Figure 7.1 Structure of sildenafil and other molecular structures.
o to be a safe agent in most groups of patients (29). Sildenafil is an oral medication, licensed for clinical use in three doses: 25, 50, and 100 mg. It should be taken ~ 1 h before sexual activity, after which time plasma levels should be at a peak. Further time may be required if taken with a high-fat meal as this increases transit time in the gut, but no dose adjustment is necessary (24). After starting on 50 mg per day, the dose can be titrated up or down, depending on tolerance and efficacy, and should not normally exceed 100 mg, as adverse events are more likely to occur at higher doses with no proven increase in efficacy (30).
Sildenafil is cleared chiefly by the cytochrome P450 enzyme CYP3A4 with minor involvement by CYP2C9 (30). Reduced function of these enzymes results in higher plasma levels and so for certain groups of patients, a lower dose is recommended. Reduced clearance occurs in elderly patients over the age of 65: patients with severe renal impairment (creatinine clearance <30mL/min) and hepatic impairment (e.g., due to cirrhosis). For patients in these groups, sildenafil should not be prescribed >25 mg. Some pharmacological agents inhibit CYP3A4, and for this reason the lowest dose of sildenafil should also be prescribed for patients taking ketoconazole and itraconazole (antifungal agents), saquinavir, erythromycin, cimetidine, and diltiazem. Coadministration of ritonavir and sildenafil is not recommended as ritonavir inhibits both CYP3A4 and CYP2C9, causing a drastic increase in the plasma concentration of sildenafil (24). Grapefruit juice is a weak inhibitor of CYP3A4 in the gut wall, and may result in modest increases in plasma concentration (30). Concomitant use with alpha adrenoceptor antagonists should also be avoided (discussed subsequently).
Sildenafil is mostly well tolerated (22). In the more recent clinical trials, only ^2-3% of men discontinued treatment due to adverse effects, which is a similar proportion to those taking placebo (31). Most men who discontinue treatment do so because of partner reluctance, perceived ineffectiveness of the drug, or lack of motivation. Up to one-third of men experience one or more adverse effects, but where effects do occur, they are mostly mild and transient (minutes to hours) (29,31). The frequencies of adverse effects vary from study to study and become more frequent where higher doses are used. Most common adverse effects are headaches (7-39%), facial flushing (7-35%), dyspepsia (7%), and rhinitis (4%) (22,29,32). These effects appear to be the result of a mild transient decrease in blood pressure because of the effect on peripheral vessel vasodilatation (31). Visual disturbances have also been reported by a small proportion of men, but these disturbances tend to be very transient, as a high plasma concentration is needed to affect PDE6 in the retina. Hypotension, orthostatic hypotension, and syncope have also been reported, but incidences were <2% and comparable to placebo (33). Very rarely, priapism (an erection lasting for >6 h) may occur and sildenafil should be used with caution in individuals who are predisposed to priapism (individuals with sickle cell anaemia, leukaemia, or multiple myeloma).
Sildenafil is effective for a large proportion of patients with psychogenic or organic causes for their ED. The highest proportion of positive responders is amongst men with a psychogenic etiology (84%) (34). Those with an organic etiology respond in 68% of cases, those with diabetes in 59%, and those with post-prostatectomy in 43%.
Prostate cancer: Whether prostate cancer is treated with the various surgical techniques available, radiotherapy or brachytherapy, up to 60% of all patients acquire ED within 18 months of treatment (35,36). Men with ED who have undergone a radical prostatectomy have an almost 100% occurrence of ED if the procedure was non-nerve-sparing. This is reduced to 40-70% if one or both nerve bundles are spared. Evidence from patients undergoing radical prostatectomy for cancer suggests that the neurovascular bundle must be intact on at least one side for sildenafil to have its effect (37,38). Nevertheless, Nehra and Goldstein (39) suggest that for post-prostatectomy patients, sildenafil should be the first line treatment regardless of the state of the neurovascular bundle. This is because there is evidence that with time, some function can return. If both nerve bundles are spared, then up to 80% of men respond to treatment, this figure is reduced to 15% if there is no sparing of the nerves during surgery. For the group of patients who receive radiotherapy as treatment for prostate cancer, studies show that the outcome of sildenafil use is dependent on the level of erectile function before treatment with sildenafil (40). Such patients should be started on a 50 mg dose and titrated up to 100 mg if required (36). Up to three-quarters of the radiotherapy group treated with sildenafil reported improvement.
