Cornell University

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CORNELL
Cornell University
Weill Medical College

Cornell Institute for Reproductive Medicine

Center for Male Reproductive Medicine and Microsurgery

"State-of-the-Art Compassionate Care for the Infertile Couple"

DRUG TREATMENT FOR ED

Viagra (Sildenafil citrate)

ViagraTM is the first oral agent with proven benefit in the treatment of erectile dysfunction. Early media coverage generated worldwide demand for this medication. It is an effective and safe first line medication. What every physician and patient should know about this drug follows.

Sildenafil citrate is an inhibitor of an enzyme that is concentrated in penile erectile tissue (although it is present in some other tissues). This enzyme known as phosphodiesterase type 5 (PDE5) turns off erection, therefore, Viagra by blocking it promotes the development and maintenance of an erection. Sildenafil is rapidly absorbed, with maximal blood concentrations occurring within one hour after administration. Its effect last on average 4 hours, that is, after taking the medication, there is a 4 hour window in which to pursue sexual activity. In my experience there are some men in whom the effect may last as long as 8 hours. It is best taken on an empty stomach as fatty food interferes with its absorption. Therefore, patients are instructed to take the medication 21-2 hours after a meal and wait another hour before starting sexual stimulation. Stimulation is required for Viagra to work. There is also a suggestion that alcohol may interfere with the medications absorption.

In my experience, treatment with Viagra allows approximately 65% of men to resume sexual intercourse. Viagar has been shown to effective across a wide spectrum of medical conditions, although it is least effective in certain diabetics and early after radical prostatectomy. Headache, flushing, transient visual disturbances and dyspepsia are the most common side effects occurring in 6-18% of men using Viagra.

The benefit of sildenafil in men with angina or a history of heart attacks who have ED who are NOT taking nitrates has been shown to be similar to men without these conditions. From a safety standpoint, in carefully selected patients there is no evidence to show that Viagra is associated with heart attacks or an increased incidence of death. The overall incidence of cardiac side effects is approximately 5% for those with a history or compared to 3% in men without coronary artery disease. These figures are the same as for placebo (sugar pill) in the Viagra trials. More recent studies confirm the safety of Viagra and it can be concluded that for patients with coronary artery disease who are not taking nitrate (nitroglycerin) therapy, sildenafil is a well tolerated and effective treatment for ED.

Viagra should not be used by certain patients: patients who are on any form of nitrate therapy (pill, spray, paste or patch) as the combination of the 2 drugs has been shown to lower the blood pressure to a dangerous level. Men with significant cardiac disease are at higher risk of problems. These patients include: heart attacked within the last 3 months; poorly controlled high blood pressure; poorly controlled angina (cardiac chest pain); stroke within the last 3 months; severe congestive heart failure; and heart valve disease. There is a group of men with cardiovascular disease who may benefit from a cardiologists input prior to starting Viagra and these include: men with moderate angina; mild congestive heart failure; heart attack or stroke in the recent past more than 3 months less than 6 months ago.

The advantage of this medication is the simplicity of its use. After thorough discussion of the potential side effects and review of medications, those patients who are considered safe candidates are simply given a prescription for six 50 mg tablets. They are instructed to take only one dose per 24 hour period. For the first dose, the patient is instructed to take one pill one hour before planned intercourse. If this dose is ineffective on two different occasions, the patient doubles the dose (100mgs). At the end of this home trial, the patient speaks with Dr. Mulhall or his nurse for a refill of the minimum, effective dose. Patients who are not successful are asked to return to consider alternative forms of therapy.

Currently there are 2 other agents that work in a similar fashion to Viagra that are under FDA review, both of which has received approvable letters, indicating the likelihood of release in 2003. Tadalafil (proposed trade name, Cialis) is being developed by Lilly-ICOS and vardenafil (proposed trade name, Nuviva) is being developed by Bayer. Both of these drugs have been shown to be effective and safe in trials to date. It is likely that the precautions used for Viagra prescribing will be used also for these newer agents. As more information comes to light on these agents it will be posted on this website.

