Can we revise the pharmacodynamics of commercial inhibitors of 5-alpha phosphodiesterase, such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra)?

Pharmacodynamics of Commercial PDE-5 Inhibitors

The commercial inhibitors of phosphodiesterase type 5 (PDE-5) work by selectively inhibiting PDE-5 enzyme, enhancing the nitric oxide-cGMP pathway to cause smooth muscle relaxation in the corpus cavernosum, resulting in increased blood flow and erection. 1, 2

Mechanism of Action

• All PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) share a common mechanism of action: they inhibit the enzyme phosphodiesterase type 5, which is responsible for degrading cyclic guanosine monophosphate (cGMP) in the corpus cavernosum 2
• During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum, activating guanylate cyclase which increases cGMP synthesis 2
• The increased cGMP triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection 2
• PDE-5 inhibitors have no effect in the absence of sexual stimulation, as they require the initial release of nitric oxide to activate the pathway 2

Selectivity and Potency

• Vardenafil shows high selectivity for PDE-5 compared to other phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, 3,4,7,8,9, and 10) 2
• Sildenafil, tadalafil, and vardenafil are all potent, reversible, competitive inhibitors of PDE-5 1
• The pulmonary vasculature contains substantial amounts of PDE-5, making these inhibitors effective for pulmonary arterial hypertension as well 1

Pharmacokinetic Differences

Onset of Action

• Maximum effects are observed after different time intervals: sildenafil (60 minutes), tadalafil (75-90 minutes), and vardenafil (40-45 minutes) 1
• Successful intercourse has been reported for 35% of patients treated with sildenafil within 14 minutes, 21% with vardenafil within 10 minutes, and 16% with tadalafil within 16 minutes 3

Duration of Action

• Sildenafil and vardenafil have similar half-lives of approximately 4-5 hours 2, 3
• Tadalafil has a significantly longer half-life of 17.5 hours, allowing for a longer duration of action 3
• This longer half-life of tadalafil provides an erectogenic potential lasting more than 24 hours 4

Food Interactions

• High-fat meals affect the pharmacokinetics of sildenafil and vardenafil, reducing maximum concentration (Cmax) by 18-50% 2, 3
• Tadalafil absorption is not affected by food intake 3

Clinical Efficacy

• High-quality evidence indicates that all PDE-5 inhibitors (sildenafil, vardenafil, tadalafil) significantly improve erectile function compared to placebo 1
• Success rates for successful sexual intercourse were similar across medications: 69% for sildenafil, 68% for vardenafil, and 69% for tadalafil versus approximately 35% for placebo 1
• Dose-response relationships vary: efficacy improves with higher doses for sildenafil (50mg vs 25mg) and vardenafil (20mg vs 10mg vs 5mg), but not significantly for tadalafil (20mg vs 10mg vs 5mg) 1
• In a trade-off network meta-analysis, sildenafil 50mg showed the greatest efficacy but also had the highest rate of adverse events, while tadalafil 10mg had intermediate efficacy with the lowest rate of adverse events 5

Adverse Effects

• Common side effects include headache, flushing, rhinitis, and dyspepsia across all three medications 1
• Less common adverse effects include visual disturbances, myalgia, and nasal congestion 1
• All PDE-5 inhibitors cause mild vasodilation with small decreases in blood pressure that are generally clinically insignificant 6
• The incidence of serious adverse events is less than 2%, with no significant difference between PDE-5 inhibitors and placebo 1

Drug Interactions

• All PDE-5 inhibitors are contraindicated with nitrates due to synergistic hypotensive effects 1, 6
• The duration of interaction with nitrates varies: sildenafil and vardenafil interactions dissipate by 24 hours, while tadalafil interactions may persist for 48 hours due to its longer half-life 6
• Vardenafil is metabolized predominantly by CYP3A4, with some contribution from CYP3A5 and CYP2C isoforms 2
• Concomitant use with potent CYP3A4 inhibitors (ritonavir, indinavir, ketoconazole) or moderate inhibitors (erythromycin) results in significant increases in plasma levels of vardenafil 2
• Caution is needed when combining PDE-5 inhibitors with alpha-blockers due to potential orthostatic hypotension 6

Clinical Considerations

• PDE-5 inhibitors are recommended as first-line therapy for erectile dysfunction unless contraindicated 1
• There is insufficient evidence to support the superiority of one agent over the others in terms of efficacy 1
• Patient preference may be influenced by the pharmacokinetic differences among these medications, particularly onset and duration of action 3
• For patients prioritizing high efficacy, sildenafil 50mg appears to be the treatment of choice, while those prioritizing tolerability might prefer tadalafil 10mg 5