Do not turn a blind eye to alkyl nitrite (poppers)!

Abstract

Recreational users of poppers must be informed about the risk of developing poppers-associated maculopathy and the possible cumulative risk when taking poppers in combination with sildenafil. We suggest that it is an accumulative increase in cGMP which is harmful for the photoreceptor cells and may cause poppers-associated maculopathy (Fig. 1). A possible association between the use of poppers and maculopathy with visual loss was first described in 2004 (Pece et al. 2004). Poppers is the popular name for alkyl nitrite which is a short-acting, volatile drug used by inhalation. To better understand this possible association, we looked into the medical history and drug use of 10 patients with poppers-associated maculopathy. Seven patients (70%) were HIV positive, for which one patient was treated with a proteinase inhibitor at time of onset. Sixty per cent used sildenafil in combination with poppers: three were HIV positive and three were HIV negative. It may be that patients, who use poppers most, are those who get HIV and are more prone to the development of a maculopathy due to a higher cumulative dose of poppers. However, if poppers alone were a sufficient cause of maculopathy, far more women and heterosexual men would be expected among a cohort of users. Among the general population, 4% use poppers. In the homosexual community, about two per cent of the population, 30% take poppers and 6% are HIV positive (Swearingen & Klausner 2005). Hence, an additional factor like the concentration of cGMP may be the key substance damaging the photoreceptor cells in poppers-associated maculopathy. Upon oxidation, alkyl nitrites give rise to nitric oxide (NO). NO stimulates guanylate cyclase which converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). Guanylate cyclase (GC) is found in the cell body of the photoreceptor cell, that is the retinal cones (Ferrendelli & De Vries 1983). cGMP is an important substance in the photo-transduction cascade which allows Ca2+ and Na2+ to enter the cell, causing depolarization of the cell. However, very high levels of calcium will damage the photoreceptor cell (Sharma & Rohrer 2007). When patients are infected with human immunodeficiency virus (HIV), their cytokines IL-1, IL-6, interferon-gamma and TNF-alpha will increase. These cytokines activate inducible nitric oxide synthase 2 (iNOS-2), which has been shown to increase the level of NO and cGMP in the retina. In the present series, one patient was treated with a proteinase inhibitor. Proteinase inhibitors inhibit cytochrome P450 3a4. As sildenafil is broken down by cytochrome P450 3a4, proteinase inhibitors will cause an increased and prolonged concentration of sildenafil in the blood of patients using sildenafil. This indicates that also treatment of HIV patients with proteinase inhibitors might add to the development of a poppers-associated maculopathy. The three patients who were HIV negative used sildenafil besides poppers. One patient used poppers frequently for years, without any visual problems. But when he first used a combination of sildenafil and poppers, he noticed a sudden decline in visual acuity. Sildenafil, a phosphodiesterase inhibitor, prevents the degradation of cGMP. Phosphodiesterase VI is a component of the photo-transduction cascade of the photoreceptor cells. So inhibition of phosphodiesterase VI, as can be seen after the use of sildenafil, causes an increased concentration of cGMP in the photoreceptor cells. Inhibition of phosphodiesterase IV was found to induce an accumulation of cGMP with degeneration of cones in pigs (Martínez-Fernández de la Cámara et al. 2013). So, sildenafil, HIV and/or proteinase inhibitors influence a common pathway through which a rise in cGMP is induced and may thus increase the risk of developing a poppers-associated maculopathy.