Organic Nitrates Toxicity - An Overview

Introduction:

Nitrates exist in the environment in organic and inorganic forms. The oxidation of nitrogen-containing compounds leads to the production of nitrates. Inorganic chemicals manufactured for agriculture are primarily responsible for the excess nitrates in the environment. Nitrate-containing organic molecules are mostly used as explosives or for medical purposes.

Food and drinking water are the primary sources of exposure to inorganic nitrates, whereas organic nitrates are mainly absorbed orally, dermally (through the skin), and through respiration.

Microorganisms in the upper gastrointestinal tract reduce nitrate to nitrite, causing the primary toxic effects of the inorganic nitrate ion. Although organic nitrate can also produce nitrite ions, it is thought that the principal effect depends on producing an active radical, nitric oxide. Nitrites are formed in the blood when organic nitrates are metabolized in the liver. Most of the body's nitrates and nitrites are eliminated through the urine.

What Is Organic Nitrate Toxicity?

• Organic nitrates are given as Nitroglycerin, Isosorbide dinitrate, and Isosorbide mononitrate. These drugs act as a prodrug (molecule or drug converted into an active form after metabolization) for releasing nitric oxide, a potent vasodilator.

• Nitric oxide acts by activating a guanylyl-cyclase compound in blood vessel cells. This results in a cascade of events followed by relaxation of the muscle. Organic nitrates are mainly used to manage cardiac conditions like angina pectoris, coronary artery disease, heart failure, etc.

• The drug has dilation effects on both arteries and veins, and the combined effects reduce the load on the heart. Nitrates can be taken sublingually (below the tongue), orally, intravenously, etc.

• A toxic dose of these drugs causes various symptoms, leading to organic nitrate toxicity.

What Are the Different Types of Organic Nitrates?

1. Nitroglycerin (GTN): It is a volatile organic compound formulated by adsorbing on the tablet's inert matrix. The drug is given sublingually (under the tongue) and acts within 1 to 2 minutes. For more than 100 years, this drug has been used to treat angina pectoris (a type of heart disease caused by reduced blood flow to the heart).

Nitroglycerin is also used to manage coronary artery disease (plaque build-up in the heart's blood vessels leading to a reduced blood supply).

Available Forms of Nitroglycerine:

1. Sublingual tablets.

2. Topical ointments.

3. Transdermal patches.

4. Transmucosal ointments.

5. Aerosolized spray.

6. Liquid solutions for intravenous injection.

B. Isosorbide Dinitrate: Angina pectoris can be treated and prevented using isosorbide dinitrate, a prodrug of nitric oxide. Isosorbide dinitrate is given sublingually due to its good absorption when taken orally. Isosorbide dinitrate in the United States was approved in 1966 and is still widely used today. Several brands of generic drugs, such as Isordil, Dilatrate-SR, Sorbitrate, and sublingual and oral extended-release tablets and capsules. When treating acute angina attacks with sublingual forms, dosages typically range from 2.5 mg to 5 mg, repeated every 5 to 10 minutes for a maximum of three doses. The recommended dose is 4 mg to 40 mg, two to four times per day. As nitrate tolerance can develop with continuous use, it is recommended to have a daily 8-hour to 10-hour nitrate-free period each day.

C. Isosorbide Mononitrate: This is an inactive form of nitric oxide used to prevent angina pectoris (not used for treatment). In 1991, it was approved for use in the United States. The tablet is available under Monoket 10 mg and 20 mg. It is recommended to take 20 mg of Isosorbide mononitrate twice daily, given 7 hours apart.

How Does Nitrate Accumulation Occur in the Plant?

Some plants, like oat hay, sorghum, corn, beet, etc., can accumulate nitrate. The ability to accumulate nitrate differs from one plant to another. The factors responsible include the soil type, availability, and form of nitrogen in the soil, as well as many other factors and chemical or physical plant damage. Nitrate accumulation occurs more commonly in the leaves and stems of plants.

Nitrogen is considered to be important for proteins. Nitrate accumulates not only if excess nitrate is present in the soil but also when the plant grows slowly and cannot metabolize nitrogen into proteins.

Plants grown in low light tend to accumulate nitrate. Another factor is the long and poor storage of the crops, which tends to increase the accumulation of nitrites. Stored vegetables may contain nitrites due to the microbial reduction of nitrate into nitrite.

What Are the General Side-effects of Organic Nitrates?

The general side effects of organic nitrates include:

• Headache.

• Dizziness.

• Weakness.

• Flushing.

• Syncope (fainting).

• Tachycardia (increased heartbeat).

• Palpitations.

• Postural hypotension.

• Dermal forms can cause local rash and irritation.

• Nausea and vomiting.

• Peripheral edema.

What Are the Symptoms and Management of Organic Nitrate Toxicity?

• Toxicity from Nitroglycerin or similar drugs results from increased dilation of the blood vessels, which decreases blood pressure. As a result, increased heart rate, such as increased heart rate and palpitations, can also be seen.

• The increased blood in the skull results in increased pressure, leading to chronic headaches, confusion, fever, vertigo, nausea, vomiting, and visual disturbances. Additionally, increased pressure inside the skull will progress to respiratory distress, decreased heart rate, seizures, coma, and eventually death.

What Is the Treatment for Organic Nitrate Toxicity?

• As the clinical effects of organic nitrates are not observed to be significant, no antidote is available to counteract the effect of Nitroglycerin.

• Increasing the body fluid volume can help maintain the side effects of dilation of the blood vessels.

• Administration of normal saline intravenously and elevating the patient’s legs might provide adequate support.

• Drugs that constrict the blood vessels (vasoconstrictors), such as Adrenaline are not recommended as they might cause other side effects.

• Methemoglobinemia has been rarely reported as a consequence of nitrate toxicity. Laboratory blood reports from patients with methemoglobinemia show a "chocolate brown" appearance. The condition is treated by an intravenous administration of methylene blue, at 1 to 2 mg/kg of the patient's body weight.

How to Decrease the Risk of Nitrate Toxicity?

Identifying and removing the source is important for decreasing nitrate toxicity. The recommended dose of nitrates should be known. Knowledge about nitrates is needed to avoid complications. When nitrate toxicity occurs, it should be identified quickly, and proper treatment should be given to prevent mortality.

How to Reduce the Risk of Nitrate Toxicity?

Feeding sufficient energy levels, vitamins A and E, and trace minerals can reduce the risk of nitrate toxicity.

Conclusion:

An overdose of the drugs Nitroglycerin, Isosorbide dinitrate, and Isosorbide mononitrate, causes various symptoms, leading to organic nitrate toxicity. Organic nitrates are mainly used for the treatment of heart conditions. The symptoms of organic nitrate toxicity include headaches, dizziness, seizures, nausea, increased heart rate, etc. Most of these consequences are related to dilated blood vessels. However, the clinical effects of nitrate toxicity are not significant; thus, studies are yet to determine the management of the same.