Managing Erectile dysfunction
Erectile dysfunction (ED), previously and less precisely called impotence, is the most common sexual problem in men1,2. ED is defined as the “inability to achieve or maintain an erection sufficient for satisfactory sexual performance”3. A minimum period of three months of such inability is required to establish a definite diagnosis of ED, with the exception of known cases of trauma or surgically induced ED4,5. ED should be distinguished from other kinds of sexual dysfunctions such as loss of libido, premature ejaculation or anorgasmia, although some patients might also experience a combination of these disorders5. ED causes a significant impact on the quality of life, self-esteem, and mental wellbeing of men as well as on their interpersonal relationships6-8.
The worldwide prevalence of ED is predicted to be at 322 million men by 2025, a rise of 170 million men for the 30-year period from 1995, when it was at 152 million men2. The Massachusetts Male Aging Study found that 52% of men aged 40 to 70 years had a certain degree of ED9. Similarly, a Canadian survey in a primary care setting reported that the overall prevalence of ED was 49.4% in men aged 40 to 88 years10. In Malaysia, a population-based survey on men aged 40 and above revealed that up to 70% of the population had some degree of ED, of whom 45.9% had moderate-to-severe ED; this result was comparable to other Western and Asian population studies11-12. A recent study found that the prevalence of ED was 69.5% among men who visited urban public primary care clinics in Malaysia13.
ED can be classified according to the etiology of the disorder or severity of the symptoms (i.e. mild, moderate or severe). The etiology classification is more widely used and it is further classified into organic and psychological causes. Organic origins of ED include vascular, neurological, hormonal and drug factors, whereas psychogenic origins are usually a result of central nervous system inhibition in the erectile mechanism in the absence of obvious physical injury1. Certain medications (usually those used to treat chronic illnesses) can cause sexual inability. Drugs that may cause medication-induced ED are beta-blockers, diuretics, anticholinergics, tricyclic antidepressants, anticonvulsants, antipsychotics, anti-Parkinsonism agents and certain hormonal drugs14-15. Psychogenic factors are the most common causes for intermittent ED in young men, but often secondary to organic causes in older patients16. While 80% of ED is of organic origin, many men also suffer ED of mixed organic and psychogenic origins17.
The prevalence of ED increases with age and this has been demonstrated by many studies2,6,11,12. However, it is not an inevitable consequence of aging. Studies have shown that ED is associated with medical illness or comorbidities such as diabetes mellitus, atherosclerosis, hypertension, and cardiovascular disease1,9,10,11 as well as lower urinary tract symptoms6,11,12. Lifestyle-related factors such as obesity, smoking, sedentary lifestyle, and emotional and stress-related problems can also increase the risk of ED2,4,6,12,18. In contrast, ED can enhance the risk of developing coronary artery disease, especially in younger men19.
Despite the high prevalence of the disorder, many men do not seek treatment until the symptoms become unbearable1,12. This is probably due to shame, embarrassment, fear or the general perception of sexual dysfunction as a consequence of ‘normal aging’ and not as ‘severe’ as other medical conditions21. A lack of awareness of available treatment options is probably another reason for not seeking treatment5. The management of ED can be divided into psychotherapy, pharmacotherapy, and mechanical and surgical therapy. Psychotherapy, also known as behavioral therapy, can be used alone or as an adjunct to other treatment modalities. Pharmacotherapy includes the use of oral phosphodiesterase-5 (PDE5) inhibitors, sublingual apomorphine, intracavernosal vasoactive drug injection and intraurethral suppositories6. The mechanical route, involving the use of vacuum constriction devices, is another non-invasive management technique for ED. Surgical options, including implantation of prosthetic devices or vascular surgeries, are generally invasive. Since the presence of diabetes, hypertension and heart disease can increase the risk of developing ED, optimal management of these diseases and lifestyle modification may be useful in preventing and managing ED. The preferred first-line treatments are lifestyle modifications or alterations in pharmacotherapy for other conditions (that cause ED), oral PDE5 inhibitors, and testosterone supplementation (only for ED patients with hypogonadism). Second-line therapies include intracavernosal or intraurethral alprostadil and vacuum pump devices. Penile prosthesis is usually the last treatment option when the first- and second-line therapies have failed5,22.
