Continuing Education Activity
Nitroglycerin is a vasodilatory drug used primarily to provide relief from anginal chest pain. It is currently FDA approved for the acute relief of an attack or acute prophylaxis of angina pectoris secondary to coronary artery disease. Off-label, non-FDA approved uses include treatment for hypertensive urgency/emergency, coronary artery spasm, angina secondary to cocaine use, congestive heart failure (CHF), and chronic anal fissures. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, monitoring, and toxicity of nitrous oxide, so providers can direct patient therapy successfully in instances where nitrous oxide provides a benefit to patient care.
- Identify the approved and off label indications for using nitroglycerine.
- Summarize the mechanism of action of nitroglycerine.
- Outline any contraindication to using nitroglycerine, as well as describing its adverse event profile.
- Describe interprofessional team strategies for improving care coordination and communication to properly use nitroglycerine to improve patient outcomes in the varied scenarios where it can be effective.
Nitroglycerin is a vasodilatory drug used primarily to provide relief from anginal chest pain. Nitroglycerin has been FDA approved since 2000 and was first sold by Pfizer under the brand name Nitrostat. It is currently FDA approved for the acute relief of an attack or acute prophylaxis of angina pectoris secondary to coronary artery disease. Off-label, non-FDA approved uses include treatment for hypertensive urgency/emergency, coronary artery spasm, angina secondary to cocaine use, congestive heart failure (CHF), and chronic anal fissures.
Although nitroglycerin has a vasodilatory effect in both arteries and veins, the profound desired effects caused by nitroglycerin are primarily due to venodilation. Venodilation causes pooling of blood within the venous system, reducing preload to the heart, which causes a decrease in cardiac work, reducing anginal symptoms secondary to demand ischemia. Arterial vasodilation will still occur as well and contribute towards the relief of anginal symptoms, but its effects are not as significant. Vasodilation of the coronary arteries will cause increased blood flow to the heart, increasing perfusion, but this effect remains minimal compared to the effects of venodilation.
Mechanism of Action
Similar to other nitrates used to treat anginal chest pain, nitroglycerin converts to nitric oxide (NO) in the body. NO then activates the enzyme guanylyl cyclase, which converts guanosine triphosphate (GTP) to guanosine 3',5'-monophosphate (cGMP) in vascular smooth muscle and other tissues. cGMP then activates many protein kinase-dependent phosphorylations, ultimately resulting in the dephosphorylation of myosin light chains within smooth muscle fibers. This activity causes the relaxation of smooth muscle within blood vessels, resulting in the desired vasodilatory effect.
Nitroglycerin is most commonly administered as a tablet that is absorbed sublingually. It is given in hospitals as well as prescribed for outpatient use. Patients may be prescribed nitroglycerin to take as prophylaxis for anginal chest pain prior to an event that may provoke anginal symptoms. They must be instructed to allow the nitroglycerin to dissolve in their mouth and allow their oral mucosa to absorb the drug. There currently are three doses available: 0.3 mg, 0.4 mg, and 0.6 mg. The dose is repeatable every 5 minutes until the achievement of relief. If anginal pain persists after three doses, prompt medical attention is required. After administration, the onset of vasodilatory effects occurs within 1 to 3 minutes, with a max effect occurring within 5 minutes. Nitroglycerin is primarily eliminated via metabolism in the liver and has a mean half-life of approximately 2 to 3 minutes.
There are intravenous (IV) routes of administration for nitroglycerin used most commonly in emergency rooms and intensive care units (ICU). It is administered as a 5% dextrose in water drip and is indicated when sublingual nitroglycerin has failed to provide symptomatic relief or if rapid and continued relief of symptoms is necessary. The drip is frequently used to treat acute coronary syndromes, hypertensive emergency, and acute congestive heart failure (CHF) exacerbations. When administered, its effect requires tight monitoring, as discussed below.
Transdermal methods of nitroglycerin administration are also commonly administered in emergency rooms during acute angina attacks. It is a 2% ointment that is applied directly to the patient's skin and allowed to absorb. It is typically for patients that cannot tolerate the sublingual administration of nitroglycerin or have a previous adverse reaction to the sublingual tablet. Absorption takes about 5 to 10 minutes for full effect. The ideal application is on a surface with minimal amounts of hair as it can inhibit absorption, and care is necessary to not apply repeatedly to the same area if multiple doses are required. Repeated application of the ointment to the same area can cause skin irritation and dermatitis. Transdermal patches are also available at varying doses per hour (0.1 mg, 0.2 mg, 0.4 mg, and 0.6 mg), but these are rarely used and reserved for angina prophylaxis only. Similar application precautions as apply to the ointment also apply to the patches.
