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At the heart of general practice since 1960

How I coped with the death of my son

Scott Chambers gives a critique of lifestyle and pharmacological treatment options

Over the past 20 years there has been a radical shift in our understanding of the aetiology of erectile dysfunction (ED) as we gain greater insight into molecular, neurological and physiological aspects of erection1. Two main concepts have emerged: first, ED is no longer considered an inevitable part of ageing. Second, the majority of ED has an organic origin, contrasting with the previously accepted view that the majority of cases were due to psychological disturbances1,2.

Despite this, psychological disturbances are still responsible for a significant proportion of ED, with about 20-30 per cent of patients having psychogenic ED. A further sizeable proportion of patients suffer ED of both organic and psychological origin (mixed ED). Psychological issues also contribute to the severity of organic ED. Of the organic causative factors, disruptions to the vascular system account for some 70 per cent of cases.

Indeed, because of the association between vascular disease and ED, it is now accepted that ED represents an 'early warning sign' for cardiovascular disease and may be apparent prior to the presentation of any other clinical symptoms. For example, ED is four times more likely to be present in men with diabetes, hypertension or CHD than in those without these diseases3.

Lifestyle choices

In the past 30 years significant advances have been made in the management of ED, from psychosexual therapy and penile prostheses in the 1970s, revascularisation, vacuum constriction devices and intracavernosal injection therapy in the 1980s, to transurethral and oral drug therapy in the 1990s4.

Despite the availability of these different treatment options, lifestyle changes represent an important first step in patient management, as poor lifestyle choices can make a significant contribution to the condition, and can be modified with appropriate support.

While effective lifestyle modification can benefit the global health of an individual, the actual evidence relating to its long-term benefit in ED is limited. But lifestyle changes that can be suggested that may aid patient outcome include:

·smoking cessation

·reduction in alcohol intake

·stress management

·exercise and weight reduction

·adoption of a healthy diet

·avoidance of recreational drugs.

Effective communication and education is also a critical factor in improving patient management and should involve both the patient and their partner wherever possible, particularly when determining a treatment strategy5. Without such an approach the patient may continue on a downward spiral with possible deterioration of their symptoms.

First-line therapy

The ultimate aim of any therapy for ED is to normalise the sexual response and free the patient from the pressure of performing sexually within a designated timeframe.

Many couples prefer non-invasive, easily-administered treatments that are reversible and offer convenience, without impacting upon the natural spontaneity. Thus, oral therapy is considered by the World Health Organisation6 and other country-specific guidelines7,8,9 to be a first-line approach.

There are two main classes of oral pharmacological agents currently licensed for the management of ED in the UK: the PDE5 inhibitors, which affect the local regulation of erectile function by potentiating the effects of nitric oxide (NO) and the dopamine agonist, apomorphine, which acts centrally. Both classes of agent have been shown to significantly enhance erectile function in clinical trials, thereby increasing the likelihood of successful sexual intercourse, independently of the aetiology or the severity of ED.

PDE5 inhibitors

Inhibitors of PDE5 were originally developed for the treatment of angina, due to their predicted vasodilatory effects on the coronary vasculature10. But the first PDE5 inhibitor to be developed commercially, sildenafil, was shown in clinical trials to have no effect on angina.

Intriguingly, proerectile responses were reported by a significant number of patients, leading to its commercial development as a treatment for ED10. PDE5 inhibitors potently and selectively inhibit the breakdown of cGMP by PDE5, thereby potentiating the pro-erectile responses to NO (see figure 1).

As sexual arousal is necessary to stimulate the production of NO, these agents do not provide benefit in its absence. Three PDE5 inhibitors are currently licensed for use in the UK ­ sildenafil, tadalafil and vardenafil ­ and while clinical studies have shown that all agents offer broadly similar levels of efficacy in terms of erectile response, there are a number of differences in their pharmacodynamics and pharmacokinetics which may translate to different efficacy and safety profiles.

PDE5 inhibitors are effective across a broad spectrum of patients with ED of varying severity and aetiology.

All agents in this class produce small reductions in blood pressure and are thus contraindicated in patients who are receiving organic nitrates due to the augmentation of hypotensive effects when both agents are co-administered.

Likewise, concomitant administration of a-blockers, such as doxazosin, with PDE5 inhibitors has been shown to lead to symptomatic hypotension in some patients. So co-administration of PDE5 inhibitors and a-blockers should be performed with caution. PDE5 inhibitors are generally well-tolerated and have similar side-effect profiles, with reported adverse events including headaches, flushing, dyspepsia and nasal congestion.

