Nitrates for Treating Angina

Nitrates have been a mainstay in the treatment of angina for over 100 years. Today, nitrates are used both to treat acute episodes of angina (in the form of sublingual nitroglycerin or nitroglycerin oral spray), and chronically (in pill form or as a skin patch) to help prevent angina.

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How Do Nitrates Work?

Nitrates work by dilating arteries and veins, both in the heart and elsewhere in the body. This general dilation of blood vessels reduces stress on the heart muscle, and thus reduces the amount of oxygen the heart requires. Reducing heart’s oxygen requirements allows the heart to do more work without developing ischemia, even if blood flow through the coronary arteries is partially blocked by atherosclerosis.

Nitrates also dilate the coronary arteries. Since the coronary arteries are already dilated when an atherosclerotic plaque is obstructing blood flow, this direct dilating effect is of limited use in people with typical coronary artery disease. However, in people with Prinzmetal angina — which is largely caused by coronary artery spasm — nitrates are often very helpful.

How Are Nitrates Used?

Sublingual (SL) nitroglycerin (nitroglycerin that is rapidly absorbed from under the tongue) is the oldest form of nitrate therapy. SL nitroglycerin is the quickest way to relieve an episode of angina brought on by exercise or stress and commonly provides relief within minutes.

Also, taking SL nitroglycerin just before engaging in activities that are likely to cause symptoms (such as climbing a hill or walking in the cold) can help prevent episodes of angina. SL nitroglycerin begins dilating blood vessels within two minutes, and its effect can last up to 30 minutes.

Nitroglycerin spray, delivered into the mouth by a metered-dose device, works similarly to SL nitroglycerin — it is simply another method of delivering a rapid-acting dose of nitroglycerin.

Short-acting nitrates (SL or sublingual) should be carried by anyone who is being treated for angina.

The long-acting nitrates (pills or skin patches) are considered a second-line form of therapy for angina. They are prescribed if beta-blockers (first-line therapy) cannot be tolerated, or are ineffective in eliminating symptoms.

The most commonly used pill form of nitrates is isosorbide dinitrate (Isordil, Sorbitrate). With oral nitrates, the effect on blood vessels begins within approximately 30 minutes and lasts for up to six hours.

Transdermal nitroglycerin patches, which deliver nitroglycerin through the skin, provide effective nitrate therapy for eight to 14 hours.

Nitrate Tolerance

The biggest problem with the use of long-acting nitrates has been the phenomenon of "tolerance." Nitrate tolerance means that the benefits of nitrate therapy can become reduced when nitrates are used around the clock. Simply speaking, when the blood vessels are always exposed to nitrates, they stop dilating in response to the nitrates, and the anti-anginal effect of the drug disappears.

Nitrate tolerance can be prevented by scheduling the dosing of chronic nitrate therapy to provide daily nitrate-free intervals. So: oral nitrates or nitrate skin patches should only be used for 12 to 16 hours per day, with an eight to 12 hour "nitrate-free" interval. For most patients, this means that nitrates are used during waking hours, and not during sleep. In some patients with nocturnal angina, however, the nitrate-free interval may need to be scheduled during waking hours.

Other Precautions With Nitrates

Nitrates should not be used in patients with hypertrophic cardiomyopathy (in whom nitrates can cause a dangerous obstruction to blood flow within the heart), or in patients who are taking Viagra (sildenafil) or other similar agents for erectile dysfunction. (Taking nitrates and Viagra together can produce severe hypotension — low blood pressure.)

Asians tend to have a reduced response to nitrates and are less likely to receive benefit from their use.

The most common side effects of nitrates are headache and flushing, though lightheadedness from hypotension can also occur. Patients with a history of migraine headaches often cannot tolerate nitrates.

2 Sources
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  1. Soman B, Vijayaraghavan G. The role of organic nitrates in the optimal medical management of angina. e-Journal of Cardiology Practice. 15(2).

  2. Bertel O. Nitrattoleranz [Nitrate tolerance]. Schweiz Med Wochenschr. 1988;118(50):1892-1898.

Additional Reading
  • Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 126:3097.

By Richard N. Fogoros, MD
Richard N. Fogoros, MD, is a retired professor of medicine and board-certified in internal medicine, clinical cardiology, and clinical electrophysiology.