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💊 SILDENAFIL — MASTER FILE FOR PHYSICIANS

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1. MECHANISM OF ACTION

Selectivity: >1000-fold for PDE5 over other PDE isoforms.
Critical point: Sildenafil requires NO release (i.e., sexual stimulation or intact NO signaling) to work — it does not independently create erections or lower vascular tone.

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2. APPROVED INDICATIONS

• SSRI-induced anorgasmia (men) — reversible in some cases
• Anecdotal use for female sexual dysfunction
• Antifibrotic activity tested in COPD-associated pulmonary hypertension and interstitial lung disease
• Persistent pulmonary hypertension of the newborn (PPHN) — used but FDA has cautioned against chronic pediatric dosing (see safety section)

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3. PHARMACOKINETICS (ADME)

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4. DOSING

Erectile Dysfunction (Viagra)

Pulmonary Arterial Hypertension (Revatio)

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5. CONTRAINDICATIONS

Nitrate washout rule: Do not give nitroglycerin within 24 hours of sildenafil (48 h for tadalafil, 12 h for avanafil).
There is no pharmacologic antidote to the PDE5 inhibitor–nitrate interaction.

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6. ADVERSE EFFECTS

Common (dose-dependent)

Ophthalmological

• Blue-green chromopsia / photosensitivity / blurred vision — due to inhibition of retinal PDE6 (involved in phototransduction). Transient and dose-related.
• Non-arteritic anterior ischemic optic neuropathy (NAION) — rare (~1 in 1,000,000). Vision loss begins within 24 hours. Risk increased in patients with pre-existing disc anomalies, diabetes, hypertension. Advise immediate discontinuation and ophthalmology referral for any sudden vision change.

Hearing

• Sudden sensorineural hearing loss — reported; may be unilateral and temporary. FDA mandated label warning in 2007. Strong temporal association; causality not definitively proven.

Cardiovascular

• No independent increase in MI or death rates in controlled trials.
• Increased cardiovascular demand from sexual activity — evaluate exercise tolerance before prescribing in patients with cardiac history.

Rare but serious

• Priapism — not reported in premarketing trials but a known class effect. Treat with intracavernosal phenylephrine (100 μg/mL, 0.3–0.5 mL q10–15 min, 29G needle; monitor vitals).

Pediatric safety

• Chronic use in children associated with increased mortality — not recommended (Barst et al., 2014).

Sickle cell disease

• Not recommended — associated with serious vaso-occlusive crises.

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7. DRUG INTERACTIONS

Pharmacokinetic (CYP3A4/CYP2C9)

Pharmacodynamic

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8. SPECIAL POPULATIONS

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9. COMPARISON WITH OTHER PDE5 INHIBITORS

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10. CLINICAL PEARLS

1. No stimulation = no erection. Sildenafil is not an aphrodisiac — it depends entirely on endogenous NO release from sexual arousal.
2. The nitrate rule is absolute. Even a single sublingual GTN given to a chest-pain patient who took sildenafil within 24 hours can be fatal.
3. Counsel on timing: Take 1 hour before activity on an empty stomach for optimal effect. Fatty meal significantly delays absorption.
4. Trial period matters: Patients should attempt the drug at least 8–10 times before concluding failure. Dose can be escalated if tolerated.
5. Cardiac pre-assessment: Any man with cardiac disease, age >70, diabetes, or hypertension should have cardiac evaluation including exercise tolerance assessment before prescription.
6. NAION warning: Patients with a small optic disc ("disc at risk"), prior NAION, or significant microvascular disease are at higher risk — discuss this before prescribing.
7. α-blocker interaction: If a patient is already on an α-blocker (e.g., tamsulosin for BPH), start sildenafil at 25 mg. Avoid concurrent use of α-blocker and PDE5 inhibitor at initiation.
8. Revatio ≠ Viagra: In PAH, dosing is TID and the indication is completely different — do not interchange brands without confirming indication and dose.
9. HIV patients on protease inhibitors: Drastically increased sildenafil exposure → cap at 25 mg / 48 h for ED. Revatio is contraindicated in these patients for PAH (ritonavir-boosted regimens).
10. Sickle cell: Avoid entirely due to vaso-occlusive crisis risk.

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11. MONITORING

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12. KEY REFERENCES

• Goodman & Gilman's The Pharmacological Basis of Therapeutics — PDE5 Inhibitors, pp. 699–700
• Smith and Tanagho's General Urology, 19th Ed. — Phosphodiesterase Inhibitors, pp. 631–632
• Kaplan & Sadock's Synopsis of Psychiatry — Sildenafil, pp. 2128–2133
• Murray & Nadel's Textbook of Respiratory Medicine — Pulmonary Vascular Disease / PDE5 Inhibitors
• Barst RJ et al. (2014) — Sildenafil and mortality in children with PAH
• Chebbi A et al. (2025) — Oral drug treatments of erectile dysfunction: AFU/SFMS systematic review [PMID: 40915356]

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Disclaimer: This master file is a clinical reference summary compiled from peer-reviewed medical textbooks (Goodman & Gilman, Harrison's, Kaplan & Sadock's, Smith & Tanagho's, Murray & Nadel's) and current literature. It is intended for use by licensed healthcare professionals. Clinical decisions must be individualized based on patient history, comorbidities, and current guidelines.