Nitroglycerin

Absorption

Nitroglycerin is rapidly absorbed and is often used in emergency situations for this reason. After a sublingual dose of 0.5 mg of nitroglycerin in patients with ischemic heart disease, the peak concentration (Cmax) was 2.56 ng/mL and the mean Tmax was 4.4 minutes.
The Cmax following a 0.6mg dose of sublingual nitroglycerin was 2.1 ng/mL and the Tmax was 7.2 minutes. The absolute bioavailability following sublingual administration was about 40%. The bioavailability of nitroglycerin depends on several factors, such as mucosal metabolism and hydration status, which both affect the absorption of sublingual drugs.

Toxicity

The oral LD50 of nitroglycerin in rats is 105 mg/kg and the LD50 of the intravenous form in rats is 23.2 mg/kg.
Nitrate overdosage can result in following conditions: severe hypotension, persistent throbbing headache, vertigo, palpitation, visual disturbance, flushing and perspiring skin (later becoming cold and cyanotic), nausea and vomiting (possibly with colic and even bloody diarrhea), syncope (especially in the upright posture), methemoglobinemia with cyanosis and anorexia, initial hyperpnea, dyspnea and slow breathing, slow pulse (dicrotic and intermittent), heart block, increased intracranial pressure with cerebral symptoms of confusion and moderate fever, paralysis and coma followed by clonic convulsions, and possibly death due to circulatory collapse.
Methemoglobinemia can rarely occur at conventional doses of organic nitrates. This condition is dose-related and it can be even more pronounced in patients with genetic abnormalities of hemoglobin that favor methemoglobin formation. Methemoglobinemia can be managed with the administration of methylene blue unless the patient has a known G-6-PD deficiency.
There are no known antidotes to an overdose of nitroglycerin, and it is not known whether its metabolites can be removed from the circulation. Hypotension associated with nitroglycerin overdose can be managed with different symptomatic and supportive measures, including the elevation of the lower limbs, administration of intravenous saline or other fluids to maintain central fluid volume, and administration of oxygen and artificial ventilation. Gastric lavage may be used in case of ingestion of excess nitroglycerin.

Description

Nitroglycerin, formally 1,2,3-propanetriol trinitrate, is a venerable explosive and, in small doses, a life-saving drug. It was first prepared in 1846 by chemist Ascanio Sobrero at the University of Turin, who was reluctant to publish his work because of the compound’s extreme explosiveness. After numerous accidents, the manufacture and distribution of the pure liquid was soon banned in many jurisdictions.
Recognizing the potential usefulness of nitroglycerin, Swedish chemist and entrepreneur Alfred Nobel sought to make a practical explosive formulation that could be handled reasonably safely. In 1867, he invented dynamite, a mixture of nitroglycerin and sorbents such as diatomaceous earth. He soon developed methods for dynamite manufacture, obtained patents in several countries, and marketed his product. The wealth he amassed allowed him to establish the eponymous prizes in several fields of endeavor.
Soon after he discovered nitroglycerin, Sobrero and others found that tasting the substance caused intense headaches. (In those days, chemists often sampled newly prepared compounds, sometimes with disastrous results.) The headaches suggested that nitroglycerin is a vasodilator; and by the late 1870s, English physician and pharmacologist William Murrell used small doses to alleviate angina pectoris and hypertension.
Today, 140 years later, cardiac patients carry capsules or sprays of dilute nitroglycerin to take sublingually in the event of chest pain or other coronary symptoms. Despite the explosivity and other hazardous properties of pure nitroglycerin (see hazard information table), it is hailed as one of the most important chemical discoveries.

Description

Nitroglycerin is an oily, poisonous, clear to pale yellow, explosive liquid.Nitroglycerin is made by nitrating glycerol. Early industrial processes used a batch process in which glycerol was added to a mixture with approximately equal volumes of nitric acid and sulfuric acid.The sulfuric acid serves to ionize the nitric acid and removes water formed in the nitration process.

Chemical properties

Clear, colourless or slightly yellow solution

Chemical properties

Nitroglycerin is a pale yellow liquid or crystalline solid (below 13℃).

History

It was first prepared in 1846 by the Italian chemist Ascanio Sobrero (1812–1888), who nitrated glycerol using a mixture of nitric acid and sulfuric acid. Sobrero, who was injured in an explosion doing his research, realized the compound’s danger and abandoned work on nitroglycerin. Twenty years after Sobrero’s discovery, Alfred Nobel (1833–1896) developed its use commercially. Nobel mixed nitroglycerin with other substances, searching for a safe way to transport it and make it less sensitive to heat and pressure.
nitroglycerin when it was first marketed,and Nobel continued to experiment with methods to make nitroglycerin safer.One of these was mixing nitroglycerin with materials to make a solid form of nitroglycerin. Nobel discovered that when nitroglycerin was mixed with a silica-based diatomaceous earth material called kieselguhr,a relatively stable product resulted.The mixture produced a paste that Nobel could pack into cardboard tubes;these could then be inserted into holes drilled into rock structures and detonated.In 1867,Nobel patented his mixture and called it dynamite,a name derived from the Greek word dunamis, meaning power.Nobel also perfected a blasting cap made from mercury fulminate (Hg(ONC)2) and potassium chlorate (KClO3) to detonate the nitroglycerin.

