HISTORY AND CLINICAL EXAMINATION The History

19 May

A complete and accurate history of ED is essential for a reliable diagnosis. Com- munication about this issue can be loaded with cultural, religious, secular, and personal connotations and therefore the problem of ED must be approached with the right attitude. The clinician should at least appear to be open, sensitive, respectful, confident, and nonjudgemental. Questions should be unambiguous. Language must  be  clear  and  uninhibited  by  complex  medical  terminology. Never make an assumption about what the patient is trying to say. Use open ques- tions to elicit the bulk of the information, and clarify issues by asking closed questions and by reflecting ideas back to ensure that you have understood what the patient means. It is also important to understand the patient’s perspective and expectations. The media in particular can distort someone’s point of view and myths and misunderstandings may need to be undone (only if you are sure yourself!). Keep in mind the pathophysiology of ED, and ask relevant questions about each system.

Start with general information about the man’s life and work. Employment related stress and relationship difficulties are often involved in the etiology. Ask about the problem, its duration, frequency, and specifics such as whether the erection can be elicited but not maintained (suggestive of a veno-occlusive disorder). Ask about his past medical history and current treatments. As we have already seen, an elderly diabetic  is in the highest risk group for ED. What is the patient’s motivation for seeking help, and why now? There is some- times a mismatch of expectation between the patient and his sexual partner. ED is often situational, occurring only in the presence of a partner, but the man may enjoy  satisfactory  masturbation  and  have  spontaneous/nocturnal  erections. Note  that  loss  of  nocturnal  erections  is  a  strong  indicator  of  a  physical problem, but can also be as a result of a major depressive disorder. Ask specific questions about other cardiovascular, neurological, and endocrinological symp- toms. [For a more detailed description of neurological factors affecting ED refer to Lundberg et al. (15); for endocrinological factors refer to Heaton and Morales (16); for cardiological factors refer to Jackson et al. (17).] Does the man smoke or drink alcohol to excess or use recreational drugs? Some questions may be asked if the clinician suspects a specific etiology. For instance, is there a psychological reason, such as hidden guilt, about having sex outside the relation- ship, whether it be with a woman or another man? Gay sex is still a taboo subject for many, and the apparent inability of the society to come to terms with it can leave an individual feeling guilty or anxious about his sexual preference. Alter- natively, there may be a fear of getting a woman pregnant, or contracting/passing on a sexually transmitted infection?

On occasion, a man may alter his history over time and reveal more infor-mation. He may have several issues that have prevented him from being totally frank.  Being  nonjudgemental  will  smoothen the  doctor – patient  relationship and result in a better consultation for both the professional and the patient.

Use of Questionnaires

The use of questionnaires, such as the International Inventory of Erectile Func- tion (IIEF), are sometimes of relevance, and are a useful way of measuring improvement over time (18). The IIEF is a self-report tool that has been used in the clinical trials to assess the response of a subject to oral treatments for ED. It comprises 15 questions which cover five key areas of sexual function in men:  erectile  function;  intercourse  satisfaction;  orgasmic  function;  sexual desire; and overall satisfaction. The two key questions in relation to the studies on ED are question 3 which asks about the ability to achieve an erection sufficient for penetration—“When you attempted intercourse, how often were you able to penetrate (enter) your partner?”—and question 4 which asks about the ability to maintain the erection long enough for satisfactory intercourse—“During sexual intercourse, how often were you able to maintain your erection after you had penetrated  (entered)  your partner?”  Other questionnaires have  been  used in research. Some, like the IIEF, have been validated and found to have a high degree of sensitivity and specificity (19).

