- Email: [email protected]
New treatments for erectile dysfunction
SEXUALITY
New Treatments for Erectile Dysfunction Glenn Matfin, M.B.Ch.B. • ED is a common complaint to women’s physicians • What to advise your patient and her partner
Vice President, Medical Affairs Inverness Medical Innovations
Erectile dysfunction (ED) is an increasingly common problem, affecting up to 30 million American men. This largely results from increased risk factors and an aging population. ED is now also recognized as a marker for cardiovascular disease. The ED patient should be thoroughly evaluated for coexisting vascular disease. The pathophysiology of ED is becoming better understood, largely as a result of the development of new therapies. Once the underlying processes are known, more selective targeting of these will lead to novel “designer drugs.” rectile dysfunction (ED) has largely replaced the term “impotence.” It is defined as the persistent inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse (1). ED is a common problem, and is rapidly increasing because of an aging population, and increased risk factors. ED is a distressing condition that can have serious negative implications on not just an individual’s sex life, but also on his general health and his and his partner’s overall quality of life. Despite this, up to 90% of sufferers are still reluctant to present their problems to their doctors. The aim of this brief review is to discuss the approach of the health-care provider to ED. This will enable more effective diagnosis, investigation, and treatment of ED. Keep in mind that ED is a disorder of couples. Any attempt at therapy should be cognizant of the needs and desires of both parties.
E
It has been estimated that the disorder affects up to 30 million men in the United States. Aging is a major etiological factor in this condition. However, even among younger men (those in their 40s), nearly 40% report at least occasional difficulty obtaining or maintaining an erection. This figure approaches 70% in 70-year-olds. Erection is a complex process that involves the autonomic nervous system, neurotransmitters, factors that affect the smooth muscle of the arteries and veins supplying the penile tissue, and the trabecular smooth muscle of the sinusoids of the corpora cavernosa. Erection occurs when the trabecular smooth muscle that sur-
40
Sexuality, Reproduction & Menopause, Vol. 1, No. 1, October 2003 © 2003 American Society for Reproductive Medicine Published by Elsevier Inc.
rounds the sinusoidal spaces of the corpora cavernosa relax, allowing increased amounts of blood to flow in. This is caused by parasympathetic impulses from the sacral segments of the spinal cord that release nitric oxide, a nonadrenergic-noncholinergic (NANC) neurotransmitter. At the same time, the veins controlling outflow of blood from the venous plexus compress, trapping the blood within the penis and increasing the pressure approaching those found in arteries rather than veins. Because the erectile tissues of the cavernosa are surrounded by a nonelastic fibrous covering, high pressure in the sinusoids causes ballooning of the erectile tissue to such an extent that the penis becomes hard and elongated. At the same time, contraction of the somatic-innervated ischiocavernous muscles forcefully compresses the blood-filled corpora cavernosa, producing a further rise in intercavernous pressures. During this phase of erection, inflow and outflow of blood cease. Parasympathetic innervation must be intact and nitric oxide synthesis must be active for erection to occur. Nitric oxide activates guanyl cyclase, an enzyme that increases the concentration of cyclic guanosine monophosphate (cGMP), which in turn causes smooth muscle relaxation. Other smooth muscle relaxants (e.g., prostaglandin E1 analogues and ␣-adrenergic antagonists), if present in high enough concentrations, can independently cause sufficient cavernosal relaxation to result in erection. Many of the drugs that have been developed to treat ED act at the level of these mediators. Later, vasoconstriction occurs and is then responsible for detumescence.
