The European Association of Urology first published Guidelines on Erectile Dysfunction in 2000, and the EAU subsequently updated the Guidelines in 2001, 2002, 2004, 2005 and 2009. In particular, in 2009, the EAU included premature ejaculation in the Guidelines and changed the title to Guidelines on Male Sexual Dysfunction. This revision was based on a systematic review of the literature, and experts searched Medline 2009 for the following terms: “erectile dysfunction,” “sexual dysfunction,” “ejaculation,” and “premature ejaculation. “Medline was searched for relevant literature from January 2009 to January 2013.
The Guidelines recommend first-line treatment for male erectile dysfunction (Erectile dysfunction , ED): oral pharmacotherapy (PDE5i), vacuum device therapy, and shock wave therapy. Among them, PDE5i is popular among doctors and patients and widely used in clinical practice because of its rapid onset of action and convenience. However, the safety of PDE5i is also a concern for doctors and patients. Therefore, the Guidelines on PDE5i are interpreted to help general practitioners to apply PDE5i more rationally.
1.Oral drug treatment
The European Medicines Agency (EMA) recommends three highly effective Phosphodiesterase Type 5 Inhibitors (PDE5i): sildenafil, tadalafil and vardenafil. PDE5i acts as a treatment for erectile dysfunction by relaxing smooth muscle, increasing arterial blood flow and decreasing venous blood flow.
1.1 Sildenafil
Sildenafil is prescribed in doses of 25, 50, and 100 mg, with the guideline recommending a starting dose of 50 mg, with dose adjustment based on patient outcomes and side effects. In a controlled study of sildenafil versus placebo for the treatment of mild ED, the erection improvement rate was 25% in the placebo group and 56%, 77%, and 84% in the sildenafil 25, 50, and 100 mg groups, respectively, after 12 w of drug administration. The study reported an erection improvement rate of 66.6% in patients with concomitant diabetes after taking sildenafil. Long-term consumption of a high-fat diet by patients may reduce the efficacy of the drug.
1.2 Tadalafil
Tadalafil is prescribed at 10mg and 20mg as needed. The Guidelines recommend a starting dose of 10 mg, with dose adjustment based on patient efficacy and side effects. In a tadalafil versus placebo-controlled study for mild ED, erectile improvement was 35% in the placebo group and 67% and 81% in the tadalafil 10 and 20 mg groups, respectively, after 12 w of drug administration. Although the efficacy of on-demand tadalafil for ED with diabetes is poor, a tadalafil versus placebo-controlled study of ED with diabetes showed a 21.8% rate of successful sexual activity in the placebo group and 45.4% and 49.9% rates in the on-demand tadalafil 10 and 20 mg groups, respectively. 49.9%. The efficacy of the drug was not affected by diet.
1.3 Vardenafil
The drug can be therapeutically effective after 30 min of vardenafil in patients prescribed 5, 10 and 20 mg as needed. The Guidelines recommend a starting dose of 10 mg, with dose adjustment based on patient efficacy and side effects. In a controlled study of vardenafil versus placebo for the treatment of mild ED, the rate of erectile improvement was 30% in the placebo group after 12 w of the drug, and 66%, 76% and 80% in the vardenafil 5, 10 and 20 mg groups, respectively. Although the efficacy of on-demand vardenafil for ED with diabetes is poor, a controlled study of vardenafil versus placebo for ED with diabetes showed a 23% rate of successful sex in the placebo group and a 49% and 54% rate of successful sex in the on-demand tadalafil 10 and 20 mg groups, respectively. Diet can reduce the efficacy of the drug when the fat content of the diet is greater than 57%.
1.4 Drug selection
To date, no data are available on the efficacy of the three drugs and patient preferences using a multicenter double- or triple-blind approach. Patients need to know the characteristics (short- or long-acting) and possible side effects of each drug to decide which PDE5i to use, using the frequency of patient sexuality and patient experience.
1.5 On-demand or long-term dosing
Age, diabetes and surgical injury can lead to structural changes within the cavernous sinus. Animal studies have shown that long-term administration of PDE5i can improve and prevent these changes, but data from human studies are lacking.
Rosano GM et al. showed that long-term tadalafil improves endothelial function and therefore has sustained efficacy after discontinuation of the drug. A study of ED patients with type 2 diabetes also confirmed the findings of Rosano GM et al.
The study showed that patients did not achieve longer sustained efficacy after discontinuation of 10 mg vardenafil once daily for mild to moderate ED compared to as-needed dosing.
2. Measures for PDE5i-naïve patients
The two most important reasons for patients not responding to PDE5i are: incorrect use of the drug and the drug not working. The following reasons need to be identified.
(1) Check whether the drug taken by the patient is regular and the quality of PDE5i in the black market is not qualified;
(2) Check if the drug is being used correctly. This includes.
