Sildenafil: Looking Beyond Erectile Dysfunction: A Dermatological Perspective

Introduction Sildenafil, a phophodiesterase-5 inhibitor, has been used since the 1990s for the treatment of erectile dysfunction. Later, its use broadened to include the management of patients with pulmonary arterial hypertension. Currently, the spectrum of sildenafil further expands to cover a number of dermatological entities and will be explored in this exposition. Pharmacokinetics Following oral administration, sildenafil gets rapidly absorbed, reaching peak plasma concentrations within 30 min to 2 h. The half-life of sildenafil is 3–5 h, with its metabolism occurring primarily in the liver and excretion taking place through the fecal route.[1] Clinical Uses in Dermatology Raynaud's phenomenon Raynaud's phenomenon (RP) is an episodic, vasospastic condition, occurring secondary to digital vascular compromise, following exposure to cold and/or emotional stressors. Besides the uncomplicated primary RP, the secondary variant observed in connective tissue disorders presents more severely, with potentially disabling ulceration or tissue necrosis.[2] Sildenafil has been employed in the treatment of refractory RP in connective tissue disorders complicated by digital ischemia and/or gangrene.[3,4] The mechanism of action of sildenafil in RP is depicted in Figure 1.[5,6]Figure 1: Mechanism of action of sildenafil in Raynaud's phenomenonLichtenstein[7] was the first to utilize sildenafil (50 mg/day for 4 weeks) in ten patients with RP (both primary RP and RP secondary to systemic lupus erythematosus, CREST syndrome or systemic sclerosis) and demonstrated excellent to complete relief of symptoms along with healing of digital ulcers following treatment. Besides, in this series, most patients were unresponsive to calcium channel blockers. Fries et al.[8] described sildenafil (50 mg BID) to be effective and well tolerated in patients with secondary RP unresponsive to vasodilatory therapy (that included calcium channel blockers, Bosentan, pentoxyfylline, IV prostaglandin, and ACE inhibitors). In all patients who had chronic digital ulcerations, trophic lesions began to clearly, visibly heal during sildenafil treatment, with two patients elucidating complete healing. However, ulcers reappeared when sildenafil treatment was stopped. While patients were taking sildenafil, the mean frequency of Raynaud's attacks was significantly lower, the cumulative attack duration was notably shorter and the mean Raynaud's condition score had remarkably declined. Besides, capillary blood flow velocity increased in each patient, and the mean capillary blood flow velocity more than quadrupled in all patients post sildenafil therapy. Moreover, treatment with sildenafil was tolerated by most patients, except two, who withdrew from the study due to treatment related headache and muscle pain of the lower extremities. However, in the placebo-controlled SEDUCE study, sildenafil (20 mg TID) did not shorten the time of healing of digital ulcers in systemic sclerosis. Nonetheless, results were in favor of sildenafil in the intention to treat and per protocol study subjects, with significantly lower number of digital ulcers at week 8 and 12 of treatment, substantiating the benefit of sildenafil for the same.[4] Interestingly, in a case report of a 53-year-old male with RP, secondary to chemotherapy with carboplatin for oral squamous cell carcinoma, sildenafil proved ineffective in ameliorating the condition. Although, on switching to tadalafil, RP improved, and was linked to the longer half-life of tadalafil versus sildenafil (17 h vs. 3.8 h).[9] In the pilot study by Brueckner et al.,[10] although sildenafil (50–150 mg/day) demonstrated initial benefit in digital ulcer healing (within the treatment period of 6 months), a significant proportion of patients developed new digital ulcers, suggesting failure of sildenafil in preventing new structural defects. Even so, only one patient highlighted mild improvement by angiography. This concludes the existence of other pathogenic mechanisms for the development of digital ulcers which needs appropriate management. Combination therapy can therefore provide a superior alternative, targeting a wide array of pathogenic mechanisms for the same. Simultaneous use of sildenafil and bosentan (an endothelial receptor antagonist) has been effectively utilized particularly in recalcitrant systemic sclerosis patients associated with RP [Table 1].[11–15]Table 1: Reports elaborating the use of sildenafil and bosentan combination in Raynaud's phenomenonAlopecia Choi et al.