Any treatment regimens should always take into consideration the partner’s attitude to the problem and the likely response to effective treatment. Causes of ED ED is commonly classified as psychogenic, organic, or mixed psychogenic and organic (2). Organic etiologies are the most common. Psychogenic causes of erectile dysfunction include performance anxiety, a strained relationship with a sexual partner, depression, and overt psychotic disorders such as schizophrenia. Psychogenic factors can be further exacerbated by the side effects of many of the therapies used to treat these disorders, which can themselves cause ED. Organic causes span a wide range of pathologies. They include neurogenic, hormonal, vascular, drug-induced, and penile-related etiologies. Neurogenic disorders such as Parkinson’s disease, stroke, and cerebral trauma often contribute to ED by decreasing libido or preventing the initiation of erection. In spinal cord injury, the extent of neural impairment depends on the level, location, and extent of the lesion. Somatosensory involvement of the genitalia is essential to the reflex mechanisms involved in erection; this becomes important with aging and conditions such as diabetes that impair peripheral nerve function. Extensive pelvic surgery, especially radical prostatectomy (even so-called nerve-sparing surgery), are still common causes of ED due to both direct and indirect nerve damage. Hormonal causes of ED include a decrease in androgen levels due to both primary and secondary hypogonadism. Androgen levels may also be decreased because of aging (“andropause”). However, the role of testosterone replacement in ED remains complex and controversial (3). Testosterone levels are predominantly related to libido, but are also involved in the chemical mediator cascade required for erection. If testosterone levels are low (preferably confirmed by a measure of free hormone), replacement should be considered. Hyperprolactinemia from any cause interferes with both reproduction and erectile function. This is because an Sexuality, Reproduction & Menopause, Vol. 1, No. 1, October 2003
41
elevated prolactin results in increased dopaminergic activity, which inhibits the release of gonadotropin-releasing hormone (GnRH), which in turn decreases the release of pituitary gonadotropic hormones. Common risk factors for generalized penile arterial insufficiency include hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, and pelvic irradiation. A history of peripheral or other vascular disease may be present. In hypertension, erectile function is impaired not so much by the increased blood pressure as by the associated stenotic arterial lesions. Focal stenosis of the common penile artery most often occurs in men who sustained blunt pelvic or perineal trauma (e.g., from bicycling accidents). Failure of the veins to close completely during an erection (veno-occlusive dysfunction) may occur in men with large venous channels that drain the corpora cavernosa. Other disorders that impair venous occlusion are degenerative changes involving the tunica albuginea, as in Peyronie’s disease. Many drugs are reported to cause ED, including antidepressants, antipsychotics, antiandrogens, and antihypertensive medications (see Table 1). Cigarette smoking can induce vasoconstriction and penile venous leakage because of its effects on cavernous smooth muscle, and can double the risk of ED. Alcohol in small amounts may increase libido and improve erection; however, in large amounts it can cause central sedation, decreased libido, and transient ED.
Diagnosing ED A diagnosis of ED requires careful history (medical, sexual, and psychosocial), physical examination, and laboratory tests aimed at determining what other tests are needed to rule out organic causes of the disorder. Because many medications, including prescribed, over-thecounter (OTC), and illicit drugs, can cause ED, a careful drug history is indicated. As well as potentially causing ED, many OTC agents are taken as therapies for ED and androgen replacement.
As more understanding about the pathophysiology of ED is discovered, it is anticipated that “designer drugs” will be developed for specific targets. ED as a Marker of Cardiovascular Risk ED is associated with many of the traditional cardiovascular risk factors (aging, diabetes, hypertension, hyperlipedimia, and smoking). ED has also recently been recognized to be associated with nontraditional cardiovascular risk factors (such as endothelial dysfunction). The presence of ED, therefore, can be an early warning sign of underlying vascular disease (coronary, cerebrovascular, and peripheral). Indeed, the severity of ED can correlate with the severity of coronary atherosclerosis (4). In view of these findings, appropriate investigation and management of existing vascular disease should be undertaken by the healthcare provider as part of the global care of the ED patient. Another consideration with respect to the presence of coexisting vascular disease in the ED patient is the safety of sexual activity itself. Sexual intercourse is typically associated with a workload of 3– 4 METS (metabolic equivalent of energy expended in the resting state). This workload is similar to walking 1 mile in 20 minutes on the flat, or climbing two flights of stairs. If the ED patient can manage this level of workload, he should be safe from the cardiovascular standpoint (although more rigorous sexual activity can involve 5– 6 METS or greater). If there
42
Sexuality, Reproduction & Menopause, Vol. 1, No. 1, October 2003
Table 1: Medication-related Causes of Erectile Dysfunction (ED) Medication Class
Examples
Antihypertensives
Thiazide diuretics Spironolactone Centrally-acting: • Methyldopa • Clonidine Beta-blockers: • Propranolol • Atenolol • Metoprolol ACE inhibitors: • Lisinopril Tricyclic antidepressants (TCAs): • Amitriptyline • Doxepin • Imipramine • Protriptyline Selective serotonin reuptake inhibitors (SSRIs): • Fluoxetine • Paroxetine • Sertraline Monoamine oxidase (MAO) inhibitors: • Phenelzine Benzodiazepines Antipsychotic agents: • Chlorpromazine • Thioridazine • Risperidone Phenytoin Carbamazepine Levodopa Gemfibrozil Clofibrate Cimetidine Flutamide Finasteride Cyproterone acetate Aminoglutethimide Leuprolide Estrogens
Psychiatric medications
Anticonvulsants Anti-Parkinson agents Lipid regulators Anti-ulcer agents Anti-androgens
is any doubt, a thorough cardiovascular work-up should be considered. Exercise testing can guide advice in the presence of reasonable concern (sexual workload is equivalent to 3– 4 minutes on the standard Bruce treadmill protocol) (5).
