How Does Sildenafil Work – Mechanism of Action

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:

1. Sexual Stimulation: Releases nitric oxide (NO) in penile tissue
2. NO Activation: Triggers guanylate cyclase enzyme
3. cGMP Production: Creates cyclic guanosine monophosphate (cGMP)
4. Smooth Muscle Relaxation: cGMP dilates penile arteries
5. 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:

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:

1. Absorption:
   • Rapidly absorbed orally (30-120 minutes)
   • High-fat meals delay absorption by 60 minutes
2. Metabolism:
   • Primarily processed by liver enzymes CYP3A4 (major) and CYP2C9 (minor)
   • Converts to active metabolite N-desmethylsildenafil (50% potency)
3. 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

1. Start with 50mg dose
2. Adjust to 25mg if experiencing side effects
3. Increase to 100mg if insufficient response
4. Never exceed 100mg/24 hours
5. 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

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