Apomorphine

Apomorphine is administered sublingually and can generate an erection within 20 minutes11. It acts centrally by selectively stimulating dopamine D1 and D2 receptors, which activate specific pro-erectile neural events in the paraventricular nucleus of the hypothalamus.

Stimulation of NO and oxytocin by these processes results in relaxation of the smooth muscle in the corpora cavernosum, engorgement of the sinusoids and erection. As apomorphine is an emetic, the most common side-effects associated with its use are nausea and vomiting11. Apomorphine does not appear to be as effective as PDE5 inhibition in terms of erectile response.

Other oral agents

A number of other oral agents have been investigated, including phentolamine (an a-adrenergic receptor blocker) and yohimbine (an a1/a2-adrenoreceptor antagonist). Phentolamine acts by shifting the balance away from

a-adrenergically mediated contraction of corporal cavernosum and thus flaccidity, towards parasympathetic mechanisms, thereby activating NO synthase11.

Yohimbine is thought to act centrally on adrenergic receptors in the brain associated with libido and penile erection. But its use in treating ED is viewed with some suspicion. Neither phentolamine nor yohimbine are currently licensed in the UK for treating ED.

Psychosexual therapy

Psychosexual therapy may offer some benefit to those patients who have ED of a clear psychogenic origin or in those who refuse medical and surgical intervention. It may also be useful in combination with pharmacological treatment in those with ED of mixed aetiology12.

Its primary objective is to decrease performance anxiety by increasing the range of sexual activities not requiring an erection of sufficient rigidity for penetration, thereby increasing a couple's intimacy and their ability to openly communicate about sex13.

Second-line therapy

Vasoactive drugs that can be administered both intracavernosally by injection or intraurethrally are available for those patients who do not respond to oral drug therapy or for those who cannot tolerate such agents. Indeed, intraurethral and intracavernosal therapy are now used almost exclusively in those who fail to respond to oral therapy13.

Intracavernosal alprostadil (prostaglandin E1)

Alprostadil is a synthetic prostaglandin E1 and is currently the most widely used agent given by either intracavernosal injection or by intraurethral application. It possesses vasoactive properties which generate an erection by inhibiting the prevailing a1 adrenergic activity that promotes the smooth muscle contraction that maintains the penis in a flaccid state.

Intracavernosal injection therapy with alprostadil is effective in 60-90 per cent of patients with ED and is associated with a rapid onset of erection (five to 15 minutes) producing erections firm enough for penetration that last 30-60 minutes14.

But patient comfort and education are essential elements in the success of this treatment, while the involvement of the patient's partner may be necessary in those with limited manual dexterity7. Side-effects of intracavernosal injection therapy include priapism, penile pain and fibrosis.

Intraurethral alprostadil

Recently, a semi-solid pellet formulation of alprostadil has become available and is administered transurethrally via a polypropylene applicator with a hollow stem13. There is a high degree of patient satisfaction with this method due to its perceived lack of invasiveness, although its clinical success is somewhat lower than that achieved with intracavernosal injection of alprostadi · 7,12. In some cases, the use of a constrictive band at the base of the penis may provide more rigid erections.

Hormone treatment

Only a small proportion of cases of ED are caused by hormone abnormalities. The most frequent hormone abnormality is a reduced level of testosterone caused by hypogonadism which can be restored by appropriate testosterone replacement. But testosterone replacement therapy should only be reserved for patients with confirmed hypogonadism4.

Vacuum devices

Vacuum erection devices are a non-invasive treatment option that comprise an external cylinder which is fitted to the penis, allowing air to be pumped out, thereby promoting blood flow into the penis and subsequent erection5.

The erection is maintained by fitting a constriction band around the base of the penis. These devices are useful in patients in whom oral therapy has failed or is unacceptable and in those who are averse to needles and other invasive therapies. However, they can be cumbersome and thus detract from natural spontaneity.

Third-line therapy

Penile prosthesis and surgery

There are two main types of penile prostheses which are inserted into the penis during surgery, and used to generate an erect state. Semi-rigid, malleable rods maintain the penis in a state of permanent rigidity, but also allow the penis to be bent out of the way when the patient is not sexually active.

The inflatable implant is more sophisticated and involves insertion of a hydraulic device which causes stiffening of the penis when a pump, implanted in the scrotum, is activated. Such prostheses should only be considered in those in whom other approaches have failed or who are unwilling or unable to continue with medical treatment or external devices, because permanent damage to the erectile tissue may arise after surgery5.

Indeed, since effective oral treatments have become available, these techniques play a minimal role in management.

