI). Except for visual disturbances, the other reported sideeffects of PDE5 inhibitors (headaches, flushing, slight lowering of blood pressure, etc.) are likely caused by PDE5 inhibition in smooth muscle tissues outside the penile corpus cavernosum. The pharmacokinetic properties of PDE5 inhibitors have great impact on efficacy [35], several of which can be measured and quantified describing bodily distribution of a PDE5 inhibitor (Table 2). The bioavailability, maximum plasma concentration (Cmax), the time (Tmax) required for attaining Cmax, and time (t1/2) required for elimination of one-half of the inhibitor from plasma are all important factors. The bioavailability, which is the percentage of ingested inhibitor that actually appears in the plasma, is about onethird as much for vardenafil (15%) as that for sildenafil (40%). The bioavailability for tadalafil is unknown at present.

Pharmacotherapy for Erectile Dysfunction Sildenafil, vardenafil, and tadalafil have broadly similar Tmax (sildenafil and vardenafil Tmax occurs in less than 1 hour, the tadalafil Tmax occurs in 2 hours), but the Cmax of vardenafil is significantly lower than that for either of the other two inhibitors. This might be expected based on the higher biochemical potency of vardenafil. The T1/2 of tadalafil is considerably longer than that of the other two PDE5 inhibitors, providing a much longer therapeutic effect [49]. This may be preferred for certain patterns of sexual activity, but could expose the patient to greater risk of sideeffects. PDE5 inhibitors must dissociate from PDE5, exit the smooth muscle cells and then be transported to the liver via the bloodstream before they can be degraded. Disappearance of the inhibitor from plasma may imply, but does not prove, its disappearance from the cells in which it produces its effects. It is conceivable that PDE5 inhibitors with the highest affinities and lowest disassociation rates from the catalytic site for PDE5, vardenafil, would dissociate from the enzyme more slowly, resulting in a more delayed clearance from corpus cavernosum cells. The clinical significance of this reduced intracellular clearance is unclear at this time.

Vasoactive Intestinal Polypeptide Vasoactive intestinal peptide (VIP) is a naturally occurring neurotransmitter known to exert regulatory actions on blood-flow, secretion, and muscle tone, present in considerable amounts in the male genital tract [50]. Though VIP is a potent relaxant of both the corpus cavernosum and penile vascular smooth muscle in vitro, it is ineffective at inhibiting the neurogenic relaxation in corpus cavernosum strips, suggesting that VIP may not be released from the nerves during field stimulation [51]. Furthermore, VIP does not induce penile rigidity adequate for intromission when injected intracavernously in potent [51] and impotent men [52] indicating that it is not likely to be the primary neurotransmitter mediating penile erection. L-Arginine

Nitric oxide, the NANC neurotransmitter of primary importance in regulating corpus cavernosum smooth muscle relaxation, is derived from L-arginine by nitric oxide synthase (NOS). Recent studies show that L-arginine augments endothelium-dependent vasodilation in hypercholesterolemic rabbits and human [53,54]. The

135 rationale for L-arginine therapy is related to the supposition that dietary supplementation with NO-precursor L-arginine may normalize endothelium-dependent vasodilation and have a beneficial effect on erectile function.

Alprostadil (PGE1) Following the discovery that PGE1 relaxed human corpus cavernosum smooth muscle [55,56], the mechanism of action was determined and PGE1 used for the treatment of erectile dysfunction [57– 59]. PGE1 mediates relaxation of corpus cavernosum smooth muscle via activation of EP prostaglandin receptors (EP2/4) by increasing the intracellular concentration of cAMP in corpus cavernosum smooth muscle [60–63]. PGE1 may also act by inhibiting the release of noradrenaline from sympathetic nerves [64] and suppressing angiotensin II secretion in the cavernosal tissues [65]. The ability of human corpus cavernosum to degrade PGE1 probably aids in regulating the activity of PGE1 and reducing the risk of undesirable side-effects such as prolonged erection and priapism. Papaverine Intracavernosal papaverine injection was the first clinically effective pharmacological therapy for ED. A nonopiate derivative of poppy plant, papaverine is a smooth muscle relaxant. In vitro, papaverine evoked relaxation of isolated corpus cavernosum smooth strips, penile arteries, cavernous sinusoids and the penile veins and attenuated contractions induced by stimulation of adrenergic nerves and exogenous noradrenaline [66,67]. Injection with 80 mg papaverine in normal volunteers and subjects with psychogenic impotence produced rigid erections. Papaverine caused marked vasodilation of the penile arteries and decreased venous outflow as recorded by Doppler [68]. Papaverine is a nonspecific phosphodiesterase inhibitor that initiates an increase in intracellular cAMP and cGMP leading to corporal smooth muscle relaxation and penile erection. Combinations Phentolamine, papaverine, PGE1, VIP and linsidomine are the vasoactive agents most commonly used in combination therapy to treat erectile dysfunction. Combination therapy is more efficacious with lower incidence of side-effects and cost per dose. In vitro enhancement by phentolamine of VIP and PGE1-induced relaxation (cAMP-mediated) J Sex Med 2004; 1: 128–140

