PDE-5 Inhibitors and Nitrates: What to Do in the Critically Ill Patient?

Let us say that you have a 50-year-old female patient who presents to the emergency department with a history of pulmonary arterial hypertension and signs and symptoms consistent with acute decompensated heart failure. The patient presents with acute shortness of breath and is in severe respiratory distress. Vital signs include blood pressure of 182/90 and heart rate of 110. A beside ultrasound is performed, confirming the presence of significant pulmonary congestion. Non-invasive ventilation is initated and you would like to order a nitroglycerin drip for this patient. However, upon reviewing her medication list, you notice that is on sildenafil as an outpatient for her pulmonary arterial hypertension.

You recall that the combination of PDE-5 inhibitors and nitrates is a “no-no”; this movie scene may even come to mind:
[youtube https://www.youtube.com/watch?v=viK121c8iZI]

Even knowing about this interaction you ponder about this some more, and you really and truly believe that nitroglycerin can benefit your patient. So what are you going to do?

Phosphodiesterase-5 (PDE-5) inhibitors are often recommended for the treatment of pulmonary arterial hypertension. These agents act by inhibiting the hydrolysis of cyclic guanosine monophosphate (cGMP) to gunosine monophosphate (GMP), which allows for selective relaxation of the pulmonary vasculature. This thereby reduces pulmonary vascular resistance and increase functional capacity in patients with pulmonary arterial hypertension. We all know how these agents work in the more common indication that these agents are utilized for (erectile dysfunction), but to review briefly, in the setting of sexual stimulation, PDE-5 inhibitors augment the effects of nitric oxide through inhibition of the breakdown of cGMP, which allows for smooth muscle relaxation in the corpus cavernosum.

Nitroglycerin (and other organic nitrates) form free nitric oxide radicals that activate guanylate cyclase, which catalyzes the synthesis of cGMP, leading to smooth muscle relaxation. Using PDE-5 inhibitors in the setting of organic nitrates could potentiate the vasodilatory effects of the latter, leading to profound and potentially life-threatening systemic hypotension.

There have been very few studies that have evaluated the safety of the use of organic nitrates in the setting of concomitant PDE-5 inhibitors. One small study evaluated the safety of intravenous nitroglycerin in 34 patients with a history of coronary artery disease who had ingested 100 mg of sildenafil or placebo. After 45 minutes, nitroglycerin was initiated, and the dose was titrated upward every ten minutes to a maximum of 160 mcg/min. The investigators found that at doses between 5 and 80 mcg/min, the decrease in systolic blood pressure (SBP) decrease was 4 to 6 mmHg higher with sildenafil compared to placebo. However, as doses escalated upward, only 25% of the patients were able to tolerate the maximum dose due to the incidence of adverse events.
In addition, investigators of a case series of three patients demonstrated that the use of an extended course of systemic oral nitrates in three patients in combination with sildenafil can effectively reduce pulmonary arterial pressure in the setting of pulmonary arterial hypertension and advanced heart failure. None of the patients in the case series manifested any complications associated with this combination therapy.

So going back to our patient…will you be starting that nitroglycerin infusion after all? Granted, if the situation was a bit different and the patient presented with an acute coronary syndrome instead, I would be a bit more cautious in reaching for the nitroglycerin infusion and utilize other standard therapies for relieving the ischemia associated with such an event for that very reason- that is, we do have other therapies available that may provide the patient with some relief without placing the patient at unnecessary risk for a potentially life-threatening event secondary to a drug interaction. However, the scenario described above is a somewhat relatively unique combination of diseases in a critically ill patient that may present to your emergency department. You may not be able to push and/or escalate the dose of the nitroglycerin infusion as high or as quickly as you would like, but provided that you have the dedicated resources, equipment, and personnel available to closely monitor such a patient in whom you believe this therapy might provide some benefit, it may be considered an option.

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