Nitroglycerin

Article Author:
Kyle Kim
Article Editor:
Derek Schaller
Updated:
10/10/2019 1:56:42 PM
PubMed Link:
Nitroglycerin

Indications

Nitroglycerin is a vasodilatory drug that is 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. This 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.[1][2][3][4]

Mechanism of Action

Similar to other nitrates used to treat anginal chest pain, nitroglycerin is converted 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 causes the relaxation of smooth muscle within blood vessels, resulting in the desired vasodilatory effect.[5][6][7][8]

Administration

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 may be repeated every 5 minutes until relief is achieved. 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 is very tightly monitored and 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 on to the patient's skin and allowed to absorb. It is typically used 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. Ideal application is on a surface with minimal amounts of hair as it can inhibit absorption, and care must also be taken 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 the ointment should be taken with the patches.

Adverse Effects

Nitroglycerin has many adverse effects of significance, most resulting from the vasodilatory effects of the medication. [9]These include:

  • Dizziness
  • Weakness
  • Palpitations
  • Vertigo
  • Headaches
  • Nausea
  • Vomiting
  • Diaphoresis
  • Syncope

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. Risk of syncope is greatly increased with concurrent use of a phosphodiesterase-5 (PDE-5) inhibitor. A further discussion is included below under contraindications.

Flushing, exfoliative dermatitis, and drug rash have also been reported in some patients taking nitroglycerin.

Contraindications

Allergic reactions to nitroglycerin are extremely rare but have been reported. Nitroglycerin is contraindicated in patients that have reported allergic symptoms to the medication.

A 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 been proven to accentuate the hypotensive effects of nitrates and precipitate syncopal episodes.

Monitoring

Nitroglycerin levels are not currently monitored by any testing as its half-life is approximately 2 to 3 minutes, and the drug is rapidly metabolized 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 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. Prior to 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 should be used with caution in breastfeeding mothers. It is not currently known whether nitroglycerin is excreted in breast milk.

Toxicity

Overdose toxicity from nitroglycerin is mainly a consequence of an 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 can be given to counteract the effect nitroglycerin. Since the effects are related to venodilation and relative arterial hypovolemia, efforts to increase central fluid volume have been proven to be effective. Intravenous administration of normal saline in addition to passive elevation of the patient's legs may provide adequate support, but no controlled trials have been conducted 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 rarely been reported 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 is described as 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 should be used with caution in breastfeeding mothers. It is not currently known whether nitroglycerin is excreted in breast milk.


References

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[4] Bosson N,Isakson B,Morgan JA,Kaji AH,Uner A,Hurley K,Henry TD,Niemann JT, Safety and Effectiveness of Field Nitroglycerin in Patients with Suspected ST Elevation Myocardial Infarction. Prehospital emergency care : official journal of the National Association of EMS Physicians and the National Association of State EMS Directors. 2018 Dec 17;     [PubMed PMID: 30556765]
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[6] Pavasini R,Camici PG,Crea F,Danchin N,Fox K,Manolis AJ,Marzilli M,Rosano GMC,Lopez-Sendon JL,Pinto F,Balla C,Ferrari R, Anti-anginal drugs: Systematic review and clinical implications. International journal of cardiology. 2018 Dec 4;     [PubMed PMID: 30538056]
[7] Hollas MA,Ben Aissa M,Lee SH,Gordon-Blake JM,Thatcher GRJ, Pharmacological manipulation of cGMP and NO/cGMP in CNS drug discovery. Nitric oxide : biology and chemistry. 2019 Jan 1;     [PubMed PMID: 30394348]
[8] Long B,Koyfman A,Gottlieb M, Management of Heart Failure in the Emergency Department Setting: An Evidence-Based Review of the Literature. The Journal of emergency medicine. 2018 Nov;     [PubMed PMID: 30266198]
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