Psychotherapy or behavioral therapy such as sexual counseling and education helps in relieving anxiety and depression and hence in improving sexual function23. It is normally the treatment of choice when psychogenic ED is suspected or in the absence of obvious organic cause3. Also, it can be used as adjunct therapy for the treatment of organic ED. The integration of psychotherapy with other treatment modalities helps to increase the effectiveness of the overall treatment23.
i. PDE5 inhibitors
PDE5 inhibitors were the first oral pharmacotherapy agents discovered for ED and remain the first-line treatment for ED regardless of the etiology22. The three PDE5 inhibitors currently available on the Malaysian market are sildenafil, tadalafil and vardenafil. They are potent, competitive and reversible inhibitors of PDE5. They inhibit PDE5 and, thus, enhance the effect of nitric oxide (NO), which is responsible for degrading cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. As a result, the level of cGMP increases leading to increased smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil, the first PDE5 inhibitor, was introduced in 1998, and has a wide spectrum of efficacy in many ED patients regardless of etiology, severity or age, and has a good safety profile5. All three PDE5 inhibitors are relatively similar in their effectiveness and the clinical data available do not prove the superiority of one agent over another22. However, their pharmacokinetic profiles such as onset of action, dosing and duration of therapeutic effect are different due to the variations in their molecular structures. Tadalafil has a longer half-life and duration of action than sildenafil and vardenafil24. These drugs undergo hepatic metabolism, which is primarily mediated by cytochrome P450 enzymes. Thus, dosage reduction is necessary in patients with mild-to-moderate liver impairment. Patients with severe liver impairment should avoid using this group of drugs22.
Evidence has shown drug-drug interactions between the PDE5 inhibitors and CYP3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole and grapefruit juice. Concomitant use of these two groups of drugs can enhance both the pharmacological and adverse effects of PDE5 inhibitors and, hence, is not recommended25. Also, these drugs interact with nitrates and are contraindicated in men with ED who are also receiving nitrates for the treatment of ischemic heart disease22,26. They should be used with caution in patients who are also receiving beta-blockers concurrently, for example, patients with benign prostatic hyperplasia24. The adverse effects of PDE5 inhibitors are related to peripheral vasodilation and include headache, flushing, nasal congestion and dyspepsia22. Visual changes can occur with the use of sildenafil and vardenafil, but not tadalafil. This is because sildenafil and vardenafil have some similarity in their molecular structure and possess some cross-reactivity with PDE6, which is responsible for visual changes22.
A selective PDE5 inhibitor called udenafil has been recently developed. A recent randomized, double-blind, placebo-controlled trial in Korea demonstrated that once-daily dosing with udenafil 50 mg or 75 mg significantly improved erectile function as compared to placebo27. Also, a meta-analysis of five randomized controlled trials concluded that udenafil is an effective and well-tolerated drug for ED, with the common adverse effects of flushing and headache28. The results suggested that it might be a promising treatment option in the future.
ii. Sublingual apomorphine
Apomorphine is a centrally acting dopamine receptor-2 agonist that is administered sublingually. It acts by stimulating the hypothalamic dopaminergic pathways that control the erection of the penis. A study by Dula et al. (2000)29 demonstrated that sublingual apomorphine was more effective than placebo in treating ED and was associated with tolerable side effects. However, as shown in a number of studies, sublingual apomorphine is less effective and less preferred by patients when compared to oral sildenafil30,31.
