In most countries, the phosphodiesterase inhibitors are the initial form of pharmacotherapy for men with ED. They are orally active agents that are typically taken, on demand, prior to intercourse. Three such drugs, sildenafil, tadalafil, and vardenafil, are licensed for use around the world. A number of newer agents are available in a few countries (udenafil, mirodenafil) and others (avanafil, lodenafil, SLX-2101) are currently under development.
The normal pathway for penile erection is initiated by sexual arousal, which stimulates release of nitric oxide at nerve endings in the penis (Figure 1). Another source of nitric oxide is vascular endothelial cells. Nitric oxide diffuses into vascular smooth muscle cells in the penile corpus cavernosum to cause stimulation of guanylyl cyclase and elevation of cyclic guanosine monophosphate (cGMP) in these cells. This leads to activation of cGMP-dependent protein kinase (PKG), phosphorylation of several proteins, and lowering of cell calcium or reduction in sensitivity to calcium, which results in smooth muscle relaxation. The increased accumulation of blood in corpus cavernosum caused by this relaxation is the underlying basis for penile erection. Lack of proper cGMP elevation could be due at least in part to insufficient release of nitric oxide from nerve endings or endothelium. PDE5 inhibitors enhance erectile function during sexual stimulation by penetrating into smooth muscle cells and inhibiting PDE5, which is an enzyme that degrades cGMP. This results in decreased degradation of cGMP, which maintains higher cellular levels of cGMP in both corpus cavernosum and the vessels supplying it. This increases relaxation of the smooth muscle, which dilates the corporeal sinusoids resulting in increased blood flow, allowing an erection to occur. The pathway shown in Figure 1 may not work properly if the cGMP level in corpus cavernosum smooth muscle cells is not elevated sufficiently or if relaxation of smooth muscle in the tissue is deficient/incomplete [1,2].
Figure 1. Regulation of penile corpus cavernosum smooth muscle relaxation and effect of phosphodiesterase type 5 (PDE5) inhibitors. cGMP = cyclic guanosine monophosphate; PKG = cGMP-dependent protein kinase.
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PDE5 was discovered by Corbin and colleagues [3,4]. A cartoon depicting the PDE5 structure is shown in Figure 2. The enzyme is a homodimer containing two identical subunits with molecular weight of about 100,000 daltons per subunit. Each of the two subunits has a catalytic domain and a regulatory domain. The catalytic domain is the target of PDE5 inhibitors and it contains a single binding site for cGMP. When cGMP occupies this site the catalytic machinery, which is located very near the catalytic cGMP-binding site, breaks the cyclic phosphate bond of cGMP to form linear 5′-GMP. This dampens or terminates cGMP action. Because they have similar structures as cGMP, sildenafil, or other PDE5 inhibitors can also occupy the catalytic site, thus blocking access to cGMP. In fact, sildenafil occupies the site about 1,000 times more avidly than does the natural substrate, cGMP. However, the catalytic machinery does not break down the PDE5 inhibitors. Occupation of the catalytic site by these inhibitors competitively inhibits cGMP breakdown as cGMP cannot bind to gain access to the catalytic machinery. Inhibition of cGMP breakdown leads to elevation of cGMP in smooth muscle cells of the penile corpus cavernosum, resulting in relaxation of the muscle and penile erection.
Figure 2. Cartoon of phosphodiesterase type 5 (PDE5) structure showing competitive inhibitory effect of PDE5 inhibitor on the catalytic domain. cGMP = cyclic guanosine monophosphate; P = phosphate; NH2 = amino terminus; S = Serine-102; A and B = GAF A and GAF B subdomains, respectively; PKG = cGMP-dependent protein kinase.
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Major research efforts have led to the production and development of compounds that are selective and potent in inhibiting particular PDEs . Some of these inhibitors have a similar overall structure as sildenafil and some, such as tadalafil, have significantly different structures (Figure 3). A part of the structure of each PDE5 inhibitor also resembles the structure of cGMP (see circled component). This is important since these drugs are competitive inhibitors (antagonists) of cGMP for PDE5, and they are believed to form some of the same molecular interactions as cGMP forms with amino acids in PDE5.
