Comparison of Phosphodiesterase Type 5 (PDE5) Inhibitors

P. J. Wright


Int J Clin Pract. 2006;60(8):967-975. 

In This Article

PDE5 Inhibitors

The PDE5 inhibitors are the recommended first-line treatment for ED.[4] However, their use is not recommended in men who have recent history of stroke or myocardial infarction (within the last 6-8 weeks), or who have significantly low blood pressure, uncontrolled high blood pressure, unstable angina, severe cardiac failure, severe liver impairment or end-stage kidney disease requiring dialysis. Prescribers should consult the prescribing information of the individual PDE5 inhibitors.

Although the PDE5 inhibitors show the same mechanism of action, these drugs have some pharmacological differences that translate into differing clinical effects.

Following sexual stimulation, penile erection occurs through the release of nitric oxide (NO), which causes dilation of the blood vessels of the corpus cavernosum via an accumulation of cyclic guanosine monophosphate (cGMP). PDE5, an enzyme that breaks down cGMP, can be inhibited and thereby the vasodilatory effect of NO is enhanced (Figure 1). All three PDE5 inhibitors share this common mechanism of action and are only pharmacologically active when cGMP synthesis is activated. The action of the PDE5 inhibitors therefore requires sexual arousal.

Schematic diagram illustrating the mechanism of action of the phosphodiesterase type 5 (PDE5) inhibitors. Following sexual arousal, nitric oxide is released from the synapses of neurones in the corpus cavernosum of the penis. This results in accumulation of cyclic guanosine monophosphate (cGMP), produced from Guanosine triphosphate (GTP), which causes smooth muscle relaxation leading to an erection. By preventing cGMP breakdown, PDE5 inhibitors enhance erectile function

As competitive inhibitors of PDE5, this class of drugs has structures derived from cGMP. Sildenafil and vardenafil have very similar molecular structures (Figure 2). In contrast, tadalafil has a different chemical structure from sildenafil and vardenafil, while still retaining the elements required for inhibition of PDE5. These structural differences are reflected in the pharmacokinetic properties of tadalafil and its selectivity for PDE isozymes.

Structures of the phosphodiesterase type 5 inhibitors

Eleven distinct PDE isozymes have been identified and characterised based on several factors including amino acid sequence, substrate specificity and inhibitor sensitivity. In vitro studies have demonstrated that the PDE5 inhibitors have different selectivities for the PDE isozymes ( Table 1 ).[13] In general, the PDE5 inhibitors are potent and selective inhibitors of PDE5, with an IC50 of 0.96 nm for sildenafil, 0.16 nm for vardenafil and 0.94 nm for tadalafil.[13] However, the PDE5 inhibitors exhibit a range of specificities for the other PDE isozymes.

Some differences exist in the selectivity of the PDE5 inhibitors for PDE6, an enzyme in the retina that plays an important role in the transfer of light impulses into nerve impulses. Inhibition of this enzyme is thought to cause disturbances in colour perception.[14] In vitro studies have shown that sildenafil and vardenafil exhibit significant inhibition of PDE6 isolated from human retinas. As shown in Table 1 vardenafil and sildenafil are three and seven times more selective for PDE5 than for PDE6, respectively, whereas tadalafil is over 700-fold more selective for PDE5 than for PDE6.

Tadalafil is more selective for PDE11 relative to PDE5 than sildenafil and vardenafil. Although PDE11 is expressed in various tissues ( Table 1 ), its physiological function remains to be elucidated.