Sexuality, Reproduction & Menopause, Vol. 1, No. 1, October 2003
43
Table 1: Continued Medication Class
Examples
Miscellaneous
Agents of abuse: • Alcohol • Marijuana • Cocaine • Amphetamines Opioids including methadone Ketconazole metachlorpramide
Approximately 25% of ED is causally related to drugs. Some drugs available over-the-counter (OTC), such as antihistamines and decongestants, can also cause ED.
Another major cardiovascular concern in ED patients is the concomitant use of nitrate therapy (such as sublingual nitroglycerin) and phosphodiesterase type 5 (PDE-5) inhibitors. PDE-5 inhibitors are revolutionary new treatments for ED. This combination of agents is contraindicated due to the profound hypotension (and even death) that can occur. Short-acting nitrates for angina should not be taken within 24 hours of PDE-5 inhibitors and vice versa. In contrast, long-acting nitrates should not be taken within a week of PDE-5 inhibitors. Concerns regarding the cardiovascular safety of the PDE-5 inhibitor sildenafil (Viagra) has largely been dispelled in consensus statements in the United States (6).
Treatment Methods Any treatment regimens should always take into consideration the partner’s attitude to the problem and the likely response to effective treatment. ED therapies may include psychosexual counseling, androgen replacement therapy (when deficiency is confirmed), oral and intracavernous drug therapy, vacuum constriction devices (for venous leak), and surgical treatment (prosthesis and vascular surgery). Among the commonly prescribed drugs are sildenafil, yohimbine, and alprostadil. Sildenafil (Viagra) is a selective inhibitor of PDE- 5, the enzyme that inactivates cGMP. This acts by facilitating corporeal smooth muscle relaxation in response to sexual stimulation. PDE-5 inhibitors have revolutionized ED therapy. One of the side effects of sildenafil is the visual complaint of seeing a “bluish haze.” This is due to an inhibition of PDE-6, which is present in the retina. Newer PDE-5 inhibitors are available in Europe (tadalafil [Cialis] and vardenafil [Levitra]). Levitra was recently approved in the United States by the FDA for the treatment of ED. Due to a better PDE-5:PDE-6 selectivity ratio, use of these agents does not produce color vision changes (7). Side effects common to this class of drug includes the typical vasomotor disturbances of headache, flushing, and rhinitis. All the PDE-5 inhibitors currently available are generally well tolerated. Differences in efficacy and safety (which might be anticipated due to marked differences in potency and half-life) remain to be evaluated from further clinical trials and post-marketing studies and surveillance (see Table 2). However, the contraindication of concomitant nitrates and the newer PDE-5 inhibitors remains. These therapies are currently being evaluated by the FDA. Yohimbine, an ␣2-adrenergic receptor antagonist, acts at the adrenergic receptors in the brain centers associated with libido and penile erection (8). It can be effective in 30%– 40% of psychogenic ED patients. (However, one of the major difficulties when assessing new therapeutic agents for ED is the placebo response of 30%–35%.) Both sildenafil and yohimbine are taken orally. Alprostadil, a prostaglandin E1 analogue, acts by producing relaxation of cavernous smooth muscle. It is either injected directly into the cavernosa or placed in the urethra as a minisuppository. When injected into one of the cavernosa, free diffusion into the opposite side occurs.