Nightly dosing of sildenafil appears to increase the return of spontaneous nocturnal erections after nerve-sparing retropubic radical prostatectomy (NSRRP) (41).
Depressive disorder: Depression can be a complex problem to sort out but worth doing, since moderate to complete ED is 1.82 times more likely to occur in depressed men (8), and there is an increased incidence of depressive symptoms in men with ED (42). When associated with ED, it is important for the clinician to determine whether it is the causative factor of ED, a product of ED, or whether the two simply coexist. Treatment may then depend on what is considered to be the underlying causative factor. As an example, a man with limb loss may become depressed. He may then be treated with an antidepressant that results in a degree of ED [most classes of antidepressant cause some degree of ED (43), with the exception of bupropion and nefazodone (44)]. This further loss of sexual function then exacerbates the depression. This example illustrates one of the relationship models between depression and ED (i.e., ED due to antidepressant use). Note that many other medications are also responsible for ED, which affects treatment adherence. Other possibilities include depression secondary to ED or conversely ED as a symptom of depression. Depression resulting from another comorbidity which then manifests as ED is another possibility (45). It is therefore important to investigate for common risk factors such as diabetes (discussed subsequently). Assessment of nocturnal erections either by questioning or by investigation can occasionally lead to more discriminating questions about psychiatric state, since major depression can result in loss of nocturnal erections (46), which demonstrates an organic cause. One of the uses of sildenafil in cases of depression is to counteract the effect of antidepressants (47,48).
Diabetes mellitus: Diabetes is possibly the greatest risk factor for having ED (6). In a small-scale study using Rigiscan as an objective measure, it was found that sildenafil increases the period of penile rigidity in a dose dependent manner (25). In a much larger, double-blind, flexible dose-escalation study done over a 12 week period, diabetic men with ED were given sildenafil (49). Using the IIEF as a measure, 56% of diabetic men receiving sildenafil reported an improvement in their erections compared with only 10% in the placebo group. This figure was even higher when a diabetes type II group was studied independently (50). It was found that patients with fewer diabetic complications were more likely to benefit, probably because there is less neural and vascular damage. Many in the diabetes subgroup require the higher doses of sildenafil, and unsurprisingly, the proportion experiencing adverse effects tends to be greater than that seen in the general population (51). There appears to be little difference in the efficacy of sildenafil between type I and type II diabetes.
Hypertension: ED is commonly seen in patients with hypertension (6). In a retrospective analysis, Kloner et al. (52) examined the effect of antihypertensive medication on the efficacy of sildenafil. They found that sildenafil is effective in patients taking antihypertensives and is comparable to results seen in the general population of men taking sildenafil. There were no significant drug interactions between sildenafil and antihypertensive medications noted in the clinical trials that included men taking diuretics, beta-blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, or nothing. There have been rare reports of spontaneous hypotensive events after the use of sildenafil in combination with alpha-blockers (30). However, generally it was found that regardless of whether the patient was taking a single antihypertensive drug, a combination of up to three different ones or none at all, about one-third experienced some adverse effects, mostly flushing and dizziness. Webb et al. (53) found that silde-nafil can produce additive (but not synergistic) reductions in blood pressure when using amlodipine. Sildenafil does cause mild and transient decreases in blood pressure. The mean maximum fall in blood pressure observed with a 100 mg dose of sildenafil is a systolic decrease of 8.4 mmHg and a diastolic decrease of 5.5 mmHg (30). For this reason, it is inadvisable to give sildenafil to men with a blood pressure <90/50 mmHg.