Some of the pharmacokinetic parameters of the PDE5 inhibitors are illustrated in Table 2 . All three PDE5 inhibitors are rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of sildenafil (Cmax) are reached in less than 1 h.[15] Vardenafil has similar pharmacokinetics to sildenafil and is absorbed with a median time to peak plasma concentration (Tmax) of approximately 1 h (for 20 and 40 mg doses).[16] Peak plasma concentrations of tadalafil are reached after approximately 2 h.[17]

Food (in particular fatty food) is known to delay the absorption of sildenafil and vardenafil, but it has no effect on the rate and extent of absorption of tadalafil.[15,17,18] When taken with food the rate and extent of sildenafil absorption is reduced with the maximal plasma concentration of sildenafil decreased by almost 30% and the mean time to the maximum concentration delayed by approximately 1 h, compared with administration in the fasted state.[15] As with sildenafil, a high-fat meal delays the absorption of vardenafil by up to 1 h and decreases the maximal concentration of vardenafil by approximately 20% compared with the fasted state.[19] Food has no effect on the rate and extent of absorption of tadalafil,[17] so this agent can be taken without regard to food. The pharmacokinetics of the three currently available PDE5 inhibitors are not affected by alcohol, although men may wish to refrain from alcohol, as alcohol consumption has been shown to be associated with ED.[20]

Sildenafil and vardenafil both have a terminal half-life of approximately 4 h,[15,16] and tadalafil has a half-life of 17.5 h. All three currently available PDE5 inhibitors are eliminated by hepatic metabolism. Sildenafil is predominantly metabolised by cytochrome P450 into an N-desmethyl metabolite that also has some PDE5 activity. This metabolite is thought to account for approximately a fifth of the drug's activity.[21] Vardenafil also has an active metabolite that accounts for approximately 7% of total pharmacological activity.[21] The activity of tadalafil is solely through the parent drug, as it does not have any active metabolites. All the PDE5 inhibitors are excreted as metabolites predominantly in the faeces and to a lesser extent in the urine ( Table 2 ). Given that the PDE5 inhibitors are principally metabolised by hepatic enzymes via cytochrome P450 isoform 3A4, inhibitors of this enzyme (e.g. ritonavir, indinavir, saquinavir, ketoconazole, itraconazole, cimetidine and erythromycin) may reduce clearance of the PDE5 inhibitor.

None of the three PDE5 inhibitors act immediately. Most studies have illustrated that the drugs have an onset of action between 30 and 60 min, but the rate of onset of each drug varies between individuals. The prescribing information for sildenafil recommends dosing 60 min before sexual activity,[21,22] although achievement of an erection that led to successful intercourse was reported in 35% (vs. 22% for placebo) of patients within 14 min and in 51% (vs. 30% for placebo) of patients within 20 min of sildenafil dosing (both statistically significant compared with placebo) in one study.[23] Vardenafil also has a similar duration of onset, with a recommendation in the prescribing information that patients should take vardenafil 25-60 min before sexual activity.[16,24] However, one study reported onset of action with vardenafil 10 mg at 10 min that was statistically significant compared with placebo (21% vs. 14% of intercourse attempts were successful). Of note, 72% of the population were previous responders to PDE5 inhibitors.[25] The prescribing information for tadalafil states that patients should wait 30 min before engaging in sexual activity, although a study has shown onset of action for tadalafil as early as 16 min.[26] In this study, 16% of intercourse attempts with tadalafil were successful within 16 min, vs. 8% with placebo.[26] However, onset times of the three products cannot be compared directly because separate clinical trials with different designs were used to determine the onset of erectogenic effects.

The PDE5 inhibitors show marked differences in their duration of effect. According to the prescribing information, the duration of effect with sildenafil and vardenafil is approximately 4-5 h.[21,24] However, consistent with its half-life of 17.5 h, tadalafil's duration of effect is up to 36 h.[27,28] This broad window of responsiveness allows patients with ED more freedom to choose when they participate in sexual intercourse.