Physical Examination

Physical examination is often of great importance in clarifying suspected etiolo- gies. Start with a general examination, and keep in mind some of the vascular, endocrinological, and neurological causes of ED. Assess the degree of androgen- ization checking for body hair and any evidence of gynecomastia. Examine the genitalia carefully for any abnormalities. Check whether the foreskin can be retracted, and look for conditions such as phimosis or balanitis. Deep palpation of the penis can reveal fibrotic thickening (Peyronie’s plaques) in a proportion of men presenting to sexual dysfunction clinics. Cremasteric and bulbocavernous reflexes should be elicited as well as saddle sensation and deep tendon reflexes of the legs. The size and consistency of the testicles should be assessed. If urinary symptoms are present, rectal sphincter tone and prostatic examination are neces- sary. Cardiovascular risk assessment should be undertaken [see Appendix and Jackson et al. (17)].

Blood Investigations

Order blood investigations depending on your findings. In our clinic, men are offered tests for fasting glucose; prolactin levels; high density lipoprotein ratio and triglycerides; a 9 am testosterone, SHBG and free androgen index. Other specific tests may be appropriate (e.g., LH and free testosterone; TSH).

Some centers are able to offer further investigations. To assess erectile function,  nocturnal  penile  tumescence  (NPT)  can  be  assessed  using  strain gauges. However, rigidity is seen as an important factor for assessment and tumescence  and  rigidity  can  be  assessed  using  the  Rigiscan  monitor.  This device is involved in both provocative testing of erectile response in the clinic or  laboratory  as  well  as  home  nocturnal  testing.  The  patient  can  take  the device home for nocturnal testing after receiving some tuition on its use. Rigiscan can be used to investigate suspected cases of neurological or psychological causes (20). Another device, the NEVA (nocturnal electronic volumetric assess- ment) is worn while asleep at home and is of particular use in the investigation of vascular disorders.

Erectile capacity can be undertaken by observing the response to an intra- cavernous injection of alprostadil or papaverine. This can be quantified by the use of Doppler ultrasound and undertaken in the hospital setting. Other stimuli such as vibration and erotic videotape material may be helpful to augment the response, particularly in the clinical setting. The MIDUS (Male Impotence Diag- nostic Ultrasound System) is a Doppler machine that is used in clinics to measure penile blood flow. Unlike Duplex Doppler Ultrasonography performed in the hospital, the Knoll/MIDUS Ultrasound System is designed as an office-based system. Doppler Duplex sonography will allow for visualization of the vascula- ture in patients eligible for reconstructive surgery.

Electrophysiological testing may be indicated in specific cases [e.g., nerve conduction studies, GSA (genital sensory analyzer)].

A consensus statement of recommendations has been published following the second international consultation on sexual dysfunction (21).

TREATMENT  OPTIONS  FOR ED IN  MEN

Guidelines for treatment have changed considerably over the past decade, and will continue to do so as new drugs and treatment options become available and are evaluated. Treatment can be subdivided into first, second and third line therapies, and includes drug therapies as well as psychotherapies and surgery. All  patients  should  be  provided  with  some  general  information  about  ED, which will include normalizing the condition, which can be reassuring for the man and his partner. The role of organic and psychological factors should be described and unbiased information provided on all suitable treatment options.

Pharmacotherapy for Men with ED

Few licensed drugs are currently available for the treatment of men with ED. Those that are available elicit their effect by one of two mechanisms. The agent boosts either the neuronal control mechanism or the local control mechan- ism (13). As we shall see, oral therapies can have their effect on either system, whereas the intracavernosal and intraurethral systems act locally to produce an erection.

First Line (Oral) Therapies

Oral agents used to treat ED should be reliable, have minimal side effects, and be simple to use (22). The oral therapies currently licensed for ED are the phospho- diesterase 5 inhibitors (PDE5 inhibitors), which have a peripheral mechanism of action,  and apomorphine, which acts  centrally. These agents require  sexual stimulation to initiate the neuronal activation required to start the hemodynamic erectile response. This is in contrast to the PGE mediated response initiated by intracavernosal and intraurethral alprostadil administration that “forces” an erec- tion (see later). Yohimbine is another oral agent that has been shown to have some efficacy, but this is currently unlicensed in the UK although available on prescription  in  the  UK  and  US.  There  are  several  advantages  of  the  oral agents. Because they are administered orally, they are noninvasive, unlike intra- cavernosal and intraurethral medications and surgery. Taking a tablet is also more discreet, which is an important characteristic because it restores some of the spontaneity of sexual activity and removes the need for interruptions. In addition,

oral methods of drug delivery are not associated with fibrosis (a potential adverse effect  when using intracavernosal injections), neither  is there any penile or urethral pain that can occur with alprostadil use when given by injection or as the intraurethral pellet. As a consequence, oral therapies are now considered to be first line therapy.