Cardiovascular disease: In patients with cardiovascular disease, it is important to determine whether any treatment for ED would be contraindicated (e.g., where sexual activity is inadvisable). Men with cardiovascular disease tend to have an increased number of risk factors such as smoking and diabetes. These men are also quite prone to depression, which compounds the problem (45). Nevertheless, those who have a low risk cardiovascular status that is stable and well controlled can be treated within the primary care setting (17). Those in the high risk category should be referred for specialist cardiac evaluation before treating ED. Specific contraindications in this group include hypotension, men with a recent history of stroke or myocardial infarction (within 6 months), and patients receiving nitric oxide donors (e.g., nicorandil and nebivolol) or organic nitrate therapy in any form including sprays and sublingual tablets. This is because organic nitrates increase available NO and PDE5 inhibitors increase the response to NO. A synergistic response occurs causing blood pressure to fall rapidly. If a nitrate is to be given after sildenafil administration, then a washout period of 25 h is a minimum requirement (i.e., five times the half-life of sildenafil). This period must be increased in patients who demonstrate decreased clearance of sildenafil as mentioned earlier.
Coronary heart disease: In a subanalysis of patients with coronary heart disease and ED, there was a 70% improvement in patient's erections (placebo 20%) (54). Much attention has been given by the media that sildenafil may increase the likelihood of a serious cardiovascular event such as a myocardial infarction or an ischaemic attack. This notion is not supported by evidence which concludes that the prevalence of such events in the treated and control group is similar (55,56). Recommendations from an independent expert panel agree that there is no evidence that there is any increase in risk to patients with or without diagnosed cardiovascular disease when using sildenafil (17).
Coronary artery disease: In patients with coronary artery disease, investigators found that there was no direct adverse effect on cardiovascular status in men with severe coronary artery disease. In addition, a small positive effect on coronary blood flow was seen (57). In a more recent study, the investigators concluded that sildenafil had no effect on rate of recovery from exercise, nor does it potentiate myocardial ischemia in patients with stable angina (who are not taking nitrates) (58). Data suggests that sildenafil is well tolerated and effective in heart transplantation patients who are fit for sexual activity (33,59).
Use in patients with a history of transient ischemic attacks (TIAs) has not been studied. Because some patients experience TIAs following a drop in blood pressure, sildenafil should be used with caution in these patients and should not be used in patients with a recent cerebral vascular accident.
Wagner and Mulhall (60) found that age does not seem to greatly influence therapeutic response to sildenafil. While ED is strongly associated with increasing age, it is not a direct consequence of it. In their study, Wagner and Mulhall found that 69% of elderly men with various comorbidities responded favorably to treatment. This compares well with the 74% of positive responders in the general population of men. The main point about elderly men is that there is often concurrent conditions that reduce response. Nevertheless, even in the most affected group (elderly men with diabetes), half of all those treated had some response. It should be remembered that elderly men have a reduced clearance to sildenafil, which results in increased efficacy and incidence of adverse events. With this in mind, the producers recommend that for men over the age of 65, a starting dose of 25 mg should be considered and only increased if the patient reports efficacy and tolerance (30).
Other conditions: Other conditions have been studied where sildenafil treatment has been used (29). In men with spina bifida, there is an 80% reported improvement in erections as well as a significant increase in sexual confidence. Men with SCI have shown improvement in their erections of between 75 and 94%, with up to 72% of SCI patients reporting successful attempts at intercourse (61). This shows that there is a high efficacy of sildenafil in SCI patients who have preserved reflexogenic erections. Men with multiple sclerosis show an 89% improvement after 12 weeks of treatment with sidenafil. In those patients who receive dialysis, 80% reported a 10-point increase in IIEF scores. One group in which caution should be exercised is men with Parkinson's disease. This is because those who have autonomic failure may suffer postural hypotension.
In men who were previously treated with intracavernous injections, 75% responded to sildenafil treatment, and of these, 64% were happy to continue oral therapy (29). Unfortunately, some remain resistant to first line oral therapy, and require second line intracavernous/intraurethral therapies.