Although several comparative trials are currently being undertaken, results of published head-to-head comparative trials of different PDE5 inhibitors are lacking. Therefore, caution must be used when comparing results as studies have used different designs, enrolled different patient populations (e.g. exclusion of patients who failed to respond to sildenafil) and utilised different efficacy measures, all of which may impact on treatment outcomes. However, all three PDE5 inhibitors have been clearly shown to be effective in the general population of men with ED.[29,30,31,32]

The 12-week efficacy of sildenafil was examined in a flexible-dose study of 329 patients (mean age 59-60 years; mean duration of ED 4.7-5.0 years; ED severity and previous ED therapies not stated). Patients initially took sildenafil 50 mg but were able to titrate up to 100 mg or down to 25 mg. In reply to the global assessment question 'Did this drug improve your erections?', 74% of the 163 patients receiving sildenafil responded 'yes', compared with 16% of the 166 patients receiving placebo (p < 0.0001).[33] Similarly, in a 12-week study of vardenafil, 81% of 153 patients responded positively to the same question, stating that vardenafil 20 mg had improved their erections, compared with 39% of the 111 patients taking placebo (p < 0.0001).[29] Patients in this study (mean age 57-58 years) mostly had moderate (28-37%) or severe (30-42%) ED, which had persisted for a mean duration of 5.1-6.6 years. Overall, 66-77% of patients had previously taken sildenafil (non-responders to sildenafil were excluded). Evidence for the efficacy of tadalafil is provided by data from 11 integrated 12-week studies (p < 0.001).[32] In total, 84% of the 1050 patients taking 20 mg tadalafil had a positive response to the question 'Did this drug improve your erections?, compared with only 33% of the 591 patients taking placebo. In these studies, the majority of men (mean age 56-57 years) had either moderate (27%) or severe (33-34%) ED and 88-90% of patients had ED of ≥12 months' duration. Most of the 11 studies excluded non-responders to prior sildenafil treatment (details of previous ED treatment usage not provided).

In the above 12-week studies, responses to the question 'Did your erection last long enough for you to have successful intercourse?' [Sexual Encounter Profile (SEP) Question 3] also demonstrated benefits of all three PDE5 inhibitors over placebo. The mean success rate (SEP3) in patients treated with sildenafil (50 mg titrated up to 100 mg or down to 25 mg if necessary) was 65% vs. 20% taking placebo (p < 0.001).[33] Likewise, the mean success rate (SEP3) in patients treated with vardenafil 20 mg was 65% compared with 32% of patients taking placebo (p < 0.0001).[29] After taking 20 mg of tadalafil, the mean success rate (SEP3) was 68% compared with 31% taking placebo (p < 0.001).[32]

Studies also show that the PDE5 inhibitors are effective in specific patient populations, such as those with ED and stable cardiovascular disease, diabetes or clinical depression. According to the European licensed indications, all three treatments can be used in men with cardiovascular disease, provided these patients have been properly assessed and are not taking nitrates (whose concomitant use with PDE5 inhibitors is contraindicated). In patients with ED and cardiovascular risk factors, erectile function was improved in 71% of men taking sildenafil compared with 24% in the placebo group.[34] Sildenafil should be used with caution in men taking α-blockers because simultaneous co-administration may lead to symptomatic hypotension in some patients. Sildenafil (>25 mg) should not be taken within 4 h of taking an α-blocker.[21] Although no published studies have specifically demonstrated the benefits of vardenafil in patients with cardiovascular risk factors, vardenafil is also considered to be effective in most cardiac and hypertensive patients. Concomitant use of vardenafil with α-blocking drugs (e.g. doxazosin) is not recommended, unless the patient has been stabilised on his α-blocker therapy. The maximum dose of vardenafil must not exceed 5 mg in such patients. In addition, vardenafil should not be taken within 6 h of an α-blocker, with the exception of tamsulosin, for which this precaution should not be necessary.[24] Tadalafil has been shown to have comparable efficacy in patients with ED with or without cardiovascular risk factors and in men with a history of hypertension.[35] The European label for tadalafil states that this therapy is not recommended in combination with α-blockers. However, in a single study in 18 healthy volunteers, tadalafil had no clinically significant effect on blood pressure changes caused by tamsulosin, which is a selective A1 α-blocker licensed for the treatment of benign prostatic hypertrophy.[36]

