Sildenafil Citrate (additional uses)

Author: Letizia Marzari
Date: 07/02/2014


by Marzari Letizia, Zandrino Enrico


Sildenafil citrate , generally sold as Viagra, is probably the most popular drug used to treat erectile dysfunction, a kind of disease that is quite relevant even from a social point of view. However, the clinical use of this drug goes beyond the treatment of male impotence, as we' ll see.


Sildenafil was synthesized by a group of pharmaceutical chemists working atPfizer's, in England. The initial trials were developed to study the effects of this molecule on angina pectoris , (a symptom of systemic heart disease). Those trials were partially unsuccessful, but researchers saw the effects of sildenafil citrate on male impotence. As a matter of fact, the first clinical trials were conducted in Morriston Hospital in Swansea. Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, so Pifzer decided to market it for erectile dysfunction rather than for angina.
The drug was patented in 1996 with the name Viagra and was approved for use in erectile dysfunction by the FDA on March 27, 1998, becoming the first oral treatment approved to treat erectile dysfunction in the United States. The drug was spread all over the world although in some countries with some problems in poor countries, were sildenafil citrate was commercialized later (in Brazil arrived only in 2010).


Sildenafil citrate ( C22H30N6O4S )is taken by the patient in the popular form of a blue pill, so there is an oral assumption and it is quickly absorbed by the intestine. This drug reaches the pick of concentration in blood in 1 hour, and this time coincide also with the pick of his effectiveness in 1 hour, although in some patients some effects may be visible even earlier.

Our body can use only 40% of Sildenafil citrate, because of his first (partial) hepatic degradation. In blood, Sildenafil is bound with many plasmatic proteins. If we analyze the metabolic process that Sildenafil undergo in liver’s cells, we discover that it is metabolized by two differents forms of cytochromeP450 which have a similar enzimatic activity: cytochromeP450 3A4 (the main one) and cytochrome P450 2C9 . The main molecule that derives from this process is N-dimetil sildenafil , which is actually is still active, although is effectiveness is reduced of about 50%. Sildenafil and N-dimetil sildenafil are eliminated through bile. A small amount is eliminated through urine. Obviously, in an old patient with hepatic or renal failure
drug’s metabolism is reduced and its effects last longer than 3,5 , which is its ordinary half-life.


Sildenafil acts as an inhibitor of cGMP - phosphodiesterase type 5 (PDE5) in the smooth muscle cell (main in the corpus cavernosum). It is necessary to describe the whole pathway that provokes smooth muscle cell relaxation to understand Sildenafil action.
Nitric oxide (NO) is one of the most powerful molecule in giving vasodilatation.
NO is produced in a reaction in which is formed NO + L-citrulline from L-arginine. Parallel, a molecule of NADPH is oxidated to NADP+. The complete reaction is:

L-arginine + NADPH + H+ + O2 --> L-citrulline + NO + NADP+

The enzyme is the NO synthase (NOS), that uses not only NADPH as cofactor, but also BH4. Without BH4 we have the dangerous production of O2-. Moreover, this ROS can oxidize BH4 and with this oxidation it prevents BH4 from working as a cofactor in this reaction.
There are 3 different kinds of NOS. Two are constitutive, so are always active in the cell, while the other is inducible.
iNOS synthase is present in immune system and cardiovascular system. It’s the inducible one.
nNOS synthase is present in SNC (NANC fibers), skeletal muscle, myocardium.
eNOS synthase is present in endothelial cells and myocardium. It is the most important of the three in smooth cell relaxation and alongside with nNOS is Ca -calmodulin dependent.
This mechanism is activated in the endotelial cells by Acetylcoline, Bradykinin and shear stress.

NO is an apolar molecule that crosses the plasma membrane and activates the soluble guanylate cyclate interacting with its receptive domain (N-terminal). Guanylate cyclase is an enzyme belonging to the family of lyases. Guanylate cyclase action consists in catalyzing the reaction of synthesis of cGMP from GTP thanks to its C- terminal.
cGMP is a second messenger useful for signal in many metabolic pathways, but in this specific case it is responsible for relaxation of the smooth cell using 3 different ways.

1) Activation of PKG, that is a kinase that phosphorylates and inhibits sarcolemmatic Ca++ channels voltage-dependents; the lack of intracellular Ca++ allows muscle cell relaxation.
2) Activation of sarcolemmatic K+ channels, which brings about hyperpolarization and again muscular cell relaxation.
3) Activation of light myosine chain phosphatase; the light chain, without the inorganic phosphate can’t exercise its contractile function.
cGMP degradation is due to the action of phosphodiesterase type 5, which is present in 6 different isoforms. This enzyme turns cGMP into GMP, destroying the phospho-ester bond.
Sildenafil is a competitive inhibitor of the enzyme, since it simulates cGMP, so it is successful in increasing the cytoplasmatic concentration of cGMP and helps cell relaxation.

Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction, 1996.

Also Tadalafil (Cialis), Avanafil (Stendra) and Vardenafil (Levitra) operate by the same mechanism.


1)Male erectile dysfunction. NO is particularly active in penis corpus cavernosum cells. Corpus cavernosum is made of two sponge-like and symmetrical regions clad of endothelium and separated by connective tissue.
Parasympathetic system leads to the relaxation of smooth cells in the helicine arteries wall: this increases arteries diameter and blood flow. This arteries communicates with corpus cavernosum which is filled by blood coming from the deep artery of penis. NO is necessary for the beginning of erection, since it has a relaxing function on corpus cavernosum and corpus spongiosum cells (that compresses urethra during erection). The volume of the organ increases in length and thickness and this exercises a compression of the veins on the tunica albuginea. This compression prevents veins from draining blood from corpus cavernosum and puts in tension tunica albuginea, becoming responsible for the characteristic tumescence of penis.

Conversely, the sympathetic system acts as an activator of smooth cell contraction that reduces blood flow and veins under tunica albuginea are allowed to drain blood. Moreover, when penis is flaccid, anastomosis between arteries and veins are opened (their sphincters are relaxed) and filled with blood, so corpus cavernosum and corpus spongiosum are almost completely empty.
Male erectile dysfunction is due to many causes:
- Drugs (antidepressants, nicotine),
- Neurogenic disorders,
- Cavernosal disorders (as in Peyronie’s disease),
- Performance anxiety, stress, mental disorders,
- Surgical events (prostatectomy),
- Kindney failure,
- Diabetes,
- Multiple sclerosis,
- Arsenic poisoning,
- Smoking (that provokes arterial narrowing)
- Aging (there is a relevant reduction of NO production after 40s).
Without sexual stimulation, and therefore lack of activation of the NO/cGMP system, sildenafil should not cause an erection.
All phosphodiesterase type 5 inhibitors are useful to treat erectile dysfunction, because they make NO/cGMP effects last longer. That is why Sildenafil is used as the standard treatment for erectile dysfunction in all settings mentioned before, including diabetes, renal failure, multiple sclerosis and prostatectomy: Sildenafil always helps erection, because it strengthens the mechanism which constitutes the base of it. (Nightly vs on-demand sildenafil for penile rehabilitation after minimally invasive nerve-sparing radical prostatectomy: results of a randomized double-blind trial with placebo, 2013 and Efficacy and safety of sildenafil citrate in hemodialysis patients, 2004) The etiology that makes erectile dysfunction less curable are multiple sclerosis and diabetes, although, even in these cases, as already said, a poor effect seems to be always present. Sildenafil citrate for erectile dysfunction in patients with multiple sclerosis, 2012 and Arterial erectile dysfunction different severities of endothelial apoptosis between diabetic patients responders and non responders to sildenafil, 2013.
To heal erectile dysfunction, it is taken not more than once per day between 30 minutes and 4 hours prior to sexual intercourse.
The use of the biggest dose of Sildenafil (100 mg) may worry some patients or the doctor that prescribes it, or some patients who do not have results with 50 mg are sometimes suspicious that 100 mg could work better. Actually, some studies confirms Sildenafil safety and tolerability in treatment of erectile dysfunction (Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction, 1996.) and other studies states that Sildenafil effectiveness is strongly dose-dependent: patients should be encouraged to use 100 mg if they are unable to achieve completely hard and fully rigid erections or SSI with the 50 mg dose. (Improvement in erection hardness and intercourse success with first dose of sildenafil citrate 100 mg, 2013 and Erectile function, erection hardness and tolerability in men treated with sildenafil 100 mg vs. 50 mg for erectile dysfunction, 2013.)
If even 100 md dose is not efficient, the new idea is the intracavernous injection, which demonstrated itself really available. (Erectile function, erection hardness and tolerability in men treated with sildenafil 100 mg vs 50 mg for erectile dysfunction, 2013.)
Having good erections and ejaculation is also required in some kind of assisted reproductive technology (ART) and PDE5 inhibitors proved to be very useful also for this aim. (PDE5 inhibitors for the management of temporary penile erectile dysfunction during treatment with assisted reproductive technology, 2013.)
Sexual efficiency is also related with total serum levels of testosterone. The great efficacy of Sildenafil made researchers suspect that the drug could act also by increasing testosterone levels. A study lead with 140 men affected by erectile dysfunction proved that the drug works even on the hypothalamic-pituitary-gonadal axis. As a matter of fact, it is demonstrated that Sildenafil produces a raising in serum DHT, Oestradiol, Androstenedione, total and free Testosterone levels and a decrease of Luteinizing hormone.
So, it is proved that Sildenafil is associated with increased testosterone levels, that exercise a more powerful effect on the testis. (Sildenafil increases serum testosterone levels by a direct action on the testes, 2013.)
The help for erection is not only through hydraulic and hormonal way, but may be also nervous. In fact, a study in 2013 demonstrated that Sildenafil is also active on central nervous system, especially in the medial preoptic area and nucleus accumbens, where there is an increment of dopamine and serotonin release during sexual arousal if the patient is treated with local Sildenafil administration.
(Experimental evidence for sildenafil's action in the central nervous system: dopamine and serotonin changes in the medial preoptic area and nucleus accumbens during sexual arousalhttp, 2013.)

