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SYMPOSIUM |
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| Year : 2006 | Volume
: 22
| Issue : 3 | Page : 235-240 |
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Pharmacotherapy of erectile dysfunction: Current standards
Kew-Kim Chew
Keogh Institute for Medical Research, Australia
Correspondence Address:
Kew-Kim Chew
Keogh Institute for Medical Research, 'A' Block Queen Elizabeth II Medical Centre, Nedlands Australia 6009
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0970-1591.27631
 Abstract | | |
Pharmacotherapy is currently the therapeutic option of choice for erectile dysfunction. Comprising mainly intracavernosal injection therapy using alprostadil or alprostadil combined with phentolamine and/or papaverine and oral phosphodiesterase-5 inhibitors, it is safe and effective if appropriately prescribed and administered. The medications in current use produce satisfactory erectile responses by enhancing cavernosal vasodilatation mainly through their ability to promote relaxation of the smooth muscle cells in the corpora cavernosa involving the synthesis and activity of nitric oxide via the cyclic guanosine monophosphate and cyclic adenosine monophosphate biochemical pathways. The main side-effects and complications of intracavernosal injections are postinjection pain, prolonged erections, priapism and penile fibrosis. There may be a variety of side-effects with phosphodiesterase-5 inhibition but these are usually inconsequential. Recent serious ill health and the need for ongoing long-acting nitrate therapy or frequent use of short-acting nitrates for angina are absolute contraindications to the use of phosphodiesterase-5 inhibitors. Caution has to be exercised in prescribing phosphodiesterase-5 inhibitors for patients with impaired renal or hepatic functions or receiving multi-drug therapy for any systemic disease. All patients presenting with erectile dysfunction should be investigated and treated for cardiovascular risk factors. They should also be counseled regarding lifestyle factors particularly healthy balanced diet, regular physical exercise and inappropriate social habits.
Keywords: Erectile dysfunction, intracavernosal injection therapy, pharmacotherapy, phosphodiesterase-5 inhibitors
How to cite this article:
Chew KK. Pharmacotherapy of erectile dysfunction: Current standards. Indian J Urol 2006;22:235-40 |
The management of erectile dysfunction (ED)[1],[2] evolved from its fatalistic acceptance and use of folk medicine through the ages to testosterone supplementation, psychotherapy and prosthetic surgery in the 1970s. Then, heralded by Giles Brindley's dramatic demonstration of his personal response to intracavernosal phenoxybenzamine at the American Urological Association Meeting in Las Vegas in 1983, came the era of pharmacotherapy. Alprostadil, the synthetic equivalent of prostaglandin E 1 (PGE 1 ) soon became the medication of choice in intracavernosal injection (ICI) therapy, until its dominance in the treatment of ED was supplanted by the orally effective phosphodiesterase-5 inhibitors.
The debut of each of the modern innovative pharmacotherapeutic options for ED represented a remarkable quantum leap in medical therapeutics. As a result, not only has there been a periodic paradigm shift in the management strategy for ED, but a plethora of scientific and clinical research has also contributed to new knowledge and better understanding of general and cardiovascular health as well as sexual and reproductive health.
This review covers the various topical issues pertinent to the pharmacotherapy of ED and its current standards.
| Therapeutic options for ED | |  |
Not every man with ED requires therapeutic intervention for his affliction. Some may want only explanation and reassurance. In all men, however, the presentation of ED should be taken as a window of opportunity for the search for, and the identification of, cardiovascular and other risk factors with which ED is commonly associated. Regardless of how his ED may be managed, it is important, in the patient's overall and long-term interests, to diagnose and treat any cardiovascular disease which may still be asymptomatic and previously unrecognized. As for his ED, the decision to treat has to be made by the patient, guided by the attending clinician with information and advice tailored to his needs. Partner participation in the decision-making process, where possible, would be highly desirable and may help improve treatment outcome as well as patient and partner satisfaction.
When the informed decision to treat has been made, all available options (namely, psychosexual counseling, use of external mechanical devices, pharmacotherapy, complementary medicine, prosthetic and vascular surgery), including possible benefits, precautions, side-effects and complications, should be fully discussed with the patient. Therapeutic goals should be set and unrealistic expectations resolved.
In the absence of contraindications, pharmacotherapy will usually be the therapeutic option of choice. Appropriately prescribed and administered and if available and affordable, it is safe and is effective in most patients with ED.