Figure 3. Molecular structures of phosphodiesterase type 5 (PDE5) inhibitors as compared with that of cyclic guanosine monophosphate (cGMP). Circled component represents the part of each structure that is believed to mimic the structure of cGMP.
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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 . This concept of potency can be assessed by measuring the concentration of a particular PDE5 inhibitor in vitro that inhibits PDE5 activity by 50%, and is known as IC50 (Table 1). Highly potent drugs are expected to have affinities (IC50 values) in the nanomolar (nM) range. Vardenafil, SLX-2101 (Surface Logix, Inc., Brighton, MA, USA), and mirodenafil are within a class of biochemically high-affinity PDE5 inhibitors as compared with sildenafil, tadalafil, and udenafil, and avanafil has an intermediate potency. However, as discussed further, factors such as pharmacokinetics have strong impact on the dose required. Higher potency does not mean that a PDE5 inhibitor has a greater clinical effect, but that less of it is needed for the desired effect.
Table 1. Pharmacodynamics of the phosphodiesterase type 5 (PDE5) inhibitors
|Inhibitor||IC50 for PDE5||PDE selectivity||Source|
|Udenafil||8.2 nM||Low activity against PDE3, PDE6||Doh H et al. |
|SLx-2101||0.24 nM||—||Sweetnam et al. |
|Avanafil||1 nM||“Highly” selective||Kotera J et al. |
|Mirodenafil||0.33 nM||Similar to sildenafil||Lee et al. |
|Sildenafil||3.5–10 nM|| ||Francis SH et al. |
|Sildenafil*||3.7 nM||Low activity against PDE6 Very low activity against PDE1||Francis SH and Corbin JD |
|Vardenafil||0.14–1 nM|| ||Francis SH et al. |
|Vardenafil*||0.091 nM||Low activity against PDE6 Very low activity against PDE1||Francis SH and Corbin JD |
|Tadalafil||1.8–10 nM||—||Francis SH et al. |
|Tadalafil*||1.8 nM||Low against PDE11||Francis SH and Corbin JD |
|Tadalafil||—||Slight against PDE11||Weeks JL et al. |
The biochemical selectivity of an inhibitor for PDE5 is a key factor in determining its side-effect profile . Once a large enough separation exists between the affinity (IC50) of the inhibitor for PDE5 and its affinity for nontarget PDEs (or other proteins), the less likely it is that it can achieve sufficient plasma concentrations to activate the nontarget site at therapeutic doses. 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. PDEs are comprised of 11 families of enzymes that catalyze the termination of second messenger activity in cells by breaking the phosphodiester bond of either cAMP, cGMP, or both. These families (PDE1 to PDE11) are known or implicated in a broad range of cellular functions. PDE5 is present in high concentrations in the smooth muscle of corpora cavernosa of the penis. Sildenafil and vardenafil cross-react slightly with PDE6, i.e., their IC50s for PDE5 are only four- to 10-fold lower than those for PDE6. This may explain the complaint of some patients that sildenafil or vardenafil causes visual disturbances as PDE6 predominates in the retina. Tadalafil cross-reacts with PDE11 to some extent, but the consequences of this effect are unknown. PDE11 is found in the heart (cardiac myocytes), testes (germinal cells and Leydig cells), and anterior pituitary. Neither of the PDE5 inhibitors cross-reacts to a large extent with any of the other PDEs. Except for visual disturbances, the other reported side effects of PDE5 inhibitors (headaches, flushing, slight lowering of blood pressure, etc.) are likely caused by PDE5 inhibition in smooth muscle and other tissues outside the penile corpus cavernosum.
