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New Drugs, Old Drugs

Erectile dysfunction

Chris G McMahon

MJA 2000; 173: 492-497

Abstract - Mechanism - Injection therapy - Transurethral alprostadil - Selective inhibitors - Guidelines - Conclusion - References - Authors' details
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Abstract

  • Erectile dysfunction (ED) is a common condition and can usually be managed pharmacologically, with drugs delivered by intracavernosal injection (ICI), transurethrally or orally.
  • The cardiovascular status of the patient and his overall fitness for renewed sexual activity must be assessed before treatment for ED is initiated.
  • The efficacy of sildenafil is related to the extent and severity of ED, and is significantly reduced in patients with severe vasculogenic ED, ED associated with diabetes and after radical prostatectomy.
  • Alprostadil (prostaglandin E1) is the drug of first choice in patients treated with ICI; it is effective in 72.6% of men with ED and is associated with a low risk of priapism and cavernosal fibrosis.
  • Transurethral alprostadil is significantly less effective than alprostadil ICI, producing improved erections in 30%-40%, but rigid erections in only 10%, of men with ED.
  • There is Level II evidence that:
    • alprostadil ICI is an effective treatment for ED
    • papaverine ICI is associated with a high risk of cavernosal fibrosis and priapism
    • papaverine ICI should be restricted to informed patients refractory to treatment with alprostadil ICI
    • transurethral alprostadil is less effective than alprostadil ICI
    • sildenafil is an effective treatment for ED.

Erectile dysfunction (ED) is the inability to achieve and maintain an erection of sufficient rigidity for satisfactory sexual intercourse.1 Community-based epidemiological studies suggest that sexual dysfunction, particularly ED, is a common disorder in men, and is associated with reduced quality of life.2,3 While it was previously thought that most impotence in men was psychogenic, we now know that there is a physical basis for most men's impotence. One of the most significant advances in our understanding has been the recognition that blood flow into the corpora cavernosa is regulated by smooth muscle tone, and that this mechanism can be pharmacologically altered.


Mechanism of erection

An erection is initiated when psychoneuroendocrine stimuli activate efferent autonomic nerves to relax penile vascular and corpus cavernosal trabecular smooth muscle. The mechanism of erection is described in Box 1. The penis loses its rigidity when the activation of sympathetic constrictor nerves after ejaculation increases the tone of the smooth muscles and the helicine arteries and trabeculae, resulting in decreased arterial inflow and increased venous outlow. The mechanisms that maintain flaccidity are unknown.

Priapism is an uncommon, but potentially serious, adverse effect associated with some of the therapies described below -- its management is outlined in Box 2.


Intracavernosal injection therapy

Self-administered intracavernosal injection (ICI) therapy, using vasodilator drugs which relax the arterial and trabecular smooth muscle, is an effective treatment for ED4 (E2). (See Box 3 for an explanation of level-of-evidence codes.5)

Papaverine

 Papaverine is a potent, non-specific smooth muscle relaxant which increases smooth muscle intracellular adenosine 3',5'-monophosphate (cAMP) by its action as a non-selective cAMP phosphodiesterase inhibitor, causing vasodilatation of penile vascular and sinusoidal smooth muscle.6 Papaverine has a relatively short plasma half-life (1-2 hours) and is extensively metabolised in the liver. After intracavernosal injection, the peak serum concentration is several times lower than after extracavernosal injection, suggesting that the corpus cavernosum is a separate pharmacokinetic compartment from which elimination of papaverine is much slower than from the systemic circulation.7

A meta-analysis of the largest published studies on the use of papaverine reports that it is effective in 53% of men with ED, as measured by the ability to produce an erection of sufficient rigidity for sexual intercourse8 (E1). However, the efficacy of ICI papaverine is limited by local adverse effects, principally priapism (in 7%)8 and intracavernosal fibrosis, presenting as penile deformity or curvature (reported in one study in 50% and 95%, respectively, of long term users).9 Fibrosis is related to poor injection technique, frequent injections and long term use. Because of these adverse effects, papaverine should be restricted to informed patients in whom other medications are ineffective. Papaverine hepatotoxicity is rarely a clinical problem and may manifest either as an increase in liver transaminase concentrations, which is relatively common (> 1%), or as a drug-induced hepatitis, which is rare (< 0.1%).10