Pharmacotherapy: Rationale and choices
The physiology of the smooth muscle cell (SMC) in the trabeculae of the cavernosal sinusoids and in the walls of the cavernosal and helicine arteries is central to the unique erectile function of the penis. The functional state of the penis is a neuro-vascular event representing the balance between the degree of relaxation and that of contraction of the SMC.[3]
Nitric oxide (NO), produced by the vascular endothelium and the nonadrenergic noncholinergic parasympathetic nerve endings under the influence of the various isoforms of NO synthase, is the principal chemo-mediator for SMC relaxation, thus penile erection, through the production of cyclic guanosine monophosphate (cGMP).[4] While neuronal NO initiates erection, endothelial NO maintains the erectile response.[4] Alongside this, through the cyclic adenosine monophosphate (cAMP) pathway, prostanoids and vasoactive intestinal polypeptide also contribute to SMC relaxation.[3]
SMC contraction, on the other hand, is brought about principally by noradrenaline via the a 1 sympathetic pathway and is responsible for penile flaccidity and detumescence. Other chemo-transmitters for SMC contraction include endothelin, neuropeptide Y and prostanoids.[3]
Currently available pharmacotherapeutic agents for ED act mainly by enhancing SMC relaxation through the selective and nonselective inhibition for the phosphodiesterases which are involved in the degradation of cGMP and cAMP to GMP and AMP respectively. a 1 adrenergic blockers are used to decrease SMC contraction.
Pharmacological manipulation of the biochemical processes involved in SMC relaxation and contraction therefore provides the rational basis for the pharmacotherapy of ED.
Phamacotherapeutic agents for ED may be categorized according to their modes of action, routes of administration and mechanisms of selectivity.[5] In general, those in current use are either centrally acting or peripherally acting agents, with the latter targeting mainly SMC relaxation via the cGMP or cAMP pathways [Table - 1]. Some may have more than one route of administration or delivery.
In day-to-day clinical practice, pharmacotherapy of ED really boils down to a choice between ICI therapy using alprostadil, alone or in combination with other vasoactive agents and oral phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil and, in Korea, udenafil). Sublingual apomorphine is a commercially available centrally acting agent. Like topical and transurethral alprostadil and other medications, including yohimbine, it has limited use and success.
| Intracavernosal injection therapy | | |
Since the use of PGE 1 for ED was first reported in 1986, alprostadil, its synthetic equivalent, has been the main agent employed in ICI therapy. Other vasoactive agents for ICI include phentolamine and papaverine, which may be used in combination with alprostadil (Double mix: alprostadil + phentolamine; Trimix: alprostadil + phentolamine + papaverine). On account of its significantly higher risk of priapism and penile fibrosis, papaverine was replaced by alprostadil as a single agent for ED. Intracavernosal injection therapy was the only pharmacotherapeutic option available for the management of ED for well over a decade.
The aim of ICI therapy is to produce an erectile response of sufficient quality and duration so that the patient is able to achieve satisfactory sexual intercourse. Adverse drug reaction, infection, bleeding disorders, severe pain, predisposition to priapism (e.g. myeloproliferative disease) and presence of penile abnormality (such as Peyronie's disease) may preclude patients from ICI therapy. Anticoagulant therapy is not a contraindication to ICI provided the prothrombin time or the international normalized ratio (INR) is within the therapeutic range. It is important that patients are meticulously instructed on the injection technique and, for those with impaired vision and poor manual dexterity, their partners, if agreeable, may perform the injection and be tutored accordingly.
Both the success and satisfaction rates of intracavernosal alprostadil therapy were in excess of 90%[6] and no significant associated systemic side-effects were reported,[7] the latter probably related to the rapid metabolism of alprostadil in the penis and its first pass clearance in the lungs and liver. Side-effects comprise only infrequent nonspecific complaints of headache and dizziness.
Possible side-effects or complications of ICI therapy are confined to the penis and include postinjection penile pain, prolonged erection, priapism and penile fibrosis.[6],[7] Postinjection pain may involve the scrotal, perineal and gluteal areas and occasionally the lower limbs.
Intracavernosal injection therapy should usually cause no more than some penile discomfort if it is performed correctly using an ultra-fine gauge-30 needle. Patients with diabetic neuropathy and after radical lower abdominal and pelvic surgery are more likely to experience postinjection pain.[6] Using papaverine in preference may be an option when significant postinjection pain occurs in spite of good injection technique.
