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Australian Journal of Pharmacy : October 2005
pharmacy ed cdi: drug review • approved CPE compared with 24 per cent of attempts made by men on placebo.11 Efficacy of vardenafil One study of vardenafil showed that after 26 weeks of treatment, 85 per cent of men reported improved erections and sexual satisfaction.12 Up to 89 per cent of men with mild erectile dysfunction and 39 per cent of men with severe erectile dysfunction reported restoration of normal erectile function. A recently published multi-centre, double-blind, placebo- controlled study of vardenafil in men with both type 1 and type 2 diabetes reported a significant improvement in sexual functioning for men taking vardenafil.12 Vardenafil also improved sexual functioning in men following radical prostatectomy.12 Safety of PDE-inhibitors All the PDE-5 inhibitors appear to be well tolerated in most patients; the most common side effects include headache, flushing, dyspepsia, back pain, nasopharyngitis, and nasal congestion.3 Both diabetes and sexual intercourse are associated with increased risk of an adverse cardiovascular event. In monitoring sildenafil (Viagra), it became clear that heart attacks and deaths as a result of angina were not observed more frequently in sildenafil users than in the general population.3 In a FDA publication (Food and Drug Agency of the US), fewer deaths were associated with sildenafil use than might have been expected statistically given the mortality rate for men in the reported age group.18 Vardenafil has a pharmacokinetic profile similar to sildenafil and, while this does not mean that it has the same safety profile that post-marketing surveillance has attributed to sildenafil, it perhaps has fewer pharmacokinetic concerns than has tadalafil. Given that tadalafil is longer-acting than both vardenafil and sildenafil and that trials with tadalafil have been conducted for only six months, and also that patients at risk of cardiovascular events have been excluded from clinical studies with all three PDE-5 inhibitors, it is not clear whether tadalafil has the same lack of risk of cardiovascular events attributed to sildenafil. However, in men taking organic nitrates, the PDE-5 inhibitors are absolutely contraindicated.10,11,12 This is because of the vasodilatory nature of these drugs. There is concern that blood pressure may be lowered acutely and cause dizziness, faintness and falls. Also, if blood pressure drops suddenly, there may be a reflex speeding up of heart rate to compensate for the blood pressure drop in order to renormalise the blood pressure. The concern would be that reflex tachycardia in patients who have cardiovascular conditions such as angina may increase the workload on an already fragile heart and lead to further stress on the heart. In healthy patients, although there is a mild and transient decrease in blood pressure, there is no evidence of any increase 842 ? THE AUSTRALIAN JOURNAL OF PHARMACY VOL.86 OCTOBER 2005 in heart rate.3 However, because of ethical issues, there have been no studies of patients with any of the PDE-5 inhibitors who do have cardiovascular problems, such as angina, to see if there is evidence of stress on the heart following blood pressure drop. There is absolutely no evidence as yet to show that taking any of the PDE-5 inhibitors further increases the risk of adverse cardiovascular events. It is, however, known that any patient who does have cardiovascular problems may be at further risk of heart attack and stroke merely by engaging in energetic sexual activity. Other recent labelling instructions also recommend that men who are taking alpha-blockers (also potent vasodilators) to treat their high blood pressure or prostate problems should not take sildenafil in a dose greater than 25mg within four hours of taking the alpha-blocker.10 Interestingly, recent studies show that the PDE inhibitors may actually improve flexibility of blood vessels, the lack of which is considered to be part of the pathologic process common to both erectile dysfunction and vascular disease. Recent studies have reported that sildenafil improved relaxation of arteries, improved the flexibility of the coronary arteries, and that acute and chronic dosing of sildenafil increased brachial artery diameter and thus improved blood flow.19 Drug Interactions of PDE-5 inhibitors CYP3A4 inhibitors All the PDE-5 inhibitors are principally metabolised by the cytochrome P450 system CYP3A4 isoforms. Thus drugs which inhibit CYP3A4 may put up blood levels of PDE-5 inhibitors causing toxic side effects (tachycardia, headache, increased blood pressure). Drugs which induce CYP3A4 can increase the metabolism of the PDE-5 inhibitors resulting in a loss of efficacy. Nitrates All PDE-5 inhibitors inhibit phosphodiesterase type 5 (PDE5) which is responsible for the metabolic degradation of cyclic guanosine monophosphate (cGMP).3 Organic nitrates (glyceryl trinitrate, isosorbide mononitrate) exert their action by activation of guanylate cyclase, which increases cGMP.3 Because of the potential for excessive hypotensive effects as a result of increased cGMP, the concomitant use of sildenafil and organic nitrates is contraindicated. It is feared that excessive hypotensive effects might result in reflex tachycardia, which could further stress a heart already at risk from angina or ischaemia. Dopamine Receptor Agonists (Apomorphine) Both animal and human studies demonstrate that male sexual behaviour is partly regulated by dopamine mechanisms, and that penile erection can be induced by apomorphine, a dopamine receptor agonist that stimulates dopamine D1 and D2.3 Although early studies of apomorphine showed it to be ineffective when orally administered, and it had only limited effectiveness when injected because of side effects, more recent