2) Priapism. Some studies show that Sildenafil has also a quite paradoxical effect in healing "priapism: It is a particular medical condition, considered as a medical emergency, in which the erect penis does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. Actually, the duration time of a normal erection before it is classifiable as priapism is still controversial. It is due to several causes and treatment is different for each type. Moreover, early treatment can be beneficial for a functional recovery. Among the most frequent causes, we find haematological disorders, especially sickle cell disease, sickle-cell trait, and other conditions such as leukemia, beta-thalassemia, Fabry’s disease and neurologic disorders such as spinal cord trauma (priapism has been reported in hanging victims).
But priapism may also be associated with glucose-6-phosphate dehydrogenase deficiency, which leads to decreased NADPH levels, a co-factor involved in the formation of nitric oxide, which may result in priapism. The connection is quite simple: NO is a vasodilator that can act also downstream of corpus cavernosum, and doing this, it solves the first etiological cause of priapism: low blood flow from the organ to the body, which causes blood stagnation and prolonged erection.
On this point, were made several studies both on mice and men and their conclusion is the same. (Sildenafil citrate-restored eNOS and PDE5 regulation in sickle cell mouse penis prevents priapism via control of oxidative/nitrosative stress, 2013. Glucose-6-phosphate dehydrogenase deficiency associated stuttering priapism: report of a case, 2008. Potential risks of chronic sildenafil use for priapism in sickle cell disease, 2011.)
As reported in those articles, Sildenafil use to heal priapism gives good results both on priapism due to sickle cell disease and on priapism due to glucose-6-phosphate dehydrogenase deficiency, but a chronic Sildenafil use for priapism in sickle cells disease hides some potential risks. The efficacy is particularly evident in a prevention program, rather than in treatment. (Feasibility of the use of phosphodiesterase type 5 inhibitors in a pharmacologic prevention program for recurrent priapism, 2006. Long-term oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism, 2006.
Actually, there are some forms of priapism that don’t affect veins: we find arterial priapism (as a consequence of the break of a cavernous artery) or idiopathic priapism (which has a psychological origin). Those forms are less treatable with Sildenafil.
To sum up, we have many traditional drugs used to treat priapism (Phenylephrine, Terbutaline, Methylene blue) and surgery in the most critical cases, but also Sildenafil is a drug that could be used for this purpose, although obviously it is not the default treatment.
As already said, this use of Sildenafil it is quite paradoxical, especially if we consider that Sildenafil itself is sometimes responsible for cases of priapism (especially when taken in an excessive dose). (Sildenafil induced priapism, 2006. Sildenafil citrate ingestion and prolonged priapism and tachycardia in a pediatric patient, 2007. Priapism Induced With Single Oral Dose Of Sildenafil: A Rare Case Report, 2010. Sildenafil induced priapism, 1999.)

3) Dysmenorrea. Sildenafil appears to help women who are suffering from moderate to severe menstrual cramps, according to some studies, one of which was funded by the U.S. National Institutes of Health. In this case the administration is not oral, but the same molecule, if administered vaginally, provides nearly double the pain relief compared to a second group of women who received a placebo, or dummy drug. Ibuprofen and other nonsteroidal anti-inflammatory drugs are the current first-line treatment for menstrual cramps, but they do not work well for all women and can cause ulcers and kidney damage through prolonged use. The researchers thought Viagra could dilate blood vessels and increase blood flow to the uterus, which might help relieve pain: their intuition was correct. Sildenafil efficacy is excellent in treatment of menstrual cramps, but also in the most severe pelvic inflammatory disease (actually it starts to be used for small menstrual cramps, but not yet for PID). Moreover, this local application doesn’t presents many of the side effects that are typical of the oral use. "(Vaginally administered erectile dysfunction medication may alleviate menstrual cramping, study suggests, 2013. and Sildenafil citrate in the treatment of pain in primary dysmenorrhea: a randomized controlled trial, 2013.)

