Continuing Education Activity

Nitrates are useful in the management and treatment of angina. They are a group of medications that cause vasodilation by donating nitric oxide. This activity reviews the indications, action, and contraindications for nitrates as a valuable agent in the management of angina and other cardiovascular diseases.

Objectives:

• Identify the mechanism of action of nitrates.
• Describe the adverse effects of nitrates.
• Review the appropriate monitoring and toxicity of nitrates.
• Outline inter-professional team strategies for improving care coordination and communication to advance nitrate use and improve outcomes.

Indications

Nitrates are a class of medications (not to be confused with the byproduct of nitrogen fertilizers) that cause vasodilation by donating nitric oxide (NO).[1] Nitrates exert their effects by dilating venous vessels, coronary arteries, and small arterioles; its maximal vasodilation is in the venous vessels.[2]

Nitrates were first discovered in 1847 as a treatment for chest pain.[1][2] The type of nitrates used and the administration route differs depending on the type of cardiovascular disease. The purpose of nitrate use is multifaceted. For patients with stable and predictable angina, long-acting nitrate can be used as prophylaxis, increasing exercise tolerance in patients.[3] This effect can be beneficial since patients with coronary artery disease tend to have other co-morbidities. For patients with acute anginal pain, short-acting nitrates are useful for symptom relief.[3]

The use of nitrates is indicated in the following cardiovascular diseases: angina pectoris, acute coronary syndrome, arterial hypertension, and heart failure.[1][2]

The main types of nitrates are as followed[4]:

• Nitroglycerin (NTG) – angina pectoris (treatment/prophylaxis), acute coronary syndrome, heart failure, hypertension
• Isosorbide mononitrate (ISMN) – chronic angina pectoris (treatment)
• Isosorbide dinitrate (ISDN) – angina pectoris (treatment/prophylaxis)
• Pentaerythrityl tetranitrate (PETN) – Not commonly used in the United States
• Erythrityl tetranitrate (ETN) – Not commonly used in the United States

Mechanism of Action

Nitrates exert their pharmacological effect by being activated by mitochondrial or cytosolic aldehyde dehydrogenase (ALDH2) into nitric oxide (NO), an endothelium-derived relaxing factor (EDRF).[2] NO is generally produced by the endothelium to dilate the blood vessels; however, endothelial dysfunction in diseases such as atherosclerosis can deplete NO levels.[2] When administered, nitrates convert to NO, which then activates soluble guanylate cyclase.[2] This action results in increased levels of intracellular cyclic guanosine monophosphate (cGMP) and its dependent protein kinases, such as cGMP-dependent protein kinase I (cGK-I). cGK-I inhibits inositol-1,4,5-trisphosphate-dependent calcium release. The decreased intracellular calcium levels subsequently inhibit myosin light chain kinase, and the unphosphorylated myosin light chain causes myosin head to detach from actin, resulting in smooth muscle relaxation.[5] The NO-cGMP-cGK-I signaling pathway causes vasorelaxation, platelet disaggregation, and prevention of platelet adhesion.[2][6]

The venodilation increases the venous capacitance and lowers the preload; this subsequently lowers the left ventricular end-diastolic pressure, resulting in a reduction in myocardium workload, which decreases the oxygen demand of the heart.[2][6] At higher doses, nitrates can also exert significant coronary artery dilation, allowing blood flow to ischemic areas during coronary artery occlusion and vasospastic angina.[7]

Administration

Nitrates have many different forms with various routes of administration.[3] Nitroglycerin, also known as glyceryl trinitrate (GTN), can be administered as a patch, ointment, capsule, spray, intravenous infusion, or a sublingual tablet.[3] Sublingual nitroglycerin is the therapy of choice for acute anginal episodes since it avoids first-pass metabolism, allowing for immediate and short anginal relief.[3] Transdermal, ointment, and spray are other options with similar efficacy but are less popular.[3] The capsule form of nitroglycerin has a longer duration of action and require larger doses. Intravenous nitroglycerin is useful for hypertensive emergencies.[2][3]

Other forms of commonly used nitrates include isosorbide dinitrate, isosorbide mononitrate, and isosorbide mononitrate sustained-release (SR). These forms are taken orally and have a longer duration of action. However, due to hepatic metabolism, the oral forms require relatively larger doses.[3][7]

Below are commonly prepared forms of nitrates[3][4][8]:

