Sildenafil
Also known as: Viagra, Revatio
PDE5 Inhibitor | Erectile Function & Pulmonary Hypertension
Overview
Sildenafil is the first PDE5 inhibitor to reach the market and remains one of the most widely recognized pharmaceuticals in the world. Originally developed by Pfizer scientists investigating treatments for angina and hypertension, sildenafil's pronounced effect on erectile function was discovered during Phase I clinical trials in 1992. It received FDA approval for erectile dysfunction in 1998 under the brand name Viagra, and subsequently gained a second FDA approval in 2005 as Revatio for the treatment of pulmonary arterial hypertension (PAH). Sildenafil is a shorter-acting PDE5 inhibitor with a half-life of 3-5 hours and a therapeutic window of approximately 4-6 hours. Unlike tadalafil, sildenafil absorption is significantly reduced by high-fat meals, and its lower selectivity for PDE5 over PDE6 (the retinal phosphodiesterase) can produce transient visual disturbances such as a blue-tinged color shift at higher doses. Despite the availability of longer-acting alternatives, sildenafil remains a first-line treatment for ED due to its well-established efficacy, extensive safety data spanning over 25 years, and wide generic availability.
Key benefits
- First and most extensively studied PDE5 inhibitor with over 25 years of clinical data
- Rapid onset of action (30-60 minutes) allows event-based dosing
- FDA-approved for both erectile dysfunction (Viagra) and pulmonary arterial hypertension (Revatio)
- Flexible dosing range (25-100mg) permits individualized titration
- Shorter duration of action may be preferred by patients who want time-limited pharmacological effect
- Extensive generic availability makes it one of the most affordable PDE5 inhibitors
- Well-established safety profile across diverse patient populations
- Proven efficacy in difficult-to-treat ED including diabetic and post-prostatectomy patients
Mechanism of action
Sildenafil selectively inhibits phosphodiesterase type 5 (PDE5), the enzyme responsible for the hydrolysis and degradation of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle. During sexual arousal, nitric oxide (NO) is released from nerve terminals and endothelial cells in the corpus cavernosum, activating soluble guanylate cyclase and increasing intracellular cGMP concentrations. Elevated cGMP activates protein kinase G (PKG), which phosphorylates multiple targets leading to smooth muscle relaxation, vasodilation of penile arteries, and engorgement of the corpora cavernosa with blood. By inhibiting PDE5, sildenafil prevents cGMP breakdown, prolonging and amplifying this vasodilatory cascade. Sildenafil requires sexual stimulation to be effective, as NO release is the initiating signal. In pulmonary arterial hypertension, the same PDE5 inhibition relaxes pulmonary vascular smooth muscle, reducing pulmonary artery pressure and pulmonary vascular resistance, thereby decreasing right ventricular afterload and improving exercise capacity. Sildenafil also has moderate inhibitory activity against PDE6, the phosphodiesterase isoform in retinal photoreceptors, which underlies the transient visual color changes reported by some users.
Molecular data
- Type
- Small molecule phosphodiesterase type 5 (PDE5) inhibitor
- Half-life
- ~3-5 hours
Indications
What the research community uses this compound for, with self-reported effectiveness.
Sexual Health
Cardiovascular
Pulmonary
Performance
Dosing protocols
Common protocols by delivery method. Adjust the curve below to model accumulation in your own cycle.
Delivery method
| Protocol | Dose | Frequency | Duration |
|---|---|---|---|
| — | 50mg | As needed, 30-60 min before sexual activity | — |
| — | 25mg | As needed, for patients >65 years, hepatic impairment, renal impairment, or CYP3A4 inhibitor use | — |
| — | 100mg | As needed, max once per 24 hours | — |
| — | 20mg | Three times daily, approximately 4-6 hours apart | — |
Delivery method
| Protocol | Dose | Frequency | Duration |
|---|---|---|---|
| — | 10mg (equivalent to 20mg oral) | Three times daily as IV bolus | — |
Safety
Reported adverse effects, contraindications, and what to monitor on cycle.
Common side effects
- Headache (16% incidence, most common side effect)
- Flushing / warmth (10%, due to systemic vasodilation)
- Dyspepsia / indigestion (7%)
- Nasal congestion / rhinitis (4%)
- Visual disturbances -- blue-tinged vision, increased brightness perception, blurred vision (3%, due to PDE6 cross-reactivity in retinal photoreceptors)
- Dizziness (2%)
- Diarrhea (3%)
- Rash (2%)
Rare side effects
- Non-arteritic anterior ischemic optic neuropathy (NAION) -- extremely rare, causal relationship uncertain but FDA black box warning issued
- Sudden sensorineural hearing loss -- extremely rare, usually unilateral, may be accompanied by tinnitus
- Priapism (prolonged erection >4 hours) -- rare but constitutes a medical emergency
- Hypersensitivity reactions (urticaria, facial edema)
- Epistaxis (nosebleed)
- Seizures -- reported in post-marketing surveillance, extremely rare
Contraindications
- Concurrent use of any organic nitrate medication (absolute contraindication)
- Concurrent use of guanylate cyclase stimulators (e.g., riociguat)
- Known hypersensitivity to sildenafil or any tablet excipient
- Severe hepatic impairment (starting dose 25mg recommended in moderate impairment)
- Severe renal impairment with CrCl <30 mL/min (starting dose 25mg recommended)
- Recent stroke or myocardial infarction (within 6 months per original labeling)
- Unstable angina or angina during sexual intercourse
- Uncontrolled hypertension or symptomatic hypotension (resting BP <90/50 mmHg)
- Hereditary degenerative retinal disorders including retinitis pigmentosa
- History of NAION (relative contraindication -- increased recurrence risk)
- Conditions predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia)
References
Primary literature and clinical-trial data informing this entry.