Adrenergic blockers

It is well recognised that drugs which block Alpha-adrenoceptors (such as prazosin) can produce erection, and even priapism. Thus, intracavernosal injection of Alpha-adrenergic-blocking drugs seems a logical way of producing penile erection. Phentolamine, a competitive Alpha-adrenoceptor antagonist with affinity for Alpha1- and Alpha2-adrenoceptors, produces tumescence, but rarely an erection, when injected intracavernosally. However, when phentolamine is combined with papaverine, 68% of users respond with a rigid erection8 (E1).

Alprostadil

 Alprostadil (prostaglandin E1, or PGE1) is an eicosanoid derived from arachidonic acid (see Box 4 for a profile of alprostadil). The mechanism of its vasodilating action is not completely understood. Alprostadil increases levels of intracellular cAMP by modulation of adenyl cyclase, leading to a decrease in the free calcium concentration and subsequently to smooth muscle relaxation.11 It may also modulate the presynaptic release of noradrenaline.

Alprostadil has a short duration of action and a plasma half-life of less than one minute because of rapid pulmonary clearance of up to 80% after the first pass through the lung. When injected intracavernosally, approximately 30% of the drug is metabolised within the corpora cavernosa, which may explain why significantly fewer episodes of priapism occur with alprostadil than with papaverine.

Multiple studies have shown that alprostadil has superior efficacy and reduced risk of priapism and intracavernosal fibrosis compared with papaverine (alone or combined with phentolamine). A meta-analysis found that alprostadil resulted in an erection of sufficient rigidity for sexual intercourse in 72.6% of men with ED8 (E1).

The principal side effect of intracavernosal injection of alprostadil is pain at the site of injection, which occurs in up to 30% of patients. Priapism is a rare complication.

Although early experience suggested that fibrosis was uncommon with alprostadil ICI, recent long term studies show an incidence of fibrosis and scar formation of 9%-23.3% in mid-term and long-term users, so patients should be warned of the possibility of penile fibrosis before starting treatment12,13 (E4). Studies in human fibroblasts have shown that alprostadil suppresses collagen synthesis induced by transforming growth factor (TGF-beta1). An imbalance between PGE1 and TGF-beta1 in the corpora cavernosa, as a result of anoxia or endothelial damage due to ischaemia, hypercholesterolaemia or hyperglycaemia, may cause increased extracellular matrix deposition, inhibition of smooth muscle growth, and eventually fibrosis.14 Inhibition of collagen synthesis by alprostadil may, in part, explain the low incidence of cavernosal fibrosis with this drug.

Polyagent intracavernosal injection therapy

Intracavernosal injection therapy with alprostadil in combination with other agents such as papaverine, phentolamine and atropine may be effective in patients in whom maximum-dose alprostadil monotherapy is ineffective.15,16 A comparative study reported a 91.6% response rate to a combination of alprostadil, papaverine and phentolamine15 (E32). Polyagent ICI appears effective as "salvage therapy" in patients with severe arteriogenic ED and mild to moderately severe cavernosal venous leakage in whom alprostadil alone is ineffective.16 However, a significant number of patients remain refractory to ICI therapy.

Treatment guidelines proposed by the 1998 New South Wales Health Complaints Commission Inquiry into Impotence Treatment emphasise the importance of adhering to good manufacturing practices to ensure sterility of polyagent medication.17


Transurethral alprostadil

Alprostadil can also be administered as a microsuppository into the distal urethra. A translucent hollow-stem applicator is used to insert the microsuppository after urination, the residual urine acting as both a lubricant and a diluent for the microsuppository. The drug is absorbed directly into the urethral endothelium and is transferred into the corpora cavernosa primarily by venous channels that communicate between the corpus spongiosum and the corpora cavernosa. These channels appear to increase in number, but particularly in size, with age.

