Phosphodiesterase 5 inhibitors
Phosphodiesterase 5 (PDE5) inhibitors, found in abundance in the corpus cavernosum, is an enzyme that breaks down cyclic GMP, an intracellular second messenger for nitric oxide (NO). PDE5 inhibitors competitively antagonize the action of PDE5, raising intracellular levels of cyclic GMP in corpus cavernosum smooth muscle, leading to smooth muscle relaxation in the corpus cavernosum and an erection in response to sexual stimulation.
In Japan, the three agents in this class presently available on prescription are sildenafil, vardenafil and tadalafil.
- (a) Sildenafil (Viagra) [Recommendation Grade A]
This was the first PDE5 inhibitor clinically used worldwide. It has been prescribed to over 1 000 000 patients in Japan (more than 20 000 000 worldwide). Onset of action occurs 30–60 min after oral administration.73 A meta-analysis of 11 placebo-controlled RCTs collated data from over 3000 subjects, assessing efficacy using the global assessment question (GAQ), ‘Did the treatment that you used for your erections improve your erections during the time of therapy?’ The efficacy rate, or proportion of the sildenafil group who answered ‘yes’ for the 12-week study period, was 76% (placebo group 22%). Of these, improvement in erections was reported by 65% (placebo 12%) of subjects with severe ED according to the IIEF.74
A safety study collated the results of a placebo-controlled double blind trial and an open label study (sildenafil group 6986 subjects, placebo group 5054), examining the incidence of cardiovascular events, and area of concern when sildenafil was first released. No difference was seen in the incidence of myocardial infarction between the sildenafil group (0.58/100 person-years), placebo group (0.95/100 person-years), nor was any difference seen in the overall death rate of 0.37/100 versus 0.53/100.75 A Japanese clinical trial yielded similar efficacy and safety rates to overseas studies.76 Only the 25 mg and 50 mg dosages are allowed in Japan, so we are unable to use the 100 mg tablets available elsewhere. If sildenafil is taken after a meal, absorption is delayed, lowering blood concentration levels and reducing its effectiveness. A study of 12 non-Japanese subjects examining the interaction between alcohol and sildenafil, a commonly seen combination, found that alcohol (0.5 g/kg body weight) had no effect on the pharmacokinetics of sildenafil.
Diastolic blood pressure in supine and reclined positions were significantly lower in the alcohol/sildenafil group than in the alcohol/placebo group.77
- (b) Vardenafil (Levitra) [Recommendation Grade A]
Onset of action occurs 30 min after oral administration.78 A meta-analysis of nine placebo-controlled RCTs collated data from over 4286 subjects participating in 12 week studies. Improved erections were reported by 69% of the vardenafil group, and 26% of the placebo group (P < 0.00001).79 In a 2-year long-term study, 90–92% of subjects who completed the trial answered ‘yes’ to the GAQ. There were no cardiovascular events.80 A Japanese clinical trial yielded similar efficacy and safety rates to overseas studies.81
Vardenafil is contraindicated in patients taking Class Ia (e.g. quinidine, procainamide) or Class III antiarrhythmic agents (e.g. amiodarone), and in patients with long QT syndrome.56 The dosages available in Japan are 5, 10 and 20 mg (although 20 mg tablets cannot be used in elderly patients aged over 65). The efficacy of vardenafil is reduced if it is taken after a high fat meal. The interaction between alcohol and vardenafil was examined in a study of 12 healthy non-Japanese subjects. It found that alcohol (0.5 g/kg body weight) had no effect on the pharmacokinetics of vardenafil.82 Comparisons between an alcohol group, vardenafil group, and alcohol/vardenafil group, found only that alcohol raised the heart rate, with no effects of vardenafil.
- (c) Tadalafil (Cialis) [Recommendation Grade A]
Onset of action occurs 30 min after oral administration, and is maintained for 36 h.83 This prolonged duration of action is the big difference between this agent and the abovementioned two. Another characteristic of tadalafil is that it also inhibits PDE11. The significance of inhibiting PDE11, mainly found in the prostate, testis and skeletal muscle, is unknown. In a meta-analysis of five placebo-controlled RCTs, 41–81% of 1112 subjects with mild to moderate ED reported improved erections (placebo 35%). They further reported successful intercourse in 73–80% of sexual opportunities from 30 min to 36 h after taking tadalafil.84
Back pain is a typical adverse reaction of tadalafil, occurring at a frequency of 5%. A safety study collated the results of a placebo-controlled double blind trial (tadalafil group 12 487 subjects, placebo group 2047) and an open label study, found no difference in the incidence of cardiovascular events between the tadalafil group (0.40/100 person-years) and the placebo group (0.43/100 person-years).85 A Japanese clinical trial yielded similar efficacy and safety rates to overseas studies.86 The dosages available in Japan are 5, 10 and 20 mg. Absorption of tadalafil is affected very little by meals.