(1) Lack of adequate sexual stimulation ;
(2) not taking sufficient doses;
(3) The time between taking the drug and having sex is too long;
④Diet affects the absorption of the drug.
Physicians should instruct patients on the timing of attempting sex based on the half-life of the three PDE5i inhibitors. For example, the half-life of sildenafil and vardenafil is about 4h, and 6~8h after taking the drug is the time window of efficacy; the half-life of tadalafil is 17.5h, and 36h after taking the drug is the time window of efficacy.
ED is a typical symptom of hypertension, diabetes and dyslipidemia, and treating the underlying disease can improve the efficacy of PDE5i in treating ED. Modifying risk factors for ED (obesity, smoking, and lack of exercise) can benefit patients with ineffective PDE5i.
Patients respond differently to sildenafil, tadalafil, and vardenafil, so when one drug does not work for a patient, the physician may choose another drug. If drug therapy fails, the physician may choose vacuum compression device therapy or intracavernous penile injection.
3.Safety of PDE5i
Long-term use of PDE5i may cause minor adverse effects, but it does not affect the patient’s compliance. Studies have shown that the rate of subject shedding due to adverse effects in the PDE5i treatment group is similar to that of placebo.
3.1 Cardiovascular safety
Results from clinical studies and post-marketing data for PDE5i indicate no increase in the incidence of myocardial infarction in patients treated with PDE5i. According to known data, sildenafil did not affect myocardial contractility, cardiac output, or myocardial oxygen consumption. PDE5i did not adversely affect exercise duration or myocardial ischemia in patients with stable angina during exercise testing. It was similarly safe and well tolerated by patients on long-term or as-needed dosing.
3.2 Concomitant administration of PDE5i with nitrates is strictly prohibited
Concomitant use of organic nitrates such as nitroglycerin, isosorbide mononitrate and isosorbide nitrate with PDE5i is strictly prohibited. They can lead to accumulation of guanosine cyclophosphate, decreased blood pressure and hypotension. Patients taking PDE5i with chest pain should not take nitroglycerin within 24 h of sildenafil or sildenafil and within 48 h of tadalafil. If angina occurs while ED patients are taking PDE5i, patients should receive nitroglycerin only at appropriate intervals and under close observation as described above.
3.3 Antihypertensive drugs
Hypertension and ED are often co-morbid, and the safety of PDE5i is of wide concern when ED patients taking antihypertensive drugs are treated with PDE5i. The Guidelines emphasize that PDE5i has a slight synergistic effect with antihypertensive drugs. Even if patients are taking multiple antihypertensive medications, the adverse effects of PDE5i are not made worse.
3.4 Alpha-blockers
PDE5i interacts with α-blockers. In some cases, both can lead to postural hypotension.
3.4.1 Patients taking α-blockers (especially doxazosin) should take 50 mg or 100 mg tadalafil with caution; otherwise, hypotension is likely to occur within 4 h of taking an α-blocker. The recommended application is tadalafil 25mg.
3.4.2 Patients taking α-blockers can start vardenafil with α-blockers once the dose has stabilized.
3.4.3 The combination of vardenafil and tamsulosin does not result in a significant decrease in blood pressure.
3.4.4 Doxazosin is not recommended in combination with tadalafil, but tamsulosin can be used in combination with tadalafil.
The interactions described above were all from healthy volunteers who had not taken an alpha blocker. The interaction of other types of PDE5i with α-blockers needs to be studied in depth.
The use of PDE5i in combination with α-blockers is an important guideline for clinicians treating patients with BPH and ED.
3.5 Dose adjustment
Drugs that inhibit the cytochrome P34A pathway can inhibit the metabolism of phosphodiesterase 5 inhibitors, which in turn increases blood concentrations of phosphodiesterase 5 inhibitors such that patients require only smaller doses of PDE5i. these drugs are: ketoconazole, itraconazole, erythromycin, clarithromycin and HIV protease inhibitors (ritonavir and saquinavir). the results of a study by Gur S et al. in February 2013 concluded that the combination of PDE5i with cytochrome P34A inhibitors increases the blood concentration of PDE5i, so the dose of PDE5i needs to be adjusted.
However, some drugs can activate cytochrome P3A4 and accelerate the metabolism of PDE5i, so that patients need higher doses of PDE5i. these drugs are: rifampicin, phenobarbital, phenytoin sodium and carbamazepine. gur S et al. concluded that the combination of tadalafil and bosartan decreased the blood concentration of tadalafil, so the dose of this drug needs to be adjusted.
Sexual dysfunction is very common in patients with chronic nephritis. The Guideline emphasizes the need to adjust the dose of PDE5i in patients with severe renal and hepatic impairment.