Inhibitors of phosphodiesterase 5:        As we have already seen, NO is required for normal erectile function (13). NO is a gas and is derived from L-arginine (an amino acid) and oxygen in the presence of the enzyme NOS. NO, interacts with soluble guanylate cyclase, which then dephosphorylates gua- nosine tri-phosphate (GTP) to produce the second messenger cyclic guanosine mono-phosphate (cGMP). It is the amount of cGMP present that determines the extent of relaxation in corporal smooth muscle by stimulating the reduction of intracellular calcium (23,24).

Phosphodiesterase (PDE) is a molecule that has many different isoforms, and is found in most mammalian tissue (24). PDE5 is the predominant isoenzyme found in the corpus cavernosum and is a cGMP-binding, cGMP specific PDE (24,25). Its role in the reversal of the penile erection is to decrease the levels of cGMP so that vasoconstriction and trabecular smooth muscle contraction take place. Theoretically, by blocking the action of PDE5, the erection should be maintained. This is the proposed mechanism of action of the PDE5 inhibitors.

PDE5 inhibitors are not suitable for all patients, and it may take several attempts at taking them before they have the desired effect (26). All PDE5 inhibi- tors are absolutely contraindicated for patients who are taking any form of nitrate, including sublingual sprays and nitrates used recreationally (e.g., amyl nitrate). There are currently three licensed PDE5 blocking drugs available in the UK and US: sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis).

Sildenafil (Viagra).          Since its introduction in 1998, sildenafil has been the subject of many clinical trials on men within the age range of 19 – 87 years. It the most studied of the PDE5 inhibitors and currently the most widely used treatment for ED. Sildenafil has been shown to be effective and well tolerated by patients with various etiologies (22,27,28). Sildenafil has a molecular structure similar to that of cGMP [see Fig. 7.1 (24)] and is highly selective for PDE5, with some selectivity for PDE6 found in the retina, which would reasonably account for the transient [usually minutes (24)] visual disturbance that some men experience. In a complex interaction between the molecules, sildenafil increases its own binding affinity by a positive feedback mechanism, making more cGMP available (24). More cGMP means more NO available to relax smooth muscle, which results in improved erections.

Sildenafil is rapidly absorbed, and has a plasma half-life of    4 h (25). Of the circulating sildenafil, 96% is bound to plasma proteins and therefore is not excreted in urine (24). When correctly taken just once daily, there is no signifi- cant accumulation of the drug in the body, as it takes just over 24 h to achieve total clearance. Clinical experience since its introduction has shown sildenafil

Caffeine

Figure 7.1    Structure of sildenafil and other molecular structures.

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 rec- ommended. Reduced clearance occurs in elderly patients over the age of 65: patients with severe renal impairment (creatinine clearance ,30 mL/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 pre- scribed 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 treat- ment 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 individ- uals 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 under- gone a radical prostatectomy have an almost 100% occurrence of ED if the pro- cedure 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 noc- turnal 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 possi- bility (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 antidepres- sants (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 combi- nation 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 sub- lingual  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, investi- gators 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 treat- ment. This compares well with the 74% of positive responders in the general popu- lation 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 treat- ment 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 gov- ernment 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 effec- tive, 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 etiol- ogies 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 metab- olizes 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 cardiovas- cular 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 com- plications. 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 combi- nation 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 con- ditions 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 varde- nafil 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 concen- tration around 1 h and 40 min after administration. Absorption is not compro- mised 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 inhibi- tors,  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 hypo- tensive 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, hypoten- sion, 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 under- gone  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).

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