136 suggests a synergistic interaction while the interaction between phentolamine and sildenafil (cGMP-mediated) appears to be additive [69]. The same investigators also show that sildenafil and PGE1 has additive and synergistic effect, respectively, with phentolamine-induced relaxation. Employing phentolamine as an adjunct reduces the predominance of adrenergic tone through the blockade of a-adrenoceptors and increases the efficacy of vasodilators that initiate erection via other independent relaxatory pathways.

Topical Therapies

Topical therapy for the treatment of ED has been proposed as a means of circumventing some of the negative factors associated with intracavernous injection (ICI) and IUS intrurethral suppositories (IUS). Currently, topical therapies for the treatment of erectile dysfunction remain in clinical trials and have yet to be released for widespread use. However, topical applications have the potential to avoid the systemic effects noted with oral therapies while being perceived as minimally invasive. Topical therapy may also provide benefit to patients unresponsive to systemic therapy or who use medications that cannot be taken concomitantly with oral treatments. Organic nitrate donors were the first topical agents to be used in the treatment of erectile dysfunction [70]. Case reports have demonstrated that blood flow to the penis and tumescence are increased after application of a nitro-based paste [71,72]. The effects on penile blood flow appear to be local since application of the gels elsewhere on the body does not induce erection. Topical minoxidil has also been reported in placebo controlled double blind trials [73,74].

Topical PGE1 Alprostadil is a naturally occurring prostaglandin E1. Various formulations and injection techniques, urethral suppositories and gels using PGE1 have been used in the treatment of erectile dysfunction over the past 15 years. Alprostadil relaxes smooth muscle of the corpus cavernosum. The physiologic endpoint is dilation of the cavernosal arteries, relaxation of the corporal smooth muscle, and resultant increase in arterial inflow velocity and venous outflow resistance. Thus alprostadil affects the corporal venoocclusive mechanism and not ejaculation or orgasm. J Sex Med 2004; 1: 128–140

Padma-Nathan et al.

Topical Minoxidil Topical minoxidil has been recently used as an investigational drug in the treatment of erectile dysfunction, but investigations are limited. While Minoxidil does not have a direct vasodilatory effect, its metabolite minoxidil O-sulfate [75] does have a direct vasodilatory effect on arterial smooth muscle, causing a reduction in peripheral resistance and blood pressure. The precise mechanism of action of minoxidil is not certain [76,77], but it appears to be a relatively weak corporal smooth muscle cell relaxant [78]. Topical minoxidil is a prodrug, which means for this to be effective it would have to be metabolized through the liver and then recirculated to the penis. Topical administration should be to the skin of interest. Systemic effects resulting from topically administered Minoxidil are unlikely but theoretically could occur if the drug is overused. Skin abrasion or irritation such as excoriations, psoriasis, or sun burn can increase the systemic absorption of topical minoxidil. Topical Papaverine Although injection of papaverine into the corporal bodies for the treatment of sexual dysfunction has become widespread and well accepted [79], the use of papaverine as a topical therapy has a much shorter experience that has not moved beyond preliminary clinical trials. Topical absorption of serum papaverine is less than 1% of a comparable intravenous dose, indicating minimal systemic uptake after topical administration to the genitalia [80]. Topical Nitroglycerin The use of nitroglycerin ointments, pastes, plasters or patches has been tried for the treatment of erectile dysfunction. The mechanistic basis for nitroglycerine-induced relaxation of human corporal smooth muscle is likely to be multifactorial. Disease (diabetes)-related changes in the responsivity of isolated human corporal smooth muscle strips to nitroglycerine-induced relaxation may indicate diminished utility of this compound in diabetic patients. Other contraindications to the use of topical nitroglycerin include those who have allergic reactions to organic nitrates or to the adhesives used on the nitroglycerin patches. Conclusion

Numerous central and peripheral pharmacotherapeutic agents are currently utilized for the safe and

Pharmacotherapy for Erectile Dysfunction effective treatment of erectile dysfunction. The putative mechanism of actions of these drugs, based on existing experimental evidence, are reviewed. Future challenges will be to continue the investigation of the biochemistry and physiology of erectile and other sexual functions since pharmacotherapeutic advances for erectile dysfunction and for disorders of sexual desire, ejaculation and orgasm follow basic science research in sexual medicine. Corresponding Author: Harin Padma-Nathan, MD, 9100 Wilshire Blvd, Suite 360 East Tower, Beverly Hills, CA, USA. Tel: (310) 858-4455, x204; Fax: (310) 247-3844. E-mail: [email protected] References

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