How Does Sildenafil Work – Mechanism of Action
Key Takeaways
- Sildenafil inhibits PDE5 enzymes, boosting blood flow to the penis
- Requires sexual stimulation to trigger nitric oxide release
- Starts working in 30-60 minutes; effects last 4-6 hours
- Metabolised by liver enzymes CYP3A4 and CYP2C9
- 50mg is the standard starting dose for erectile dysfunction
- Avoid with nitrates due to dangerous blood pressure drops
This guide explains how sildenafil works for erectile dysfunction, detailing its unique mechanism of action as a PDE5 inhibitor that enhances blood flow to the penis. We'll cover the pharmacokinetics of sildenafil, including onset time and duration of effects, how sexual stimulation triggers its vasodilation effects, and why it's considered a first-line ED treatment worldwide.
The Erection Pathway: Key Players
Before exploring sildenafil, we must understand natural erectile physiology:
- Sexual Stimulation: Releases nitric oxide (NO) in penile tissue
- NO Activation: Triggers guanylate cyclase enzyme
- cGMP Production: Creates cyclic guanosine monophosphate (cGMP)
- Smooth Muscle Relaxation: cGMP dilates penile arteries
- Blood Inflow: Corpora cavernosa fill with blood, causing erection
PDE5 enzymes normally break down cGMP, ending erections. Erectile dysfunction often involves insufficient cGMP production or excessive PDE5 activity.
Sildenafil's Mechanism: Targeting PDE5
Sildenafil works through precise biochemical interference:
Action | Biological Effect | Clinical Result |
---|---|---|
PDE5 inhibition | Blocks cGMP breakdown | Prolongs cGMP activity |
Enhanced NO pathway | Amplifies natural arousal signals | Stronger blood vessel dilation |
Arterial relaxation | Increases penile blood flow | Firmer, sustained erection |
Crucially, sildenafil does not directly cause erections. It requires sexual stimulation to initiate the NO-cGMP pathway. Without arousal, the biochemical "switch" remains off.
Metabolic Journey: Absorption to Elimination
Sildenafil's effects depend on complex pharmacokinetics:
- Absorption:
- Rapidly absorbed orally (30-120 minutes)
- High-fat meals delay absorption by 60 minutes
- Metabolism:
- Primarily processed by liver enzymes CYP3A4 (major) and CYP2C9 (minor)
- Converts to active metabolite N-desmethylsildenafil (50% potency)
- Elimination:
- Half-life: 3-5 hours
- Excretion: Faeces (80%), urine (13%)
- Duration: Effects persist 4-6 hours
Critical Interactions & Contraindications
Sildenafil's mechanism explains key contraindications:
- Nitrates/NO Donors:
- Combined PDE5 inhibition and NO donation causes dangerous blood pressure drops (>25mmHg reduction)
- Avoid amyl nitrite ("poppers") and angina medications like nitroglycerin
- Riociguat:
- This pulmonary hypertension drug also acts on the NO pathway
- Concurrent use risks life-threatening hypotension
- CYP3A4 Inhibitors:
- Ketoconazole, ritonavir, and grapefruit juice inhibit sildenafil metabolism
- Increase blood concentrations substantially
Optimising Effectiveness
Several factors influence sildenafil's performance:
- Dose Timing: Take 60 minutes pre-activity
- Food Intake: Avoid heavy/fatty meals beforehand
- Alcohol: >3 units impairs efficacy
Sildenafil Dosage Guidelines
- Start with 50mg dose
- Adjust to 25mg if experiencing side effects
- Increase to 100mg if insufficient response
- Never exceed 100mg/24 hours
- Maximum frequency: Once daily
Clinical Considerations
- Cardiac Patients: Requires stress test if heart disease suspected
- Liver/Kidney Impairment: Reduce dose to 25mg
- Vision Changes: Discontinue if NAION history or sudden vision loss
- Priapism Risk: <0.1% incidence but requires emergency treatment
FAQs
How exactly does Sildenafil help with erectile dysfunction?
Sildenafil works by inhibiting phosphodiesterase type 5 (PDE5) enzymes, which normally break down cyclic guanosine monophosphate (cGMP). By blocking PDE5, Sildenafil allows cGMP to accumulate, enhancing the natural erection process when sexual stimulation occurs. This results in improved blood flow to the penis and sustained erection.
Why does Sildenafil require sexual stimulation to work?
Sildenafil doesn't directly cause erections but enhances the natural erectile response. Sexual stimulation is necessary to trigger the release of nitric oxide (NO), which initiates the biochemical pathway that Sildenafil amplifies. Without arousal, this pathway isn't activated, so Sildenafil has no effect.
Why is Sildenafil dangerous to take with nitrates?
Sildenafil and nitrates both affect the nitric oxide pathway. When combined, they can cause a dangerous drop in blood pressure (>25mmHg reduction). This is particularly risky for patients taking nitrates for angina (chest pain) or those using recreational "poppers" (amyl nitrite).
How does food affect Sildenafil's absorption?
High-fat meals can delay Sildenafil's absorption by up to 60 minutes and may reduce peak concentrations by about 29%. For fastest results, take Sildenafil on an empty stomach or after a light meal.
Which medications interact with Sildenafil?
Key interactions include:
- Nitrates/Nitric oxide donors: Dangerous blood pressure drop
- CYP3A4 inhibitors (e.g., ketoconazole, ritonavir): Increase Sildenafil levels
- Riociguat: Risk of life-threatening hypotension
- Alpha-blockers: Potential additive blood pressure effects
Always disclose all medications to your doctor before taking Sildenafil.
How is Sildenafil metabolised in the body?
Sildenafil is primarily metabolised by liver enzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). It converts to an active metabolite (N-desmethylsildenafil) with about 50% of the parent drug's potency. The drug is eliminated mainly through feces (80%) and urine (13%), with a half-life of 3-5 hours.
![]() | Authored by Nabeel |
Medical Content Manager
Nabeel is a co-founder, and medical content manager of Chemist Doctor. He works closely with our medical team to ensure the information is accurate and up-to-date.
![]() | Reviewed by Dr. Waqas (GMC:7928708) |
Medical Doctor
Dr. Waqas is a GMC-registered doctor at Chemist Doctor, specialising in general health. He balances clinical precision with cultural sensitivity.
![]() | Approved by Usman |
Medical Director
Usman is a co-founder, and medical director of Chemist Doctor. He leads the organisation's strategic vision, bridging clinical and operational priorities.
Review Date: 12 August 2025
Next Review: 14 February 2026
Published on: 11 August 2025
Last Updated: 12 August 2025
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