Sildenafil drug interaction
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Sildenafil Drug Interactions: A Comprehensive Overview
Introduction to Sildenafil and Its Mechanism of Action
Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is widely used for the treatment of erectile dysfunction and pulmonary arterial hypertension (PAH) 27. Its mechanism involves the enhancement of the nitric oxide (NO)-cGMP pathway, leading to smooth muscle relaxation and increased blood flow .
Interaction with Endothelin Receptor Antagonists
Macitentan and Sildenafil Interaction
A study investigating the pharmacokinetic interactions between macitentan, an endothelin receptor antagonist, and sildenafil found that while macitentan did not significantly affect sildenafil's pharmacokinetics, sildenafil increased the plasma concentrations of macitentan's active metabolite, ACT-132577 . This interaction was deemed minor and not clinically relevant, suggesting no need for dose adjustments when these drugs are co-administered .
Bosentan and Sildenafil Interaction
Conversely, the interaction between bosentan, another endothelin receptor antagonist, and sildenafil is more significant. Bosentan reduces sildenafil's plasma concentration by approximately 55.4%, while sildenafil increases bosentan's concentration by 42% . This mutual interaction necessitates careful monitoring and potential dosage adjustments, especially in patients with PAH 36.
Interaction with Blood Pressure-Lowering Drugs
Organic Nitrates
Sildenafil significantly potentiates the hypotensive effects of organic nitrates such as glyceryl trinitrate and isosorbide mononitrate. Studies have shown that co-administration leads to substantial reductions in blood pressure, which can be dangerous 210. Therefore, sildenafil is contraindicated in patients using organic nitrates due to the risk of severe hypotension 210.
Calcium Antagonists
In patients taking the calcium antagonist amlodipine, sildenafil causes additive but not synergistic reductions in blood pressure. The interaction is less severe compared to nitrates, and while it does result in a modest decrease in blood pressure, it is generally well-tolerated .
Interaction with CYP3A Inhibitors
Clarithromycin and Itraconazole
Sildenafil's metabolism is significantly affected by CYP3A inhibitors such as clarithromycin and itraconazole. Both drugs increase sildenafil's systemic exposure by approximately two-fold, indicating a moderate pharmacokinetic interaction . This necessitates caution and potential dose adjustments when sildenafil is co-administered with strong CYP3A inhibitors .
Fluconazole
In infants, the co-administration of sildenafil with fluconazole, a CYP3A inhibitor, requires dose adjustments due to increased sildenafil exposure. Physiologically-based pharmacokinetic (PBPK) modeling suggests reducing sildenafil doses by about 60% when given with fluconazole to maintain therapeutic levels without causing toxicity .
Interaction with Antiepileptic Drugs
Sildenafil has been shown to enhance the anticonvulsant effects of several antiepileptic drugs (AEDs) in animal models. This interaction appears to be both pharmacodynamic and pharmacokinetic, depending on the specific AED involved . For instance, sildenafil increases the plasma and brain concentrations of levetiracetam, indicating a pharmacokinetic interaction .
Recreational Use and Interaction with Club Drugs
Sildenafil is often used recreationally, particularly among homosexual and bisexual males, sometimes in combination with club drugs. This combination can reverse the impotence-inducing effects of club drugs but also poses significant risks, especially when combined with antiretroviral medications used in HIV treatment. These interactions can lead to reduced sildenafil metabolism and increased adverse effects .
Conclusion
Sildenafil interacts with a variety of drugs, including endothelin receptor antagonists, blood pressure-lowering drugs, CYP3A inhibitors, and antiepileptic drugs. These interactions can significantly alter sildenafil's pharmacokinetics and pharmacodynamics, necessitating careful monitoring and potential dose adjustments. Understanding these interactions is crucial for optimizing sildenafil therapy and ensuring patient safety.
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