Trazodone

Trazodone is an anti-depressant with the uncommon side-effect of prolonged erection (priapism). This occurs in approximately 1/10,000-20,000 users. It has been used for the treatment of erectile dysfunction without any clear evidence that it is truly effective. Its mechanism of action in promoting erection is not well known, but it is believed that is exerts its primary effect by stimulation of the serotonin receptors in the brain. The medication has been used at the dose of 50-200 mg by mouth each night at bed time (no relationship to intercourse timing). While some studies have cited trazodone’s effectiveness to be as high as 60%, the arrival fo Viagra has decreased the use of this medication significantly. The side effects of trazadone include drowsiness in 31%, dry mouth in 1% and fatigue in 19%. At the Sexual Medicine Program at New York Presbyterian Hospital the combination of trazadone and Viagra is not allowed

Phetolamine

Oal administration of the phentolamine, which blocks the action of adrenaline in the penis (the major inhibitor of erection) has been shown to result in erection in men with mild ED. Recently, this drug has received recognition as VasomaxTM (Schering-Plough, NJ, USA) and has in a number of trials, in men with low-grade ED been shown to be better than placebo. It has yet to be put before the FDA for final approval and it is unclear if this drug will ever come to the market.

Yohimbine

This drug is derived from a tree bark and acts on receptors in the brain to stimulate area that are believed to be involved in sexual function. It ahs been sued for many years, however, there is no good evidence to show that this drug is any better than placebo (sugar pill). Currently, its role as therapy in men with erectile dysfunction is minimal. It is associated with potentially serious side effects such as palpitations and high blood pressure, especially in patients with cardiovascular disease.

Apomorphine

Apomorphine has been used as a pharmacologic agent for over a century. Previously, it has been used primarily in Parkinson’s disease and is approved in a number of countries for this indication. The route of administration for this Parkinson’s disease has been both by pill and injection with doses used up to 30 mg. It is a stimulator of dopamine receptors in an area of the brain (hypothalamus) that is key to the triggering of erection. TAP Pharmaceuticals licensed apomorphine for the treatment of erectile dysfunction in 1996 and the medication has been reformulated so that it can be delivered in under the tongue. The trade name for the drug is UprimaTM and is available is Europe and Asia at 2mg and 3 mg doses. It is currently under review by the FDA. It appears from trials that this agent is an effective drug in men who have some erectile function left (mild and moderate ED) and who have had ED for a short period of time (less than 2 years). The medication is rapidly-acting, causing erections to occur as quickly as 5 minutes after administration. In men who get erections in response to UprimaTM about 70% get the erection within 20 minutes. Sexual stimulation is required for this medication to work. Because it is given under the tongue, it may be taken with food. The medication dissolves in about 10 minutes. It is a safe medication whose most common side effects include (at 3mg) nausea, headache and dizziness (which occur in les than 5% of men). It is unclear when this drug will come to market

Intraurethral Agents (Suppositories)

1. Alprostadil (MUSETM)

Intra-urethral administration of alprostadil suppository (MUSETM, Vivus, Menlo Park, CA, USA) induces an erection sufficient for sexual intercourse in 30-40% of men. A pellet, the size of a grain of rice, is placed 1 inch into the urine channel following urination while the patient is standing. The reported side effects include pain and dizziness, albeit in less that 5% and 2% of men respectively. PGE1 has four dosage strengths (125, 250, 500, and 1000 mg), although the lower doses are not effective in the average man with ED. MUSE was introduced as a treatment for the impotent male in 1997. It bypassed the need for the direct injection of a drug into the penis. This factor alone has made it appealing to many physicians as well as patients. In Dr. Mulhall’s experience MUSETM has an average overall success rate of 35% on office administration, as defined by the ability to obtain an erection sufficiently rigid for sex. It also showed that the at-home consistency rate was 55% in men with established in-office drug efficacy. No significant side effects have occurred in our patients. The incidence of priapism (prolonged erections) is negligible, with one study reporting 1,373 home administrations without the incidence of priapism or fainitng, which, is consistent with our experience.