4) Pulmonary hypertension. Pulmonary hypertension can be acute or chronic. The acute form is an increase of pulmonary arteries pressure which derives from pulmonary embolism and distress respiratory syndrome. The chronic form is the most common and is related to heart diseases (congenital or not), vasculitis, pulmonary emphysema, interstitial fibrosis, apnea during sleep, sickle cell disease, beta-talassemia or it may be idiopathic. Histologically, the disease develops thanks to an endothelial modification and proliferation of the cells in the arteries wall: resistance is increased and we have hypertension. One of the standard symptom of pulmonary hypertension is right ventricle failure, which is secondary to the increase of pressure in pulmonary circulation.
Sildenafil relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This, in turn, reduces the workload of the right ventricle of the heart and improves symptoms of right-sided heart failure. Because PDE5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, sildenafil acts selectively in both these areas without inducing strong vasodilation in other areas of the body.
(Long-term treatment with high-dose of sildenafil in a thalassemic patient with pulmonary hypertension, 2012 and Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension, 2005.). Differently from other treatments, Sildenafil proved to be successful versus PHA, but it appears to have no effect on mortality or serious adverse events (Efficacy and safety of sildenafil treatment in pulmonary arterial hypertension: A systematic review, 2014.)
One of the causes of PHA is the high-altitude pulmonary edema associated with altitude sickness such as that suffered by mountain climbers. (Phosphodiesterase type 5 and high altitude pulmonary hypertension, 2005.)
Since PHA may also occur in newborn, it is used also to treat this disease in pediatric patients. (Oral sildenafil and inhaled iloprost in the treatment of pulmonary hypertension of the newborn, 2014. and Sildenafil add-on therapy in paediatric pulmonary arterial hypertension, experiences of a national referral centre, 2014.).
Sildenafil joins some more advanced therapies based on Bosentan, Prostacyclins, calcium channel blockers and lung transplant.

5) After Fontan procedure. Fontan procedure is a palliative surgical procedure used in children with complex congenital heart defects. It involves diverting the venous blood from the right atrium to the pulmonary arteries without passing through the morphologic right ventricle and it is used especially for those children who only has a single effective ventricle or they present an abnormality of the pumping ability of the heart.

This procedure is quite efficient, but there are some contraindications: after Fontan procedure, blood must flow through the lungs without being pumped by the heart. Therefore children with high pulmonary vascular resistance may not tolerate very well a Fontan procedure, although in some situations its use is almost inevitable.
Sildenafil can be used to help blood circulation in pulmonary vessels since it has a vasodilator action, especially in those patients that develop plastic bronchitis after the Fontan procedure. Sildenafil manages to reduce the resistance, in accordance with a principle very similar to that at the base of treatment of the standard pulmonary hypertension (after Fontan procedure the condition may be even more critical, with a complete stenosis, that is why we have differentiated the two cases).
(Sildenafil Improves Exercise Hemodynamics in Fontan Patients, 2014. Pulmonary vasodilation therapy with sildenafil citrate in a patient with plastic bronchitis after the Fontan procedure for hypoplastic left heart syndrome, 2006. Lost unilateral capillary perfusion during nonpulsatile pulmonary circulation: successful recovery by oral sildenafil, 2012.)

6) Muscular dystrophy. Sildenafil, alongside with Tadalafil and other PDE5 inhibitors is useful also in treating muscular dystrophies of different kind, including genetic dystrophy such as Becker muscular dystrophy (X- linked), which is very similar to Duchenne dystrophy because they both lack of working dystrophin
Dystrophin is a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin’s rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle.