Phosphodiesterase type 5 inhibitors are also effective in patients with ED and diabetes. This group of patients had improved erections following treatment with sildenafil (56% of 131 patients taking sildenafil vs. 10% of 127 patients taking placebo; p < 0.001).[37] This was again a flexible-dose study, where patients had the option to adjust the dose to 100 or 25 mg based on efficacy and tolerability. In patients with ED and diabetes, similar benefits were seen in men taking vardenafil 20 mg [72% of 131 men on vardenafil vs. 13% of 133 men on placebo; p < 0.0001[38]; patients not responding to sildenafil were excluded] and tadalafil 20 mg [64% of 72 men on tadalafil vs. 25% of 71 men on placebo; p < 0.001[39]; all patients irrespective of previous response to ED treatments]. In men with ED following bilateral nerve-sparing radical prostatectomy, tadalafil improves the mean Internal Index of Erectile Function (IIEF) erectile function domain score, percentage of successful penetration attempts and percentage of successful intercourse attempts.[40] Emerging evidence shows that earlier administration of PDE5 inhibitors after prostatectomy may improve outcomes, and introduces the possibility of using PDE5 inhibitors as a prophylactic measure to preserve penile smooth muscle and erectile function after radical prostatectomy.[41]

The adverse event profiles of the PDE5 inhibitors are generally similar ( Table 3 ). Class-specific side effects include headache, flushing, nasal congestion, dyspepsia and myalgia, which are a reflection of vasodilatory effects on the capillary smooth muscle in other parts of the body.[14,29,30,32] Another consequence of the vasodilatory effects of PDE5 inhibitors is that their concurrent administration with nitrates or the potassium channel activator nicorandil is contraindicated, as hypotension can result.[42] As described earlier, differences in PDE selectivity may explain other differences in the side effect profiles of the PDE5 inhibitors. Rare postmarketing reports of non-arteritic anterior ischaemic optic neuropathy (NAION) causing sudden loss of vision in patients taking PDE5 inhibitors led the US Food and Drug Administration to update the labels of all three products. The labels now advise doctors to stop PDE5 inhibitors therapy in the sudden event of loss of vision in one or both eyes and to discuss the increased risk of NAION in patients who have already experienced NAION. At present, however, it is not possible to determine whether these events were related to PDE5 inhibitors or to other factors.[43]

Some patients will inevitably fail to respond to their initial choice of treatment. However, it is important to remember that patients who have failed to respond to a PDE5 inhibitor will not necessarily fail to respond to other drugs in the class.[44] Similarly, patients should not be deemed true treatment failures until they have failed to respond to maximum dose medication on at least eight occasions. Indeed, in a study of 137 men previously unresponsive to sildenafil, 55% became successful after re-education and counselling.[45] Although the reason for this selective response is unclear, many patients who truly fail to respond to one PDE5 inhibitor may actually respond to a different PDE5 inhibitor. Moreover, other non-responding patients may derive benefit from a regular dosing schedule, suggesting that in some patients reversal of ED may result from more continuous exposure to PDE5 inhibitors.[46] Some patients also fail to respond to ED treatment for other reasons, such as associated androgen deficiency. This may be overcome by instituting treatment with androgen replacement therapy.[47,48] However, specialist referral should be considered for patients who do not respond adequately to oral treatment.

The goal of treatment for patients with ED is restoration of a natural and normal sex life.[49] The needs and preferences of patients should therefore be taken into account when the healthcare provider considers the available treatment options. Moreover, with many similarities in the effectiveness and tolerability of the PDE5 inhibitors, treatment decisions will be increasingly influenced by patient preference.

