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%).]
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.
来源:DrugBank
代谢
甘露醇单硝酸酯是硝酸甘油的主要循环代谢物。
... Glyceryl ... /mononitrate is/ major circulating ... /metabolite/ of nitroglycerin.
The metabolism of nitroglycerin... appears to involve reduced glutathione in a reaction catalyzed by an enzyme known as organic nitrate reductase, which is predominantly located in the soluble fraction of liver homogenate.
Nitroglycerin is degraded in the liver by reductive hydrolysis and partially in plasma by spontaneous hydrolysis... The major urinary metabolites include glyceryl mononitrate, 1,2-glyceryl dinitrate and 1,3-glyceryl dinitrate... Reactive hydrolysis in the liver by hepatic inorganic nitrate reductase leads to the formation of the free nitric oxide radical.
Initial hydrolytic reduction by interaction of inorganic nitrate with reduced glutathione occurs both spontaneously and with enzymes, which can be extracted fron the soluble fraction of the liver.
IDENTIFICATION: Glyceryl trinitrate is used as an anti-anginal vasodilating agent. It slightly volatile odorless oily liquid with sweet, aromatic and pungent taste. Soluble in water, ethanol, methanol and miscible with ether, acetone and chloroform. Indications: Prophylaxis and treatment of angina and left ventricular failure. Control of hypertension during cardiac surgery. Congestive cardiac failure unresponsive to usual therapy. HUMAN EXPOSURE: Main risks and target organs: Toxic effects of glyceryl trinitrate are caused by vasodilatation and methemoglobinemia. Venous and arterial vasodilatation causes lowering of blood pressure leading to shock. Heart, blood vessels and red blood cells are the target organs in glyceryl trinitrate poisoning. Summary of clinical effects: Features of poisoning may appear within a few minutes to one hour or more after exposure. There is tachycardia and hypotension followed by bradycardia and collapse. Flushing of the face, headache, dizziness, restlessness, syncope, convulsions and coma may be present. Some of the other features are vomiting, diarrhoea, cyanosis and methaemoglobinaemia and respiratory failure. Effects of glyceryl trinitrate are enhanced by alcohol. Contraindications to the use of glyceryl trinitrate is in patients with hypo, head injury, severe anemia, cerebral hemorrhage and in patients predisposed to closed-angle glaucoma. Intravenous administration contraindicated in constrictive pericarditis and uncorrected hypovolaemia. Routes of entry: Oral: Toxic effects can occur by ingestion. Inhalation: Inhalation of dust may cause toxic effects. Dermal: Toxic effects may occur when absorbed through skin. Prolonged skin contact can cause skin eruptions. Parenteral: Toxic effects can occur by the administration of excessive intravenous doses. Absorption by route of exposure: Oral: Glyceryl trinitrate is readily absorbed from the oral mucosa but rapidly metabolized so that it has only a fleeting duration of action. It is also readily absorbed from the gastrointestinal tract, but owing to extensive first-pass metabolism in the liver its bioavailability is reduced. A study involving 5 healthy persons indicated a bioavailability of less than 1% following administration by mouth of glyceryl trinitrate capsule and oral solution. However the weakly pharmacologically active dinitrate metabolites reached relatively high concentrations after oral glyceryl trinitrate administration and it was suggested that these metabolites may be responsible for the activity of oral glyceryl trinitrate. Dermal: Glyceryl trinitrate is also absorbed through the skin from an ointment base. Distribution by route of exposure: The time to peak concentration depends on the route of administration; it occurs after 2 minutes, 40 minutes and one hour after sublingual, oral and dermal administration respectively. Bioavailability is 38% after sublingual and 1% for oral administration. Biological half-life by route of exposure: This drug has a very short plasma half life. Elimination half-life of nitroglycerin is 1.7 to 2.9 minutes. When glyceryl trinitrate was given sublingually peak plasma concentrations appeared within 4 minutes and at least half of the intact glyceryl trinitrate was cleared from the blood in 1 to 3 minutes. Peak plasma concentration following dermal application of 45 mg nitroglycerin ointment occurred in about 1 hour. Metabolism: Glyceryl trinitrate is metabolized by hydrolysis to dinitrates and the mononitrate. The half-life for dinitrate metabolites is about 40 minutes approximately 20 times that of glyceryl trinitrate. Elimination by route of exposure: In 10 healthy volunteers given glyceryl trinitrate 560 ug sublingually, about 22% of the administered dose was excreted in the urine after 24 hours mainly as the mononitrate. Mode of action Toxicodynamics: Glyceryl trinitrate has dilator properties on vascular smooth muscle in virtually all vascular beds. The beneficial effects in therapeutic doses and the effects seen with overdose are attributable to the physiologic consequences of systemic venous and arteriolar vasodilatation. The cardiac preload, systemic blood pressure and systemic vascular resistance all show a progressive decrease. A state of hypotension and circulatory collapse and shock may result. methemoglobinemia may occur in patients following an overdose or after therapy. Pharmacodynamics: Glyceryl trinitrate relaxes smooth muscle including vascular smooth muscle, and reduces systolic