Which mechanism best explains why nitrates are CONTRAINDICATED within 24 hours of sildenafil use in a patient with ischemic chest pain?

• A Combined alpha-1 blockade causing reflex tachycardia exacerbating ischaemia
• B Synergistic cGMP accumulation causing profound refractory hypotension ✓
• C Sildenafil directly inhibits nitric oxide synthase reducing nitrate efficacy
• D Combined effect increases myocardial oxygen demand via chronotropy

Explanation

Sildenafil inhibits PDE-5, which degrades cGMP. Nitrates (via nitric oxide) increase cGMP in vascular smooth muscle causing vasodilation. Combined use results in synergistic, additive cGMP accumulation leading to profound, potentially fatal systemic hypotension and coronary hypoperfusion. This interaction is the basis of the absolute contraindication to nitrate use within 24 hours of sildenafil (48 hours for tadalafil). The mechanism is NOT alpha-1 blockade or NOS inhibition.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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Written and medically reviewed by the StethoPrep medical team.