iii. Androgen-replacement therapy
The use of androgen-replacement therapy is effective in patients with testicular failure (hypogonadism) and is useful in patients with a low level of testosterone3. However, it is inappropriate and can be harmful when used in eugonadal patients, especially in those with unrecognized prostate cancer because it can increase the risk of prostatic hyperplasia or prostate cancer16,32. Androgen-replacement therapy such as testosterone enanthate or cypionate can be administered to ED patients intramuscularly3. The oral and transdermal formulations of testosterone for the treatment of ED have also been shown to be equal and more effective, respectively, than intramuscular formulations, according to a meta-analysis33. On the other hand, bromocriptine, an anti-Parkinsonism agent, is indicated for men with hyperprolactinemia and works by decreasing the prolactin level, leading to improved sexual function3,32.
iv. Intracavernosal injection therapy
Vasoactive drugs that relax the penile smooth muscles and blood vessels such as papaverine, phentolamine and prostaglandin E1 (alprostadil) are used alone or in combination for the treatment of ED. Intracavernosal injection therapy was the most common treatment option for ED before the approval of sildenafil in 199834.
Self-injecting alprostadil into the corpora of the penis helps in relaxing the cavernous and arterial smooth muscle, thus facilitating penile erection34. It is important to educate patients on the self-injection technique and the possible side effects. The initial dose should be administered by the patient under the supervision of a healthcare provider to avoid improper injection or treatment failure. The injection should not be done more than once within a 24-hour period22. The common side effects include priapism (defined as prolonged erection lasting for more than four hours and seen more often with papaverine), pain, hypotension, penile corporal fibrosis, hematoma and ecchymosis, which often lead to a high discontinuation rate22,35. Discontinuation can also be attributed to the consequent lack of spontaneity in sexual relations, resulting in a general loss of interest3. Therefore, it should be used with caution in patients with severe psychiatric disease, poor manual dexterity, or poor vision, those who cannot tolerate transient hypotension, and those receiving anticoagulant therapy3.
v. Intraurethral suppositories
Alprostadil, a synthetic vasodilator identical to PGE1, is also available in suppository form and can be administered transurethrally for the treatment of ED. This treatment option is suitable for men for whom oral pharmacotherapy has not been successful, for whom oral pharmacotherapy is contraindicated, or who have suffered adverse effects from oral pharmacotherapy5.
Although shown to have greater efficacy than placebo and well tolerated in a randomized controlled trial36, the postmarketing studies of this suppository did not produce satisfactory results for efficacy and the responses generally lacked consistency37,38. When comparing transurethral to intracavernosal alprostadil, the latter was superior in terms of efficacy and safety39-40. Despite this, studies have shown that transurethral alprostadil is easier to use, less invasive, more attractive and better accepted by patients compared to intracavernosal alprostadil40. Additionally, the combination of alprostadil suppositories with oral PDE5 inhibitors or penile constrictive devices showed a higher efficacy22.
The administration of the first dose of this suppository should also be supervised by healthcare providers, as it poses a risk of syncope or hypotension3. The adverse effects associated with it include pain, burning sensation and discomfort in the penis, chest pain, dizziness, hypotension and syncope36,37.
vi. Topical alprostadil cream
According to two multicentre, randomized, double-blind, parallel-group studies by Padma-Nathan and Yeager (2006)41, a topical cream of alprostadil showed a small, but significant, improvement in efficacy and patient satisfaction when compared to placebo. It was considered as safe and well tolerated. The adverse events reported were mild, mainly local manifestations such as a burning sensation, pain and erythema of the penis41. The overall clinical effectiveness of this form of delivery of alprostadil is yet to be investigated.
vii. Melanocortin receptor agonists
The role of melanocortin receptor agonists in treating ED was discovered after the systemic administration of alpha melanocyte stimulating-hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH) in rodent models showed penile erection42.
A double-blind, placebo-controlled crossover study by Wessells et al. (2000)43 found that Melanotan II, a synthetic analogue of alpha-MSH, was a potent initiator of penile erection in the absence of sexual stimulation and that it could increase sexual desire in patients with ED. The reported side effects were nausea, yawning and stretching43.