Prolonged erection and priapism from intracavernosal alprostadil may be effectively avoided by commencing treatment with a discreet dose of alprostadil (5 mcg in most patients and 2.5 mcg in patients with spinal cord injury). The dose may then be judiciously gradually increased if necessary, up to a maximum of 50 mcg, to achieve the desired erectile response. Only 5% of men with ED treated with alprostadil reported prolonged erections and 1% had priapism.[7]
Penile fibrosis was reported in 12-23% in various studies and spontaneous regression and resolution of the fibrotic changes occurred in 47-52% of these patients.[6],[8]
Patients should be specifically warned about all these possible complications, prior to commencing ICI therapy. Clear written instructions should be given regarding measures for detumescence in the event of a prolonged response. Arrangements and facilities must be available for the urgent treatment of priapism.
| Phosphodiesterase-5 inhibitors | | |
Sexual stimulation leads to the release of NO in the corpora cavernosa and results in an increase of cGMP which produces smooth muscle relaxation and increases blood flow. Sildenafil, tadalafil and vardenafil are the currently commercially available selective inhibitors of cGMP-specific Type 5 phosphodiesterase (PDE-5), the enzyme responsible for the degradation of cGMP in the corpora cavernosa. They therefore enhance the effects of cGMP and permit an erectile response to be achieved or sustained.
The mechanism of phosphodiesterase-5 inhibition is shown in [Figure - 1].
The efficacy of sildenafil in the treatment of ED had been demonstrated in 21 randomized, double-blind, placebo-controlled trials involving more than 3000 patients aged 19-87 years with ED of various etiologies.[9] A low incidence of serious or clinically significant adverse events, including cardiovascular events, was reported.[9]
Studies with similar outcome have been reported for tadalafil and vardenafil.[10],[11]
When a patient is considered for PDE-5 inhibition, it is important that his fitness for physical and sexual activity be assessed and that he be appropriately counseled if sexual activity is inadvisable. In general, sexual intercourse should be safe if a patient can cope with an effort of 5-6 metabolic equivalents (METS) such as climbing 20 stairs in 10-15 seconds without increasing the heart rate by more than 20-30 beats per minute or provoking symptoms such as shortness of breath or chest pain.[12] Post-infarction patients who reach 5-6 METS without ischemia or arrhythmia on stress electrographic testing can in all likelihood resume their normal sexual activity without any risk and none of the patients with negative exercise test had ischemia during sexual intercourse on Holter monitoring.[12]
Adequate sexual stimulation is essential for maximizing the treatment outcome of PDE-5 inhibition. PDE-5 inhibitors should be avoided in patients with myocardial infarction, serious arrhythmia or stroke within the preceding six months, with systolic blood pressure of < 90 mmHg, with cardiac failure or coronary artery disease causing angina and with retinal disorders. Caution is advocated in patients receiving complicated multi-agent anti-hypertensive therapy. Concurrent use of cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., cimetidine, erythromycin, ketoconazole, saquinavir, ritonavir) or CYP3A4 inducers (e.g., rifampicin) may alter the plasma levels of PDE-5 inhibitors.
Nitrates are contraindications to PDE-5 inhibition. While PDE-5 inhibitors are absolutely contraindicated in a patient needing and receiving ongoing long-acting nitrate-containing medications, the use of a PDE-5 inhibitor following a dose of a short-acting nitrate such as sublingual glyceryl trinitrate or sublingual (or transdermal) isosorbide dinitrate may be permissible, provided the patient is well-motivated and understands fully all that may be involved and provided the use of the short-acting nitrate is infrequent and has preceded by not less than eight (preferably 24) hours the intention of using the PDE-5 inhibitor.[13] The re-dosing of a nitrate-containing medication subsequent to the use of PDE-5 inhibitor should follow the Second Princeton Consensus.[14] The attending doctor has the duty of care to fully review the medications of his/her patients, particularly those with known cardiovascular diseases, to identify any pharmacologically incompatible medication in the patients' therapeutic regimen. It is possible that many such medications, including nitrate-containing medications, may be discontinued or replaced with suitable alternatives, so that the patient regains his eligibility for PDE-5 inhibition.[15] Any such change in a treatment regime should be undertaken with the knowledge and concurrence of the respective specialists concerned.
Although the mechanism of action of sildenafil, tadalafil and vardenafil is identical, treatment outcome and side-effect profile may be different in different patients. It would be helpful if the patient is able to indicate which of the three PDE-5 inhibitors suits him best. The advantage of tadalafil is its long terminal half-life, which gives the responder a longer period of responsiveness. The characteristics of these PDE-5 inhibitors and their possible side-effects are shown in [Table - 2].
