Sildenafil citrate, otherwise known as Viagra, is used as an orally effective treatment for erectile dysfunction (ED) and pulmonary arterial hypertension. ED is the persistent inability to achieve or maintain an erection sufficient for sexual performance.1
Pulmonary arterial hypertension is characterised by an increase in pulmonary arterial blood pressure above the norm (=25mmHg at rest).2 Sildenafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE-5), with a low IC50 of 3.4nM.3 IC50 defines the molar concentration of the antagonist that produces 50 per cent of the maximum inhibitory response.4 A low IC50 indicates a potent inhibitor. Following oral administration of sildenafil, maximum plasma concentrations are achieved within 30-120 minutes. The half-life of sildenafil is approximately four hours, indicating rapid onset of action.5 Newer PDE-5 inhibitors include vardenafil and tadalafil.6 Tadalafil has a longer duration of action (half-life of 17.5 hours) compared to Vardenafil which is rapidly metabolised (half-life of 4-5 hours). These PDE5-inhibitors are highly plasma protein bound and are primarily metabolised by cytochrome P450 3A4 and to a lesser extent by CYP2C9 microsomal isoenzymes in the liver. Co-administration with known cytochrome P450 inhibitors can therefore affect the biotransformation and metabolism of these PDE-5 inhibitors, resulting in toxic plasma concentrations.5
Mode of action
PDE-5 is an enzyme which is part of the phosphodiesterase superfamily (PDE1-11),7 that is most prominently expressed throughout the smooth muscle of the corpus cavernosum and the pulmonary vasculature. Cyclic guanosine monophosphate (cGMP), a ubiquitous second messenger molecule, mediates the effects of nitric oxide (NO).8 NO is a transmitter released from activated parasympathetic, nitrergic neurons, as well as from the endothelial cells of sinusoids supplying the target tissues. NO interacts with the haem group of the enzyme soluble guanylate cyclase (sGC) present in the smooth muscle cells of the target tissues, resulting in the conversion of guanosine triphosphate (GTP) into cGMP.9 PDE-5 inactivates cGMP by converting it into guanosine monophosphate (GMP), and terminating the signalling cascade.10 Inhibition of PDE-5 therefore raises the intracellular levels of cGMP, which activates cGMP-dependent protein kinase (PKG). PKG interacts with the inositol triphosphate (IP3) receptor, Ca2+-ATPase and cGMP-gated ion channels, which causes K+ channels to open, resulting in hyperpolarisation of the muscle cell membrane, stopping Ca2+ influx.11 The reduced intracellular concentrations of Ca2+ induce the downstream events that lead to smooth muscle relaxation (Figure 1). The resultant increase in blood flow through the cavernosal artery causes expansion of the corpus cavernosum, which pushes against Buck’s fascia, occluding venous outflow. This results in engorgement and penile erection.12 It must be noted that PDE-5 inhibition will have no effect without sexual stimulation.13
Alternatively, the resulting effect of smooth muscle relaxation in the pulmonary vasculature is pulmonary vasodilation.14
[CaptionComponent="904"]Ocular effects
Sildenafil is, however, not entirely selective to PDE-5; it also has an inhibitory effect on PDE-6 (IC50 30nM). PDE-6 is found in the outer segments of rod and cone photoreceptors, where it is involved in the phototransduction cascade. Therefore, its inhibition produces visual effects.16 Concentrations of cGMP in the outer segments of photoreceptors are high in darkness; it binds to non-selective cation channels on the outer segment membrane, preventing their closure, leading to photoreceptor depolarisation.16 Light induces photoisomerisation of the chromophore, 11-cis retinal in rhodopsin, into all-trans retinal. The subsequent activation of metarhodopsin II activates transducin (the G-protein coupled to rhodopsin). The activated transducin binds to the inhibitory Pg-subunit of PDE-6, causing PDE-6 activation and catalysis of cGMP, which results in reduced outer segment cGMP levels.17 Therefore, the non-selective cation channels close, stopping Na+ and Ca2+ influx. Efflux of K+ from the inner segment continues, producing a net photoreceptor hyperpolarisation, a graded response to light which leads to a reduction in presynaptic glutamate release.13
Figure 2 shows how visual sensitivity is affected by PDE-6 inhibition. AMPA receptors on the dendrites of OFF-bipolar cells are therefore not activated, causing Na+ channels to close and thereby OFF-bipolar cell hyperpolarisation. Reduced glutamate release also means that APB receptors on the dendrites of ON bipolar cells are not activated; opening Na+ channels and producing ON-bipolar cell depolarisation. These signals are then transmitted to ganglion cells which send visual information to the primary visual cortex. Minor inhibition of PDE-6 would therefore impair the visual signalling pathway.18 Sildenafil not only affects retinal function at the level of the photoreceptors, but also the neuronal network of the inner retina.19
[CaptionComponent="905"]There may also be a direct effect on PDE-5, as PDE-5 is expressed on endothelial and smooth muscle cells of the retinal and choroidal blood vessels, as well as ganglion and bipolar cells. This might explain the increased blood flow velocity in these vessels after administration of either sildenafil or tadalafil.15
Effects on the visual system as are follows:
- Transient tritanopia (problems in blue/green colour discrimination) has been reported. This may be due to S-cone outer segment dysfunction or changes in post-receptoral processing
- Photophobia may occur. Acute changes in outer and inner retinal function, measured by the ERG, occur after administration of sildenafil20
- Non-arteritic anterior ischaemic optic neuropathy22
- Optic atrophy23
- Reduction in flicker fusion frequency (the maximum flicker rate detectable).21
However, no significant effects on visual acuity, spatial contrast sensitivity or pupil responses have been reported.13
Non-ocular side effects of PDE-5 inhibitors include:
- Headaches due to dilation of blood vessels in brain
- Flushing
- Nasal congestion
- Dyspepsia. Nitrergic responses are important for the gastrointestinal tract sphincters, therefore muscle relaxation causes oesophageal reflux.24
Sildenafil is contraindicated in individuals taking nitrates for angina, as the drug-drug interaction can lead to hypotension.