The interaction between alcohol and tadalafil was examined in a study of around 100 healthy non-Japanese subjects. It found that alcohol (0.6 g/kg body weight) had no effect on the pharmacokinetics of tadalafil. Comparisons between a tadalafil/alcohol group and a tadalafil/placebo group found only that tadalafil enhances the hypotensive effect of alcohol.87
- (d) Comparisons of the three PDE5 inhibitors
The efficacy and tolerability of these three agents have been confirmed in comparative trials and postmarketing surveillance. A number of comparative studies have examined the question of which PDE5 inhibitor is superior.88,89 Such studies are inevitably imperfect due to the fact that the primary endpoint relies on subjects' impressions, and the fact that blind trials are impossible because of the characteristics of on demand dosing, differences in onset and duration of action, and reduced absorption with meals. The best course is therefore to explain to each patient the characteristics of each agent (see Table 5), and have them make the choice [Recommendation Grade C1].
Table 5. Characteristics of the phosphodiesterase 5 (PDE5) inhibitors
|Protein binding rate (%)||96||91||97|
|Use with alpha-blockers||Caution required||Caution required||Caution required|
|Effect of meals||Delayed absorption and onset of action||None (reduced effect with high fat meal)||None|
- (e) Evaluation of efficacy
Clinical efficacy is often evident with the first dose. Due to the need to determine the appropriate dosage and sexual stimulus, patients should be carefully advised on the optimum use of their medication. Therapeutic effect therefore improves with repeated use.
Even after a lack of response to several doses of a PDE5 inhibitor, it is still premature to call it ineffective. A study of 236 subjects referred by their general practitioner due to apparent non-response to sildenafil found that 98 subjects (41.5%) responded after re-education using videotapes and written material.
The reason for the initial treatment failure was inappropriate use (e.g. after a heavy meal, no sexual stimulation, wrong timing, only tried a few times) in 81% of cases.90
Reported salvage rates for initial treatment failures are of the order of 42–59%,91–95 indicating that half of these patients can be salvaged with re-education. The European Association of Urology (EAU) Guidelines accordingly state that a minimum of four doses is required for non-response to be diagnosed2[Recommendation Grade B].
There are also undoubtedly many cases where treatment is stopped despite initial success. One study reported a dropout rate of 57% over 3 years.96 A Japanese study of 667 subjects with initial treatment success found that 48% discontinued treatment over the 3-year follow-up period.97
- (f) Adverse reactions and contraindicated concomitant medication
Concomitant use of PDE5 inhibitors and nitrates lowers blood pressure to dangerous levels, and is therefore contraindicated. Caution is advised in administering a PDE5 inhibitor in conjunction with an alpha-blocker (either for treatment of hypertension, e.g. terazosin, or for BPH, e.g. tamsulosin), due to augmentation of the hypotensive effect of the latter, so the former should be introduced at a low dosage.56
The PDE5 inhibitors have known class-specific adverse reactions. Some typical adverse reactions are headache, dyspepsia, facial flushing, nasal congestion, and visual disturbance (caused by PDE6 inhibition – glare, seeing everything tinted blue, unrelated to nonarteritic anterior ischemic optic neuropathy [NAION]: see below). These adverse reactions are usually mild to moderate in degree, and transitory.
There have been a few reports of priapism, an early cause of concern, associated with sildenafil,98 and one case with tadalafil.99 Although this is an extremely rare adverse reaction, an erection lasting more than 4 h requires immediate treatment.