Response to PDE-5 inhibitors initially may be inadequate in some patients. A patient should not be regarded as having failed treatment unless at least six-eight recommended maximum doses have been tried with adequate sexual stimulation. Poor responders may sometimes achieve a better response after a lapse of time. This may be seen in patients with diabetes who may return with much improved glycemic control and in those who had undergone radical surgery for prostate cancer and are recovering from neuropraxia or intra-operative nerve injury which may have occurred in spite of attempts at nerve conservation.[16]
For the patient recovering from radical prostate or other pelvic surgery where erectile function may have been compromised, early erectogenic penile rehabilitation with PDE-5 inhibitors or with intracavernosal alprostadil in the case of nonresponders to PDE-5 inhibition, should be initiated. This offers effective prophylaxis against the possibility of permanent cavernosal tissue changes and results in a higher rate of spontaneous recovery of erectile function and better response to treatment with erectogenic medications.[16] Compared to PDE-5 inhibition, in patients with diabetes and after radical lower abdominal and pelvic surgery or radiation therapy, treatment outcome of ICI therapy is generally more favorable.
Opportunistic or on-demand dosing, usually 45-60 minutes prior to intended sexual activity, has been how PDE-5 inhibitors are prescribed. No evidence of tolerance or tachyphylaxis has been reported with repeated use of PDE-5 inhibitors.[17] Chronic or scheduled dosing, daily or at other appropriate frequency, may improve treatment outcome and increase the response rate.[18] It will, however, be prudent to exclude the risk of untoward side-effects on account of chronic PDE-5 inhibition.
| The role of testosterone in ED | | |
Testosterone modulates the expression of NO synthase in the corpus cavernosum and the production of NO and acts on the cavernosal arterioles enhancing penile rigidity. It influences genital sensitivity and the pleasurable enhancement of erectile activity.
Testosterone deficiency is an infrequent cause of ED.[19] However, if it is the confirmed cause, treatment with testosterone supplementation is rewarding. Correction of androgen deficiency not only restores erectile function but also improves general well-being and libido. As it influences NO production through its modulating effect on NO synthase, testosterone enhances the treatment outcome for ED with PDE-5 inhibitors.
Notwithstanding this, age-related testosterone deficiency is a clinical diagnosis based on a remarkably nonspecific symptom-complex which has to be corroborated with repeated appropriate confirmatory laboratory serum testosterone estimations. It commits the patient to a lifelong treatment regime requiring a careful surveillance program for possible serious side-effects. Other confounding factors, such as obesity, depression and obstructive sleep apnea, have to be excluded or treated. These, in themselves, are known independent risk factors for ED.
| Combination pharmacotherapy for the hard-to-treat ED | | |
Although response to the currently available pharmacotherapy is mostly satisfactory, a significant number of patients with ED are unable to achieve an adequate response. There is, therefore, the need to explore if there may be beneficial outcome from a rational combination of the therapeutic agents in current use, until newer agents become available.[20]
At least three plausible combinations would merit consideration:
a. Combination of a centrally acting with a peripherally acting agent e.g. sublingual apomorphine with oral PDE-5 inhibitor.
b. Combination of an agent acting via the cGMP pathway with one via the cAMP pathway e.g. oral PDE-5 inhibitor with intracavernosal alprostadil.
c. Combination of an agent enhancing SMC relaxation with one decreasing SMC contraction, e.g. oral PDE-5 inhibitor with a 1 adrenergic blocker.
Alprostadil combined with phentolamine and/or papaverine (Double Mix and Trimix) has in fact been part of the protocol in ICI therapy when response to alprostadil alone is inadequate. Combination pharmacotherapy had been studied using research animal models and in various human clinical settings, generally with favorable treatment outcome.
Further research will be needed to confirm the usefulness of such combinations as intracavernosal alprostadil and oral PDE-5 inhibitor and to provide rational guidelines for this and other combinations of proven value to be part of the management strategy for ED. The risk of possible side-effects may be minimized if the relevant exclusion criteria and prerequisites, based on a sound understanding of the pharmacological properties of the agents used, are strictly observed and treatment protocol meticulously followed.
| Algorithm for pharmacotherapy of ED | | |
An algorithm [Figure - 2] is presented for the pharmacotherapy of ED. This captures most of the issues that have been discussed and suitably reflects the current standards for the management strategy of this prevalent, under-diagnosed and under-treated affliction.
| Conclusion | | |
Pharmacotherapy is currently the main therapeutic option for ED. When appropriately prescribed, it is safe and effective. This comprises mainly ICI therapy using alprostadil,or alprostadil combined with phentolamine and/or papaverine, and PDE-5 inhibitors.
For the nonresponders, there is a need for newer pharmacotherapeutic options for ED and opportunities exist for further research so that new therapeutic guidelines may be established.
As well as treating ED, it is imperative that possible cardiovascular risk factors in patients with ED be investigated for, identified and treated. Where appropriate, lifestyle changes such as diet, exercise and social habits, need to be discussed and initiated.
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[Figure - 1], [Figure - 2]
[Table - 1], [Table - 2]
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