References

1 Melman A, Gingell JC. Epidemiology and pathophysiology of erectile dysfunction. J Urol 1999; 161: 5-11

02 Kaiser FE. Erectile dysfunction in the aging man. Med Clin North Am 1999; 83: 1267-78

03 Kim S et al. Tadalafil. Formulary 2002; 37: 289

04 Lue TF. Erectile dysfunction.

N Engl J Med 2000; 342: 1802-13

05 Ralph D, McNicholas T. UK management guidelines for erectile dysfunction. BMJ 2000; 321: 499-503

06 Jardin A et al. Recommendations of the First International Consultation on Erectile Dysfunction, co-sponsored by the World Health Organisation. Plymouth: Health Publications Ltd, 2000

07 Wespes E et al. Guidelines on erectile dysfunction. Eur Urol 2002; 41: 1-5

08 The Process of Care Consensus Panel. The process of care model for evaluation and treatment of erectile dysfunction. Int J Impot Res 1999; 11: 59-70

09 Erectile dysfunction practice guidelines. Can J Urol 2002; 9: 1583-7

10 Rosen RC, McKenna KE. PDE-5 inhibition and sexual response: pharmacological mechanisms and clinical outcomes. Annu Rev Sex Res 2002; 13: 36-88

11 Vitezic D, Pelcic JM. Erectile dysfunction: oral pharmacotherapy options. Int J Clin Pharmacol Ther 2002; 40: 393-403

12 Wagner G, Saenz de Tejada I.

Update on male erectile dysfunction. BMJ 1998; 316: 678-82

13 Kirby RS. Impotence: diagnosis and management of male erectile dysfunction. BMJ 1994; 308: 957-61

14 Cohan P, Korenman SG. Erectile dysfunction. J Clin Endocrinol Metab 2001; 86: 2391-4

Useful websites

The International Index of Erectile Function questionnaire to evaluate erectile dysfunction can be found at www.bestmedicine.com

www.basrt.org.uk

www.brook.org.uk/content

www.menshealthforum.org.uk

www.malehealth.co.uk

www.relate.org.uk/NearestRelate.asp

www.relate.org.uk

www.impotence.org.uk

www.prostate-cancer.org.uk

www.allabouted.org

www.informed.org.uk

www.besttreatments.co.uk/btuk/

conditions/erection_problems

A GP's view

Choosing the right oral treatment

Professor Mike Kirby gives an overview of the comparative benefits of different PDE5 inhibitors

Sildenafil, better known as Viagra, was the first drug to become available that could be taken as a pill for the treatment of erectile dysfunction.The drug was originally researched as a treatment for angina because of its ability to relax the blood vessels.

It was not until the men in the original clinical trial began reporting the unexpected additional effect of enhanced erections that it was realised that an effective tablet for ED may have inadvertently been discovered. A subsequent decade and a half of research and development led to the launch of the drug in 1998.

Sildenafil works on chemicals that control the relaxation of muscles and blood vessels in the penis, and in this way helps to restore the natural erection which occurs in the presence of sexual stimulation. The recommended dose is 50mg taken between 30 minutes and four hours prior to sexual activity.

Often psychological counselling is also necessary because many men may take months or even years to pluck up the courage to come and talk about the problem. It is also helpful to include the sexual partner in the discussions about the treatment.

The condition is often entrenched and treatment with sildenafil should be attempted on at least eight separate occasions, starting at a 50mg dose and rising to 100mg before considering alternative treatment.

Tadalafil (Cialis) works in the same way but it differs significantly in its chemical structure. It has a longer-lasting effect than sildenafil, working as soon as 16 minutes, but its effect lasts for up to 36 hours, in the presence of sexual stimulation. It is also unaffected by the use of food or alcohol. This longer action of the drug may suit some patients who do not wish to plan to have sex at a specific time during the day or night.

Vardenafil (Levitra) is another drug that works in the same way. In laboratory testing it appears to be more potent than either sildenafil or tadalafil and it has a rapid onset of action. Similar to the other two drugs, it is highly effective in treating ED, with seven-eight patients out of 10 being pleased with the results. Vardenafil's effects last for up to five hours after taking a tablet.

With all three drugs, the side-effects are mild. The common side-effects include flushing, headache, stuffy nose and sometimes indigestion. Slight visual colour disturbance sometimes occurs with sildenafil, though only rarely with vardenafil and tadalafil.

None of these drugs should be taken by patients who are taking oral nitrates because they can cause sudden drops in blood pressure when used together.

Mike Kirby is visiting professor to the faculty of health and human sciences, University of Hertfordshire, and a GP in Letchworth, Herts, who specialises in cardiovascular medicine and urology

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