In addition to biochemical properties discussed above, pharmacokinetic properties of PDE5 inhibitors (ingestion/food interaction, movement in the circulation, tissue uptake, elimination) have great impact on efficacy . Several common pharmacokinetic parameters that can be measured and quantified describe distribution of a PDE5 inhibitor. The bioavailability, maximum plasma concentration (Cmax), 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 (Table 2). Sildenafil, vardenafil, udenafil, and avanafil have broadly similar tmax, which predicts a similar time of onset of action. The t1/2 values of tadalafil and udenafil are longer than those of the other two PDE5 inhibitors, which could be caused by the slower intestinal absorption and/or slower degradation of this drug by the liver, or it could be caused by other factors. The extended t1/2 of tadalafil provides a longer therapeutic effect , and this may also be the case for udenafil and SLx-2101. The Cmax of vardenafil is significantly lower than that for sildenafil and tadalafil, which might be expected based on its lower bioavailability.
Table 2. Pharmacokinetics of the phosphodiesterase type 5 inhibitors
|Parameter||Tadalafil 20 mg ||Sildenafil 100 mg ||Vardenafil 20 mg ||Udenafil 100 mg [13,14]||SLx-2101 ||Avanafil 100 mg ||Mirodenafil 100 mg ||Lodenafil 160 mg |
|Cmax ng/mL||378||450||20.9||416.2||No data||No data||No data||157|
|Bioavailability|| ||40%||14.5%|| || || || || |
PDE5 inhibitors are believed to be degraded in the liver. Therefore, as they are not degraded by PDE5 or any other enzyme in smooth muscle cells of corpus cavernosum, they must dissociate from PDE5, exit the smooth muscle cells, and then be transported to the liver via the bloodstream before they can be degraded (Figure 1). The rate of exit of a PDE5 inhibitor from smooth muscle cells should be considered when comparing PDE5 inhibitors as this could affect its duration of action. Disappearance of the inhibitor from plasma may imply, but does not prove, its disappearance, or clearance, from the cells in which it produces its effects. Since the inhibitor binds tightly to PDE5 in these cells, as portrayed in cartoon form in Figure 1, this could significantly retard its exit from these cells and prolong effects of PDE5 inhibitors in patients. It is conceivable that PDE5 inhibitors with higher affinities for PDE5 would dissociate from the enzyme more slowly, resulting in a more retarded clearance from corpus cavernosum cells. Studies of clearance of PDE5 inhibitors from plasma are documented, but studies of clearance of these inhibitors from smooth muscle cells are rare.
There is clear evidence that sildenafil is efficacious in the treatment of the broad population of men with erectile dysfunction when taken on demand at a doses of 25, 50, and 100 mg. There are multiple level 1 studies with consistent outcomes [20–43]. The overall grade of recommendation is grade A. In addition (again with a Grade A recommendation) there is clear evidence that sildenafil is efficacious in men where the ED has arisen as a consequence of specific diseases such as diabetes [44–47], depression [48–51], spinal cord injury [52,53], multiple sclerosis [54,55], cardiovascular disease [56–59], hypertension , and finally it is effective in men with lower urinary tract symptoms and ED .
Although side effects do occur with sildenafil (most notably headache, flushing, indigestion, nasal congestion, and occasional visual changes), providing that the drug is used in line with the labeling recommendations, there is no convincing evidence in the literature of any significant safety issue, including cardiovascular, visual, and aural safety [20–74] (Consistent level 1 studies, Overall grade of recommendation is grade A).
There is clear evidence that tadalafil is efficacious in the treatment of ED in the broad population when taken on demand at doses of 10 and 20 mg. There are multiple level 1 studies with consistent outcomes [75–88]. The overall grade of recommendation is grade A. In addition there are two level 1 studies that confirm that tadalafil is also efficacious when taken daily [89,90]. Although several doses have been tested, the doses that have been licensed are 2.5 and 5 mg. The overall grade of recommendation is grade A. Further, there is clear evidence that tadalafil is efficacious in a number of special populations of men where the ED has arisen as a consequence of a specific disease such as diabetes [91,92], men with ED who have undergone bilateral nerve sparing radical prostatectomy , men with ED who have undergone external beam radiotherapy for prostatic cancer , men with ED secondary to spinal cord injury  and men with lower urinary tract symptoms and ED [96,97].
