Nitrate organic

Presently, three enzyme systems have been identified as being capable of metabolizing organic nitrates, namely, a cytochrome P-450 (CYP) enzyme, a glutathione-S-transferase (GST), and a membrane-bound enzyme that has yet to be named. A recent review has addressed this topic (Bennett et al., 1994). Here, we examine the evidence, for and against, implicating each of these enzymes as the pharmacologically pertinent system. 

Chemical class General structure Examples Oxidation state (NO + 1) Mechanisms of NO generation 

Organic nitrates R3C-ONO2 Nitroglycerin, isosorbide dinitrate +5 Mostly enzymatic 

Organic nitrites R3C-ONO Isoamyl nitrite, isobutyl nitrite +3 Enzymatic and chemical hydrolysis 

Ferrous nitro complexes [(CN)sFe +]NO Sodium nitroprusside +3 Chemical reduction and enzymatic 

Various esters of nitric acid (HNO3) and polyvalent alcohols relax vascular smooth muscle, e.g., nitroglycerin (gly-ceryltrinitrate) and isosorbide dinitrate. The effect is more pronounced in venous chan in arterial beds. 

These vasodilator effects produce hemodynamic consequences that can be put to therapeutic use. Due to a decrease in both venous return (preload) and arterial afterload, cardiac work is decreased (p. 308). As a result, the cardiac oxygen balance improves. Spasmodic constriction of larger coronary vessels (coronary spasm) is prevented. 

Organic nitrates are used chiefly in angina pectoris (p. 308, 310), less frequently in severe forms of chronic and acute congestive heart failure. Continuous intake of higher doses with maintenance of steady plasma levels leads to loss of efficacy, inasmuch as the organism becomes refractory (tachy-phylactic). This nitrate tolerance can be avoided if a daily nitrate-free interval is maintained, e.g., overnight. 

At the start of therapy, unwanted reactions occur frequently in the form of a throbbing headache, probably caused by dilation of cephalic vessels. This effect also exhibits tolerance, even when daily nitrate pauses are kept Excessive dosages give rise to hypotension, reflex tachycardia, and circulatory collapse. 

Molsidomine itself is inactive. After oral intake, it is slowly converted into an active metabolite. Apparently, there is little likelihood of nitrate tolerance . 

FIGURE 4.17 Energetics of NO, photodissociation (adapted from Davis et at., f993). 

The absorption drops off strongly in the actinic region, with the result that they are not photodissoci-ated rapidly in the troposphere (Roberts and Fajer, 1989 Turberg et al., 1990 Clemitshaw et al., 1997). 

There are several different possible primary processes, depending on the photolysis wavelength. For example, ethyl nitrate in principle has three paths  

Nitroglycerin (NTC) is distinguished by a high membrane penetrability and very low stability. It is the drug of choice in the treatment of angina pectoris attacks. For this purpose, it is administered as a spray, or in sublingual or buccal tablets for transmucosal delivery. The onset of action is between 1 and 3 minutes. Due to a nearly complete presystemic elimination, it is poorly suited for oral administration. Transdermal delivery (nitroglycerin patch) also avoids presystemic elimination. 

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Dimethylformamide Halocarbons, inorganic and organic nitrates, bromine, chromium(VI) oxide, aluminum trimethyl, phosphorus trioxide... 

Sodium nitrate is also used in formulations of heat-transfer salts for he at-treatment baths for alloys and metals, mbber vulcanization, and petrochemical industries. A mixture of sodium nitrate and potassium nitrate is used to capture solar energy (qv) to transform it into electrical energy. The potential of sodium nitrate in the field of solar salts depends on the commercial development of this process. Other uses of sodium nitrate include water (qv) treatment, ice melting, adhesives (qv), cleaning compounds, pyrotechnics, curing bacons and meats (see Food additives), organics nitration, certain types of pharmaceutical production, refining of some alloys, recovery of lead, and production of uranium. 

Erythrityl is readily absorbed from the GI tract. It undergoes extensive first-pass metaboHsm ia the Hver by glutathione organic nitrate reductase. Time to onset of effect is 5—10 min by subHngual adrninistration and 20—30 min when swallowed. The duration of effects for the two routes ate up to 3 and 6 h, respectively. Adverse effects are similar to those described for nitroglycerin (99). 

Applicabdity Limitations Photolysis is appropriate for difficult-to-treat chemicals (e.g., pesticides, dioxins, chlorinated organics), nitrated wastes, and those chemicals in media which permits photolyzing the waste. The waste matrix can often shield chemicals from the light (e.g., ultraviolet light absorbers, suspended solids, solid wastes). The photolysis process typically requires pretreatment to remove suspended materials, and the by-products formed may be more toxic than the parent molecules. 