It has been noted that sildenafil is available both on the internet and on the black market as a recreational drug. After more than 5 years on the market, it is now known that long term use is safe and that sildenafil remains effective over a period of years (32,62). Some men require an increased dose after some time of using the drug, but this is regarded as a consequence of underlying morbidity rather than a tachyphylaxis (62). As we have seen, use of other medications with sildenafil is safe in most cases. We have seen no studies done in men who use recreational drugs. Sildenafil treatment is not cheap; in the UK and most other countries, many men have to pay for their treatment because of government intervention. The economic validity of these restrictions is questionable when the impact of the psychological factors on individuals, their families, and their work are considered.
Sildenafil is not suitable for all patients. For those in whom it is not effective, they should move to another oral agent or to second and third line therapies or consider other salvage techniques (63).
Tadalafil (Cialis). The structure of tadalafil is shown in the Fig. 7.1 (64). This newer PDE5 inhibitor was introduced in the UK in 2003. The initial clinical trials have tested doses ranging from 2.5 to 25 mg (65,66). Investigators used IIEF scores, the Sex Encounter Profile (SEP), and Global Assessment Question (GAQ) to measure outcomes. The outcomes reported by men with various etiologies for their ED have indicated that the 10 and 20 mg doses are most effective, and these doses are now marketed. Tadalafil is rapidly absorbed and demonstrates a maximum response within 2 h. It has a half-life of 17.5 h. Brock et al. (65,66) team found that the longer half-life of the drug allowed 73% of their trial subjects to remain able to attempt intercourse over a period of 36 h when taking the 20 mg dose. The implication of this finding is that careful planning of the initiation of sexual activity is not necessary, and this is preferable to some patients.
As with the other PDE5 inhibitors, the liver p450 enzyme CYP3A4 metabolizes tadalafil, which neither inhibits nor induces the enzyme. Nevertheless, patients with diminished liver function should only be treated with caution. Another perceived advantage is that there is no pharmacodynamic interaction with alcohol, and so patients taking this oral therapy are not required to avoid alcohol (67). Food does not affect the rate and extent of absorption either.
Tadalafil appears to be well tolerated and has acceptable adverse effects as perceived by patients since in a series of five randomized, double-blind placebo-controlled trials (65) 89% of men completed the trial. The group receiving the maximum dose of 20 mg had the largest drop-out rate because of the associated increase in adverse effects. Nevertheless, where adverse effects do occur they are mild and transient and decrease in severity with continued treatment. The rarest effect was visual disturbance, with only one individual affected throughout the trials. The most common adverse effects were headache (14%) and dyspepsia (10%). Other less reported effects include back pain, nasal congestion, myalgia, and flushing. These last four effects were comparable to those reported by men taking placebo.
Further safety and efficacy trials have been conducted on volunteers with diabetes and cardiovascular disorders in whom ED can be a marker for cardiovascular disease.
Diabetes: In the diabetes group (68), 10 and 20 mg doses were tested on men with type I or type II diabetes mellitus with and without microvascular complications. Eight eight-percent of subjects completed the trial, 3% had recognized adverse events (although some were taking placebo), and 2% discontinued due to perceived lack of efficacy. Most success was reported in the 20 mg group, with two-thirds of men reporting significantly enhanced erections. The group receiving 10 mg had results that were comparable to men taking sildenafil at various doses.
Hypertension: Emmick et al. (69) worked with two groups of men who had stable angina and hypertension. Tadalafil had no clinically relevant effects on blood pressure in healthy subjects, but did have a mild vasodilator effect. When tested on patients with stable angina taking short-acting nitrates, there was a repeatable rapid decrease in the blood pressure of some men. With long-acting nitrates, the decrease was minimal and tolerance developed in some individuals by day 2. However, in a small subset of those tested, there was an appreciably large drop in blood pressure, and for this reason, men taking short- or long-acting nitrates should not be prescribed tadalafil. The group who had hypertension were monitored while they took tadalafil in combination with their antihypertensive medications. The study showed that there was no significant difference in blood pressure regardless of the number and classes of agents, although some men experienced flushing. This effect was also seen in men not taking concomitant therapy for hypertension. For all groups with stable angina or hypertension, there was no significant increase in cardiovascular adverse events. The number of events that did occur did not deviate from that expected after adjusting for differences in the population under investigation. More work involving larger numbers needs to be done with men taking anti-hypertensives. Studies should also be done to investigate the effect of tadalafil on men with other cardiovascular conditions. There is a great deal of safety and efficacy work yet to be done using tadalafil in patients with various conditions similar to what is outlined earlier about sildenafil.