[16] evaluated the role of sildenafil in promoting hair growth in vivo; confirming the same using the anagen induction assay in C57BL/6 mice, as well as in cultured human dermal papilla cells (hDPCs). The cultured hDPCs were treated for 48 h with various concentrations of sildenafil (0.1–10 μM) and assessed for its effect on hair growth. It was observed that cellular proliferation was higher in hDPCs treated with sildenafil than in vehicle-treated control cells. Besides, escalated expression of growth factors like vascular endothelial growth factor and platelet derived growth factor was documented, outlining a dose-dependent increase following treatment with sildenafil. In addition, sildenafil up-regulated phosphorylation of extracellular signal-regulated kinase (ERK) in endothelial cells and hDPCs in a time-dependent manner [Figure 2].[16] Because ERK is an important member of the mitogen-activated protein kinase family involved in regulation of cell growth; sildenafil by activating signal transduction pathways may regulate cell proliferation in hDPCs, and in this way enhance hair growth. Furthermore, the authors discovered spontaneous entry of hair follicles into the anagen phase from the telogen phase following application of a topical preparation of sildenafil (0.1%–1%) on the shaved back of C57BL/6 mice within 7 days of treatment initiation that was confirmed on histopathology. Furthermore, an approximately 2-fold increase in the size of perifollicular blood vessels was documented with sildenafil, which was absent in the control group. Based on these findings, the authors hypothesized the utility of sildenafil as an additional therapeutic agent for alopecia.[16]Figure 2: Proposed mechanism of action of sildenafil in alopeciaHowever, in a pilot study on 8 children with alopecia areata (≤25% of scalp surface involvement), 1% sildenafil applied twice daily for 3 months did not delineate propitious outcomes. Of the 8 patients, only one outlined terminal hair growth, thus speculating the efficacy of sildenafil in AA.[17] More studies therefore become essential for obtaining a concrete conclusion in this regard. Lymphatic malformations Lymphatic malformations (LMs) are low-flow vascular abnormalities characterized by excessive growth of lymphatic tissue during prenatal and postnatal development. This often results in obstructive and functional complications involving vital organs, recurrent infections and disfigurement. Besides, current procedural treatments have only been partially successful, with high rates of recurrences.[18] The first report outlining the benefit of sildenafil for LM was published in 2012, following which there have been a few more reports highlighting the same [Table 2].[19–23] The mechanism underlying the role of sildenafil in LM is not quite clear. It is stated that by blocking PDE-5, sildenafil suppresses breakdown of cGMP, giving rise to relaxation of smooth muscles and vascular dilation, details of which are represented in Figure 3.[19,24]Figure 3: Mechanism of action of sildenafil in lymphatic malformationsTable 2: Reports outlining the utility of sildenafil in lymphatic malformationsLivedoid Vasculopathy Livedoid vasculopathy (LV) is a clinical condition characterized by excruciating, recurrent ulcers on the lower limbs. There exist a number of treatments for LV, with varying clinical responses. In an anecdotal report, sildenafil (12.5 mg BID, and escalated to 25 mg TID over 2 weeks) was found to bring about complete healing of peri-malleolar ulcers (within 3 months) in a 46-year-old woman who had been unresponsive to nicotinic acid, warfarin, pentoxifylline, prednisolone and aspirin. Besides, at 4 months' follow-up, no evidence of disease activity was observed.[25] In another exposition, sildenafil (50 mg BID, as monotherapy) was effective in bringing about complete healing of LV like ulcers over the dorsum of the foot, the malleoli and the anterior/posterior portions of both legs in a 57-year-old male with antiphospholipid syndrome (APS). Within 3 weeks of treatment with sildenafil, marked alleviation of pain was noticed, and by 3 months, all ulcers had fully healed. Besides, even after 18 months of follow-up, no recurrence was observed.[26] Apart from its vasodilatory properties, sildenafil elaborates angiogenic and anti-thrombotic actions, which may be of value in LV.