44
Sexuality, Reproduction & Menopause, Vol. 1, No. 1, October 2003
Table 2: Comparison of Impotence Drugs
Duration of activity Time to onset Common side effects
Viagra
Cialis
Levitra
ⱕ5h 60 min Headache, facial flushing, altered/ bluish vision
ⱕ 36 h 30 min Headache, dyspepsia, back pain
ⱕ5h 16 min Headache, facial flushing
Sources: European Agency for the Evaluation of Medicinal Products, product labeling, published reports.
Despite new therapies being developed, surgery still has a role in the management of ED. As more understanding about the pathophysiology of ED is discovered, it is anticipated that “designer drugs” will be developed for specific targets.
Glenn Matfin, M.B.Ch.B. 51 Sawyer Road, Suite 200 Waltham, MA 02453 [email protected]
References 1.
2. 3.
4.
5.
NIH Consensus Development Panel on Impotence. NIH Consensus Conference: impotence. JAMA 1993;270:83-90. Lue TF. Erectile dysfunction. N Engl J Med 2000; 342:1802-13. AACE Medical Guidelines. AACE medical guidelines for clinical practice for the evaluation and treatment of male sexual dysfunction: a couple’s problem—2003 update. Endo Pract 2003;9:77-95. Greenstein A, et al. Does severity of ischemic coronary artery disease correlate with erectile dysfunction. Int J Impot Res 1997;9:123-6.
6.
7.
8.
Jackson G. Cardiovascular safety in erectile dysfunction treatment. Br J Diabetes Vasc Dis 2002;2: 301-4. Cheitlin MD, et al. Use of sildenafil (Viagra) in patients with cardiovascular disease. Circulation 1999;99:168-77. Snow KJ. Erectile dysfunction in patients with diabetes—advances in treatment with PDE-5 inhibitors. Br J Diabetes Vasc Dis 2002;2: 282-7. Matfin G, Bodansky J. Oral yohimbine in the treatment of diabetic and non-diabetic erectile dysfunction. J Sexual Health 1995;15:15.
Sexuality, Reproduction & Menopause, Vol. 1, No. 1, October 2003
45
New Treatments for Erectile Dysfunction Glenn Matfin, M.B.Ch.B. • ED is a common complaint to women’s physicians • What to advise your patient and her partner
Vice President, Medical Affairs Inverness Medical Innovations
Erectile dysfunction (ED) is an increasingly common problem, affecting up to 30 million American men. This largely results from increased risk factors and an aging population. ED is now also recognized as a marker for cardiovascular disease. The ED patient should be thoroughly evaluated for coexisting vascular disease. The pathophysiology of ED is becoming better understood, largely as a result of the development of new therapies. Once the underlying processes are known, more selective targeting of these will lead to novel “designer drugs.” rectile dysfunction (ED) has largely replaced the term “impotence.” It is defined as the persistent inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse (1). ED is a common problem, and is rapidly increasing because of an aging population, and increased risk factors. ED is a distressing condition that can have serious negative implications on not just an individual’s sex life, but also on his general health and his and his partner’s overall quality of life. Despite this, up to 90% of sufferers are still reluctant to present their problems to their doctors. The aim of this brief review is to discuss the approach of the health-care provider to ED. This will enable more effective diagnosis, investigation, and treatment of ED. Keep in mind that ED is a disorder of couples. Any attempt at therapy should be cognizant of the needs and desires of both parties.
E
It has been estimated that the disorder affects up to 30 million men in the United States. Aging is a major etiological factor in this condition. However, even among younger men (those in their 40s), nearly 40% report at least occasional difficulty obtaining or maintaining an erection. This figure approaches 70% in 70-year-olds. Erection is a complex process that involves the autonomic nervous system, neurotransmitters, factors that affect the smooth muscle of the arteries and veins supplying the penile tissue, and the trabecular smooth muscle of the sinusoids of the corpora cavernosa. Erection occurs when the trabecular smooth muscle that sur-
40
Sexuality, Reproduction & Menopause, Vol. 1, No. 1, October 2003 © 2003 American Society for Reproductive Medicine Published by Elsevier Inc.