Administration of intraurethral suppositories, while less intimidating than intracavernosal injection, is also somewhat complex. These medications should be given initially in the clinic, with instruction and demonstration of competence as well as effectiveness prior to dispensing a prescription for at-home use. In our experience, lack of effectiveness is the reason for patient drop-out with this route of administration. We currently use this medication in selected patients. A starting dose of 500 or 1000 mcg is used. The patient is instructed to void just prior to use of the medication. This lubricates the urethra and makes the administration of the suppository easier. To minimize venous leak and promote absorption, the patient is instructed to stand while the medication is absorbed. Gentle massage helps absorption. The effectiveness is assessed at 5, 10, and 30 minutes. Loss of erection is expected within one hour. Recently, the company has supplied a constriction device (ACTIS) that is placed at the base of the penis just prior to medication administration. This theoretically will increase intracavernosal concentrations and decrease systemic absorption. It may be worn during intercourse if desired. The effectiveness of MUSETM in combination with the ACTIS device is under investigation.

Penile Injections

Virag and Brindley were the first authors to report the ability of penile injection to produce an erection, using papaverine and phenoxybenzamine, respectively. To date, a number of medications have been used for this purpose, most commonly papaverine, phentolamine and alprostadil. These medications have been administered in a variety of combinations with good effect. The success rate, defined by the production of an erection, rigid enough for intercourse has been in excess of 75%.

While Viagra has become the most prescribed medication for the treatment of ED, injection therapy still represents a cornerstone of therapy. In a recent study patients were asked to compare penile injections to sildenafil with regard to hardness of erection, overall sexual satisfaction and preference for future use. All patients, regardless of etiology of ED, reported a more rigid erection using injections versus sildenafil. The majority of patients chose to continue using injections as their preferred treatment.

The use of combination agents is preferred to single agents to minimize side effects and maximize effectiveness. For example, the combination of papaverine, phentolamine, and alproastadil was shown to be more effective than high dose alprostadil alone, but has a lower incidence of painful erections (due to the lower concentration of alprostadil). The advantage of intracavernosal agents compared to currently available oral agents, is that these medications induce erection even in the presence o only minimal stimulation. The disadvantages include, more complex route of administration, potential for bleeding, bruising, and penile fibrosis, and a higher incidence of priapism (albeit all uncommon side effects).

It is mandatory that the patient receive detailed instructions on the use of this type of therapy and is administered his first dose in the clinic. In our clinic, each visit is an important combination of physician assessment, trial dose administration, and patient education. The patient is given instructions on cleaning the phallus. An alcohol swab is used to cleanse the intended area of injection. An insulin type syringe is then used to administer the medication. The injection is given at the ten or two o’clock position on the penis (away from the ventrally located urethra), away from visible veins, and never in the midline. To minimize the chance of scar formation, the sight is changed with each dose. The needle is aimed at a right angle to the skin and pushed in to the hub, ensuring delivery of the medication into the correct location. After administration of the medication, the patient holds direct pressure to the area of injection for a few minutes. Patients taking blood thinners are advised to continue pressure for 6 minutes. The staff gives the first dose with the patient watching. This is a very low dose (which varies depending on the choice of drug). Patients with pure nerve damage ED are started lower than those with suspected vascular ED. After administration and assessment of erectile response 5, 10, and 30 minutes later, the patient waits in the clinic until the erection goes away. With each visit the dose of medication is increased. The patient’s role in administration of the medication also progressively increases. The dosage goal is to produce an in-clinic erection of 60% maximum (barely adequate for penetration) that lasts less than one hour. It is presumed that at home with less anxiety, more appropriate stimulation, etc., the effect will be greater. Ultimately, the patient (or his partner) must also demonstrate the ability to draw up the drug and properly inject it with an aseptic technique without staff assistance. At this point, he is graduated from the clinic and given prescriptions for at-home use. As with all forms of medical therapy, the patient is given instructions to seek prompt medical attention for prolonged erections.

The potential side effects, scarring, priapism (see page on Priapism on this website), bleeding, bruising, can be thus minimized by using combination medications, carefully titrating to the correct dose in the clinic, and thoroughly educating the patient on injection technique. Scarring can occur as a nodule, plaque, or penile curvature. Patients in our clinic are instructed that prolonged erections constitute a medical emergency. If the patient has an erection that lasts longer than two hours that is not relieved by ejaculation, they are instructed to call the answering service for advice and should be in the Emergency Department by the fourth hour.