Another adverse reaction, NAION, was first reported in 2000, and attracted a great deal of attention in 2005. The package inserts for each PDE5 inhibitor was also changed at that time. NAION is a condition affecting the optic nerve of unknown etiology that presents as a sudden, pain free, visual field defect (usually unilateral). It is often first noticed upon awakening. Fundal examination reveals findings of optic nerve edema. An American epidemiological survey estimated the yearly incidence in Caucasians aged 50 years and over as 2.3–10.2 per 100 000. This yields an estimated 1500–5000 new cases each year in the USA.100,101 The Ischemic Optic Neuropathy Decompression Trial (IONDT) cohort study (418 subjects, 5 years) identified vision impairment at the commencement of the observation period and diabetes as statistically significant risk factors for NAION.102 There are no effective treatments or preventive measures for this condition. The aims of treatment are to prevent enlargement of the lesion in the affected eye, and protect the unaffected eye. NAION and ED share common risk factors, so the relationship between NAION and ED is the same as that between ED and cardiovascular diseases. Although some are of the opinion that concurrent ED and NAION are the product of chance,103 there are also some reproducible case studies, and at present all that can be said is that the relationship between NAION and PDE5 inhibitors is unclear.
There have been no epidemiological studies conducted in Japan, and the incidence of NAION in this country is unknown. The search engine on the Japanese Ministry of Health, Labour and Welfare yielded no reports by the use of any PDE5 inhibitors.104 Patients should be informed of this adverse reaction, and advised to stop their medication and see an ophthalmologist if they experience any visual disturbance [Recommendation Grade C1].
- 1Intracavernous injections [Recommendation Grade B]
This involves injecting prostaglandin E1 (PGE1) into the corpus cavernosum. The usual dosage is 5–20 μg of PGE1 dissolved in 1 mL of physiological saline. The mechanism of action is that PGE1 binds to EP receptors within smooth muscle cells in the corpus cavernosum, activating adenylate cyclase. This results in increased levels of cyclic AMP, smooth muscle relaxation, and an erection. PGE1 is metabolized by 15-hydroxy-PGE1 dehydrogenase present in the corpus cavernosum.105 This treatment shows high efficacy and moderate tolerability in most ED patients. The main adverse events are local in nature, acutely penile pain (50%) and rarely priapism (ischemic, 1%), and chronically penile fibrosis (2%) and hematoma/subcutaneous hemorrhage (8%).106 In particular, priapismNB is a serious condition requiring urgent treatment, corresponding to the ‘acute penis’. The cavernosous injections should therefore only be prescribed by institutions able to deal with this adverse reaction.
Although this treatment is effective in patients in whom PDE5 inhibitors are ineffective or contraindicated, it has not been approved for clinical use in Japan. Some trials are underway, led by Okayama University.107
Priapism is defined as ‘an erection that is maintained for greater than 4 h despite the absence of both physical and psychological stimulation’. The choice of 4 h for this definition was made on the basis of experience of how long patients take to get to hospital, and how long it takes to organize investigations and treatment. Edema of the corpus cavernosum smooth muscle begins 12 h after the onset of priapism, and after 24 h endothelial cells (a source of NO, the trigger for erections) begin to die off, with platelets adhering to the site. Necrosis of corpus cavernosum smooth muscle is seen after 48 h.108 The time limit of 4 h was set on the basis of this report, to allow a reasonable safety margin.
Here we show you the recommendations by AUA how to diagnose and treat ischemic priapism, a urological emergency.109
This is readily made on the basis of the history and observation of the erect penis. It can also be readily determined whether it is ischemic or not by aspirating the corpus cavernosum, and carrying out arterial blood gas analysis.
First insert a 19 or 21 gauge butterfly needle into the corpus cavernosum, aspirate blood and flush with physiological saline. Then inject 1 mL of 100–500 μg/mL phenylephrine, the α-agonist. Repeat the above procedure every 3–5 min until 1 h has passed. This procedure relieves 43–81% of cases of priapism. Recurrent cases require surgical treatment, and should be referred to a urologist.
- 2Vacuum constriction devices [Recommendation Grade B]
These devices apply negative pressure, drawing blood into the shaft of the penis, and then apply a rubber band to the base of the penis to keep this blood in the penis. This is therefore a pseudo-erection rather than a physiological erection. Although an erection capable of intercourse is achieved in 90% of cases, reported satisfaction rates vary widely from 27% to 94%.110 The only such devices presently approved in Japan are the Vet-Co (internet sales, http://www.jinseido.co.jp/jin/etc/impo.html)111 and the vacuum constriction device ‘Kanki’ (Takei Ikakouki Co. Ltd: Tel. 03-3255-0711).112 They each cost around 50 000 yen, and directions for use are given in an accompanying videotape, although instruction from a medical practitioner is preferable. Adverse reactions include penile pain and numbness, subcutaneous hemorrhage, and ejaculatory difficulties. Anticoagulant therapy is a relative contraindication for the use of a vacuum erection device.