• Nitroglycerin
  • Sublingual tablet – 0.3 to 0.6 mg, up to 1.5 mg as needed a day
  • Transdermal patch – 0.2 – 0.8 mg/h, one patch a day (remove at night for 12h)
  • Ointment – 7.5 – 40 mg a day
  • Capsule – 5 – 6.5 mg, 3 to 4 times a day
  • Spray – 0.4 to 0.8 mg, 1 to 3 times a day; max 3 actuations in 15 minutes
  • IV – range from 10 to 120 micrograms/min
• Isosorbide dinitrate
  • Tablet – 10 to 40 mg 3 times a day
  • Sublingual tablet – 2.5 to 10 mg
  • Spray – 1.25 mg per dose
• Isosorbide mononitrate
  • Tablet – 20 mg twice daily, 7 hours apart
  • Tablet (Sustained release) – 30 to 120 daily; max daily dose 240 mg daily

Adverse Effects

Main adverse effects from nitrate use come from dilation of the venous blood vessels. Other side effects can be reflexes from the activation of the sympathetic nervous system or re-exposure after withdrawal. These side effects include[3][7]:

• Headaches (greater than 10%)
• Hypotension (0.1 to 10%)
• Cutaneous flushing (0.1 to 10%)
• Syncope (0.1 to 10%)
• Reflex tachycardia (0.1 to 10%)
• Methemoglobinemia (rare)
• Monday disease (tachycardia, headache, and dizziness during re-exposure)

Contraindications

Several contraindications exist for the use of nitrate.[3] They are the following:

• Allergy to nitrates
• Concomitant use of phosphodiesterase (PDE) inhibitors such as tadalafil and sildenafil
• Right ventricular infarction
• Hypertrophic cardiomyopathy

PDE inhibitors and nitrates both cause vasodilation, and concomitant use may cause severe hypotension. Healthcare providers should make sure to inquire if the patients have erectile dysfunction and if they are taking medications for it.

Poor right ventricular contractility causes the patients to be pre-load sensitive, and nitrates may cause severe hypotension. Decreased left ventricular volume from decreased preload will worsen the outflow tract obstruction.

The following are conditions that require care with nitrate administration:

• Patients on chronic diuretic therapy
• Patients with low systolic blood pressure
• Patients with autonomic nervous system dysregulation
• Pregnancy and breastfeeding.

Patients on diuretic therapy can be volume depleted and can develop hypotension.

Patients who have low systolic blood pressure can develop severe hypotension.

Elderly patients and patients with autonomic nervous system dysregulation have a higher risk of postural hypotension.

Nitrates have not been evaluated fully in pregnancy and breastfeeding, so they should be avoided.

Monitoring

Generally, nitrate use does not necessitate monitoring. However, if the patient is on diuretic therapy or has low systolic blood pressure, blood pressure, and heart rate requires monitoring. Other medications may be used in conjunction with nitrates to treat reflexive mechanisms. Beta-blockers can be used with nitrates to prevent reflex tachycardia.[2] Hydralazine can be used with nitrate to improve symptoms and mortality in heart failure patients.[2]

Nitrate tolerance is a significant problem regarding chronic nitrate use.[3] Tolerance may develop quickly within 12 to 24 hours, and nitrates lose its clinical effects; this necessitates nitrate-free or low nitrate level for 10 to 12 hours a day. Health care professionals should inform the patients of anginal episodes during the nitrate-free periods as well. Chronic nitrate use without rest periods results in poor symptom control in addition to endothelial dysfunction due to the accumulation of free radicals.[7] Rebound angina may also occur from nitrate withdrawal.

Toxicity

There is currently no evidence of the teratogenicity or carcinogenicity potential of nitrate.

Methemoglobinemia can be caused by nitrate toxicity in rare cases.[7] Generally, supportive care and cessation of nitrate should be sufficient for most cases of methemoglobinemia. Methylene blue is an effective antidote if needed.[9]

Enhancing Healthcare Team Outcomes

Due to high prevalence and high rates of readmission compared to other chronic medical diseases, coronary heart disease in patients must receive treatment with significant interprofessional communication for not only symptomatic improvement but also mortality reduction.

Nitrates are the first-line medication for angina, one of the main symptoms of coronary heart disease. Multiple health care professionals such as general practitioners (GP), home care workers, pharmacists, and dieticians can work together to improve patients’ quality of life and prevent exacerbation of the disease.[10] Communication between the providers can prevent adverse drug interactions when prescribing nitrates, and limit side effects in patients who are at increased risk. Since chronic heart failure and erectile dysfunction frequently occur concomitantly,[11] pharmacists, nurses, and GPs should ensure nitrates therapy is not an option if the patient is on PDE inhibitors. Home care professional nurses should also work with GPs for elderly patients who are prone to hypotension to prevent syncope. [Level III]

Nursing can verify medication compliance at each visit and monitor for adverse events, reporting these to the prescribing clinician. Pharmacists should verify both dose and dose form prior to dispensing, and also alert the prescriber should there be any discrepancies. Pharmacists should also perform medication reconciliation and communicate any issues to the nurse or prescribing clinician.

Nitrate therapy requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]