blood pressure. It is thought that the anti-anginal effect mainly depends on reducing myocardial oxygen demand by means of peripheral vasodilatation which causes decreased venous return permitting a reduction in left ventricular volume and energy expenditure. The effect of glyceryl trinitrate in relaxing coronary vessels is not considered to increase appreciably coronary blood flow. Interactions: Alcohol enhances the effects of glyceryl trinitrate. Undue dizziness and faint feeling may occur when sublingual nitrates are taken with beta-adrenoceptor blocking drugs. Complete AV block has been reported after use of sublingual nitrates in patients receiving lignocaine by infusion. Even cardiac asystole may occur. Disopyramide (by producing dryness in mouth) may prevent dissolution of sublingual isosorbide dinitrate tablets. This may also occur with tricyclic antidepressants. Delayed dissolution of glyceryl trinitrate tablets in patients with dry mouths has been reported in a patient taking imipramine and in another patient treated with atropine. A patient developed resistance to the effects of heparin on two occasions directly after intravenous administration of glyceryl trinitrate. The interactions could not be attributed to propylene glycol in the solvent since resistance also occurred during administration of a formulation of glyceryl trinitrate without propylene glycol. Explosion flush has been observed in patients with transdermal patch when electric defibrillation was performed. Main adverse effects: The toxicity of the nitrates is unaffected by the chemical form or by the route of administration and all the nitrates have a common profile of adverse effects. Hypotension, reflex tachycardia and palpitations may occur. Postural hypotension and syncope is seen, especially in elderly patients. Rarely severe bradycardia has been reported. Throbbing headache is quite common. This symptoms is likely to recede as tolerance develops. Peripheral edema is also frequently seen. Transient hypoxemia with precipitation of angina is seen occasionally. Transient cerebral ischemic episodes unrelated to changes in blood pressure are rarely seen. In patients with cerebrovascular disease, it is recommended to initiate treatment with small doses. Although tolerance has long been associated with nitrates, its clinical implications are not clear. Tolerance is best defined as a decreasing pharmacological effect over time, often with a need for an increasing dose to achieve a given action. Tolerance may be partial or incomplete and may occur to one aspect of nitrate therapy and not to others. Disappearance of the throbbing headache is useful. However, due to an attenuation of the antihypertensive effect, these agents are not useful in the long term management of hypertension. The part played by the arterial and venous side of the circulation pertaining to the development of tolerance is not clear. By having a long (approximately 8 hours) nitrate free interval, the development of tolerance may be avoided or reduced. Decreasing the number of daily doses of glyceryl trinitrate also helps to achieve this effect. Sustained release preparations are more likely to produce tolerance than the short acting preparations.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：根据药物在人体内导致肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
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.
来源:DrugBank
吸收、分配和排泄
消除途径
Metabolism is the main route by which nitroglycerin is eliminated from the body.
代谢是将硝酸甘油从体内排出的主要途径。
Metabolism is the main route by which nitroglycerin is eliminated from the body.
来源:DrugBank
吸收、分配和排泄
分布容积
硝酸甘油的分布容积为3升/千克。
The volume of distribution of nitroglycerin is 3 L/kg.
The estimated clearance following intravenous administration is 1 L/kg/min. The apparent clearance after a sublingual dose was 21.9 L/min in a pharmacokinetic study of patients with ischemic heart disease and angina.
来源:DrugBank
吸收、分配和排泄
在人类中，舌下给药后4分钟内，血桨中即可达到硝化甘油的峰值浓度。
In human beings, peak concentrations of nitroglycerin are found in plasma within 4 min of sublingual administration.
Study of nitration equilibrium in the glycerin-aqueous nitric acid system. 1. Dependence of the equilibrium constants of nitration reactions on the temperature, acidity of the medium, and structure of the nitrated compound
摘要：
The equilibrium constants of seven sequential-parallel reactions of conversion of glycerin into glycerin trinitrate in aqueous HNO3 were measured. The effect of the acidity of the medium on the equilibrium nitration constants is correlated with processes of protonation of glycerin and its nitrates. The equilibrium nitration constants are higher for primary hydroxides than for secondary hydroxides, and they decrease in both series in going from glycerin to its dinitrates.
Study of nitration equilibrium in the glycerin-aqueous nitric acid system. 1. Dependence of the equilibrium constants of nitration reactions on the temperature, acidity of the medium, and structure of the nitrated compound
摘要：
The equilibrium constants of seven sequential-parallel reactions of conversion of glycerin into glycerin trinitrate in aqueous HNO3 were measured. The effect of the acidity of the medium on the equilibrium nitration constants is correlated with processes of protonation of glycerin and its nitrates. The equilibrium nitration constants are higher for primary hydroxides than for secondary hydroxides, and they decrease in both series in going from glycerin to its dinitrates.