Other areas of research outstanding for tadalafil include efficacy in men with depression, prostate cancer, ischemic heart disease, the elderly, those with SCI, and those who have undergone prostatectomy.
Vardenafil (Levitra). The structure of vardenafil is shown in Fig. 7.1. This is another recently introduced PDE5 inhibitor. Various doses have been trialed and 5, 10, and 20 mg tablets are now available for prescription. Trials on vardenafil have also used the IIEF (EF Domain)2, SEP3, SEP, and GAQ questions to assess efficacy.
The pharmacokinetics of vardenafil are similar in many ways to those of sildenafil. Vardenafil is rapidly absorbed and reaches its peak plasma concentration around 1 h and 40 min after administration. Absorption is not compromised by a regular meal or by a moderate amount of alcohol, but this may be delayed when taken with a high-fat meal (> 57% fat). Like the other PDE5 inhibitors, vardenafil is predominantly metabolized by the CYP34A isoform of cytochrome P450 with some contribution from CYP3A5 and CYP2C. The concomitant use of the potent CYP34A inhibitors ritonavir, indinavir, ketocona-zole, and itraconazole (oral form) is contraindicated in men over the age of 75. When used with erythromycin, the dose should not exceed 5 mg. Use with alpha-receptor antagonists is not recommended as this may lead to a hypotensive episode. The half-life of vardenafil is ~ 5 h, slightly longer than that of sildenafil.
In clinical trials, tolerability has been demonstrated with adverse reactions similar to those seen with the other PDE5 inhibitors (70,71). Most common were headache (3-22%), flushing (0-10%), and nasal congestion (3-14%). Other effects with much less common occurrence include nausea, dyspepsia, dizziness, hypertension, photosensitivity reaction, visual disturbance, hypertonia, hypotension, syncope, and erectile disturbance (72). Adverse effects have a tendency to diminish with regular use of PDE5 inhibitors over a period of weeks. In the vardenafil trials, it was noted that for nasal congestion, the trend is fairly constant for doses >5 mg.
Although there is no significant effect on exercise induced ischemia in patients with coronary heart disease with vardenafil, it should not be given to those for whom sexual activity is not advised. Vardenafil does not significantly affect blood pressure and is safe to use for men taking one or more of the anti-hypertensive medications (73).
There is still a lot of research that must be done to test the safety and efficacy of vardenafil in certain groups of patients. Patients with severe renal or hepatic impairment, hypotension (with a blood pressure <90/50 mmHg), a recent history of stroke or myocardial infarction, unstable angina, and retinal disease have been excluded from trials done to date. Until these investigations are done, these conditions must be considered as contraindications.
Two "difficult to treat" groups of patients for whom vardenafil may be of benefit are those with diabetes and those who have undergone radical prostatectomy.
Post-radical prostatectomy: In a study by Brock et al. (65) it was found that post-radical prostatectomy patients were likely to suffer from ED in the "severe" category. Improved erections were reported in 71% of patients who had undergone a bilateral nerve-sparing procedure. Vardenafil treatment was able to move the majority into the moderate range for erectile function, and was also noted to have a positive effect on depressive symptoms in this group.
Diabetes mellitus: In another study conducted by Goldstein et al. (74) men who had diabetes and ED showed a significant improvement of their erections. Erectile function scores demonstrated that some of those treated moved from having moderate ED to mild ED and the change was appreciable by up to 72%. Two-thirds of diabetic men were able to penetrate their partner, and over half maintained the erection long enough to have successful intercourse. These results are comparable to those for sildenafil (75).