Alprostadil is rapidly absorbed from the urethra (only 20% remains after 10 minutes) and produces vasodilatation in the penile vasculature; plasma levels are either low or undetectable. Transurethral alprostadil has a brief serum half-life of between 30 seconds and 10 minutes because of rapid pulmonary clearance after the first pass through the lung. No effect on spermatozoa motility, viability or membrane integrity has been shown, and the mean increase in the PGE1 content of the ejaculate (123 mg) is less than the normal day-to-day variability for prostaglandins.

In extensive double-blind placebo-controlled clinical trials sponsored by manufacturers, 65.9% of men achieved an erection adequate for intercourse after administration of transurethral alprostadil in a doctor's office,8 and 64.9% of these men reported intercourse at least once with home treatment, with significant improvements in quality of life, particularly in the domains of self-esteem and sexual and non-sexual aspects of their relationships with their partners17 (E2). The efficacy of alprostadil was found to be similar regardless of age or the cause of ED, including vascular disease, diabetes, surgery, and trauma. The use of an adjustable penile constriction band with transurethral alprostadil may augment the drug effect.

However, several postmarketing studies failed to produce similar results to those of the trials sponsored by manufacturers. One reported that only 27% of patients achieved erections sufficient for intercourse during in-office testing, and that, because of this limited efficacy, adverse effects and cost, more than 80% of patients did not continue to use transurethral alprostadil at home18 (E4). Another study comparing transurethral and intracavernosal alprostadil reported total erectile response rates of 43% and 70%, respectively, complete rigid erections in only 10% versus 48%, and rates of penile pain or burning in 31.4% versus 10.6%19 (E4).

The most frequently reported adverse effects associated with transurethral alprostadil are penile pain (32%), urethral bleeding or spotting (5%) and dizziness (3%).17 As syncope was reported in 0.4% of patients,17 the initial dose titration should be performed in the doctor's office. Discomfort after administration was commonly reported as mild and transient, but 7% of patients discontinued treatment because of adverse effects. Priapism and cavernosal fibrosis were found in less than 0.1% of patients using the transurethral preparation and less than 1% of those using the intracavernosal injection. Vaginal burning or itching was reported by 5.8% of partners. Unless a condom is used, transurethral alprostadil should not be used if the female partner is pregnant.


Selective phosphodiesterase inhibitors

Sildenafil

 Sildenafil citrate, a potent, competitive phosphodiesterase type 5 (PDE-5) isoenzyme inhibitor (see Box 4 for a profile of this drug), is the first oral medication to show significant and reliable efficacy in most patients with ED20 (E2). After the nitric oxide/cGMP pathway is activated by sexual arousal, inhibition of PDE-5 isoenzyme (see Box 1) by sildenafil results in increased cavernosal concentrations of cGMP and an augmented penile erection in men with ED.

In early studies, sildenafil was effective in restoring erectile function and improving intercourse success rates in a wide range of patients, including those with hypertension, diabetes, spinal cord injury, other concomitant medical conditions, and in patients taking a wide variety of concomitant medications. Its efficacy was related to the cause, extent and severity of ED, and was significantly reduced in patients with severe vasculogenic ED, ED associated with diabetes, and after radical prostatectomy ED20,21 (E2, E32). More recent studies report a response rate to sildenafil of 65%, significant improvement in quality of life and a 35% incidence of adverse effects22 (E33).

Failure to respond to sildenafil suggests severe vasculogenic ED resulting from advanced penile artery atherosclerosis or severe cavernosal venous leakage, or a combination of both. The action of sildenafil on the nitric oxide/cGMP pathway seems complementary to the action of other vasoactive agents, and combined therapy may be effective in patients who do not respond to a single therapy. A recent study reported that 34% of patients in whom maximum-dose ICI is ineffective responded to sildenafil, and a further 31% responded to a combination of the two, giving an overall "salvage" rate of 65%23 (E33).

Sildenafil produces an erection within 25-60 minutes and remains active even at four to five hours after being taken. Sildenafil should be administered with caution in patients with retinitis pigmentosa, as some patients with this inherited condition have genetic disorders of retinal phosphodiesterase and there is no published safety information. Sildenafil is extensively metabolised, predominantly by CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes, and is converted to an active metabolite (M1), with an in-vitro potency for PDE-5 of approximately 50% of the parent drug, which accounts for about 20% of sildenafil's pharmacologic effects. Both sildenafil and the metabolite have terminal half-lives of about four hours.

