Sildenafil was the first phosphodiesterase-5 (PDE5) inhibitor approved for use, receiving US Food and Drug Administration approval for use in erectile dysfunction on March 27, 1998. Sildenafil also has FDA approval for the treatment of World Health Organization Group I pulmonary hypertension (also known as pulmonary arterial hypertension (PAH)) in adults to improve exercise tolerance and delay clinical worsening. Sildenafil is also occasionally used off-label for the treatment of secondary Reynaud phenomenon, female sexual arousal disorder, and as an adjunct in the treatment of altitude-induced hypoxemia.
The molecular structure of sildenafil mimics that of cyclic guanosine monophosphate (cGMP). This similarity protects cGMP from degradation because sildenafil can bind to the catalytic site to act as a competitive inhibitor of cGMP-specific PDE-5, the enzyme that normally catalyzes the break down of vasodilatory cGMP. When PDE5 is active, cGMP is degraded, causing contraction of the vascular smooth muscle, thereby limiting blood flow. When PDE5 becomes inhibited, the accumulation of cGMP leads to increased cGMP-dependent protein kinase activity, which phosphorylates multiple targets in the smooth muscle cell. The result of smooth muscle cell target protein phosphorylation is a decrease in intracellular calcium, increased efflux of potassium, and deactivation of myosin light chain kinase, ultimately causing smooth muscle relaxation.
Relaxation of vascular smooth muscle in the corpus carvernosum leads to penile erection when the cavernosal sinusoids engorge with blood to compress the subtunical veins against the tunica albuginea. In patients with vasoactive pulmonary arterial hypertension, vasodilation of the pulmonary artery leads to reduced resistance to blood flow, with subsequent reductions in mean pulmonary arterial pressure.
For erectile dysfunction, most patients receive a prescription for 50 mg of oral sildenafil, taken as needed approximately 1 hour before sexual activity. The dose can be titrated upward to a maximum of 100mg or down to 25mg based on individual effectiveness and tolerance. Patients taking concomitant inhibitors of CYP3A4 may benefit from initiation at the lower dosage. Patients are advised not to exceed a maximum dosing frequency of once daily. The onset of action can occur within 30 minutes, while the duration of the effect can last up to 18 hours. In the treatment of PAH, sildenafil is available in tablets, oral suspension, and injectable forms. For tablet and oral suspension formularies, the recommended dosage is 5mg or 20mg three times daily, 4 to 6 hours apart. Injections are dosed at 2.5mg or 10mg three times a day, 4-6 hours apart as an intravenous bolus.
Warnings and Precautions
Sildenafil has systemic vasodilatory effects and, as such, should be prescribed with caution to patients who may be sensitive to such blood pressure changes such as patients with left ventricular outflow obstruction and impaired autonomic control of blood pressure. Caution is needed when combining sildenafil with alpha-adrenergic blocking drugs and other antihypertensive agents. The use of sildenafil can infrequently result in a prolonged erection lasting more than 4 hours. also known as priapism, which, if left untreated may result in damage to the penile tissue. Furthermore, sildenafil use requires caution in patients with anatomical deformation of the penis and patients with conditions potentially predisposing them to priapism such as sickle cell anemia or multiple myeloma. The use of PDE5 inhibitors, such as sildenafil, may increase the incidence of non-arteritic anterior ischemic optic neuropathy (NAION) in males over age 50. Therefore, patients with a previous history of NAION or with a “crowded” optic disk should be prescribed sildenafil with caution.
Sildenafil metabolism is catalyzed primarily by CYP3A4 and to a lesser extent by CYP2C9, thus strong inhibitors of these isoenzymes may lead to the accumulation of sildenafil with subsequent toxicity. The coadministration of sildenafil and ritonavir increased plasma sildenafil concentration (11 fold increase in the AUC) due to CYP 3A4/2C9 inhibition. Accordingly, caution is necessary for patients already on ritonavir when prescribing sildenafil. The recommendation is not to exceed a dose of 25 mg of sildenafil in 48 hours if taking ritonavir. The combination of sildenafil with the endothelin antagonist bosentan to manage pulmonary arterial hypertension has correlated with increased serum concentrations of bosentan and reduced levels of sildenafil. Combining sildenafil with other CYP3A4 inducers can similarly lead to reduced sildenafil levels; thus, such combinations are not recommended with chronic sildenafil dosing as performed in the management of PAH.
