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Apomorphine Action Mechanism
Fig. 2. Algorithm for treatment of erectile dysfunction (15).

Apomorphine. Apomorphine is a potent emetic agent that acts through central dopaminergic (D1 or D2) receptors as well as central m-, d-, and k-receptors. In the hypothalamus, it increases the centrally initiated efferences of the erectogenic axis thus, improving the erectile response in a patient with erectile failure (39). In large multicenter studies, a proerectile effect with full erections was observed after sublingual doses of 2, 4, and 6 mg apomorphine with an acceptable and dose-dependent rate of nausea side effects. A dose-dependent efficacy (defined as erections allowing intercourse/ attempts) of 48-66% vs 37% for Placebo was observed. Similarly, side effects were also

Table 3

Agents for Oral Treatment of Erectile Dysfunction

Central mechanism of action

• Yohimbine (a2 adrenergic antagonist)

• Apomorphine (dopamine receptor agonist) Peripheral mechanism of action

• Phentolamine (nonselective adrenergic antagonist)

• Phosphodiesterase isoenzyme type 5 inhibitors:

- Sildenafil

- Vardenafil

- Tadalafil strongly dose-dependent: Nausea was seen in 0.4-17% (vs 0.2-0.4% for Placebo), hypotension in 0.7-4.8 and syncope in 0.7-2.1%. These side effects tended to disappear in frequency and intensity with increasing use of the medication in an individual patient. There was no effect of apomorphine on mood and desire (40,41).

A 4-week multicenter, cross-over, placebo-controlled trial using the sublingual formulation of apomorphine (Uprima®) evaluated 90 patients with diabetes on the 4 mg dose and 86 patients on the 5 mg dose. The percent of attempts resulting in an erection firm enough for intercourse (primary end point) were 14.5 and 24.6% for placebo and 4 mg, respectively (p = 0.02) and 27.2 and 34.1% for placebo and 5 mg, respectively (p = 0.18). In the posthoc combined analysis the corresponding rates were 20.4 and 28.9%, respectively (p = 0.009). Thus, no dose response could be demonstrated in this trial. The FDA concluded from these data that even though the 4 mg dose and the combined analysis showed statistical significance, the clinical significance is questionable because of the relatively modest benefits noted over placebo (42). Indeed, the number needed to treat for the 4 mg dose treatment based on the aforementioned results is relatively high, i.e., 10 patients need to be treated in order to achieve an erection firm enough for intercourse in 1 of these patients. The rates of nausea, the most prominent adverse effect of apomorphine, were 21.2, 12.9, and 1% for 4 mg, 5 mg, and placebo, respectively. The corresponding rates of vomiting were 6.7, 1, and 0%, respectively. Moreover, three syncopal events and three episodes of significant hypotension were reported in patients taking apomorphine (42).

Peripheral Conditioners Phosphodiesterase 5 Inhibitors

Sildenafil (Viagra®). To understand the mode of action of Sildenafil, a drug believed to act predominantly through PDE 5-inhibition, the basic physiology is briefly explained. The cAMP and cGMP are synthesized from the corresponding nucleoside triphosphates by their respective membrane bound or soluble adenylate or guanylate cyclases. cAMP and cGMP are inactivated by PDE and by hydrolytic cleavage of the 3'-ribose-phosphate bond (see Fig. 1). Because the distribution and functional role of PDE isoenzymes varies in different tissues, selective inhibitors have the potential to exert at least partially specific tissue effects. Currently, more than 40 PDE-isoenzymes and -isoforms are known (43). The functional assays revealed a predominant functional role for PDE3 and 5 (44). There was no difference in PDE-expression in patients with diabetes compared with patients without diabetes with erectile dysfunction.

Sildenafil acts as conditioner on the cavernous smooth muscle side by blocking PDE5. It is the first effective oral drug that has been approved for the treatment of ED and is generally regarded as a first-line treatment of ED of various causes including diabetes. Sildenafil is taken 60 minutes before anticipated sexual activity and its effects last approximately 4 hours. The drug is available in three doses (25, 50, or 100 mg). It does not stimulate the sexual desire and provoke an erection as such, but enhances the continued relaxation of the cavernous smooth muscle initiated by the release of endogenous nitric oxide with an improved quality of erection (Fig. 1).

In a controlled, flexible-dose US multicenter trial including a mixed group of 268 men with type 1 and type 2 diabetes the rates of those with improved erections after 12 weeks of treatment with 25-100 mg sildenafil were 56% as compared with 10% in the placebo group (45). In a 12-week European multicenter trial including 219 men with type 2 diabetes the response rate was even higher achieving 64.6% on sildenafil vs 10.5% on placebo (46). The estimated percent of intercourse attempts that were successful significantly improved from baseline to end of treatment in patients receiving sildenafil (14.4-58.8%) compared with those receiving placebo (13.2-14.4%). Three quarters of the patients required the 100 mg sildenafil dose. The response rates were independent of the baseline HbA1c levels and number of chronic complications, thus suggesting that sildenafil is effective in improving ED even in cases with poor glycemic control and in presence of angiopathy and neuropathy. In a combined analysis of 11 controlled trials of sildenafil (25-100 mg) the percents of the maximum score for the six questions in the erectile function domain of the IIEF were 6% among 69 type 1 and 60.8% among 399 men with type 1 diabetes on sildenafil as compared with 39.3% among 452 men with diabetes on placebo (47).