There is much more in depth research to be done on specific groups of men using vardenafil. Men with hypertension, depression, prostate cancer, ischemic heart disease, and SCI have yet to be studied, as have the elderly male population (though studies to date have included subgroups of patients aged >65).
Apomorphine: Apomorphine is a drug used routinely in the treatment of patients with Parkinson's disease. Empirical evidence from a few Parkinson's patients treated with apomorphine has suggested that they experience increased sexual activity (76). Male patients with alcohol dependence treated with the same agent have also reported improved erectile function (77). Data from these two groups of patients suggest that apomorphine is able to induce erections.
While apomorphine is a derivative of morphine, it has greater structural and pharmacological similarities with dopamine, and acts as a dopamine agonist (78-80) (even in urine screening for opioids, apomorphine will rarely give a false positive). Dopamine and apomorphine act centrally on dopamine receptors (especially D1 and D2), and studies using rodents have demonstrated a role for dopamine in the control of sexual function in both sexes (76). This means that this drug works via a very different mechanism than most other pharmacological agents used in the treatment of ED. As we have already seen, many other agents act locally on smooth muscle to increase blood flow to the penis. While the exact mechanism of action of apomorphine is not fully understood, it appears to work on several areas of the brain to boost the neuronal signal involved in the erectile response (76). Recent large-scale trials have confirmed the connection between dopamine and sexual function in men because apomorphine is able to induce penile erections when they are sexually stimulated (81).
Apomorphine can be used to treat men with physical or psychological etiologies. It is important to note that like other oral treatments in use for ED, this drug requires the man to become sexually stimulated before an erection can be achieved. In this setting, apomorphine is self-administered sublingually (apo SL) as a 2 or 3 mg single dose, usually starting at 2 mg and only increasing to 3 mg if necessary (79,80). Good patient education is important to achieve optimum results. The tablet is placed under the tongue after a sip of water and allowed to dissolve slowly for up to 10 min without swallowing it. Best results are often not achieved until use of apo SL on the sixth occasion (82). By this point, over 90% (80) of correctly diagnosed users will achieve an erection and the majority of these will be within 20 min, making this a fast acting drug. This response is repeatable, so that by the sixth month of use there are still >90% of men able to achieve erections firm enough for intercourse [assessed using data from diary records from a double-blind placebo-controlled trial (81)].
Apo SL is rapidly absorbed and eliminated, and reaches a peak plasma concentration within 40-60 min, having a half-life of ^2-3 h (79). This means that apo SL can be taken every 8 h if required. Data suggests that no dose adjustment is required in elderly patients although this group is more prone to hypotensive episodes. There are few contraindications for use. Impaired hepatic function and renal insufficiency are not necessarily contraindicated but the dose should be limited to 2 mg. More work needs to be done in these areas, and until such time a careful assessment should be made to balance benefit against risk, especially in patients with hepatic insufficiency. There is also further work to be done to assess efficacy in patients with SCI and multiple sclerosis. The effect on patients who have had prostatectomy or pelvic surgery is also not known. Caution should be taken when treating patients with uncontrolled hypertension and patients with hypotension. Antihypertensives and nitrates (especially short-acting nitrates) do have the potential to cause an acute episode of hypotension. Caution also needs to be taken in patients who have penile deformity or other conditions that may predispose them to priapism. There are few absolute contraindications for use, but include combinations with other dopamine agonists or antagonists and patients with severe unstable heart conditions or other conditions where any sexual activity creates unacceptable risk. Excess alcohol should be avoided due to the increased risk of hypotension.
Because of the low doses involved in the therapeutic use of apo SL in the treatment of ED, there are few side effects (80). The most commonly seen are nausea (6.8%), headache (6.7%), and dizziness (4.4%). Nausea tends to diminish with subsequent dosing, so that by the eighth dose this is usually no longer a problem. Where nausea and emesis is a concern, it is safe to prescribe ondanse-tron hydrochloride, prochlorperazine maleate, or domperidone prophylactically (79). No other antiemetics have been tested for safety. Rhinitis and pharyngitis have been reported in a very small proportion on men, and in a very few cases (0.2%) syncope can occur.