The Uses of Nitroglycerin

Nitroglycerin has medicinal use as a vasodilator. The main medical use of nitroglycerin is to treat angina pectoris. Nitroglycerin was first used to treat this condition in the late 19th century. It is prescribed today in various forms (tablet, ointment, patches, and injection) for patients who suffer from angina pectoris. Nitroglycerin is marketed under various trade names: Nitro-Dur, Nitrostat, Nitrospan, Nitro-Bid, and Tridil. When used in medications, the name glyceryl trinitrate is often used instead of nitroglycerin.

The Uses of Nitroglycerin

Vasodilator (coronary) Minitran (3M Pharmaceuticals); Nitro-Bid (Sanofi Aventis); Nitro-Dur (Key); Nitrol (Rorer); Nitrolingual (Pohl Boskamp); Nitrostat (Pfizer); Transderm-Nitro (Novartis).

The Uses of Nitroglycerin

Nitroglycerin is an explosive agent contained in dynamite and an antianginal and vasodilator treatment. It is a well-known irritant in dynamite manufacturers. It can also cause allergic reactions in employees of manufacturers of explosives, or in the pharmaceutical industries. Nitroglycerin can cross react with isosorbide dinitrate.

Background

Nitroglycerin, also known as glyceryl trinitrate, is an organic nitrate and a vasodilating agent that was first discovered in 1847. Originally used to dynamite, its antianginal effects were identified in the late 1860s after it produced headaches in factory workers while workers with angina pectoris or heart failure experienced relief from chest pain. Its use as a treatment for angina dates back to 1879 and is still used to treat and prevent angina. Nitroglycerin causes vasodilation in both arteries and veins.
Nitroglycerin is used in a variety of different conditions, including angina pectoris due to coronary artery disease, peri-operative hypertension, congestive heart failure, and chronic anal fissure. It is also used to induce intraoperative hypotension.

Indications

Sublingual nitroglycerin is indicated for the acute relief of an attack or acute prophylaxis of angina pectoris due to coronary artery disease. Transdermal nitroglycerin is indicated for the prevention of angina pectoris due to coronary artery disease.
Intravenous nitroglycerin is indicated for the treatment of peri-operative hypertension; for control of congestive heart failure in the setting of acute myocardial infarction; for treatment of angina pectoris in patients who have not responded to sublingual nitroglycerin and beta (β)-blockers; and for induction of intraoperative hypotension.
Topical nitroglycerin ointment is used to treat moderate to severe pain associated with chronic anal fissure.

Definition

ChEBI: A nitroglycerol that is glycerol in which the hydrogen atoms of all three hydroxy groups are replaced by nitro groups. It acts as a prodrug, releasing nitric oxide to open blood vessels and so alleviate heart pain.

Definition

A highly explosive substance used in dynamite. It is obtained by treating glycerol (1,2,3-trihydroxypropane) with a mixture of concentrated nitric and sulfuric acids. It is not a nitro compound, but a nitrate ester CH₂(NO₃)CH(NO₃)CH₂(NO₃).

Production Methods

Nitroglycerin is made by nitrating glycerol.Early industrial processes used a batch processin which glycerol was added to a mixture with approximately equal volumes of nitric acidand sulfuric acid.The sulfuric acid serves to ionize the nitric acid and removes water formedin the nitration process.Removing the water formed in nitration increases the yield of nitroglycerin.Acids and water must be removed from the desired nitroglycerin through a washingprocess. The production of nitroglycerin is highly exothermic,and it is important to keepthe temperature below room temperature to prevent an explosion. Early production methodsused cooling coils in the nitration vessels to regulate the temperature.During the latter halfof the 20th century, safer continuous production methods replaced batch processes.In thesemethods much smaller reactors are required,as glycerol is reacted with the acids.

Indications

Nitroglycerin (also isosorbide nitrate) relaxes isolated strips of human corpus cavernosum. Its mechanism involves the stimulation of guanylate cyclase. Clinically, nitroglycerin has been of limited use in the treatment of ED.

Synthesis Reference(s)

Tetrahedron, 49, p. 7037, 1993 DOI: 10.1016/S0040-4020(01)87978-3

General Description

Colorless to pale-yellow, viscous liquid or solid (below 56°F). (Note: An explosive ingredient in dynamite (20-40%) with ethylene glycol dinitrate (80-60%).).