PT-141 is a cyclic heptapeptide melanocortin analogue and is administered intranasally to treat ED. It is ineffective orally. The results of two double-blind, placebo-controlled studies showed that PT-141 caused significant erectile responses in healthy men and patients with mild-to-moderate ED. Also, it was tolerable and the adverse effects were minimal44,45.
3. Vacuum constrictive devices
Mechanical devices such as vacuum constrictive devices are non-invasive, low-cost, easily available, over-the-counter tools for managing ED22,34. They are suitable for men who refuse pharmacological therapy or for whom it is contraindicated.
However, several drawbacks associated with the use of the devices such as general discomfort and lack of spontaneity in sexual relations, as well as complaints that they are cumbersome, difficult to use, and impair ejaculation, render them a less preferred choice for patients. The adverse effects associated with the devices are penile pain, numbness of the penis, bruising and delayed ejaculation5,34. Even so, they have a lower incidence of adverse effects when compared to intracavernosal injection therapy3.
4. Surgical therapy
Vascular surgery for ED patients aims to increase arterial inflow and decrease vascular outflow5. Venous ligation has been demonstrated to be effective in patients with venous leakage3, whereas arterial revascularization or microvascular arterial bypass has limited use clinically and is usually used in patients with congenital or traumatic vascular abnormality or insufficiency3,5.
Penile prosthesis is frequently regarded as the last resort for ED as it is highly invasive and irreversible. Yet, it gives a ‘long-term solution’ to patients and is relatively efficacious5; hence, it is suitable for patients with failure, contraindication or refusal of all the other treatment modalities. Three forms of therapy are available, namely, semi-rigid, malleable and inflatable3. The effectiveness and acceptability among the three procedures are different. The associated complications are mechanical failure, infection and erosion, which may lead to the need for repeat surgery. Certain groups of men may be at an increased risk of developing prosthesis-associated infection, such as those with urinary tract infections, diabetes or spinal cord injuries3,5.
5. Pharmacotherapy for other conditions or lifestyle modification
For patients with medication-induced ED, the situation can be improved by making changes to the pharmacotherapy, for example, by substituting another drug that is less likely to cause ED. Lifestyle modifications such as exercise, smoking cessation, weight loss and low-fat diets play an important role in managing ED, as the presence of cardiovascular risk factors are often predictors of ED2,12.
6. Other therapies
The American Urological Association guidelines do not recommend the use of trazodone, yohimbine or other herbal therapies in treating ED, as there is insufficient evidence for their efficacy and safety22. Prior to the introduction of sildenafil, oral yohimbine used to be one of the initial treatments for ED46. It is an alkaloid derived from the bark of the yohimbine tree with alpha2-adrenoreceptor inhibitory effects. As there was no evidence of its efficacy and safety from more recent clinical trials, its use has declined47.
Role of pharmacists
Several patient and medication-related problems in patients with ED could be serious and require the attention of healthcare providers. In an Asian country like Malaysia, many patients are embarrassed and reluctant to seek treatment for their sexual problems or are unaware of the treatment options1.
For those who receive treatment, some might not receive sufficient instruction for administration or education on correct drug use from healthcare providers. Besides, it is not uncommon to encounter cases of treatment failure with oral drugs such as sildenafil48-49. Hatzichristou et al. (2005)49 found that the high failure rate with sildenafil treatment was associated with inappropriate drug use, such as not using the highest recommended dose, use of sildenafil after a meal, just before sexual activity, or without sexual stimulation, and use of the maximum dose despite contraindications.
Pharmacists play an important role in helping physicians to decide and select the most appropriate treatment option for ED patients. They also play an important role in educating patients regarding the various treatment options. Dosage adjustment is particularly important in patients with treatment failure in order to achieve an excellent drug response48.
Pharmacists should also provide adequate counseling to patients, help them to regain their self-esteem and confidence, and educate them on the proper way of administrating the drugs, on possible side effects, and on methods to overcome the side effects.
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