There is more work to be done concerning the use of apo SL. But data published to date do indicate a good response (82,83). Responses from questionnaires such as the IIEF indicate that many patients and their partners report erectile function sufficient for penetration. The rapid onset of apo SL allows for a fair degree of spontaneity, and the response is predictable once satisfactory success has been achieved. This agent is available in the UK and Europe.
Yohimbine: Yohimbine (84) is an alpha2-selective antagonist currently unlicensed for use for men with ED. It is a naturally occurring alkaloid produced from the African yohimbe tree. It has been implicated as an aphrodisiac (85) but has not been properly considered as a therapeutic agent until recently. The proposed mechanism of action of yohimbine is to block presynaptic alpha2 receptors while sparing the postsynaptic alpha1 receptors. The effect of this is to enhance the release of norepinephrine in the central nervous system. It reaches a plasma concentration in just 10-15 min and has a very short half-life of just over 30 min. Previous research has shown that oral yohimbine can be used successfully to treat ED with a psychological basis. It has also been used to reverse antidepressant-induced sexual dysfunction.
Guay and Spark (84) suggest that previous studies using yohimbine have not been successful because their subjects included a large proportion of men who were smokers. They hypothesized that smoking reduces the effectiveness of yohimbine and so their study excluded this subgroup. In their small-scale study of 18 men aged between 34 and 69 years, they reported that use of low doses of yohimbine (5.4 or 10.8 mg) at home had resulted in nine of the men achieving successful penetration on 75% of occasions tried. They reported few side effects with the low doses used (mild anxiety in one subject and hot flashes in another). Also noted was a slight increase in serum cortisol. From their evidence, they suggested that yohimbine could be useful for a subset of men with mild disease or few risk factors, and recommended that yohimbine should be studied further. Random controlled trails would be useful to determine the safety and efficacy of this established pharmaceutical agent.
Second Line (Injectable and Intraurethral) Treatments
Injectable and intraurethral treatments for ED are now considered to be second line treatments after oral therapies have been tried or rejected. Also, these treatments are primarily for men with an organic cause for their ED. Patients need to be made aware of the potential for priapism. The initial doses of these agents are given under supervision as there is also a risk of a hypotensive episode needing medical attention. Patients must be taught how to inject safely and using a proper technique so as to avoid the problems of fibrosis which indicates that treatment must be discontinued.
Only alprostadil (prostaglandin E1) is licensed for use as an intracavernosal injection (ICI) in the UK and US. This drug utilizes cyclic adenosine monophosphate (cAMP) rather than cGMP (see Fig. 7.1). Prostaglandin E1 (PGE1) receptors are G-protein coupled receptors located at the surface of the smooth muscle cell. When stimulated, they activate adenylyl cyclase via the G-protein. This increases the concentration of intracellular cAMP, which acts as a second messenger in a cascade that ends with a decrease in intracellular calcium concentration and muscle relaxation. No sexual stimulation is required to elicit an erection using the ICI route of delivery. ICI alprostadil is marketed as 5, 10, 20, and 40 mg injections that have been proven to be effective and safe doses to give in the majority of cases (86). At the time of Linet and Ogrinc's studies, little else was available in the way of pharmacotherapies for ED. In the dose-response study of 296 men with various etiologies, they found that the erections would last longer the higher the dose injected. This pattern was repeated in their other placebo-controlled experiments with increasing numbers of subjects to determine optimum dose and to confirm efficacy and safety. In the largest of the trials with 683 men, 69% completed the 6 month study. There are adverse affects associated with ICI alprostadil use. The treatment was discontinued by 6% of men due to the main side effect, which is penile pain. This effect was actually experienced by half of the men participating, but not on all occasions. Most often, the men reported the pain as being mild. Five percent of the subjects experienced prolonged erections although most men continued the treatment. In the three studies, six individuals experienced priapism (an erection lasting >6h). In the large study, 87% of men reported satisfactory sexual activity, and this was reflected in the partner's questionnaire. Other rare adverse effects occurred in 1% of the men and were thought to be related to hypotension. These included irregular pulse, lightheadedness, dizziness, diaphoresis, vasodila-tion, and vasovagal reaction. It is for this reason that the initial prescribed dose must be delivered in the clinical setting under medical supervision.