rounds the sinusoidal spaces of the corpora cavernosa relax, allowing increased amounts of blood to flow in. This is caused by parasympathetic impulses from the sacral segments of the spinal cord that release nitric oxide, a nonadrenergic-noncholinergic (NANC) neurotransmitter. At the same time, the veins controlling outflow of blood from the venous plexus compress, trapping the blood within the penis and increasing the pressure approaching those found in arteries rather than veins. Because the erectile tissues of the cavernosa are surrounded by a nonelastic fibrous covering, high pressure in the sinusoids causes ballooning of the erectile tissue to such an extent that the penis becomes hard and elongated. At the same time, contraction of the somatic-innervated ischiocavernous muscles forcefully compresses the blood-filled corpora cavernosa, producing a further rise in intercavernous pressures. During this phase of erection, inflow and outflow of blood cease. Parasympathetic innervation must be intact and nitric oxide synthesis must be active for erection to occur. Nitric oxide activates guanyl cyclase, an enzyme that increases the concentration of cyclic guanosine monophosphate (cGMP), which in turn causes smooth muscle relaxation. Other smooth muscle relaxants (e.g., prostaglandin E1 analogues and ␣-adrenergic antagonists), if present in high enough concentrations, can independently cause sufficient cavernosal relaxation to result in erection. Many of the drugs that have been developed to treat ED act at the level of these mediators. Later, vasoconstriction occurs and is then responsible for detumescence.
Any treatment regimens should always take into consideration the partner’s attitude to the problem and the likely response to effective treatment. Causes of ED ED is commonly classified as psychogenic, organic, or mixed psychogenic and organic (2). Organic etiologies are the most common. Psychogenic causes of erectile dysfunction include performance anxiety, a strained relationship with a sexual partner, depression, and overt psychotic disorders such as schizophrenia. Psychogenic factors can be further exacerbated by the side effects of many of the therapies used to treat these disorders, which can themselves cause ED. Organic causes span a wide range of pathologies. They include neurogenic, hormonal, vascular, drug-induced, and penile-related etiologies. Neurogenic disorders such as Parkinson’s disease, stroke, and cerebral trauma often contribute to ED by decreasing libido or preventing the initiation of erection. In spinal cord injury, the extent of neural impairment depends on the level, location, and extent of the lesion. Somatosensory involvement of the genitalia is essential to the reflex mechanisms involved in erection; this becomes important with aging and conditions such as diabetes that impair peripheral nerve function. Extensive pelvic surgery, especially radical prostatectomy (even so-called nerve-sparing surgery), are still common causes of ED due to both direct and indirect nerve damage. Hormonal causes of ED include a decrease in androgen levels due to both primary and secondary hypogonadism. Androgen levels may also be decreased because of aging (“andropause”). However, the role of testosterone replacement in ED remains complex and controversial (3). Testosterone levels are predominantly related to libido, but are also involved in the chemical mediator cascade required for erection. If testosterone levels are low (preferably confirmed by a measure of free hormone), replacement should be considered. Hyperprolactinemia from any cause interferes with both reproduction and erectile function. This is because an Sexuality, Reproduction & Menopause, Vol. 1, No. 1, October 2003
41
elevated prolactin results in increased dopaminergic activity, which inhibits the release of gonadotropin-releasing hormone (GnRH), which in turn decreases the release of pituitary gonadotropic hormones. Common risk factors for generalized penile arterial insufficiency include hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, and pelvic irradiation. A history of peripheral or other vascular disease may be present. In hypertension, erectile function is impaired not so much by the increased blood pressure as by the associated stenotic arterial lesions. Focal stenosis of the common penile artery most often occurs in men who sustained blunt pelvic or perineal trauma (e.g., from bicycling accidents). Failure of the veins to close completely during an erection (veno-occlusive dysfunction) may occur in men with large venous channels that drain the corpora cavernosa. Other disorders that impair venous occlusion are degenerative changes involving the tunica albuginea, as in Peyronie’s disease. Many drugs are reported to cause ED, including antidepressants, antipsychotics, antiandrogens, and antihypertensive medications (see Table 1). Cigarette smoking can induce vasoconstriction and penile venous leakage because of its effects on cavernous smooth muscle, and can double the risk of ED. Alcohol in small amounts may increase libido and improve erection; however, in large amounts it can cause central sedation, decreased libido, and transient ED.
