Sildenafil citrate is a selective inhibitor of
cGMP-specific phoshodiesterase (PDE-5). It is primarily used
as an aid to erectile
dysfunction in men, and has even been suggested for use in women.
Physiologically speaking, the chemical most important in vasodilatation associated with sexual stimulation of erectile tissue in humans is NO. Recently, the highly publicized "discovery" of Nitric Oxide (NO) has lead to such terms as, "NO Sex!" However, as with many other physiologic processes, a true cascade of chemical interactions must take place for engorgement to be accomplished. While parasympathetic innervation of the genitalia is credited with vasodilatation and erectile function, local stimulation plays an important part. Stimulation of these tissues increase vascular shear forces, which in turn activate NOS (Nitric Oxide Synthase), causing the synthesis and subsequent release of NO from l-arginine. NO, in turn, facilitates the release of guanyl cyclase from its position on the cytoplasmic side of the cell membrane and allows it to convert Guanine Triphosphate (GTP) to cyclic-Guanine Monophosphate (cGMP), which, in turn, inhibits the activation of protein kinases in smooth muscle, blocking the excitation/coupling of smooth muscle myofibrils leading to vasoconstriction. This inhibition allows the accumulation of blood in the tissues of the corpus cavernosum and subsequent erection.
Second messengers, such as cGMP and cAMP are reduced
to the inactive forms, GMP and AMP respectively, by phoshodiesterase enzymes
(PDE). As their name implies, PDE break diesther phosphate bonds,
especially those associated with cAMP and cGMP. Sildenafil,
inhibits the actions of PDE-5, which is found primarily in the genitalia,
but can also be found in other vascular smooth muscle and esophageal smooth
muscle. Figure 1. illustrates the Nitric Oxide/PDE pathway and
Figure 1 - NO/PDE pathway
Recently, six deaths have been attributed to concomitant use of sildenafil and short -acting nitrates, such as nitroglycerin. Pfizer, the manufacturer of Viagra, has long held that concomitant use of long acting nitrates is contraindicated and that all nitrates should be avoided. In fact, many prescribers have replaced long-term nitrates with other medications, such as ACE inhibitors and calcium channel blockers to avoid this potential contraindication.
Much confusion has arisen regarding the circumstances of these deaths and the ramifications of using nitrates in the prehospital setting. Discussions on various e-mail services, as well as reporting in the press do not shed much light on the circumstances surrounding these deaths. It is unclear whether there was any associated myocardial infarction or even significant myocardial atherosclerotic disease in any of the victims. Further, no information on the symptomatology; sequelae, nor resuscitative efforts involved in these arrests is available at this time.
Individual case studies are anecdotal and do not provide
data with which clear clinical decisions can be reached. However,
given the gravity of the situation, it would certainly be prudent to both
question every patient who is a candidate for nitrate therapy about possible
use of sildenafil in the past 24 hours, ( sildenafil has a 4 hour half-life
and should be completely eliminated from the body within 20 - 28 hours),
and confer with your medical command authority prior to concomitant
Updated: 1 June 1998