A double-blind crossover study recruited 219 patients, with the objective of measuring patient preference between tadalafil 20 mg and sildenafil at a flexible dose. Patients randomised to the sildenafil arm were started on sildenafil 50 mg but had an option to increase their dose. However, this was limited to the first 35% of requests in order to mimic the pattern of usage in clinical practice.[50] Because the dosing instructions for sildenafil and tadalafil are different, a unique methodology using sham placebo arms was employed to maintain study blindness. Patients were randomised to determine the order in which they received tadalafil and sildenafil with their respective dosing instructions. After 12 weeks, patients were crossed over to the other treatment. Following the crossover period, the 181 evaluable patients made a blinded choice of which of the two treatments they wished to receive in the study's extension period. This study had a number of limitations with respect to the titration of sildenafil, the dose of tadalafil and the increased explanation of the tadalafil dosing instructions. Nevertheless, approximately 7 of every 10 patients who entered the extension phase chose to receive tadalafil. Another study examined patient preference in patients who were taking sildenafil (at stable fixed doses of 25, 50 or 100 mg as needed for at least 6 weeks) and were then switched to tadalafil 20 mg.[51] Again, the trial was designed to mimic everyday clinical practice and thus had some limitations. However, 9 of every 10 patients preferred to continue with tadalafil to sildenafil.

In a recent open-label European multicentre study of sildenafil and tadalafil for the treatment of ED in patients nave to PDE5 inhibitor therapy, 367 men with ED were randomised to sildenafil for 12 weeks followed by tadalafil for 12 weeks or vice versa.[52] Each 12-week period included an 8-week dose optimisation phase and a 4-week assessment phase. Patients started with either 25/50 mg sildenafil or 10 mg tadalafil (as per the prescribing information) and could titrate up or down to achieve their optimum dose (25/50-100 mg sildenafil or 10-20 mg tadalafil). Men completing both 12-week periods chose which treatment to continue during an 8-week extension phase. Efficacy was measured with the IIEF and the SEP diary. A total of 294 men completed both treatmentperiods;29% (n = 85) of men chose to continue with sildenafil and 71% (n = 206) of men chose to continue with tadalafil (p < 0.001) for the 8-week extension phase. The medication choice was not affected by treatment sequence, ED severity or aetiology, age or dosage. Both drugs were well tolerated with 11 patients (3%) discontinuing for an adverse event and three patients (0.08%) for lack of efficacy.

Taken together, these studies suggest that the pharmacological differences of the PDE5 inhibitors can affect patient preference. However, preference studies are often subject to methodological difficulties that can result in sources of bias. Based on the guidelines proposed by Mulhall[53] and Mulhall and Montorsi,[54] difficulties of such studies include the lack of double blinding, so-called period effects (when symptoms evolve or patients adapt to a treatment over time, such as gaining confidence in drug usage), carryover effects between treatment arms, sequence order, and the provision of non-equivalent doses or dosing instructions. However, the choice of open-label study design is driven by the fact that drug encapsulation or other methods of blinding therapy can affect drug pharmacokinetics. This choice is also due to differences in dosing instructions for sildenafil and tadalafil, which are non-identical because of variances in half-life, duration of action and food effects on absorption. It should be noted, however, that in the above studies, men were instructed to use each medication as reflected in the prescribing information available at the time of the study. Consequently, it is unlikely that the patient-reported efficacy and adverse events were influenced by the difference in dosing instructions. Although the study published by Eardley et al.[52] addressed many potential sources of bias, further large multicentre comparative studies are being undertaken to ascertain patient preference for the three currently licensed PDE5 inhibitors.

Following the introduction of sildenafil, reductions in specialist care and its associated costs were seen.[55] Consequently, in the management of ED, the overall cost of impotence services has been contained when using PDE5 inhibitors. All three currently available PDE5 inhibitors are similarly cost-effective, although a drug allowing a broader window of opportunity might arguably seems a more cost-effective option from the perspective of a man with ED faced with the prospect of potentially purchasing numerous packs of treatment for many years.


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