Erectile Dysfunction in Men: What Treatment Options Are Available?
Erectile dysfunction is a sensitive issue that eventually affects many men. This pathology leads to emotional tension, low self-esteem, and worsens the relationship between partners. The problem is exacerbated by the fact that only a small percentage of men dare to tell a doctor about their intimate health issues and actively seek help. Phosphodiesterase 5 inhibitors have revolutionized the treatment of erectile dysfunction. In this article, we will take a closer look at the highly selective PDE5 inhibitor avanafil.
Introduction
Erectile dysfunction (ED) is a condition that results in the inability to achieve and maintain an erection necessary for sexual intercourse. So far, there is no universally accepted and easily understandable definition of ED in epidemiological studies, so the true extent of erectile dysfunction is not known. It is undeniable that the prevalence of erectile dysfunction directly correlates with the age of the subjects (1). Research data show that the frequency of ED in the 18–59 age group is around 10% (2). About 30% of these men suffer from severe or complete erectile dysfunction (2). Among patients aged 70 years and older, ED reaches 61% (3).
Erectile dysfunction is inevitably associated with low self-esteem and emotional tension. Another reason why it is crucial to identify people with erectile dysfunction early is the risk of cardiovascular diseases. Studies have found that ED occurs on average three years earlier than cardiovascular diseases (4). Men with erectile dysfunction have up to a 75% increased risk of peripheral heart diseases (5). A cancer prevention study showed that men with ED belong to a higher-risk group for angina, myocardial infarction, stroke, transient ischemic attack (TIA), and arrhythmias (6). For this reason, it is essential to understand the physiological and pathophysiological mechanisms of erection, its diagnosis, and, most importantly, treatment options.
Factors Contributing to Erectile Dysfunction
Erectile dysfunction is often an early sign of undiagnosed or untreated diseases. There are many factors that can influence erectile dysfunction. Organic, physiological, and endocrine factors result in the inability to achieve and maintain an erection necessary for sexual intercourse. Factors causing ED can be divided into two categories: organic or psychogenic.
For a long time, it was believed that the majority of ED cases were due to psychogenic causes (depression, anxiety, stress), but it has now been proven that organic causes are responsible for 60–90% of all cases of erectile dysfunction (7). Organic erectile dysfunction is a natural consequence of aging. It progresses gradually. The time from the start of sexual stimulation to the onset of erection lengthens, penile rigidity decreases, ejaculation strength and volume decrease, and the time between erections lengthens. However, organic ED is closely related to a psychogenic component.
Erectile dysfunction can also be caused by hypertension, dyslipidemia, atherosclerosis, heart diseases, and diabetes. ED less frequently develops due to stroke, Parkinson's disease, multiple sclerosis, or other factors. Physical injuries, especially in the pelvis and spine, can damage nerves and cause erectile dysfunction. Up to 25% of cases of erectile dysfunction develop due to medication use (8).
Non-Drug Treatment of Erectile Dysfunction
The most important role in the non-drug treatment of ED is the elimination and correction of modifiable factors. Smoking, a sedentary lifestyle, and diabetes are associated with a higher risk of erectile dysfunction. Patients of any age must first be informed about the benefits of weight loss, increased physical activity, and smoking cessation for erectile function.
A meta-analysis of twenty-four clinical trials showed that weight loss significantly increases the concentration of bound and free testosterone in the blood. A low-calorie diet and bariatric surgery statistically significantly (p < 0.0001) increase testosterone concentration in the blood (9). The increase in androgen concentrations directly correlates with greater weight loss and younger age of the subjects (9).
Patients with diabetes must carefully control blood glucose levels. Uncontrolled hyperglycemia causes changes in peripheral nerves and blood vessels, disrupting erectile function (10).
The onset of ED is influenced by a variety of medications (Table 2). It is essential to determine which medications a patient with erectile dysfunction is taking and to discontinue or replace them with other types of drugs. Tricyclic antidepressants cause libido disorders, and up to 70% of patients experience erectile dysfunction (11). Selective serotonin reuptake inhibitors delay ejaculation. Beta-blockers have a negative impact on sexual function. Calcium channel blockers and angiotensin-converting enzyme inhibitors have minimal effects on erectile function, while angiotensin receptor blockers have a positive effect on sexual function (11).
First-Line Medications – Phosphodiesterase Inhibitors
The revolution in the treatment of erections occurred in 1998 when the first phosphodiesterase 5 (PDE5) inhibitor – sildenafil – appeared. Currently, four phosphodiesterase 5 inhibitors are registered in Lithuania – sildenafil, vardenafil, tadalafil, and the newest representative of this group – avanafil. After in vitro studies, it was found that avanafil acts very selectively on phosphodiesterase 5, potentially resulting in a lower frequency of specific adverse reactions and a rapid onset of action (18, 27).
The choice of a phosphodiesterase 5 inhibitor depends on the patient's personal needs, the duration and frequency of sexual intercourse, and personal experience related to the use of one drug or another. Phosphodiesterase 5 inhibitors are the first-choice drugs for treating erectile dysfunction, but they should not be taken within the last 6 months after a stroke or heart attack. These drugs are also contraindicated if the patient suffers from hypotension or uncontrolled hypertension, unstable angina, severe heart, liver, or kidney failure (13).
The onset of drug action is very important for many patients. The highest concentration of sildenafil in the blood plasma occurs 30–120 minutes after taking the drug (on average after 60 minutes) (14). The highest plasma concentration of avanafil is reached within 30–45 minutes after taking the drug on an empty stomach (13). It is believed that this may provide spontaneity for intimate relationships and make it easier to plan the start of sexual intercourse (12). It is important to note that, like many other phosphodiesterase inhibitors, the onset of avanafil's action can be delayed by fatty foods (13).