Preparation of Di- and polynitrates by ring-opening nitration of epoxides by dinitrogen pentoxide (N2O5)
作者：Peter Golding、Ross W Millar、Norman C Paul、David H Richards
DOI：10.1016/s0040-4020(01)87978-3
日期：1993.8
hydrocarbon solvents (principally CH2Cl2) to give vicinal nitrate ester products by a novel ring-opening nitrationreaction. The procedure offers easier temperature control and simpler isolation procedures compared with conventional mixed acid nitrations; it also enables selective nitrationreactions to be carried out on polyfunctional substrates. The scope and limitations of the reaction, as well as
通过新颖的开环硝化反应，使十八种各种环氧化合物与N 2 O 5在氯化烃溶剂（主要为CH 2 Cl 2）中反应，得到邻位硝酸酯产物。与传统的混合酸硝化方法相比，该方法提供了更轻松的温度控制和更简单的分离步骤。它还可以在多官能底物上进行选择性硝化反应。讨论了反应的范围和局限性，以及利用N 2 O 4与硝酸亚硝酸酯原位进行原位氧化的替代方法的范围和局限性。
METHODS OF PRODUCING NITRATE ESTERS
申请人：Straessler Nicholas A.
公开号：US20120130115A1
公开（公告）日：2012-05-24
Methods of forming a nitrate ester include combining at least one nitrate salt and sulfuric acid to form a nitrating solution and adding an aliphatic polyol to the nitrating solution. Nitrate esters formed by this method may be, for example, triethylene glycol dinitrate (TEGDN), pentaerythritol tetranitrate (PETN), diglycerol tetranitrate (DGTN), 1,1,1-tris(methylol)ethane trinitrate (TMETN), 1,2,4-butanetriol trinitrate (BTTN), nitroglycerin (NG), diethylene glycol dinitrate (DEGDN), ethylene glycol dinitrate (EGDN), metriol trinitrate (MTN), nitrocellulose (NC), or 1,2-propanediol dinitrate (PDDN).
Synthesis of nitric acid esters from alcohols in a dinitrogen pentoxide/carbon dioxide liquid system
作者：Ilya V. Kuchurov、Igor V. Fomenkov、Sergei G. Zlotin、Vladimir A. Tartakovsky
DOI：10.1016/j.mencom.2012.03.004
日期：2012.3
Organic nitric acid esters have been prepared in 89–98% yield by the nitration of the corresponding alcohols and polyols with N2O5 in liquid CO2.
通过将相应的醇和多元醇与液态二氧化碳中的N2O5硝化，可以制备有机硝酸酯，产率为89-98％。
The Synthesis and Application of Novel Nitrating and Nitrosating Agents
作者：Gholam H. Hakimalahi、Hashem Sharghi、Hamide Zarrinmayeh、Ali Khalafi-Nezhad
DOI：10.1002/hlca.19840670332
日期：1984.5.2
Alcohols and phenols are efficiently nitrated with thionylchloride nitrate or thionyl nitrate, even in the presence of an aromatic moiety. While thionylchloride nitrate is suitable for nitration of primary OH-groups in carbohydrates, thionyl nitrate is reactive enough to react with secondary OH-groups as well. These reagents permit the highly selective nitration of the 5′-,2′5′- and 3′, 5′-OH-groups
即使在存在芳族部分的情况下，醇和苯酚也可以被硝酸亚硫酰氯或硝酸亚硫酰有效地硝化。硝酸亚硫酰氯适用于碳水化合物中伯羟基的硝化，而硝酸亚硫酰具有足够的反应性，可以与仲羟基反应。这些试剂允许核糖核苷的5'-，2'5'-和3'，5'-OH-基团的高选择性硝化，以高产率产生单保护或双保护的硝基衍生物。碳酸和某些酮的烯醇形式可以用三氟甲磺酰硝酸盐/叔丁醇钾有效地硝化。Lutidine N -oxide（2,6-（CH 3）2 C 5 H 3发现NO）对硝化反应具有显着影响。类似地，亚硫酰氯亚硝酸盐和亚硫酰亚硝酸盐显示出优异的上述底物的亚硝化能力。
Practical catalytic nitration directly with commercial nitric acid for the preparation of aliphatic nitroesters
作者：Jichao An、Peipei Liu、Mengyuan Si、Wenhao Li、Pan He、Bo Yang、Guanyu Yang
DOI：10.1039/d0ob01519a
日期：——
To pursue a sustainable and efficient approach for aliphatic nitroester preparation from alcohol, europium-triflate-catalyzed nitration, which directly uses commercial nitricacid, has been successfully developed. Gram scalability with operational ease showed its practicability.