General Description

Glyceryl trinitrate is the trinitrate ester ofglycerol and is listed as available in tablet form in the USP.It is prepared by carefully adding glycerin to a mixture of nitricand fuming sulfuric acids. This reaction is exothermic,and the reaction mixture must be cooled to between 10°Cand 20°C.The ester is a colorless oil, with a sweet, burning taste. Itis only slightly soluble in water, but it is soluble in organicsolvents.
.

Air & Water Reactions

Highly flammable.

Reactivity Profile

Nitroalkanes, such as NITROGLYCERIN, range from slight to strong oxidizing agents. If mixed with reducing agents, including hydrides, sulfides and nitrides, they may begin a vigorous reaction that culminates in a detonation. Nitroalkanes are milder oxidizing agents, but still react violently with reducing agents at higher temperature and pressures. Nitroalkanes react with inorganic bases to form explosive salts. The presence of metal oxides increases the thermal sensitivity of nitroalkanes. Nitroalkanes with more than one nitro group are generally explosive. Nitroalkanes are insoluble in water. Flammable/combustible material. May be ignited by heat, sparks or flames. Nitroglycerin is incompatible with the following: Heat, ozone, shock, acids. Note: An OSHA Class A Explosive (1910.109). .

Hazard

Severe explosion risk, highly sensitive to shock and heat. Toxic by ingestion, inhalation, and skin absorption. Toxic by skin absorption. Vasodilator.

Health Hazard

Severe acute poisoning may result from ingestion of nitroglycerine or inhalation of its dust. The acute toxic symptoms include headache, nausea, vomiting, abdominal pain, tremor, dyspnea, paralysis, and convulsions. In addition, methemoglobinemia and cyanosis may occur. Ingestion of a relatively smallamount, 1.5-2.0 g, could be fatal to humans. Inhalation of its vapors or dust at 0.3 mg/m³ concentration in air produced an immediate fall in blood pressure and headache in human volunteers (ACGIH 1986). Chronic poisoning may produce headache and hallucination.
LD50 value, oral (rats): 105 mg/kg.

Fire Hazard

HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water.

Contact allergens

Nitroglycerin is an explosive agent contained in dynamite and an antianginal and vasodilator treatment available in systemic and topical forms. It is a well known irritant agent in dynamite manufacture. It can also cause allergic reactions in employees of explosives manufacturers and in the pharmaceutical industry. Transdermal systems are the main source of iatrogenic sensitization. Nitroglycerin can cross-react with isosorbide dinitrate.

Mechanism of action

Nitroglycerine reduces the load on the heart by dilating peripheral veins, reducing the myocardial need for oxygen, and facilitating redistribution of coronary blood flow in the region of the myocardium with reduced blood flow.

Pharmacokinetics

Nitroglycerin causes the relaxation of vascular smooth muscles, causing arteriolar and venous dilatation. It increases blood flow to the myocardium and reduces cardiac preload and afterload, decreasing myocardial wall stress and ameliorating anginal symptoms. Nitroglycerin also reduces coronary artery spasm, decreasing systemic vascular resistance as well as systolic and diastolic blood pressure.
Like other organic nitrates, repeated and prolonged administration of nitroglycerin can lead to the development of tolerance or desensitization of vascular smooth muscle to further nitroglycerin-induced vasorelaxation. This loss of efficacy may be associated with the inhibition of mitochondrial aldehyde dehydrogenase, which is an important enzyme involved in the bioactivation of nitroglycerin. Nitroglycerin tolerance may be accompanied by pro-oxidant effects, endothelial dysfunction, and increased sensitivity to vasoconstrictors.

Clinical Use

Nitroglycerin is used extensively as an explosive in dynamite.A solution of the ester, if spilled or allowed to evaporate,will leave a residue of nitroglycerin. To prevent anexplosion of the residue, the ester must be decomposed byadding alkali. Even so, the material dispensed is so dilutethat the risk of explosions does not exist. It has a strong vasodilatingaction and, because it is absorbed through theskin, is prone to cause headaches among workers associatedwith its manufacture. This transdermal penetration is whynitroglycerin is useful in a patch formulation. In medicine, ithas the action typical of nitrites, but its action develops moreslowly and is of longer duration. Of all the known coronaryvasodilatory drugs, nitroglycerin is the only one capable ofstimulating the production of coronary collateral circulationand the only one able to prevent experimental myocardialinfarction by coronary occlusion.

