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 respiration.

Microorganisms in the upper gastrointestinal tract reduce nitrate to nitrite, causing primary toxic effects of the inorganic nitrate ion. Although organic nitrate can also produce nitrite ions, it is thought that the principal effect is dependent on the production of 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 Nitrates Toxicity?

• Organic nitrates are given in the form of Nitroglycerin, Isosorbide dinitrate, and Isosorbide mononitrate. These drugs act as a prodrug (molecule or a drug that is 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 for the management of 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 of the drug 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 inert matrix of the tablet. 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 due to reduced blood flow to the heart).

Nitroglycerin is also used to manage coronary artery disease (build-up of plaque in the heart blood vessels leading to the 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. The use of Isosorbide dinitrate in the United States was approved in 1966 and is still widely used today. There are several brands of generic drug, 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 hours to 10 hours nitrate-free period each day.

C. Isosorbide Mononitrate: It is an inactive form of nitric oxide used to prevent angina pectoris (not used for the treatment). In 1991, Isosorbide mononitrate 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.

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 Nitrates Toxicity?

• Toxicity from Nitroglycerin or similar drugs is a consequence of increased dilation of the blood vessels. This results in decreased 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 Nitrates Toxicity?

• As the clinical effects of organic nitrates are not observed to be significant, there is no antidote 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 a dose of 1 to 2 mg/kg of the patient's body weight.

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, and thus, studies are yet to determine the management of the same.