Currendy, the range of therapy for managing ED in the general population includes oral PDE-5 inhibitors such as sildenafil citrate, sublingual apomorphine, intracavernosal injection or transurethral alprostadil, vacuum constriction devices and penile implants. However, in cardiac patients on warfarin, injections and vacuum devices are not indicated because of increased risk of haematoma or bleeding
Figure 1A. Mechanism of action of sildenafil NO(S)=nitric oxide (synthase), GC=guanyl cyclase, GTP=guanosine triphosphate, cGMP=cyclic guanosine monophosphate, PDG=phophodiesterase enzymes.
Figure IB. Mechanism of action of concurrent use of sildenafil and nitrates. NO=nitric oxide, GC-guanyl cyclase, GTP=guanosine triphosphate, cGMP=cyclic guanosine monophosphate.
PDE-5 inhibitors (sildenafil) and the heart
A balance in the rates of production and elimination regulates the concentration of intracellular cGMP necessary for smooth muscle cell relaxation and maintaining an erection (figure 1A). The rate of production is controlled through the nitric oxideguanylate cyclase activity. The rate of elimination depends on the activity of phosphodiesterase enzymes. The predominant isoform in human penile tissue is PDE type 5. The most widely used PDE-5 inhibitor is sildenafil, an orally active, potent and selective inhibitor of cGMP-specific phosphodiesterase type 5. It enhances the relaxant effect of nitric oxide released in response to sexual stimulation by increasing cGMP concentrations in the corporal smooth muscle. A metaanalysis of nine double-blind, placebo-controlled studies determined the efficacy of generic sildenafil in patients with ED and ichaemic heart disease who were not taking nitrates. The concomitant use of nitrates and sildenafil (Viagra Professional) leads to profound and prolonged blood pressure drop (up to 30 mmHg) and is contraindicated for that reason (figure IB).
It is important for cardiologists to instruct their patients what to do if they have angina during sexual activity after using sildenafil drug. The habituous intake of nitroglycerin sublingually by cardiac patients should be prohibited and patients should be instructed to visit the emergency department, notifying physicians about the use of a PDE-5 inhibitor. In these cases calcium antagonists given intravenously could be administered. Oral nitrates can be discontinued in the presence of continuing (J-blockade and/or calcium antagonist therapy in stable coronary disease patients with ED to allow for the safe use of PDE-5 inhibitors.
In contrast to an unwanted synergistic effect of the combined use with nitrates, cheap sildenafil has shown many advantageous influences on the heart. During coronary angiography, it has been shown that sildenafil increased epicardial diameters after the administration of acetylcholine in patients with coronary artery disease as well as in patients with normal endothelial function compared with placebo. The same study suggested a reduction in platelet GP Ilb/IIIa-receptor activation by sildenafil pill. Another study looked at the effect on coronary blood flow in patients with severe coronary artery disease (CAD). Average peak velocity, coronary artery diameter and coronary blood flow showed no significant changes with administration in stenosed or non-stenosed arteries. Halcox et al. assessed endothelial function by FMD. In patients with and without CAD, hyperaemic vasodilation lasted significantly longer following sildenafil administration compared with the pre-sildenafil control group. Another relevant clinical study evaluated whether sildenafil affected the ischaemic threshold in men who experienced exercise-induced angina. Sildenafil drug significantly increased the time to onset of limiting angina and increased exercise duration compared with placebo. Furthermore, a neutral effect of PDE-5 inhibition on exercise echocardiography was observed. Also in the field of heart failure favourable reports have been published. In a double-blind, two-way crossover study 24 males with chronic heart failure (CHF) were randomised to placebo or sildenafil 50 mg. Canadian Sildenafil was a well-tolerated and effective treatment in CHF patients with ED. The improvement in exercise capacity, in particular in heart rate, suggests that might decrease myocardial oxygen consumption during sexual activity. Others have reported safe and effective treatment with sildenafil (Viagra Super Active) for ED in men with New York Heart Association classes II and III chronic heart failure and relief of depressive symptoms, explaining an improvement in the perception of quality of life.
Ever since the introduction of sildenafil (Viagra Plus) seven years ago, the incidence of MI and mortality has been a matter of discussion. The pooled data from 80 studies of patients treated with between 1993 and 2000 were analysed. These data indicate that was not associated with short-term risk for myocardial infarction and are consistent with the growing body of evidence that sildenafil use is not associated with an increased risk for cardiovascular events.
Recently, more PDE-5 inhibitors have been registered for the treatment of ED, such as vardenafil and tadalafil. The main pharmacokinetic difference is in the onset and duration of these drugs. Large safety and efficacy studies concerning the recent developed PDE-5 inhibitors are still lacking.
Conclusions and recommendations
The management of ED remains primarily within the domain of urologists, psychologists and family practitioners. However, the association of ED with vascular disease does involve other medical specialists, including cardiologists, in the management of ED. ED is a common disease and its prevalence will grow considerably in the coming years. Growing evidence showing endothelial dysfunction to be the common denominator for cardiovascular disease and ED explains the high incidence of ED in patients with cardiovascular disease. Suggestions that ED predates coronary artery disease provides a tool to cardiovascular risk management in these patients. Modifying risk factors is the key in treating ED and preventive cardiovascular medicine. Management of ED in cardiovascular patients can be performed safely following the guidelines of the Princeton panel. Cardiologists should pay more attention to ED. It occurs more in their patients than they are aware of. Possibly a significant role can be played in the future by cardiac rehabilitation programmes.
Drug therapy for ED is still evolving. Good knowledge of pharmacokinetic actions and interactions is important for cardiologists in order to advise and instruct their patients in the best possible way.