The rise and fall of Viagra

New drugs for male erectile dysfunction (ED) are set to challenge the market dominance currently enjoyed by sildenafil citrate (Viagra™, Pfizer, Sandwich, UK). The new drugs, vardenafil (Bayer, Leverkusen, Germany) and Cialis™ (IC351; Eli Lilly, Indianapolis, IN, USA), both of which are phosphodiesterase-5 (PDE5) inhibitors, are currently in Phase III clinical trials and could prove more potent, and produce fewer side effects, than sildenafil.

ED is defined as the consistent inability to attain and maintain a penile erection adequate for satisfactory sexual activity. Vascular disease, diabetes, prostate surgery, psychiatric disorders and concomitant drug therapy can predispose to ED, which can be exacerbated by psychological factors.

ED is widespread: in a large community-based epidemiology survey (Massachusetts Male Aging Study; MMAS), one-third of 1290 men aged 40–70 years reported having moderate or complete ED [1]. Other studies have found that ~50% of men in this age group have some degree of ED, and 30% report moderate-to-severe impotence [2].

1. Sildenafil

Sildenafil citrate, introduced in 1998, was considered to be a major breakthrough as the first effective oral treatment for ED. Sildenafil is an active inhibitor of cGMP-specific PDE5 – the enzyme responsible for degrading cGMP in the corpus cavernosum of the penis. This inhibition, combined with nitric oxide-mediated increased formation of cGMP resulting from sexual arousal, leads to more pronounced relaxation of the corpus cavernosum smooth muscle, leading to accumulation of blood in the sinusoids and, therefore, improved penile rigidity.

Sildenafil also exerts a significant effect on PDE6, an isoform important for phototransduction in the retina. Although sildenafil is about 4,000–10,000-fold more selective for PDE5 over PDE1–4 and PDE7, it is only approximately tenfold more selective for PDE5 over PDE6. Therefore, at clinically effective doses, sildenafil is likely to inhibit PDE6, accounting for the transient colour change in vision reported by 1 in 12 patients taking sildenafil [3].

'Genetic defects in PDE6 are the cause of autosomal recessive retinitis pigmentosa and autosomal dominant night blindness,' says Patrick Vallance, Professor of Clinical Pharmacology at University College London (London, UK). In addition, experimental lesions in PDE6 cause retinal degeneration in mice [4]. 'There is no doubt that complete loss of PDE6 is bad news for the retina. The question remains whether 10% inhibition will do any longer-term damage apart from reversible changes in colour vision. Sildenafil has just not been used for long enough to tell,' adds Vallance.

The more frequent side effects of sildenafil, such as facial flushing, headache, nasal congestion and dyspepsia [3], have been assumed to be caused by vasodilation produced as a consequence of blocking PDE5 in other areas of the body. If the assumption is correct, these side effects are likely to persist with new drugs (Ian Eardley; consultant urologist at St James' University Hospital, Leeds, UK).