Although side effects do occur with tadalafil (most notably headache, flushing, indigestion, nasal congestion, and back or girdle pain), providing that the drug is used in line with the labeling recommendations, there is no convincing evidence in the literature of any significant safety issue, including cardiovascular, visual, and aural safety (Consistent level 1 studies [75–104] with an overall grade of recommendation is grade A).
There is clear evidence that vardenafil is efficacious in the treatment of ED in the broad population at doses of 10 and 20 mg taken in an on-demand fashion. There are multiple level 1 studies with consistent outcomes [105–116]. The overall grade of recommendation is grade A. Further, there is clear evidence that vardenafil is efficacious in a number of special populations of men where the ED has arisen secondary to a specific disease such as diabetes [117–119], men with ED secondary to radical retropubic prostatectomy , depression , hypertension , spinal cord injury and ED , hyperlipidemia  and men who have previously failed to respond to sildenafil .
Although side effects do occur with vardenafil (most notably headache, flushing, indigestion and nasal congestion), providing that the drug is used in line with the labeling recommendations, there is no convincing evidence in the literature of any significant safety issue, including cardiovascular, visual and aural safety [105–127].
A single phase 3 study confirms that udenafil is effective in a broad population of Korean men with ED (level of evidence: 1) . The most common adverse events were facial flushing, nasal congestion, ocular hyperemia and headache. At the time of writing, much of the other data relating to udenafil is available in abstract form only and therefore not open to critical assessment.
Mirodenafil is a new PDE5 inhibitor already available in Korea (approved in November 2007). Preliminary results from a phase 2 clinical study  and a phase 3 clinical study  provided evidence for the efficacy and safety of mirodenafil (level of evidence: 1). The optimal doses in terms of efficacy and safety were determined from this study to be 50 mg and 100 mg. The most common adverse events were facial flushing, headache, nausea, and eye redness. At the time of writing, much of the other data relating to mirodenafil is available in abstract form only and therefore not open to critical assessment.
Lodenafil carbonate is another new PDE5 inhibitor under development in Brazil. It is a dimer formed by two lodenafil molecules linked by a carbonate bridge. After ingestion, the bridge is broken delivering the active compound lodenafil. Recently, a phase 2 clinical trial has been completed in Brazil (level of evidence: 2)  supporting efficacy and safety at doses of 20 mg, 40 mg and 80 mg. Adverse reactions included headache, dyspepsia, rhinitis, flushing and color visual disorders. At the time of writing, much of the other data relating to lodenafil is available in abstract form only and therefore not open to critical assessment.
Avanafil is a pyrimidine derivative synthesized as a PDE5 inhibitor. At the time of writing, all of the clinical data relating to avanafil is available in abstract form only and therefore not open to critical assessment, but doses of 50, 100, 200, and 300 mg have been investigated. Currently, phase 3 clinical trials are running to assess efficacy and safety of avanafil in general ED population and diabetic men with ED. The results are expected in early 2010.
SLx-2101 is a new PDE5 inhibitor that it is converted to an M1 metabolite, SLx-2081, which continues to be active. At the time of writing, all of the other data relating to SLx-2101 is available in abstract form only and therefore not open to critical assessment, but doses of 5, 10, 20, 40 and 80 mg have been investigated.
Comparator Studies of Systemically Active Agents
A number of studies have compared the efficacy and safety of the oral medications used in the treatment of men with ED. The trial designs used was variable with many studies demonstrating inadequate design resulting in clear bias. Almost all the studies were pharmaceutically sponsored.
The authors consider that one trial comparing sildenafil and tadalafil could be considered a Level 1 study [150–152] with the other published studies suffering from biases such as inadequate duration, inadequate washout, and biased dosing. The single level 1 study was an open-label study, but in other respects was well conducted and of adequate size. Overall, there was no evidence of superiority for any one of the PDE5 inhibitors over the others in terms of efficacy or safety (Grade A recommendation).
The authors consider that several trials comparing the efficacy and tolerability of apomorphine and sildenafil could be considered level 1 trials [153–156]. All were all open-label studies, but were otherwise well designed trials, with adequate numbers of patients randomized. Overall there was clear evidence that sildenafil has greater efficacy in the treatment of men with ED than apomorphine.