What is the potential drug interaction between itraconazole and lisinopril (Angiotensin-Converting Enzyme (ACE) inhibitor)?

Drug Interaction Between Itraconazole and Lisinopril

Itraconazole and lisinopril do not have a clinically significant direct drug interaction that would require dose adjustments or contraindicate their combined use.

Mechanism of Potential Interaction

Itraconazole is a potent inhibitor of CYP3A4 enzymes and P-glycoprotein transporters 1, while lisinopril is not metabolized by the liver and is primarily eliminated unchanged by the kidneys 2. This fundamental difference in their metabolic pathways explains the lack of a significant pharmacokinetic interaction.

Itraconazole's Interaction Profile

• Acts as a strong inhibitor of CYP3A4 enzymes
• Inhibits P-glycoprotein transporters
• Has active metabolites that are also potent CYP3A4 inhibitors 1
• Can cause QTc prolongation 3

Lisinopril's Pharmacokinetic Properties

• Not metabolized by the liver (no CYP450 involvement)
• Eliminated primarily by renal excretion
• No clinically significant drug interactions have been reported with lisinopril 2

Clinical Implications

While there is no direct metabolic interaction between itraconazole and lisinopril, clinicians should be aware of:

1. Hemodynamic Considerations:

   • Both medications can affect blood pressure
   • Itraconazole has negative inotropic properties and is contraindicated in patients with decreased cardiac ejection fraction or history of congestive heart failure 3
   • Lisinopril lowers blood pressure as its primary therapeutic effect 2

2. Monitoring Recommendations:

   • Monitor blood pressure when initiating the combination, particularly in elderly patients or those with renal impairment
   • Be alert for symptoms of hypotension (dizziness, lightheadedness, syncope)
   • Consider therapeutic drug monitoring for itraconazole to ensure appropriate levels 3

Special Considerations

Cardiac Effects

• Itraconazole can cause QTc prolongation and has negative inotropic effects 3
• The combination with other QT-prolonging medications requires caution, but lisinopril is not known to significantly affect QT interval

Renal Function

• Lisinopril dosage should be adjusted in patients with renal impairment 2
• For patients with renal dysfunction receiving itraconazole, the oral formulation is preferred over IV to avoid accumulation of cyclodextrin vehicle 3

Management Approach

1. Before Initiating Combination:

   • Assess cardiac function (particularly ejection fraction)
   • Evaluate renal function
   • Review complete medication list for other potential interactions

2. During Treatment:

   • Monitor blood pressure regularly, especially during the first week of combined therapy
   • Watch for signs of heart failure in at-risk patients
   • Consider therapeutic drug monitoring for itraconazole 3

3. Alternative Considerations:

   • If concerns exist about cardiac function, consider alternative antifungal agents
   • For patients with heart failure history, avoid itraconazole regardless of concomitant medications 3

Conclusion

While itraconazole has numerous significant drug interactions with medications metabolized by CYP3A4, lisinopril is not among them due to its renal elimination pathway. The primary consideration when using these medications together should be monitoring for potential additive effects on blood pressure rather than a direct pharmacokinetic interaction.