The adverse effects of sildenafil, reported in clinical trials, were transient, mild to moderate in nature, and dose-dependent. The most common adverse effects were headache (15.8%), flushing (10.5%), dyspepsia (6.5%) and nasal congestion (4.2%). Discontinuation of treatment was comparable for patients receiving sildenafil (2.6%) and placebo (2.3%). Priapism was not reported in these studies or in any of the clinical trials of sildenafil.

As there is a degree of cardiac risk associated with sexual activity, doctors must assess the cardiovascular status of their patients before initiating any treatment for ED, including sildenafil. Sildenafil has been shown to potentiate the hypotensive effects of nitrates and may be associated with large and sudden drops in systemic blood pressure. It is therefore contraindicated in patients who use prescribed nitric oxide-donating drugs or nitrates in any form for ischaemic heart disease, or recreational nitrites (eg, amyl nitrite), regardless of frequency. Caution should also be exercised in patients with asymptomatic coronary artery disease stabilised with medical treatment, coronary revascularisation, congestive heart failure combined with borderline low blood pressure, or a multidrug regimen for high blood pressure.24 These patients remain at a slightly increased risk of developing angina pectoris or acute myocardial infarction, which may necessitate treatment with short-acting nitrates, including intravenous sodium nitroprusside, by ambulance or hospital emergency staff.


Guidelines for the evaluation and treatment of erectile dysfunction

Treatment for ED depends on both its cause and severity, but other factors, such as efficacy, adverse effects, acceptability to patient and partner, psychological effects, reversibility and cost, are also important. A guide to managing ED is shown in Box 5. Although the primary cause of most ED is organic, there are invariably compounding psychological factors, such as "performance anxiety"; psychosexual counselling may be an important option for both the patient and his partner. Patients and their partners should be informed of all available treatment options. Doctors remain responsible for conducting a thorough medical history, physical examination and appropriate investigations to establish the extent, severity and causes of ED. In patients regarded as fit for renewed sexual activity, first-line treatment with an oral phosphodiesterase inhibitor such as sildenafil is appropriate if there are no contraindications. Patients in whom sildenafil is ineffective, who can not tolerate its adverse effects or who have contraindications are best treated with alprostadil, either as ICI or the transurethral preparation. Men who fail to respond to maximum-dose alprostadil can be managed with ICI containing alprostadil combined with other agents such as papaverine and phentolamine. Men in whom drug treatment is ineffective may elect to undergo implantation of an intrapenile prosthesis, but many choose to limit their sexual activity to non-penetrative sex.

Conclusion

As the population ages, quality-of-life expectations will increase. Many men now recognise that ED need not be a consequence of advancing age, nor a result of chronic illness or radical prostate cancer surgery. Most patients with ED can be successfully treated with medications. Several new oral treatments for ED are currently undergoing clinical evaluation and may increase the therapeutic options considerably. Information for patients is given in Box 6.

Disclosure: Chris G McMahon is a member of the speaker panels for Pharmacia Upjohn, Pfizer and Abbott/Vivus, the manufacturers of Caverject, Viagra and MUSE. He was also a member of the Caverject and MUSE medical advisory boards, a medical consultant to Pfizer, and a clinical investigator for Pharmacia Upjohn, Pfizer, Bayer, Eli Lilly, Icos Corporation, Abbott, Senetek PLC, Pentech and American Medical Systems.