NO-sensitive GC represents the most important effector enzyme for the signalling molecule NO, which is synthesised by NO synthases in a Ca2+-dependent manner. NO-sensitive GC contains a prosthetic heme group, acting as the acceptor site for NO. Formation of the NO-heme complex leads to a conformational change, resulting in an increase of up to 200-fold in catalytic activity of the enzyme [1]. The organic nitrates (see below) commonly used in the therapy of coronary heart disease exert their effects via the stimulation of this enzyme. 

The acute adverse effects of the organic nitrates as well as molsidomine are directly related to their therapeutic vasodilation as they can cause orthostatic hypotension, tachycardia and throbbing headache. 

NO donators are a group of drugs, which are able to release NO. They include organic nitrates, sodium nitroprasside and molsidomine. 

Vasodilators are a group of dtugs, which relax the smooth muscle cells of the blood vessels and lead to an increased local tissue blood flow, a reduced arterial pressure and a reduced central venous pressure. Vasodilators reduce the cardiac pre-load as well as after-load and thereby reduce cardiac work. They are used in a variety of conditions including hypertension, cardiac failure and treatment/prevention of angina pectoris. Major groups are Ca2+-channel blockers (e.g. dihydropyridines), NO-donators (e.g. organic nitrates), K+-channel openers (minoxidil), phosphodiesterase inhibitors (e.g. sildenafil), Rho-kinase inhibitors (e.g. Y27632) or substances with unknown mechanism of action (e.g. hydralazine). Inhibitors of the... 

Favier expls described in Vol 6, FlO-Lff. Also see under Amides and Imides, Organic, Nitrated in Vol 1,A171-L Ref Daniel (1902), 297... 

Nitric acid also undergoes reactions with organic compounds wherein the acid serves neither as an oxidizing agent nor as a source of hydrogen ions. The formation of organic nitrates by esterification (O-nitration) involves reaction with the hydroxyl group ... 

Nitrometer. An app used for the estimation of nitrogen in Inorganic and organic nitrates by their reaction with Hg and sulfuric acid. For details of construction and operation see Vol 1, A373-L to A377-L... 

Nitron fonns v si sol compds with metallic nitrates, perchlorates, picrates, trinitrocresylates, as well as with organic nitrates such as NG,... 

The toxicity of IPN is evaluated by Ref 6 as follows (a) When inhaled as a vapor or adsorbed thru the skin, IPN acts as a vasodilator and produces a headache in the same manner as other organic nitrates (b) When injected subcutaneously into rats at the rate of 4cc/kg body wt, it was concluded that the max allowable concn is lOOppm and (c) When rats were exposed to different concn levels of IPN in air the following resulted ... 

Nitric oxide (NO) and nitrogen dioxide (NO2) were monitored by a Bendix chemiluminescence instrument. However, since the "NO2" readings of this type of instrument are known to include the contribution of HNO3, HONO, PAN, and other organic nitrates ( ), we report these readings as "gaseous nitrate."... 

Gaseous nitrate" is total amount of species converted to NO by the molybdenum catalyst of a commercial NO-NOx analyzer ( ). This includes N02f MONO and organic nitrates, and possibly nitros-amines and nitramines. 

Used in the manufacture of pharmaceuticals, dye intermediates, explosives, various inorganic and organic nitrates, nitro compounds and used industrially for ore flotation, metallurgy, photoengraving, and reprocessing spent nuclear fuel. 

Copper(II) sulfate Cumene hydroperoxide Cyanides Cyclohexanol Cyclohexanone Decaborane-14 Diazomethane 1,1-Dichloroethylene Dimethylformamide Hydroxylamine, magnesium Acids (inorganic or organic) Acids, water or steam, fluorine, magnesium, nitric acid and nitrates, nitrites Oxidants Hydrogen peroxide, nitric acid Dimethyl sulfoxide, ethers, halocarbons Alkali metals, calcium sulfate Air, chlorotrifluoroethylene, ozone, perchloryl fluoride Halocarbons, inorganic and organic nitrates, bromine, chromium(VI) oxide, aluminum trimethyl, phosphorus trioxide... 

Hercules (1) An organic nitration process, similar to the Bofors process but using a tee-joint for mixing. Developed by the Hercules Powder Company, Wilmington, DE, from 1957. U.S. Patents 2,951,746 2,951,877. 

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