A possible future use of Sildenafil citrate is about gastroenteritis treatment. The idea to use Sildenafil to treat gastroenteritis goes back to the use of Omeprazole, that, according to some researches, act against gastritis both as proton pump inhibitor and vasodilator. This idea suggests that Sildenafil, being a vasodilator, could exercise in a similar way.
Actually, several studies led on mice and rats seem to demonstrate that this deduction is correct.
First of all, we have a strong vasodilator and pain removal exercised on the stomach. Gastric damage could be induced by several factor; one example is the alcohol-induced gastric damage, that, according to a study on rats, is treatable with Sildenafil not only thanks to its vasodilator effect that extend NO action, but also thanks to the regulation of ATP-sensitive potassium channels (that causes hyperpolarization, so relaxation). (Sildenafil reduces alcohol-induced gastric damage: just say NO, 2008)
Another possible damaging factor is Indomethacin assumption, that gives the opportunity to test again the gastroprotective use of Sildenafil. This second study demonstrate that Sildenafil can protect the gastric mucosa against the aggressive effect of Indomethacin via increasing NO (as already said in the previous study) and also inhibiting lipid peroxidation. Therefore, sildenafil might be helpful in preventing the gastric adverse effects of non-steroidal anti-inflammatory drugs in a clinical setting. (Sildenafil citrate protects against gastric mucosal damage induced by indomethacin in rats,2013)
Sildenafil effects are similar also on the lower intestine. For example, an interesting study show how Sildenafil vasodilator action is helpful in preventing colitis, since it increases NO, but also it prevents apoptosis, cytokine release and superoxide production, all factors that are responsible for colitis genesis.
(The effect of phosphodiesterase-5 inhibition by Sildenafil citrate on inflammation and apoptosis in rat experimental colitis, 2011)
Another similar study states Sildenafil efficacy against colitis. This time the study stresses how Sildenafil acts on the lower intestine vessels: both on the NO/cGMP pathway and on ATP-sensitive potassium channels, as already resulted from the study led on Sildenafil effects on stomach.
(SIldenafil attenuates TNBS-induced colitis in rats:possible involvement of cGMP and KATP channels, 2012)
Sildenafil efficiency is the same for different kind of colitis. For example, that provoked by acid acetic is again treatable with Sildenafil, that act on all the pathways previously exposed and it is also efficient in preventing neutrophil accumulation. (The effect of Sildenafil, a phosphodiesterase-5 inhibitor, on acetic acid-induced colic inflammation in the rat, 2009)
Several colitis are classified as ischemic colitis, since the pain that derives from them is to an ischemic problem: it is easy to think how Sildenafil act solving this disease thanks to its vasodilator effect. (The effect of Sildenafil on an naimal model for ischemic colitis, 2008)
The conclusion is that Sildenafil is really effective in gastroenteritis treatment: for this reason we are also legitimated to think that are effective against gastroenteritis all the compounds that act on the NO/cGMP pathway, including NO precursor as arginine.

Treatment of obesity is probably the most unexpected side of Sildenafil effects. To make that discovery, Pfeifer researchers used mice to show that cGMP is useful in reducing the secretion of pro-inflammatory hormones, which, in turn, shifted the "color code" of fat from white to brown and we know very well how brown fat is “healthier” than white fat.
(Drug for erectile disorder show promise in the treatment of obesity, 2013.)
In conclusion, those studies were conducted on mice and this theory will require some further studies to state if Sildenafil it is really useful to cure human girth disorders, but this possibility is absolutely exciting.

Sildenafil may be a proper drug to reduce vascular oxidative stress in insulin-resistant patients. As a matter of fact, Insulin resistance features both endothelial dysfunction and increased oxidative stress: both disorders are targeted by a chronic treatment with Sildenafil. This is proved by an authoritative study, but, while Sildenafil exertion of increasing NO action and helping endothelial dysfunction is now completely clear, its effects on reactive oxygen species sources is still largely unknown. This study was led on rats, so this anti-oxidative stress on humans is still surrounded by doubt. This double effect of Sildenafil is visible only if it is administrated chronically twice daily in a 20mg/kg dose for 3 weeks. The result is that chronic sildenafil administration corrected hyperglycemia, hyperinsulinemia and hypertriglyceridemia. Even 1 week after stopping Sildenafil use on rats, NO levels were still higher than usual because of an up-regulation of eNOS. Also vascular superoxide release was reduced and those factors (NO increase, superoxide decrease) have a strong antioxidant effects. This supports therefore further investigations using chronic sildenafil administration in preventing cardiovascular alterations associated with oxidative stress.
(How does chronic sildenafil prevent vascular oxidative stress in insulin-resistant rats?, 2010. )
Moreover, the oxidative stress is also implicated in the pathogenesis of renovascular hypertension, which is actually induced by renal artery stenosis in kidney. The experiment was led again on mice, thanks to a left renal artery clipping that simulates a serious condition of stenosis. Administering Sildenafil to mice, they discovered that Sildenafil has a protective effect on the stenotic kidneys of mice. suggesting a new use of phosphodiesterase 5 inhibitors for protection against the DNA damage observed in the hypoperfused kidneys of individuals with renovascular hypertension. The evidences were very clear, because they measured all the most relevant parameters to monitor oxidative stress and DNA damage, such as mean arterial pressure, intrarenal angiotensin II, intracellular superoxide anions, hydrogen peroxide levels, nitric oxide bioavailability and they used cytometry to evaluate cell viability and the comet assay to evaluate DNA damage. Anyway, Further translational research is necessary to delineate the mechanisms involved in the prevention of renal stenosis in the clinical setting.
(Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension, 2014.)
That’s why we now hope that Sildenafil could be also a nephroprotective drug. Moreover, from another study resulted that rats treated with cyclosporine A develop a form of nephrotoxicity which is
nitric oxide deficiency-related. In those rats, Sildenafil exhibited nephroprotective effects as evidenced by significant decrease in serum creatinine and urea levels, spot urine albumin-creatinine ratio, as well as levels of renal malondialdehyde and nitric oxide, with a concurrent increase in renal level of reduced glutathione and catalase activity. (Sildenafil protects against nitric oxide deficiency-related nephrotoxicity in cyclosporine A treated rats, 2013.)