The safety of sildenafil in individuals with a known hereditary degenerative retinal disorder such as retinitis pigmentosa (RP) has not yet been studied (some individuals with RP have genetic disorders of PDE-6), and it is therefore contraindicated in these cases.25
We will now look at one of these ocular adverse effects in greater detail.
Non-arteritic anterior ischaemic optic neuropathy
Non-arteritic anterior ischaemic optic neuropathy (NAION) is a condition that arises due to insufficient blood supply (hypoperfusion), leading to ischaemia of the anterior optic nerve head.13,26 It is mainly found in individuals over 50 years of age.26 Characteristic signs include sudden loss of vision (usually on waking), optic disc oedema, pale optic disc, visual field loss (usually altitudinal, Figure 3), and a small cup-to-disc ratio in the unaffected eye. A deficiency in glucose-6-phosphate dehydrogenase (G6PD) (an enzyme involved in glucose metabolism) could be a potential protective risk factor from NAION.28
[CaptionComponent="906"]Visual defects and cases of NAION have been reported in connection with the intake of PDE5 inhibitors.
Following the intake of sildenafil, five patients (age range 42-69 years) developed NAION in one eye within minutes to hours.22 This was considered a strong association as 80 per cent of these patients did not have any vascular risk factors for ischaemic optic neuropathy. All patients developed unilateral blurry vision, altitudinal visual field defects, and optic disc oedema. Every patient had a small cup-to-disc ratio, which may be a risk factor for the development of sildenafil-associated NAION.29,30,22 A small cup-to-disc ratio may cause crowding of the retinal ganglion cell axons at the cup, making them more susceptible to damage. Subsequently, seven other patients (age range 50-69 years) who developed NAION within 36 hours post administration of sildenafil were reported.31
Case reports of two males revealed the development of non-arteritic anterior ischaemic optic neuropathy less than 24 hours post administration of 50mg sildenafil.22,32,33 More recently, two males (aged 55 and 60 years), developed bilateral NAION after ingesting 50mg Sildenafil on a regular basis.34,35 In another case, a 36-year-old man who had renal and hypotension problems, developed NAION post administration of 50mg sildenafil.36 Also, a male with hypertension (63 years of age) developed NAION and experienced a progressive monocular visual field defect following three successive doses of sildenafil.37 In addition, three other males also developed unilateral NAION following consumption of 50mg sildenafil.38,39,40 According to the FDA (Food and Drug Administration), there have been a total of 38 cases of sildenafil-associated NAION.41
Tadalafil has been associated with the development of NAION in four individuals, and one vardenafil-associated case.42,43,44,41
The above suggests a strong causal association between PDE-5 inhibitors and the development or progression of NAION. However, it cannot be confirmed with just case reports and observational studies as there is no control for confounding factors. Randomised, double-blind, placebo-controlled clinical trials give more accurate evidence. Data collected from 100 clinical trials of sildenafil (which involved more than 13,000 individuals) revealed only one case of NAION.41 Therefore, the only argument against the association is the low incidence of NAION in the large population of men who have used PDE-5 inhibitors,41 suggesting that the development of NAION after PDE-5 inhibitor use may be coincidental rather than causative. This is supported by the fact that majority of the patients who developed NAION after PDE-5 inhibitor use already had risk factors for NAION, such as a small cup-to-disc ratio, vascular risk factors such as diabetes or hypertension and unilateral NAION.13,26
However, there has been one case where a six-year-old girl who regularly used sildenafil for pulmonary hypertension developed a unilateral NAION, although she had no risk factors for NAION.45 Taking into account that NAION is rare in children, this suggests a causative link between NAION and PDE-5 inhibitor administration.26 Danesh-Meyer and Levin46 have also argued that the pharmacovigilance (safety) trials of PDE-inhibitor safety were not large enough to reliably exclude the increased risk of NAION. Therefore, patients with pre-existing unilateral NAION should not be prescribed PDE-5 inhibitors, as it could induce NAION in the unaffected eye.31 PDE-5 inhibitors may also increase the risk of NAION in patients with a history of myocardial infarction or hypertension.26
The pathogenesis of NAION is unclear. The sudden visual loss in NAION is usually on waking, therefore NAION could occur as a result of nocturnal arterial hypotension.47 Ambulatory blood pressure monitoring revealed a substantial correlation between the progressive visual loss in NAION and nocturnal arterial hypotension.48 This indicates that hypotension encourages NAION, and since PDE-5 inhibitors reduce mean systolic and diastolic blood pressures by approximately 10mmHg (causing systemic hypotension), it might increase the risk of NAION in this way.26 In addition, PDE-5 inhibitors have been shown to increase plasma concentrations of noradrenaline by 31 per cent.49 PDE-5 inhibitors may therefore stimulate the release of vasoconstrictors from the peripapillary choroid, thereby causing optic nerve head ischemia, leading to NAION.
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Lenuja Kuganeswaran is now a pre-registration optometrist. The dissertation was supervised by Professor Ron Douglas.