Diagnosing ED A diagnosis of ED requires careful history (medical, sexual, and psychosocial), physical examination, and laboratory tests aimed at determining what other tests are needed to rule out organic causes of the disorder. Because many medications, including prescribed, over-thecounter (OTC), and illicit drugs, can cause ED, a careful drug history is indicated. As well as potentially causing ED, many OTC agents are taken as therapies for ED and androgen replacement.
As more understanding about the pathophysiology of ED is discovered, it is anticipated that “designer drugs” will be developed for specific targets. ED as a Marker of Cardiovascular Risk ED is associated with many of the traditional cardiovascular risk factors (aging, diabetes, hypertension, hyperlipedimia, and smoking). ED has also recently been recognized to be associated with nontraditional cardiovascular risk factors (such as endothelial dysfunction). The presence of ED, therefore, can be an early warning sign of underlying vascular disease (coronary, cerebrovascular, and peripheral). Indeed, the severity of ED can correlate with the severity of coronary atherosclerosis (4). In view of these findings, appropriate investigation and management of existing vascular disease should be undertaken by the healthcare provider as part of the global care of the ED patient. Another consideration with respect to the presence of coexisting vascular disease in the ED patient is the safety of sexual activity itself. Sexual intercourse is typically associated with a workload of 3– 4 METS (metabolic equivalent of energy expended in the resting state). This workload is similar to walking 1 mile in 20 minutes on the flat, or climbing two flights of stairs. If the ED patient can manage this level of workload, he should be safe from the cardiovascular standpoint (although more rigorous sexual activity can involve 5– 6 METS or greater). If there
42
Sexuality, Reproduction & Menopause, Vol. 1, No. 1, October 2003
Table 1: Medication-related Causes of Erectile Dysfunction (ED) Medication Class
Examples
Antihypertensives
Thiazide diuretics Spironolactone Centrally-acting: • Methyldopa • Clonidine Beta-blockers: • Propranolol • Atenolol • Metoprolol ACE inhibitors: • Lisinopril Tricyclic antidepressants (TCAs): • Amitriptyline • Doxepin • Imipramine • Protriptyline Selective serotonin reuptake inhibitors (SSRIs): • Fluoxetine • Paroxetine • Sertraline Monoamine oxidase (MAO) inhibitors: • Phenelzine Benzodiazepines Antipsychotic agents: • Chlorpromazine • Thioridazine • Risperidone Phenytoin Carbamazepine Levodopa Gemfibrozil Clofibrate Cimetidine Flutamide Finasteride Cyproterone acetate Aminoglutethimide Leuprolide Estrogens
Psychiatric medications
Anticonvulsants Anti-Parkinson agents Lipid regulators Anti-ulcer agents Anti-androgens
is any doubt, a thorough cardiovascular work-up should be considered. Exercise testing can guide advice in the presence of reasonable concern (sexual workload is equivalent to 3– 4 minutes on the standard Bruce treadmill protocol) (5).
Sexuality, Reproduction & Menopause, Vol. 1, No. 1, October 2003
43
Table 1: Continued Medication Class
Examples
Miscellaneous
Agents of abuse: • Alcohol • Marijuana • Cocaine • Amphetamines Opioids including methadone Ketconazole metachlorpramide
Approximately 25% of ED is causally related to drugs. Some drugs available over-the-counter (OTC), such as antihistamines and decongestants, can also cause ED.
Another major cardiovascular concern in ED patients is the concomitant use of nitrate therapy (such as sublingual nitroglycerin) and phosphodiesterase type 5 (PDE-5) inhibitors. PDE-5 inhibitors are revolutionary new treatments for ED. This combination of agents is contraindicated due to the profound hypotension (and even death) that can occur. Short-acting nitrates for angina should not be taken within 24 hours of PDE-5 inhibitors and vice versa. In contrast, long-acting nitrates should not be taken within a week of PDE-5 inhibitors. Concerns regarding the cardiovascular safety of the PDE-5 inhibitor sildenafil (Viagra) has largely been dispelled in consensus statements in the United States (6).