Side Effects

Vascular headache, postural hypotension, and reflex tachycardia are common side effects of organic nitrate therapy. Fortunately, tolerance to nitrate-induced headache develops after a few days of therapy. Postural hypotension and tachycardia can be minimized by proper dosage adjustment and by instructing the patient to sit down when taking rapidly acting preparations. An effective dose of nitrate usually produces a fall in upright systolic blood pressure of 10 mm Hg and a reflex rise in heart rate of 10 beats per minute. Larger changes than these should be avoided, because a reduction in myocardial perfusion and an increase in cardiac oxygen requirements may actually exacerbate the angina.
Since nitrite ions oxidize the iron atoms of hemoglobin and convert it to methemoglobin, there may be a loss in oxygen delivery to tissues. While methemoglobinemia does not follow therapeutic doses of organic nitrates, it can be observed after overdosage or accidental poisoning.

Safety Profile

Human poison by an unspecified route. Poison experimentally by ingestion, intraperitoneal, subcutaneous, and intravenous routes. An experimental teratogen. Other experimental reproductive effects. A skin irritant. Questionable carcinogen with experimental tumorigenic data. Mutation data reported. It can cause respiratory difficulties and death due to respiratory paralysis by ingestion. The acute symptoms of nitroglycerin poisoning are headaches, nausea, vomiting, abdominal cramps, convulsions, methemoglobinemia, circulatory collapse and reduced blood pressure, excitement, vertigo, fainting, respiratory rales, and cyanosis. Toxic effects may occur by ingestion, inhalation of dust, or absorption through intact skin. Human systemic effects by intravenous route: encephalitis, miosis, corneal damage. Used as a vasodilator and as an explosive. A very dangerous fire hazard when exposed to heat, flame, or by spontaneous chemical reaction. A severe explosion hazard when shocked or exposed to 03 , heat, or flame. Nitroglycerin is a powerful explosive, very sensitive to mechanical shock, heat, or UV radiation. Small quantities of it can readily be detonated by a hammer blow on a hard surface, particularly when it has been absorbed in filter paper. It explodes when heated to 215°C. Frozen nitroglycerin is somewhat less sensitive than the liquid. However, a half-thawed or partially thawed mixture is more sensitive than either one. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Nitroglycerine, 1,2,3-propantrioltrinitrate (19.1.1), is synthesized by nitrating glycerol with nitric acid.

Potential Exposure

An explosive ingredient in dynamite (20-40%) with ethylene glycol dinitrate (80-60%). It is also used in making other explosives, rocket propellants; and medicine (vasodilator).

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: infusion of GTN reduces anticoagulant effect of heparins.
Antidepressants: tricyclics may reduce effect of sublingual tablets due to dry mouth.
Antimuscarinics: may reduce effect of sublingual tablets due to dry mouth.
Avanafil, sildenafil, tadalafil, vardenafil: hypotensive effect significantly enhanced - avoid concomitant use.
Riociguat: avoid concomitant use due to risk of hypotension.

Metabolism

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) promotes the bioactivation of nitroglycerin. Nitroglycerin is metabolized to nitrite; 1,2-glyceryl dinitrate; and 1,3 glyceryl dinitrate. Nitrite is further metabolized to nitric oxide. 1,2- and 1,3-dinitroglycerols are less biologically active than nitroglycerin but they have longer half-lives, which explains some prolonged effects of nitrates. Both dinitrates are finally metabolized to glycerol, carbon dioxide, and mononitrates that do not have vasodilatory actions.
Nitroglycerin can also chemically react with a thiol to generate an intermediate S-nitrosothiol, which resulted in further production of nitric oxide.

Metabolism

Nitroglycerin is a lipid-soluble substance that is rapidly absorbed across the sublingual or buccal mucosa. Its onset of action occurs within 2 to 5 minutes, with maximal effects observed at 3 to 10 minutes. Little residual activity remains 20 to 30 minutes after sublingual administration. The plasma half-life of nitroglycerin, given sublingually or by spray, is estimated to be 1 to 3 minutes. Nitroglycerin and other organic nitrate esters undergo first-pass metabolism and are rapidly metabolized in the liver by the enzyme glutathione organic nitrate reductase.

Shipping

UN1204 Nitroglycerin solution in alcohol with not .1% nitroglycerin, Hazard Class: 3; Labels: 3-Flammable liquid. UN3064 Nitroglycerin, solution in alcohol with .1% but not .5% nitroglycerin, Hazard Class: 3; Labels: 3-Flammable liquid. UN0143 Nitroglycerin, desensitized with not ,40% nonvolatile, water-insoluble phlegmatizer, by mass. It falls in Hazard Class 1.1D (subsidiary hazard: 6.1).

Incompatibilities

Heat, ozone, shock, acids. An OSHA Class A Explosive (1910.109). Heating may cause violent combustion or explosion. May explosively decompose on shock, friction, or concussion. Reacts with ozone causing explosion hazard.

Waste Disposal

Do not wash into sewer. Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform with EPA regulations governing storage, transportation, treatment, and waste disposal.