References
  1. NIH Consensus Conference. Impotence, NIH Consensus Development Panel on Impotence. JAMA 1993; 270: 83-90.
  2. Pinnock CB, Stapleton AM, Marshall VR. Erectile dysfunction in the community: a prevalence study. Med J Aust 1999; 171: 353-357.
  3. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999; 281: 537-544.
  4. Linet OI, Ogrinc FG. Efficacy and safety of intra-cavernosal alprostadil in men with erectile dysfunction. The Alprostadil Study Group. N Engl J Med. 1996; 334: 873-877.
  5. National Health and Medical Research Council. A guide to the development, implementation and evaluation of clinical practice guidelines. Canberra: NHMRC, AusInfo, 1999.
  6. Poch G, Kukovetz WR. Papaverine-induced inhibition of phosphodiesterase activity in various mammalian tissues. Life Sci 1971; 10: 133-144.
  7. Hakenberg O, Wetterauer U, Koppermann U, Liffimann R. Systemic pharmacokinetics of papaverine and phentolamine: Comparison of intravenous and intracorporal application. Int J Impotence Res 1990; 2 (Suppl 2): 247-248.
  8. Porst H. The rationale for prostaglandin E1 in erectile failure: a survey of world-wide experience. J Urol 1996; 155: 802-815.
  9. De Rose AF, Oppezzi GF, Scotto S. [Local complications of papaverine-induced erection: follow-up at 7 years] [Article in Italian]. Arch Ital Urol Androl 1993; 65: 289-293.
  10. Brown LS, Christopher AH, Koehler M, et al. Hepatotoxicity related to intracorporal pharmacotherapy with papaverine. Urology 1998; 52: 844-847.
  11. Paoletti R. Biochemistry and pharmacology of prostaglandin E1: introductory remarks. In: Sinzinger H, Rogatti W, editors. Prostaglandin E1 in atherosclerosis. New York: Springer-Verlag, 1986: 3-7.
  12. Chen RN, Lakin MM, Montague DK, Ausmundson S. Penile scarring with intracorporal injection therapy using prostaglandin E1: a risk factor analysis. J Urol 1996; 155: 138-140.
  13. Chew KK, Stuckey BG, Earle CM, et al. Penile fibrosis in intracavernosal prostaglandin E1 injection therapy for erectile dysfunction. Int J Impotence Res 1997; 9: 225-229; discussion, 229-230.
  14. Moreland RB, Traish A, McMillin MA, et al. PGE1 suppresses the induction of collagen synthesis by transforming growth factor-beta 1 in human corpus cavernosum smooth muscle. J Urol 1995; 153: 826-834.
  15. Padma-Nathan H. The efficacy and synergy of polypharmacotherapy in primary and salvage therapy of vasculogenic erectile failure. Int J Impotence Res 1990; 2: 257-258.
  16. McMahon CG. Comparison of the response to the intracavernosal injection of a combination of papaverine and phentolamine, prostaglandin E1 alone and a combination of all three in the management of impotence. Int J Impotence Res 1991; 3: 133-142.
  17. Padma-Nathan H, Hellstrom WJ, Kaiser FE, et al. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med 1997; 336: 1-7.
  18. Fulgham PF, Cochran JS, Denman JL, et al. Disappointing initial results with transurethral alprostadil for erectile dysfunction in a urology practice setting. J Urol 1998; 160: 2041-2046.
  19. Porst H. Transurethral alprostadil with MUSE (medicated urethral system for erection) vs intracorporal alprostadil -- a comparative study in 103 patients with erectile dysfunction. Int J Impotence Res 1997; 9: 187-192.
  20. Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998; 338: 1397-1404.
  21. Dinsmore WW, Hodges M, Hargreaves C, et al. Sildenafil citrate (Viagra) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects. Urology 1999; 53: 800-805.
  22. Jarow JP, Burnett AL, Geringer AM. Clinical efficacy of sildenafil citrate based on etiology and response to prior treatment. J Urol 1999; 162: 722-725.
  23. McMahon CG, Samali R, Johnston HM. Treatment of Intracorporal Injection Non-Responders with Sildenafil Alone or in Combination with Polyagent Intracorporal Injections. J Urol 1999; 162: 1992-1997.
  24. Cheitlin MD, Hutter AM Jr, Brindis RG, et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol 1999; 33: 273-282.


Authors' details

North Shore Private Hospital, Sydney, NSW.
Chris G McMahon, MB BS, FACSHP, Sexual Health Physician.

