Sildenafil with Nitroglycerin Interaction Details

Brand Names Associated with Sildenafil

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 12, 2023

Interaction Effect

Potentiation of hypotensive effects

Interaction Summary

Regular or intermittent concomitant sildenafil and organic nitrate use is contraindicated as hypotension due to additive effects of increased cyclic guanosine monophosphate (cGMP) levels may occur. Hypotension lasted 8 vs 4 hours with sildenafil and SL nitroglycerin in men with stable angina vs healthy men . Slowly titrated IV nitroglycerin following a single sildenafil dose may be tolerated in men with stable coronary artery disease . Avoid nitrates in acute coronary syndrome for at least 24 hours after sildenafil  or longer in hepatic or severe renal impairment. Monitor carefully if used after 24 hours. A short-acting IV nitrate with close monitoring may be tolerated .

Severity

Contraindicated

Onset

Rapid

Evidence

Established

How To Manage Interaction

Concomitant use of sildenafil and organic nitrates is contraindicated in any form, either regularly or intermittently, because of the greater risk of hypotension. Do not administer nitrates to patients with ST-elevation myocardial infarction  or non-ST elevation acute coronary syndrome who recently received a phosphodiesterase inhibitor, particularly within 24 hours of sildenafil use . Sildenafil is contraindicated in the 24-hour period after receiving a nitrate preparation, including SL nitroglycerin. Use after 24 hours can be considered, but monitor responses to initial doses carefully. A more extended period may be required in patients with hepatic or severe renal dysfunction. The preferred nitrate would be a short-acting IV nitroglycerin with close hemodynamic monitoring .

Mechanism Of Interaction

Increased levels of cyclic guanosine monophosphate (cGMP) from sildenafil and nitrates

Literature Reports

A) In a randomized crossover study in men with a history of angina pectoris and stable coronary artery disease (N=34), subjects received a single dose of sildenafil 100 mg or placebo followed 45 minutes later by IV nitroglycerin 5 mcg/minute escalating at 10-minute intervals to 10, 20, 40, 80, 120, and finally 160 mcg/minute. Hypotension that was primarily asymptomatic occurred in 26 patients who received sildenafil compared with 17 who received placebo, which was a significant difference. Most cases of hypotension required discontinuation of the nitroglycerin infusion. Two sildenafil cases were symptomatic. The median maximum tolerated nitroglycerin dose was significantly higher with placebo versus sildenafil (160 mcg/minute vs 80 mcg/minute). Only 25% of the sildenafil-treated patients reached the 160-mcg/minute dose of nitroglycerin compared with 59% of placebo-treated patients. No serious adverse events were reported. Notably, there was large interpatient variability in sildenafil plasma concentration levels following the single dose .

B) Two randomized crossover studies found the hypotensive interaction between sildenafil and sublingual nitroglycerin in men with stable angina lasted 8 hours after sildenafil administration, while in healthy male subjects, the hypotensive interaction between sildenafil and sublingual nitroglycerin was confined to 4 hours. Male patients with stable angina (n=20) and healthy male subjects (n=33) were challenged with a single sublingual nitroglycerin 400 mcg spray at 1 hour, 4 hours, 6 hours, and 8 hours after administration of a sildenafil 100 mg oral tablet to determine the time course of the hypotensive interaction between sildenafil and sublingual nitroglycerin. In angina patients, there was a greater mean maximal reduction in BP with sildenafil/nitroglycerin compared to placebo/nitroglycerin for up to 8 hours. The mean differences in maximum systolic BP reduction at 1, 4, 6 and 8 hours were -16 mmHg, -12 mmHg, -6 mmHg, and -9 mmHg, respectively. In healthy men, a significant mean maximal reduction in BP with sildenafil/nitroglycerin compared to placebo/nitroglycerin occurred only 1 hour after sildenafil administration (systolic BP -23.8 mmHg (2.8), diastolic BP -14.9 mmHg (2.3)); versus placebo/nitroglycerin (systolic BP -13.5 mmHg (2.5) diastolic BP -6.9 mmHg (1.2)). Side effects were most commonly reported when nitroglycerin was administered 1 hour after sildenafil, and included symptoms of hypotension, such as dizziness and lightheadedness .

C) A randomized, double-blind, placebo-controlled, two-way crossover study of 12 healthy men demonstrated that sildenafil potentiates the hypotensive effects of organic nitrates. The men received either 25 mg sildenafil three times daily or placebo for four days, followed by a single morning dose on day 5. Nitroglycerin was given intravenously on day 4 as a stepwise infusion one hour after the sildenafil morning dose. On day 5, nitroglycerin 500 mcg was given sublingually one hour after the morning dose of sildenafil or placebo. In both cases, the nitroglycerin was discontinued when the subject's systolic blood pressure was decreased by more than 25 mm Hg. For the intravenous infusion, two of the 12 subjects in the placebo group completed the 25-minute infusion, while none completed the infusion in the sildenafil group. Similarly, with sublingual nitroglycerin, four of the 12 subjects in the placebo group removed the sublingual tablet after three to four minutes, versus 11 of 12 subjects who removed the tablet after two to seven minutes in the sildenafil group. The most frequently occurring adverse events reported by the 12 subjects were headache and dizziness .

D) Two studies demonstrated the effects of a single oral dose of sildenafil citrate on blood pressure in men taking isosorbide mononitrate and glyceryl trinitrate for stable angina. Sixteen subjects received oral isosorbide mononitrate beginning 5 to 7 days before receiving a single dose of sildenafil or placebo. Administration of isosorbide mononitrate with sildenafil resulted in substantially greater decreases in blood pressure from baseline (-52/-29 mm Hg) as compared with those subjects receiving isosorbide mononitrate plus placebo (-25/-15 mm Hg). The second study involved 15 male subjects who were receiving sublingual nitroglycerin as needed for stable angina. A single dose of sildenafil or placebo followed by nitroglycerin sublingual one hour later was administered to patients. At least seven days later, subjects received the alternate study drug (sildenafil or placebo) and nitroglycerin sublingual one hour later. Sildenafil plus nitroglycerin resulted in an increase in mean reductions from baseline in systolic/diastolic blood pressure (-36/-21 mm Hg) compared with placebo plus nitroglycerin (-26/-12 mm Hg). Substantially greater decreases in blood pressure occur from baseline with administration of isosorbide mononitrate plus sildenafil compared to patients receiving isosorbide mononitrate plus placebo. A clinically significant reduction in blood pressure occurs with concomitant use of sildenafil and nitrates, such as isosorbide mononitrate and nitroglycerin .

Sildenafil Overview

• Sildenafil (Viagra) is used to treat erectile dysfunction (impotence; inability to get or keep an erection) in men. Sildenafil (Revatio) is used to improve the ability to exercise in adults and children 1 year of age and older with pulmonary arterial hypertension (PAH; high blood pressure in the vessels carrying blood to the lungs, causing shortness of breath, dizziness, and tiredness). Sildenafil is in a class of medications called phosphodiesterase (PDE) inhibitors. Sildenafil treats erectile dysfunction by increasing blood flow to the penis during sexual stimulation. This increased blood flow can cause an erection. Sildenafil treats PAH by relaxing the blood vessels in the lungs to allow blood to flow easily.

• If you are taking sildenafil to treat erectile dysfunction, you should know that it does not cure erectile dysfunction or increase sexual desire. Sildenafil does not prevent pregnancy or the spread of sexually transmitted diseases such as human immunodeficiency virus (HIV).

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.