[8,25] Retiform Purpura Retiform purpura (ReP) is a specific morphological pattern with a multi-factorial etiology encountered when blood vessels serving the skin are compromised, eventuating in downstream cutaneous ischemia, purpura and necrosis. Although not a conventional drug for ReP, sildenafil (20 mg TID) outlined promise in a 16-year-old girl with APS presenting with ReP and digital gangrene involving her toes, along with diminished dorsalis pedis pulses, who had failed to respond to treatment with enoxaparin, nifedipine, intravenous methyl prednisolone and topical nitroglycerine. Within 24–48 h of starting sildenafil, there was significant reduction of pain, marked increase in the dorsalis pedis pulses and fading of reticular erythema. Besides, the gangrene stabilized and the patient went on to lose only the tips of her left first and second toes. Moreover, the therapeutic effects of sildenafil were maintained at 14 months of follow-up.[27] The mechanism of action of sildenafil in ReP is similar to that of LV. Pressure Ulcers The use of sildenafil has been elaborated in a randomized controlled trial for pressure ulcers (PUs). Apart from the standard care of PUs, 60 patients were instructed to apply 10% sildenafil ointment once daily and 62 patients were given a placebo ointment. Following 2 weeks of treatment, it was seen that alleviation in the grades of PUs was significantly higher; as well as notable reduction in the surface area of ulcers was observed in the sildenafil group versus placebo (P < 0.001; P = 0.007).[28] The ability of sildenafil to improve micro-vascular reperfusion was considered to be responsible for its beneficial effects in PUs.[28] Despite promising findings elucidated in this report, more studies become mandatory to strengthen this observation. Vasculitis Uthman and Chaaban,[29] were the first to report the potential of sildenafil (25 mg TID) in treating Takayasu's arterits in a 8-year-old girl who also presented with severe ischemia of the left big toe and was unresponsive to pulse steroid, infliximab, aspirin, and low-molecular-weight heparin. In another report, a 40-year-old woman with diffuse cutaneous systemic sclerosis and small vessel cryoglobulinemic vasculitis, demonstrated remarkable improvement in the vasculitic rash following addition of sildenafil (50 mg/day) to the existent treatment which consisted of prednisolone, warfarin, frusemide, spironolactone, verapamil and colchicine.[30] The exact mechanism of sildenafil for vasculitis still needs elucidation. Adverse Effects Adverse effects of sildenafil are elaborated in Table 3.[31–42]Table 3: Adverse effects of sildenafilContraindications Contraindications of sildenafil are outlined in Table 4.[43]Table 4: Contraindications for sildenafil useUse in Special Populations Pregnancy There are no adequate and well-controlled studies of sildenafil in pregnancy. Small case studies in pregnant women with pulmonary arterial hypertension indicate a low risk of harm, although caution is warranted.[44] Lactation There is a lack of information about the effects of sildenafil on milk production and its effects on breastfed infants.[42] Pediatric patients Although used successfully in pediatric patients, chronic use is not recommended, with the appropriate need for drug monitoring.[42] Patients with ocular complications In patients with previous history of nonarteritic anterior ischemic optic neuropathy (NAION) or crowded optic disc, sildenafil needs to be prescribed with caution. Further, in males >50 years, a meticulous ocular examination becomes compulsory prior to prescribing sildenafil, because of an increased risk of NAION in these patients.[43] Dosage and Formulations Sildenafil can be administered orally, intravenously or sublingually. Tablets are available as 25 mg, 50 mg, and 100 mg strengths, whereas the oral suspension of sildenafil contains 10 mg/ml. Injectable preparations of sildenafil on the other hand have 10 mg of the drug in 12.5 ml.[42] For dermatological indications, the dose of sildenafil ranges from 50 to 100 mg/day. However, when combined with bosentan, doses of 12.5–25 mg/day are also effective.[4,7,8,11,13] Conclusion Sildenafil has proven to be useful in a number of dermatological indications. Apart from being readily available, it offers a favorable toxicity profile while treating dermatological disorders. Authors' contributions Design: A.K.B; Defnition of intellectual content: A.K.B; Literature search: A.K.B Clinical studies: A.K.B; Data acquisition: L.R, Y.P A.K.B; Data analysis: A.K.B; Manuscript preparation: L.R; Manuscript editing: A.K.B; Manuscript review: A.K.B. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.