Similar Molecules, Different Effects
Although the mechanism of action of phosphodiesterase 5 inhibitors is similar, they have pharmacological differences that determine different clinical effects. With sexual stimulation, sildenafil can induce an erection within 4–5 hours after intake (14). When the drug is taken on an empty stomach, the highest concentration in the blood plasma occurs 30–120 minutes after intake (on average after 60 minutes). When sildenafil is taken with a meal, absorption is slower: Tmax is extended by an average of 60 minutes, and Cmax decreases by an average of 29% (14).
The average maximum concentration (Cmax) of tadalafil in the blood plasma is reached on average after 2 hours, and food does not affect tadalafil absorption (27). In 90% of cases, the highest concentration of vardenafil is reached within 30–120 minutes (median – 60 minutes) when the drug is taken on an empty stomach (28). The effectiveness of vardenafil, like sildenafil, is influenced by fatty foods: with very fatty food (containing 57% fat), the rate of absorption decreases, the average Tmax value increases by 1 hour, and Cmax decreases by an average of 20% (15, 28). The absorption of avanafil is also influenced by fatty foods. If avanafil is taken with a fatty meal, the rate of absorption decreases, and Tmax increases by an average of 1.25 hours, while Cmax decreases by an average of 39% (200 mg) (12).
There are various groups of different phosphodiesterases (PDE) in various tissues of the body. Most of them are found in blood vessels, visceral, and pulmonary smooth muscles. The highest concentration of PDE5 is found in the cavernous bodies of the penis. The biochemical selectivity of PDE5 is the most important factor in reducing the frequency of specific adverse reactions (26). The most common adverse effects of PDE5 inhibitors are headache (10–16%), facial flushing (5–12%), dyspepsia (4–12%), nasal congestion (1–10%), and others (23).
Adverse Effects
Based on the model of PDE5 inhibition, attempts have been made for a long time to develop safer and more effective drugs for treating erectile dysfunction. Avanafil is a PDE5 inhibitor characterized by high selectivity for PDE5 receptors (12, 26). In many preclinical studies, the inhibitory effect of avanafil on phosphodiesterases (PDE) was investigated and compared with sildenafil, vardenafil, and tadalafil.
Avanafil acts more than a hundred times stronger on PDE5 compared to PDE6, which is exclusively found in the retina of the eye and is responsible for light transformation. Sildenafil shows 16 times greater selectivity for PDE5 than PDE6, while vardenafil shows 21 times greater selectivity (18). These data suggest that avanafil's tendency to cause visual disturbances (blue vision) is lower.
In in vivo studies with animals, the effect of avanafil and sildenafil on the retina was studied by recording their effect on electroretinogram. Due to weaker inhibition of PDE6, avanafil showed a much smaller effect on the retina and its visual receptors than sildenafil (19). This is particularly important because PDE6 inhibition can lead to the death of photoreceptor cells and retinal degeneration (20). For this reason, these drugs are not recommended for patients with retinal degenerative diseases (21).
PDE5 inhibitors also interact with PDE11, found in the testes and prostate (16). The effect of avanafil on PDE5 is more than 10,000 times stronger compared to PDE11, potentially resulting in less frequent back pain and myalgia. In studies involving tadalafil, no adverse effects on testicular function and spermatogenesis were identified, with the most common side effects being headache, back pain, and dyspepsia. Avanafil is characterized by high selectivity for PDE5 and less action on other phosphodiesterases, which could result in the drug's in vitro and in vivo effectiveness.
Avanafil – a Drug Studied in Many Clinical Trials
Avanafil was evaluated in 3 to 3-month randomized, double-blind, placebo-controlled, parallel-group studies with patients having only erectile dysfunction, patients with type 1 or type 2 diabetes with erectile dysfunction, and patients whose erectile dysfunction was caused by bilateral nerve-sparing radical prostatectomy. Avanafil was taken on an as-needed basis by a total of 1,168 patients in doses of 50, 100, and 200 mg.
Additionally, some patients were included in an open-label extension study, where 493 patients took avanafil for at least 6 months, and 153 patients for at least 12 months. The phase III clinical REVIVE study showed that successful sexual intercourse could be achieved with avanafil for mild and severe erectile dysfunction as early as 15 minutes and up to more than 6 hours after drug intake.
In the TA302 study involving men with diabetes and erectile dysfunction, avanafil was also effective more than 6 hours after drug intake and started working in as little as 15 minutes. This study showed that 16 weeks of treatment with 100–200 mg of avanafil significantly improved erections in diabetic patients. 43–54% of patients successfully performed vaginal penetration, and 34–43% successfully completed the sexual act.
Similar results were obtained with other PDE5 inhibitors. Sildenafil improved erections in 56% of cases, vardenafil in 62% (25), and tadalafil in up to 74% of cases (26). Most patients achieved a sufficient erection for sexual intercourse within 15 minutes after taking avanafil.
Avanafil is an effective and highly selective PDE5 inhibitor. The drug's efficacy has been demonstrated in many clinical trials. The preparation has a sufficiently rapid onset of action, allowing for more spontaneity in patients' intimate lives. The recommended dose of avanafil is 100 mg. Depending on efficacy and tolerability, this dose can be increased to no more than 200 mg or decreased to a 50 mg dose. The drug is rapidly absorbed in the body, reaching peak plasma concentration (Tmax) within 30–45 minutes.
Prepared by Dr. Urologist M. Anglickis. The article is reprinted from the publication "Urologija" (supplement to the journal "Internistas"). Literature sources are in the Spe-LT-008-2014 editorial office.