Sildenafil, at its lowest dose, is recommended when initiating therapy to patients who are on alpha-blockers due to potential systemic hypotension. Caution is also a requirement in patients who are taking mixed alpha/beta-blockers as well unless there is specific information regarding coadministration.
Doses greater than 100 mg of sildenafil have resulted in no increase in efficacy but an increase in side effects. Patients on sildenafil most commonly (2%) reported headaches, flushing, dyspepsia, nasal congestion, back pain, myalgia, nausea, dizziness, and rash.
Sildenafil has shown associations with changes in color vision, alterations in light perception, and hazy vision. Rarely, sildenafil has shown correlations with ototoxicity resulting in hearing loss that may be reversible in some cases.
There are no adequate and well-controlled studies of sildenafil in pregnant women. Small case-studies in pregnant women with PAH indicate a low risk of harm, though caution is warranted.
Nitrates increase cGMP formation, while sildenafil inhibits cGMP degradation causing the combination to produce severe life-threatening hypotension synergistically; coadministration of sildenafil with nitrates is contraindicated. Nitrates administration is safely after five or more sildenafil elimination half-lives (24 or more hours) have elapsed since sildenafil administration.
Similarly, severe hypotension from other causes (e.g., volume depletion) contraindicates the use of sildenafil. Other contraindications include hypersensitivity to any component of the formulation, pulmonary veno-occlusion, left ventricular outflow obstruction, PAH associated with sickle cell anemia, and multiple system atrophy. Ischemic optic neuropathy and inherited degenerative retinal disorders contraindicate sildenafil use; discontinuation of sildenafil is recommended if a sudden loss of vision occurs.
Typically, no regular monitoring is necessary for this medication. Occasionally patients may be asked to monitor their blood pressure and pulse after being newly prescribed sildenafil, after an increase in dosage, or after the addition of CYP3A4 inhibitors. During the review of systems, assessment for visual changes is recommended. In the treatment of pulmonary arterial hypertension, patients should also have monitoring for signs and symptoms of pulmonary edema.
In healthy subjects, research demonstrated that single doses up to 800 mg resulted in adverse effects similar to those seen in lower doses but with increased frequency and severity. There are no antidotes available for sildenafil. In case of overdose, patients should receive supportive care. At toxic levels, dose-related visual disturbances occurred more frequently, while blood pressure changes showed a low correlation. As sildenafil is highly bound to plasma proteins and not excreted renally, dialysis does not help expedite the clearance of sildenafil. When considering the duration of toxicity, the activity of N-desmethyl-sildenafil must be a consideration; this metabolite retains PDE5 specificity at lower potency, with plasma concentrations that approach 40% of the parent compound.
Sildenafil is a safe therapeutic option for erectile dysfunction and PAH that has been available on the market for over two decades. Some barriers to successful sildenafil therapy in the treatment of erectile dysfunction include cost and social stigma surrounding erectile dysfunction. All members of the interprofessional health team can help eliminate these barriers through compassionate education, a thorough review of systems during clinic visits, and establishing an open line of communication with the patient to better address his medical needs.
The use of sildenafil itself in the management of erectile dysfunction can significantly impact patient quality of life. ED is associated with depression, anxiety, and loss of self-esteem. A small placebo-controlled 12-week study performed in 512 men with erectile dysfunction used the Self Esteem and Relationship (SEAR) questionnaire to assess the impact of sildenafil treatment has on patients. The results of the trial revealed that sildenafil had improved the patients' depression, anxiety, depression, and self-esteem.
Current guidelines for the treatment of pulmonary arterial hypertension in adults call for closely coordinated collaboration between the patient's local healthcare team and the providers with expertise in the management of PAH. Sildenafil plays a secondary role as an alternative for patients who demonstrate acute vasoreactivity in WHO functional class II to improve 6-minute walking distance (6MWD) and for those in functional class III to improve 6MWD and improve the functional class.
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