Future treatment of scleroderma is more even likely than obesity one. Scleroderma is a chronic autoimmune disease characterized by fibrosis, vascular alterations, and autoantibodies.

There are two major forms:
- Limited systemic sclerosis involves cutaneous manifestations that mainly affect the hands, arms, and face
It is related to some complications, such as calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, telengiectasias. Additionally, pulmonary arterial hypertension may occur in one third of the patients.
- Diffuse systemic sclerosis is a bit different, especially because it is rapidly progressing and affects a large area of the skin and one or more internal organs, frequently the kidneys, esophagus, heart, and lungs. This form of scleroderma can be quite disabling.
The etiology is not clear: probably there is a genetic component, in other cases the cause seems to be an excessive immune response to Parvovirus B19 or Citomegalovirus infection.
All the organ damages are due to vascular problems: scleroderma affects arterioles in all organs. First of all, there is a degeneration of the endothelial cells and the smooth muscle cells by a process of apoptosis. The tissue is substituted by collagen and other fibrous material.
There are no treatments for scleroderma itself, but individual organ system complications are treated.
Though it is not at all the first-choice drug, Sildenafil works quite well in scleroderma treatment. Its effects are particularly evident on skin ulcers, Raynaud’s phenomenon and pulmonary hypertension that follow both forms of scleroderma as complications.
(Severe refractory fingertip ulcerations in a patient with scleroderma: successful treatment with sildenafil. Oral sildenafil in skin ulcers secondary to systemic sclerosis, 2011. Efficacy of combination therapy with bosentan and sildenafil for refractory pulmonary arterial hypertension associated with fibrotic lung in systemic sclerosis.)
The explanation of this effect goes back to the etiology of scleroderma: it is thought that reduced NO levels play a role in the pathogenesis of vascular disease in scleroderma, and Sildenafil efficacy in treating scleroderma is an indirect evidence of this.

Sildenafil is useful also against female sexual dysfunction. Sexual dysfunction is not only typical of men, but of women as well. Generally, we refer to a female sexual arousal disorder, a disorder characterized by the inability to attain sexual arousal until the end of sexual activity. Its symptoms are inadequate lubrication, anorgasmia, erectile dysfunction (clitoris is the erectile organ in women, responsible for much of sexual arousal).
The causes of this disorder are several: traumatic event during childhood, relationship factors, social context, physical factor and it can be also iatrogenic. FDA has never approved a drug treatment for disorders of female libido, although several drugs have, in studies, proven efficacious.
For example, pharmaceutical companies are beginning to promote products to treat FSD, often involving low doses of testosterone. Also Sildenafil demonstrated its efficacy with mechanisms analogue to that described for men. (Toward personalized sexual medicine (part 2): testosterone combined with a PDE5 inhibitor increases sexual satisfaction in women with HSDD and FSAD, and a low sensitive system for sexual cues, 2013. Sildenafil Works for Women with Sexual Arousal Problems, 2011.).
One of the most frequent causes of female sexual dysfunction is treatment with antidepressants, primarily selective serotonin reuptake inhibitors. In these women the problem is solved taking oral pills of 50 mg or 100 mg Sildenafil.
(Toward personalized sexual medicine (part 3): testosterone combined with a Serotonin1A receptor agonist increases sexual satisfaction in women with HSDD and FSAD, and dysfunctional activation of sexual inhibitory mechanisms. Sildenafil for Women Patients With Antidepressant-Induced Sexual Dysfunction, 1999)
Anyway, some studies have a different response on this point: that is why its efficacy is still not certain and it is necessary to have stronger evidences to begin to use it as a standard drug for this disorder. (Influence of sildenafil on genital engorgement in women with female sexual arousal disorder, 2012.)