Treatment Methods Any treatment regimens should always take into consideration the partner’s attitude to the problem and the likely response to effective treatment. ED therapies may include psychosexual counseling, androgen replacement therapy (when deficiency is confirmed), oral and intracavernous drug therapy, vacuum constriction devices (for venous leak), and surgical treatment (prosthesis and vascular surgery). Among the commonly prescribed drugs are sildenafil, yohimbine, and alprostadil. Sildenafil (Viagra) is a selective inhibitor of PDE- 5, the enzyme that inactivates cGMP. This acts by facilitating corporeal smooth muscle relaxation in response to sexual stimulation. PDE-5 inhibitors have revolutionized ED therapy. One of the side effects of sildenafil is the visual complaint of seeing a “bluish haze.” This is due to an inhibition of PDE-6, which is present in the retina. Newer PDE-5 inhibitors are available in Europe (tadalafil [Cialis] and vardenafil [Levitra]). Levitra was recently approved in the United States by the FDA for the treatment of ED. Due to a better PDE-5:PDE-6 selectivity ratio, use of these agents does not produce color vision changes (7). Side effects common to this class of drug includes the typical vasomotor disturbances of headache, flushing, and rhinitis. All the PDE-5 inhibitors currently available are generally well tolerated. Differences in efficacy and safety (which might be anticipated due to marked differences in potency and half-life) remain to be evaluated from further clinical trials and post-marketing studies and surveillance (see Table 2). However, the contraindication of concomitant nitrates and the newer PDE-5 inhibitors remains. These therapies are currently being evaluated by the FDA. Yohimbine, an ␣2-adrenergic receptor antagonist, acts at the adrenergic receptors in the brain centers associated with libido and penile erection (8). It can be effective in 30%– 40% of psychogenic ED patients. (However, one of the major difficulties when assessing new therapeutic agents for ED is the placebo response of 30%–35%.) Both sildenafil and yohimbine are taken orally. Alprostadil, a prostaglandin E1 analogue, acts by producing relaxation of cavernous smooth muscle. It is either injected directly into the cavernosa or placed in the urethra as a minisuppository. When injected into one of the cavernosa, free diffusion into the opposite side occurs.
44
Sexuality, Reproduction & Menopause, Vol. 1, No. 1, October 2003
Table 2: Comparison of Impotence Drugs
Duration of activity Time to onset Common side effects
Viagra
Cialis
Levitra
ⱕ5h 60 min Headache, facial flushing, altered/ bluish vision
ⱕ 36 h 30 min Headache, dyspepsia, back pain
ⱕ5h 16 min Headache, facial flushing
Sources: European Agency for the Evaluation of Medicinal Products, product labeling, published reports.
Despite new therapies being developed, surgery still has a role in the management of ED. As more understanding about the pathophysiology of ED is discovered, it is anticipated that “designer drugs” will be developed for specific targets.
Glenn Matfin, M.B.Ch.B. 51 Sawyer Road, Suite 200 Waltham, MA 02453 [email protected]
References 1.
2. 3.
4.
5.
NIH Consensus Development Panel on Impotence. NIH Consensus Conference: impotence. JAMA 1993;270:83-90. Lue TF. Erectile dysfunction. N Engl J Med 2000; 342:1802-13. AACE Medical Guidelines. AACE medical guidelines for clinical practice for the evaluation and treatment of male sexual dysfunction: a couple’s problem—2003 update. Endo Pract 2003;9:77-95. Greenstein A, et al. Does severity of ischemic coronary artery disease correlate with erectile dysfunction. Int J Impot Res 1997;9:123-6.
6.
7.
8.
Jackson G. Cardiovascular safety in erectile dysfunction treatment. Br J Diabetes Vasc Dis 2002;2: 301-4. Cheitlin MD, et al. Use of sildenafil (Viagra) in patients with cardiovascular disease. Circulation 1999;99:168-77. Snow KJ. Erectile dysfunction in patients with diabetes—advances in treatment with PDE-5 inhibitors. Br J Diabetes Vasc Dis 2002;2: 282-7. Matfin G, Bodansky J. Oral yohimbine in the treatment of diabetic and non-diabetic erectile dysfunction. J Sexual Health 1995;15:15.
Sexuality, Reproduction & Menopause, Vol. 1, No. 1, October 2003
45