Reprints will not be available from the author.
Correspondence: Dr C G McMahon, Suite 11, Level 3, North Shore Private Hospital, 1 Westbourne Street, St Leonards, NSW 2065.
cmcmahonATmail.usyd.edu.au

©MJA 2000
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1: Mechanism of erection
Figure 1
Non-adrenergic, non-cholinergic nerves and vascular endothelium release nitric oxide in response to sexual arousal, which activates cytoplasmic guanylate cyclase, converting GTP into cGMP. The increased levels of cGMP alter transmembrane calcium ion flux, resulting in cavernosal smooth muscle relaxation, dilatation of cavernosal and helicine arteries and engorgement of lacunar spaces. The expanding lacunar spaces compress the subtunical venous plexus against the tunica albuginea, decreasing cavernosal venous outflow, increasing intracavernosal pressure, with resulting penile rigidity. Cyclic nucleotides, such as cGMP, are hydrolysed by cyclic nucleotide phosphodiesterases.
GTP=guanosine triphosphate; GMP=guanosine monophosphate; cGMP=cyclic guanosine monophosphate.
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2: Management of prolonged erection (priapism)
  1. Always use alprostadil monotherapy as first-line ICI treatment.
  2. Use lowest possible effective dose.
  3. Inform patient of the risk of prolonged erection and the procedure to be followed if the penis is still rigid, as follows:
  • 2 hours after administration - 120mg pseudoephedrine
  • 4 hours after administration - repeat 120mg pseudoephedrine and walk briskly for 10-15 minutes
  • 6 hours after administration - regard as medical emergency and contact the treating doctor or a hospital emergency department immediately. Patients may require aspiration of corpora and irrigation with dilute vasoconstrictors or, in refractory priapism, surgical drainage.
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3: Level-of-evidence codes scale
Evidence for the statements made in this article is graded according to the NHMRC system5 for assessing the level of evidence.
E1 Level I: Evidence obtained from a systematic review of all relevant randomised controlled trials.
E2 Level II: Evidence obtained from at least one properly designed randomised controlled trial.
E31 Level III-1: Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method).
E32 Level III-2: Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case-control studies, or interrupted time series with a control group.
E33 Level III-3: Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group.
E4 Level IV: Evidence obtained from case-series, either post-test, or pre-test and post-test.
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4: Drugs: profiles of alprostadil and sildenafil Swirl image

Alprostadil

Action and onset
 Alprostadil (prostaglandin E1) induces an erection by relaxation of trabecular smooth muscle and dilatation of cavernosal arteries. Alprostadil may be administered by intra-cavernosal injection (Caverject, Pharmacia Upjohn) or by a transurethral suppository (MUSE, Abbott/Vivus Corp.). An erectile response occurs within 5-15 minutes of intracavernosal injection (ICI) and within 7-25 minutes of transurethral administration. Arousal is usually required to produce a maximal response. Detumescence usually commences within 10-20 minutes of ejaculation or cessation of sexual arousal, but complete flaccidity may not occur for a further 1-2 hours.

Dosage
Both Caverject and MUSE are administered 10-20 minutes before planned sexual activity. Dosage is individualised by initial supervised dosage titration, with the aim of establising the lowest possible effective dose (see below).
Caverject injection is available in three different concentrations in 1mL ampoules (5µg, 10µg and 20µg), with a kit containing a syringe, needle, alcohol swab and written instructions. Patients should be instructed in sterile injection technique, used needle disposal and the management of prolonged erections (< 2h; Box 2) by trained medical personnel. The maximum frequency of use is no more than three times a week, with at least 24 hours between doses.

  • For ED of vasculogenic, psychogenic or mixed aetiology, start with 5µg and titrate in 5µg increments to a maximum of 40µg until an erectile response sufficient for sexual intercourse occurs or there are intolerable adverse effects.
  • For ED of wholly neurogenic aetiology (spinal cord injury), start with 1.25µg and titrate in 1.25µg increments until an erectile response sufficient for sexual intercourse occurs or there are intolerable adverse effects.