Another aspect is the possible use against female infertility. Another aspect is the possible use against female infertility. In women who suffer from infertility, one of the possible solutions is ovulation induction. This method, in its subsequent phases, requires a good endometrial thickness and texture in order to have a satisfactory endometrial receptivity. A study lead on 42 patients and published in 2013 showed how the combined action of Sildenafil citrate and Serophene is effective as a first-line of treatment for ovulation induction. The explanation again goes back to Sildenafil vasodilator action that makes endometrium thicker.
(The effect of vaginal sildenafil citrate on uterine blood flow and endometrium in the infertile women, 2013.)

Sildenafil use for decreased muscle function in cancer is also among the possibilities. Professional athletes have been documented using sildenafil, believing the opening of their blood vessels will enrich their muscles. In turn, they believe that it will enhance their performance. Although this attitude may be dangerous, and this is not a proper medical use, it seems that Sildenafil not only helps systemic blood flow (less than in other specific districts as corpus cavernosum), but it even increases muscle protein synthesis and reduces muscle fatigue. (Sildenafil increases muscle protein synthesis and reduces muscle fatigue, 2013.). This aspect could be particularly helpful for muscular dystrophy patients (as already said before), or patients affected by cancer when reduction in skeletal muscle function is particularly dramatic. Obviously, Sildenafil is still far from being a standard choice for treating this diseases, but this aspect is absolutely fascinating.

Also for jet leg recovery treatment there are some possibilities. This is almost a curiosity: the 2007 Ig Nobel Prize in Aviation went to Patricia V. Agostino, Santiago A. Plano, and Diego A. Golombek of Universidad Nacional de Quilmes, for their discovery that Viagra helps treat jet lag recovery in hamsters. Always acting on c-GMP. cGMP signals blood-vessel dilation as well as modulation of the body's internal clock in response to changes in light/dark cycles. Their research was published in the Proceedings of the National Academy of Sciences. (Viagra cures hamster jetlag, 2007.)
However their funny and pseudo-scientific attitude may give a suggestion for some serious studies with the purpose to discover if a similar phenomenon could be partially found in humans as well. If the drug does work in humans, it could be easier to use than melatonin, although the idea of taking Sildenafil to recover from jet lag is a bit strange, especially if we consider that it has some serious side effects.


- Ophthalmic toxicity. All the PDE5 inhibitors are associated with adverse effects on several ocular structures. The cause of these effects is that these drugs interact with retinal phosphodiesterase, the enzyme involved in the phototransduction of the light signal in retinal cells, a system that exploits cGMP as intracellular signal. The OMS database contains 892 cases of adverse ocular events are associated with PDE5 inhibitors (82 related to Sildenafil). If during the assumption some ocular problem appear, we must stop the administration, because the patient risks blurred vision, altered color perception,
conjunctival hyperemia, ocular pain, photophobia: all this alterations present a clear causal relationship and association with PDE5 inhibitors treatment. For other reaction, the causal link is only possible (mydriasis, ocular haemorrhage). Although FDA data are clear and the association is logical, many studies never found those kind of side effects in Sildenafil use (Does therapeutic dose of sildenafil citrate treatment lead to central serous chorioretinopathy in patients with erectile dysfunction?, 2013. and Retinal effects of 6 months of daily use of tadalafil or sildenafil., 2009.). In our opinion, the explanation is that this risk really exist; it is very serious but quite rare, and a study with less than 100 subjects may not evidence it.

- Nasal congestion. Nasal congestion is due to the vasodilatation induced by Sildenafil, although the vasodilator effect is more evident in other districts (lung, penis, uterus). This vasodilatation increases the resistance in the air conduction pathways.

- Dyspepsia. According to FDA data, on 327398 people who take Viagra, 604 experience dyspepsia.

- Emesis. The are some isolated cases of post-coital vomiting after taking Sildenafil, although researches usually don’t report of a strict cause/effect relationship between Viagra and vomiting. (Postcoital vomiting after taking sildenafil?, 2013.)

- Diarrhea.

- Cephalalgy.

- Facial flushing. Facial flushing is obviously provoked by the vasodilatation and the excessive facial blood flow.

- Priapism. As already said, although Sildenafil is quite paradoxically used to treat some forms of priapism, but in many other cases it is still a drug that can induce priapism itself because of its strong vasodilatation that helps penis blood flow.