Alprostadil can also be delivered intraurethrally as MUSE (medicated urethral system for erection). This mode of delivery is recommended for a small subset of individuals who may have problems with injecting. PGE1 is delivered into the urethra immediately after urination (for lubrication and to help disperse the drug) using an applicator which the patient can be taught to use safely. Here, the drug is used at a much higher concentration at 125, 250, 500, or 1000 mg doses. Researchers have reported very different efficacies using MUSE in this way (87-89). Only Padma-Nathan et al., used a random controlled trial, and their subject recruitment was far greater than the other two groups (1511 vs. 100 and 103). Werthman and Rajfer (87) only reported making observations up to 10 min after administration of the drug whereas Padma-Nathan et al. (89) made observations up to 60 min after drug delivery. Also, Werthman and Rajfer's studies were conducted entirely in the clinical setting, which can inhibit the erections elicited by MUSE which often require sexual stimulation. Padma-Nathan et al., found that 65.9% of subjects had maximal penile responses (assessed on scale of 1 -5) in the clinical setting. They increased the dose delivered to each individual up to a maximum of 1000 mg. The number of men achieving the maximum penile response rose linearly with increasing dose. Of this group, 35.7% of men experienced penile pain which was usually mild; 2.4% withdrew from the study because of the pain. Hypotension occured in 3.3% of the men, and syncope in 0.4% (for this reason, the initial prescribed dose must be delivered in the clinical setting under medical supervision). The study continued by giving further subjects MUSE to use in their own home. A 3 month trial of MUSE, was completed by 87.7% of these men with <2% discontinuing because of adverse effects. The success rate for intercourse for the home trial group was 64.9%, slightly lower than that indicated in the clinical setting. These men reported penile pain as the main adverse effect. The problems associated with ICI alprostadil, such as fibrosis, hematomas, and priapism, were not seen. Slight bleeding from the penis can occur, and this is probably due to minor trauma when inserting the MUSE applicator incorrectly (87).
Papaverine and phentolamine are not currently licensed in the UK for the treatment of ED, although they have been used for many years. Papaverine is closely related to morphine and originates from the opium poppy. However, its little understood pharmacology is very different from that of morphine. It is believed to inhibit phosphodiesterase in a similar fashion to sildenafil. The starting dose is dependent on local formulation but is usually ^20 mg in the alpros-tadil nonresponder, rising in increments to 50 mg. Phentolamine is a nonselective alpha adrenoceptor antagonist with a plasma half-life of 2 h and acts to relax smooth muscles (90). The starting dose is 0.5 mg which can be repeated after
20 min if there is no response. Typically, it may be necessary to combine two or more of the agents in the nonresponding patient (hence the tri-mix preparation). Injection into the cavernosal tissue is self administered after a clinic based trial of the drugs (often in combination with each other) under medical supervision. As with ICI alprostadil, complications can arise from repeated injections into the same site. These include nodule formation and indurations of the tunica albuginea resulting in a Peyronie's-like distortion of the penis. These affects should be checked for on follow-up visits. The nodules are painless and become more likely to occur as treatment continues over time (91). These complications alongside dislike of the technique by the man and his partner as well as "needle phobia" (increasing adrenergic outflow), all lead to a limited use of these effective agents.
Moxisylyte is an injectable alpha-blocking agent and is useful where there is considerable psychological etiology requiring evidence of an erection. Effective salvage therapy for intracavernosal injection nonresponse includes augmentation with sildenafil (92) or other combination therapies.
Third Line Therapies
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