Side effects consist mainly of headache (18%), facial flushing (15%), and dyspepsia (2%). A mild and transient disturbance of color vision and also increased sensitivity to light or blurred vision has been found in 4.5% of men with diabetes (46). Concerns have been expressed regarding an increased number of deaths associated with sildenafil as compared with other treatments for ED (48). However, after an average follow-up of 6 months the prescription event monitoring study including 5601 sildenafil users from England showed an expected mortality rate of 28.9/1000 per year for ischaemic heart dis-ease/myocardial infarctions. The comparison rate in the general population of England in 1998 was 73.9/1000 per year (49), whereas the prevalence of diabetes in the cohort was 15%, which is similar to the rate of 16% included in the clinical trials of sildenafil, but higher than the rate of 3.3% of men with diabetes. Although, these results are reassuring, further follow-up of this study and other pharmacoepidemiological research is needed for confirmation. In men with severe stenosis of at least one coronary artery, acute administration of sildenafil (100 mg) did not result in adverse haemodynamic effects on coronary blood flow or vascular resistance, but coronary flow reserve was improved (50).

Apart from its effect on ED, favorable effects of sildenafil have recently been reported in pilot studies of various disorders including primary pulmonary hypertension, achalasia, and endothelial dysfunction. The endothelium modulates the actual and the demand vascular tone, the antithrombotic and antiadhesive properties of the vessel wall, vascular wall architecture, and vascular permeability. Endothelial dysfunction is regarded as an early key event in the development of atherosclerosis, which is accelerated in diabetes. It has recently been demonstrated that erectile and endothelial dysfunction are associated in patients with type 2 diabetes. Plasma concentrations of markers for endothelial dysfunction such as, soluble thrombomodulin, P-selectin, and intercellular cell adhesion molecules-1 were significantly elevated in patients with type 2 diabetes with ED compared with those without ED and were inversely related to the IIEF (51). Endothelium-dependent flow-mediated dilatation induced by 5 minutes occlusion of the brachial artery measured by ultrasound imaging is a reliable index of endothelial function that is impaired in patients with diabetes. In a recent controlled crossover trial acute (25 mg) and chronic (25 mg per day for 2 weeks) administration of sildenafil (25 mg) improved endothelial function as compared with placebo in patients with type 2 diabetes, suggesting that PDE-5 inhibition may exert favorable cardiovascular effects (52). Thus, similarly, in patients with heart failure who frequently show endothelial dysfunction, the latter was improved after single-dose administration of 25 and 50 mg sildenafil, respectively (53). These findings require further confirmation in larger studies.

According to the recommendations of the American Heart Association sildenafil is contraindicated in men taking nitrates because of the risk of hypotension and those with severe cardiovascular disease. Before sildenafil is prescribed, treadmill testing may be indicated in men with heart disease to assess the risk of cardiac ischemia during sexual intercourse. Initial monitoring of blood pressure after the administration of sildenafil may be indicated in men with congestive heart disease who have borderline low blood pressure and low volume status and men being treated with complicated, multidrug antihypertensive regimens (54).

Because sildenafil treatment is costly and ED is not a life-threatening illness, the appropriateness of insurance coverage for sildenafil has been questioned. However, recent cost-effectiveness studies using cost per quality-adjusted life-year gained as outcome measures have shown that sildenafil treatment compared favorably with intracavernosal injection therapy (55) or with accepted therapies for other medical conditions (56).

Because some men do not respond to sildenafil treatment, attempts have been undertaken to characterize these nonresponders. A recent penile biopsy study identified severe vascular lesions and atrophy of cavernous smooth muscle to represent the main factors that determined the lack in response to 100 mg sildenafil in men with ED aged from 28 to 74 years. The age, diabetes, and low testosterone level were not related to the response failures (57).

Tadalafil (Cialis®). In a 12-week multicenter trial including 216 men with diabetes (type 2: 91%), but excluding sildenafil nonresponders, the rates of men with improved erections were 64% with 20 mg tadalafil, 56% with 10 mg tadalafil, and 25% on placebo (58). Both tadalafil 10 mg and 20 mg were superior to placebo in improving penetration ability (IIEF question 3) and ability to maintain an erection during intercourse. Thus, although nonresponders to sildenafil were excluded, the effect of tadalafil was not superior to that of sildenafil. Treatment-related adverse events (>5%) on 20 mg, 10 mg, and placebo were dyspepsia (8.3, 11, and 0%) and headache (6.9, 8.2, and 1.4%). Despite more severe baseline erectile dysfunction in men with diabetes as compared with the men without diabetes with ED, tadalafil was efficacious and well tolerated. As reported for other PDE type 5 inhibitors, the response to tadalafil was slightly

Parameter

Vardenafil (20 mg)

Sildenafil (100 mg)

Tadalafil (20 mg)

Tmax (min)

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