This drug shouldn’t be assumed in some patients with specific medical conditions or is advisable to avoid Sildenafil assumption contemporary with other drugs. It follows a detailed list of contraindications.

- Cardiopathy. Almost every kind of cardiopathic patient is at risk when assumes Sildenafil, for many reasons. First of all, there is a percentage of cardiovascular risk in sexual activity itself. Moreover, Sildenafil may induce hypotension, a condition that may be dangerous for some cardiopathic patients. Those who have the higher percentage of risk are people that suffer from hypotension, aortic stenosis, multiple system atrophy. Sildenafil can bring about myocardial infarction, angina pectoris, severe hypotension, sudden cardiac death. Many of the subjects that experience those side effects are cardiopathics.
However, we have no studies that state with a statistic significance of increased cardiovascular risk in cardiopathic patients treated with Sildenafil against placebo (only isolated cases), but the administration of Sildenafil for that category always need an careful evaluation of risk/benefit. (The relationship between acute coronary syndrome and sildenafil, 2013.)

- Treatment of erectile dysfunction with other drugs. Actually, the combined use of Sildenafil with other drugs for erectile dysfunction is not clear, so this is not recommended.

- Tendency to priapism. If the subject has some anatomical defect such as accentuated angulation of penis, cavernous fibrosis or tendency to priapism (because of multiple myeloma, leukemia, SCD), Sildenafil should be administered very cautiously.

- Treatment with vitamin K antagonists. The co-administration of Sildenafil and vitamin K antagonists (drugs that inhibit coagulation, such as coumarines,) in patients that suffer from pulmonary hypertension may induce an increased hemorrhagic risk.

- Coagulopathy. If the patient is affected by coagulopathy the use of Sildenafil should be considered almost as forbidden for two reasons: first of all, if the patient as some problem with coagulation, an increased blood flow doesn’t help his condition; secondarily, it is proved that Sildenafil potentiates platelet anti-aggregation in nitroprusside sodium.

- Esophageal hypomotility. Patients with a reduce esophageal motility may present an increased risk of esophageal ulcer after assumption. In order to reduce this risk, for this kind of patients is advisable that they take Sildenafil with much water.
The most critic form of esophageal hypomotility is achalasia, a condition in which there is a progressive reduction of esophageal muscle motility until it completely disappears. Parallel, LES is completely contracted, and esophageal content is dramatically blocked in esophagus itself. The most important inhibiting neurotransmitter regulating gastroesophageal motility is Acetilcoline, but also NO plays an important role: it induces a progressive muscle relaxation and is particularly dangerous for patients who already suffer from achalasia.
(Effects of sildenafil on esophageal motility of patients with idiopathic achalasia, 2000.)

- Hereditary retinal disorders. As already stated in the previous paragraph, Sildenafil may cause some ophthalmic problems, especially in retina; if retina is hereditarily compromised (especially in retinitis pigmentosa) Sildenafil use is obviously not advisable.

- Treatment with nitrates or NO donors. The association of Sildenafil with this compounds is dangerous because they act on the same metabolic pathway an their combined effect is excessive and really worrying.

- Treatment with CYP450 3A4 inhibitors. Compounds like Ketoconazole, Erythromycin, Clarithromycin, grapefruit juice, Ritonavir, Itraconazole, Saquinavir, Cimetidine and Nicorandil are CYP 3A4 inhibitors: their action modifies the Sildenafil Pharmacokinetics and its presence in blood is dangerously increased. For this reason, it is strongly recommended an accurate evaluation of Sildenafil doses in these cases (20 mg in parallel with weak CYP 3A4 inhibitors or even no administration during stronger CYP 3A4 inhibitors as Ketoconazole).

- Aging. Old people have a reduced hepatic activity, and, as a consequence of that, also CYP 3A4 and CYP 2C9 don’t work properly. So, for the same principle described in the previous point, Sildenafil persistence in blood is dangerously increased in old patients. That is why, although some studies proved that Sildenafil is very active even in old patients ("Medical management of erectile dysfunction in aging males: Is it too late to treat?, 2014";, Sildenafil is forbidden or at least its doses have to be reduced in old people because of the increased risk of side effects.

-Pregnancy or Breastfeeding. A woman should not take Sildenafil during pregnancy essentially as a precaution. In fact, animal data have failed to reveal evidence of teratogenicity or fetotoxicity even after huge doses of Sildenafil; moreover, there are no data on the excretion of sildenafil in human milk. Even better, Sildenafil is even recommended for episodes of severe pulmonary hypertension or placental ischemia in pregnant women. (Sildenafil attenuates placental ischemia-induced hypertension, 2013)

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