Topical Administration (Creams and Gels)

Two companies at present (Nexmed and Macrochem) are developing medications, in the form of gels that are applied to the penis that are absorbed into the erectile bodies and cause erection. These medications obviously have great appeal to patients given the absence of a needle and minimal side effects. It is unclear at this time, based on early trials how effective these drugs will be in the general population of men with ED. As new information becomes available it will be posted on this website.

Simplified Approach To Drug Therapy For ED

ED is a common problem that affects men as they age. There are many effective forms of therapy available that should be offered to motivated patients. Consideration of the primary cause of ED is important in determining the likelihood of success with any given form of treatment. A history and physical examination are mandatory before the prescription of any form of erection-inducing medication. While the oral agent Viagra is currently the most popular first line medication, in patients who fail to respond to this agent, injection therapy should also be offered as second line therapy as it is easily the most effective treatment that exists. Viagra is absolutely contraindicated in patients who take nitrates of any kind but has proven to be safely used in combination with other blood pressure medications. Treatment with intraurethral alprostadil is a good option for patients who take nitrates, but are unable or unwilling to try penile injection therapy. Other oral agents, such as trazadone and yohimbine are probably, currently, of only historical value.

Suggested Reading

1. Boolell M et al. Sildenafil: an orally active type 5 cyclic GMP specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. International Journal of Impotence Research 1996:8:47-52.
2. Goldstein, I et al et al: Oral Sildenafil in the treatment of erectile dysfunction. New England Journal of Medicine 1998:338:1397-1404
3. Conti, R.C et al.: Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. American Journal of Cardiology 1999:83:29C-34C
4. Webb, D.J et al. Sildenafil Citrate and blood pressure lowereing drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist American Journal of Cardiology 83 (5a)21c-28c, March 1999
5. Zusman, R et al. Overall cardiovascular profile of sildenafil citrate. Am J Cardiol 1999, 83:35C-44C
6. Saenz de Tejada, I et al. Pathophysiology of prolonged penile erection associated with trazodone use. Journal of Urology, 165: 60-3, 1991
7. Constabile, R et al: Oral Trazadone is not effective therapy for erectile dysfunction: a double-blind, placebo controlled trial. Journal of Urology 161, 1819-1822
8. Zorgniotti, A.W.: On demand oral drug for erection on impotent men. Journal of Urology, 147: 308 A, 1993
9. Padma-Nathan et al. Hemodynamic effect of intraurethral alprostadil: the medicated urethral system for erection (MUSE). Journal of Impotence Research, 6 A42, 1994
10. Padma-Nathan, H. et al: Treatment of men with erectile dysfunction with transurethral alprostadil. New England Journal of Medicine, 336: 1-7, 1997
11. Porst, H., The rationale for Prostaglandin E1 in erectile failure: A survey of world wide experience. Journal of Urology, 155: 802-15, 1996
12. Brannigan, R.E., Spitz, A., Schatte, E.C., et al Comparison of sildenafil citrate (viagra) versus trimix intracavernosal injection (ICI) as treatment for erectile dysfunction (ED) Journal of Urology Vol. 161, 4 May 1999 214 (820)
13. Mulhall, J.P. et al. Salvaging the failed injection patient with the use of forskolin. Journal of Urology, 1996
14. Morales, A. et al. Oral and transcutaneous pharmacologic agents in the treatment of impotence. Urologic Clinics of North America, 15:87-94, 1988.
15. Mulhall, JP. Sublingual apomorphine for the treatment of erectile dysfunction. Expert Opinion on Investigational Drugs, 11(2), 1-8, 2002
16. Mulhall, JP. et al. An open-label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction. Clinical Therapeutics, 23(8):1260-1271, 2001
17. Mulhall et al. Analysis of the consistency of intra-urethral prostaglandin (MUSE®). During at-home use. Urology, 58(2):262-266, 2001.
18. Manecke, R. et al. Drug therapy for erectile dysfunction in the new millenium. Annals of Internal Medicine, 31:388-397, 1999.
19. Mulhall, JP. The pharmacological erection program. Techniques in Urology, 3(3):129-134, 1997.



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