Nitroglycerin has many adverse effects of significance, most resulting from the vasodilatory effects of the medication. These include:
Many of these adverse effects are secondary to the hypotensive effects of nitroglycerin. Patients may report symptoms of orthostatic hypotension which manifest as dizziness, weakness, palpitations, and vertigo. Profound hypotension may occur in patients with preload-dependent conditions.
Some patients can be more sensitive to the hypotension caused by nitrates, which can result in nausea, vomiting, diaphoresis, pallor, and collapse even at therapeutic doses.
Headaches can be severe, throbbing, and persistent and may occur immediately after use.
Syncope is the most dangerous adverse effect and can result in falls and their resultant injuries. The risk of syncope significantly increases with the concurrent use of a phosphodiesterase-5 (PDE-5) inhibitor. A further discussion is included below under contraindications.
There have also been reports of flushing, exfoliative dermatitis, and drug rash in some patients taking nitroglycerin.
Allergic reactions to nitroglycerin are extremely rare, but reports do exist. Nitroglycerin is contraindicated in patients that have reported allergic symptoms to the medication.
Known history of increased intracranial pressure, severe anemia, right-sided myocardial infarction, or hypersensitivity to nitroglycerin are all contraindications to nitroglycerin therapy.
Concurrent use of nitroglycerin with PDE-5 inhibitors (e.g., sildenafil citrate, vardenafil hydroxide, tadalafil) is absolutely contraindicated. PDE-5 inhibitors have proven to accentuate the hypotensive effects of nitrates and precipitate syncopal episodes.
Any testing does not currently monitor nitroglycerin levels as its half-life is approximately 2 to 3 minutes, and the drug undergoes rapid metabolism from the body. When administered as a drip in the emergency room or ICU, its effects are often very closely monitored via an arterial line for real-time blood pressure monitoring. This vigilance is necessary to maximize the effectiveness of the drip and provide rapid feedback on the patient's condition. When administered sublingually, nitroglycerin's effectiveness is typically subjectively measured via the resolution of symptoms; angina, hypertension, CHF, among others.
In the event of overdose, monitoring of vital signs may be necessary to monitor the hemodynamic effects of nitroglycerin. Continuous monitoring of blood pressure, heart rate, respiratory rate, and oxygen saturation is recommended.
Nitroglycerin is both a protein-bound drug, and it undergoes hepatic metabolism. Therefore it has numerous drug interactions. Before prescribing, providers should determine if the patient is taking any medications that may interact with nitroglycerin. Common interactions include alteplase, heparin, tricyclic antidepressants, and other anticholinergic drugs. Alcohol intake should also be limited.
Nitroglycerin is pregnancy category C, and its use requires caution in breastfeeding mothers. It is not currently known whether nitroglycerin is excreted in breast milk.
Overdose toxicity from nitroglycerin is mainly a consequence of increased vasodilatory response. Hypotension, venous pooling, increased vasodilation, and reduced cardiac output can be expected in these patients. Compensatory effects, such as tachycardia and palpitations, can also be expected. Vasodilation and venous pooling can increase the amount of blood in the cranial space, resulting in increased intracranial pressures; this can cause persistent, throbbing headaches, along with confusion, fever, vertigo, nausea, vomiting, and visual disturbances. As intracranial pressure increases, symptoms will progress to dyspnea secondary to a reduced respiratory effort, heart block, bradycardia, paralysis, seizures, coma, and, eventually, death.
No currently known antagonist is available to counteract the effect of nitroglycerin. Since the effects are related to venodilation and relative arterial hypovolemia, efforts to increase central fluid volume have proven to be effective. Intravenous administration of normal saline, in addition to the passive elevation of the patient's legs, may provide adequate support, but there are no controlled trials to prove its effectiveness. Epinephrine or other arterial vasoconstricting agents are not recommended as they will not likely improve the patient's condition, and they may cause more difficulties in the future.
Methemoglobinemia has some rare reports as a consequence of nitrate overdose. Suspicion should be raised in patients that begin showing symptoms of hypoxemia despite a lack of respiratory symptoms, normal arterial PO2, and adequate cardiac output. Blood from patients with methemoglobinemia has the appearance of being "chocolate brown" in color, with no change in color upon exposure to air. The treatment for methemoglobinemia is an intravenous administration of methylene blue, dosed at 1 to 2 mg/kg of the patient's body weight.
Enhancing Healthcare Team Outcomes
Healthcare workers like the nurse practitioner, primary care provider, pharmacists, internist, and cardiologist who prescribe nitroglycerin should be fully aware of the indications and contraindications of the drug. Overall, nitroglycerin is relatively safe, and monitoring of the levels is not required. In the event of overdose, monitoring of vital signs may be necessary to monitor the hemodynamic effects of nitroglycerin. Continuous monitoring of blood pressure, heart rate, respiratory rate, and oxygen saturation is recommended.
Nitroglycerin is pregnancy category C, and its use requires caution in breastfeeding mothers. It is currently unknown whether nitroglycerin is excreted in breast milk.