Sildenafil belongs to a class of chemicals known as PDE5 inhibitors. c-GMP-specific phosphodiesterase type 5 is found primarily in the corpus cavernosum area of the penis and in the retina. PDE5 breaks down c-GMP and allows the smooth muscle lining of the blood vessels leading to the corpus cavernosum to relax and thereby induce or improve bloodflow into the penis, creating or maintaining penile erection. Due to a variety of reasons, men sometimes experience erectile dysfunction (ED) and sildenafil, trade name Viagra (Pfizer, Inc.), is considered a first line of treatment; it is generally effective independent of the causation factor of ED, although clinically a thorough examination is indicated in the event of ED due to the fact that ED can sometimes be a symptom of a more serious underlying problem that would remain unaddressed by sildenafil, such as diabetes, heart disease, or hyper- or hypotension. PDE5 inhibitors in general, and sildanefil in particular, are proving promising in other areas of research, such as angina (the disorder on which research initially led to discovery of sildenafil), pulmonary hypertension, and even neurogenesis in a post-stroke physical environment.
The pathway via which sildenafil acts on the corpus cavernosum tissue is known as the nitric oxide (NO) pathway. Release of NO is caused by sexual stimulation; NO activates the guanylate cyclase enzyme, resulting in increase levels of c-GMP which relaxes the smooth muscle in the blood vessels reaching the corpus cavernosum, allowing attainment of erection. Sildenafil affects this process via a reduction in PDE5; PDE5 reduces c-GMP levels. Some sexual stimulation is therefore necessary (as opposed to in the case of dopamine-agonism-based sexual therapies) for sildenafil to exert its effects.
Sildenafil is indicated for use in men but is seldom used in women; however, Ishak claims that “data support several potential treatments [for female anorgasmia] such as bupropion, sildenafil, estrogen, and testosterone among others.”
Dorsey et al sum up the current state of PDE5 inhibitors (PDE5i); sildenafil is only one of several, each with unique properties and circulating lives. As a group PDE5 inhibitors are being viewed as more versatile as more research comes to light:
PDE5i will remain the mainstay initial medical treatment for ED and will play a larger role in the treatment of other medical conditions. Novel formulations in this class will allow patients to select agents that best suit their needs.
Sildanefil may be useful in a special population of donor organ recipients who experience pre-transplant pulmonary arterial hypertension resulting in right ventricular dysfunction after the transplant:
Early right ventricular dysfunction after heart transplantation (HTx) is a major complication especially in patients with pre-transplant pulmonary arterial hypertension (PH). The possibility to reverse secondary PH using sodium nitroprusside (NPS) or inhaled nitric oxide has been already established and there is a well-known stratification of the incidence of early death after HTx related to the reversibility of PH. Despite this, in a group of patients with irreversible disorders of the pulmonary vascular bed, conventional therapy may not be useful. However, the decision to disqualify non-responsive HTx candidates may be inappropriate, considering that PH unresponsiveness to NPS does not exclude the possibility to decrease pulmonary pressures with other medications. In case of non-responsive patients, the debate regarding the role of new selective pulmonary vasodilators is still open and oral sildenafil use in cardiac transplant candidates and recipients is growing. Despite this, there are many reports of the use of phosphodiesterase 5 inhibitors in patients with chronic heart failure and several studies describe the positive effects of sildenafil in reducing pulmonary vascular resistance and pulmonary arterial pressure and in increasing cardiac output. Oral sildenafil use in cardiac transplant candidates or recipients is still limited.
Fraisse and Wessel write that sildenafil may soon be used in clinical treatment of childhood pulmonary hypertension:
Sildenafil is indicated in idiopathic pulmonary hypertension, although data have been extrapolated mainly from adult trial (class I, level of evidence A, extrapolated). Recently, completed pediatric trials have seemed to support this recommendation. Longer-acting and intravenous forms of phosphodiesterase type 5 inhibitors, brain natriuretic peptides, and direct soluble guanylate cyclise activators all have appeal, but there is insufficient experience in children with acute pulmonary hypertensive disorders for recommendations on treatment.
Erectile dysfunction has not only several potential causes, but many potential treatments; therefore it stands to reason that a multifaceted approach is best. A set of clinical guidelines is outlined by Heidelbaugh:
Erectile dysfunction (ED) is the most common sexual problem in men. The incidence increases with age and affects up to one third of men throughout their lives. It causes a substantial negative impact on intimate relationships, quality of life, and self-esteem. History and physical examination are sufficient to make a diagnosis of ED in most cases, because there is no preferred, first-line diagnostic test. Initial diagnostic workup should usually be limited to a fasting serum glucose level and lipid panel, thyroid-stimulating hormone test, and morning total testosterone level. First-line therapy for ED consists of lifestyle changes, modifying drug therapy that may cause ED, and pharmacotherapy with phosphodiesterase type 5 inhibitors. Obesity, sedentary lifestyle, and smoking greatly increase the risk of ED. Phosphodiesterase type 5 inhibitors are the most effective oral drugs for treatment of ED, including ED associated with diabetes mellitus, spinal cord injury, and antidepressants. Intraurethral and intracavernosal alprostadil, vacuum pump devices, and surgically implanted penile prostheses are alternative therapeutic options when phosphodiesterase type 5 inhibitors fail. Testosterone supplementation in men with hypogonadism improves ED and libido, but requires interval monitoring of hemoglobin, serum transaminase, and prostate-specific antigen levels because of an increased risk of prostate adenocarcinoma. Cognitive behavior therapy and therapy aimed at improving relationships may help to improve ED. Screening for cardiovascular risk factors should be considered in men with ED, because symptoms of ED present on average three years earlier than symptoms of coronary artery disease. Men with ED are at increased risk of coronary, cerebrovascular, and peripheral vascular diseases.
 Ishak WW, Bokarius A, Jeffrey JK, Davis MC, Bakhta Y. Disorders of Orgasm in Women: A Literature Review of Etiology and Current Treatments. J Sex Med. 2010 Jun 25.
 Dorsey P, Keel C, Klavens M, Hellstrom WJ. Phosphodiesterase type 5 (PDE5) inhibitors for the treatment of erectile dysfunction. Expert Opin Pharmacother. 2010 May;11(7):1109-22.
 Sansone F, Rinaldi M. Oral sildenafil: potential role in heart transplantation. Review of the literature and personal experience. J Cardiol. 2010 May;55(3):291-5.
 Fraisse A, Wessel DL. Acute pulmonary hypertension in infants and children: cGMP-related drugs. Pediatr Crit Care Med. 2010 Mar;11(2 Suppl):S37-40.
 Heidelbaugh JJ. Management of erectile dysfunction. Am Fam Physician. 2010 Feb 1;81(3):305-12.
*The latter article is intended for educational / informational purposes only. THIS PRODUCT IS INTENDED AS A RESEARCH CHEMICAL ONLY. This designation allows the use of research chemicals strictly for in vitro testing and laboratory experimentation only. Bodily introduction of any kind into humans or animals is strictly forbidden by law.