Transurethral alprostadil (MUSE) is available in dosages of 125µg, 250µg, 500µg, and 1000µg. It is administered after urination, the patient remaining standing for approximately 10 minutes. The two lower dosages are recommended for initial dosing, with stepwise dose titration to a maximum of 1000µg, until either an erectile response sufficient for sexual intercourse or intolerable adverse effects occur. Because of the potential for symptomatic hypotension and syncope, the initial dose titration should be conducted under medical supervision. The maximum frequency of use is no more than two doses per 24-hour period.

Adverse effects
Alprostadil ICI: Mild penile pain (15%-20%), priapism (0.25%) and cavernosal fibrosis with long term use (5%-10%). Cavernosal fibrosis may result in the formation of nodules, penile curvature or deformity, or impaired erectile function. Adverse effects of intraurethral alprostadil include penile pain (25%-35%), urethral bleeding or spotting (5%), priapism (0.1%) and symptomatic hypotension (3%) and syncope (0.4%).

Drug interactions
Unlikely because only low or undetectable amounts of alprostadil (< 2pg/mL) are found in the peripheral venous circulation.

Slidenafil

Action and onset
Sildenafil citrate is a potent, competitive phosphodiesterase type 5 (PDE-5) isoenzyme inhibitor. When sexual arousal activates the nitric oxide/cGMP pathway via non-adrenergic, non-cholinergic nerves, inhibition of PDE-5 results in increased cavernosal levels of cGMP, relaxation of penile vascular and trabecular smooth muscle, increased cavernosal blood flow and augmented penile tumescence or erection. An erectile response to sexual arousal may occur 0.5-5 hours after dosing. Ingestion on an empty stomach may result in a response after 30 minutes, whereas ingestion after a high-fat meal may delay onset for up to 3 hours. Detumescence occurs immediately after ejaculation or cessation of sexual arousal. The erectile refractory period is often reduced, allowing subsequent arousal to produce a second erection in some men.

Dosage
Sildenafil is available in 25mg, 50mg and 100mg tablets. The recommended starting dose is 50mg, taken one hour before planned sexual activity, with subsequent dose titration (to a maximum of 100mg) until the desired erectile response is achieved. Use is limited to once-daily administration. Patients aged over 65 years, those with significant renal impairment (creatinine clearance rate, < 30mL/min) or hepatic impairment, or those taking potent cytochrome P450 3A4 inhibitors, should start with a dose of 25mg.

Adverse effects
Adverse effects are dose-related and are usually of mild to moderate severity. The most common are headache, facial and upper-trunk flushing, dyspepsia and nasal congestion. Transient alteration in colour vision may occur at a dose of 100mg. No cases of priapism were reported in initial studies.

Drug interactions
The concomitant use of potent cytochrome P450 3A4 inhibitors (eg, erythromycin, ketoconazole, itraconazole, protease inhibitors), as well as the nonspecific CYP inhibitor cimetidine, is associated with increased plasma levels of sildenafil. Concomitant administration of CYP3A4 inducers, such as rifampicin, will decrease plasma levels of sildenafil. Sildenafil potentiates the hypotensive effects of nitrates and should not be taken by patients who use nitric oxide donors or nitrates in any form.

Patients' fitness for renewed sexual activity should be assessed before initiating treatment
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5: Evaluation and treatment of erectile dysfuntion
Box 5
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6: Important messages for patients Info image
  • Erectile dysfunction is common and is usually due to physical disease.
  • The speed and extent of the male and female sexual response reduces as men and women age - patient treatment expectations should be appropriate for age.
  • Erectile dysfunction is associated with cigarette smoking, hypertension, peripheral vascular disease, diabetes mellitus and depression, and can be an indicator of other underlying, unrecognised physical disease.
  • There is always a contributing psychological component, and psychosexual therapy may result in restoration of potency, even when there is a contributing physical cause - not all men require treatment with medication.
  • Some men can be successfully treated with a combination of sexual education, changes in lifestyle and medication.
  • Many couples have fulfilling sexual relationships without penetrative sexual intercourse - not all men need to have potency restored.
  • Men with long term erectile dysfunction and chronic medical illness (eg, coronary artery disease, chronic obstructive pulmonary disease), must have their fitness for renewed sexual activity assessed before initiation of treatment.
  • Men with angina who take prescribed nitrates should not take sildenafil.
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