Atropine A-oxide

After intravenous dosing, atropine distributes rapidly, with only 5% remaining in the blood compartment after 5 min (Bcrghem et at., 1980). The apparent volume of distribution (V i) is 1-1.7 liters/kg. Atropine is partly metabolized in the liver by microsomal monooxygenases to noratropine, tropinc, atropine-A/-oxide, and tropic acid (Van der Meer et at., 1983) and partly excreted unchanged in the urine. Elimination kinetics can be fitted to a two-compartment model with a clearance of 5,9-6,8 ml/kg/min and a half-life of 2.6—4.3 hr in the elimination phase (Aaltonen etal., 1984 Kanto etal., 1981 Virtanen etal., 1982). Since the renal plasma clearance (656 18 ml/min) was found to approach the renal plasma flow (712 38 ml/min), tubular... 

The N-oxides are converted to the corresponding tertiary bases in vivo. Atropine N-oxide and scopolamine N-oxide are slowly reduced to atropine and scopolamine in the animal body. Therefore, N-oxidation is a convenient technique for prolongingthe duration of the action of the alkaloidal bases. The N-oxides are said to be less toxic. 

In contrast to GC-MS, a wide range of tropane alkaloids, including A -oxides and calystegines, can be analyzed by HPLC without prior derivatization. Enantiomeric separation of atropine 5 and scopolamine 6 racemic mixtures has been also achieved [22]. A number of HPLC methods have been published for routine quantification of the major tropane alkaloids hyoscyamine 1 and scopolamine 6 in plant samples. The use of UV detectors however is limited to compounds with UV adsorbing (aromatic or other) functionality. This disadvantage, however, is easily overcome by using HPLC coupled with MS detectors [22]. A typical HPLC separation of hyoscyamine 1 and scopolamine 6 is presented on Fig. 7.2. 

Atropine causes dilation of the pupil of the eye. A drop or two of an aqueous solution, containing 1 part in 130,000 parts of water, introduced into the eye of a cat is sufficient to produce this effect. When warmed with sulphuric acid and a small crystal of potassium dichromate, atropine develops a bitter almond odour. Evaporated to dryness on a water-bath with concentrated nitric acid, it gives a residue which becomes violet on adding a drop of sodium hydroxide solution in alcohol (Vitali s test). With a solution of mercuric chloride atropine gives a yellow to red precipitate of mercuric oxide. 

This synthetic tropidine was converted into bromodihydrotropidine by hydrogen bromide in aeetie aeid, and the solution heated with 10 per cent, sulphurie acid at 200-10°, when it passed into -tropine,and, sinee this may be partially converted into tropine by oxidation to tropinone and reduction of the latter by zinc dust and hydriodic acid, this series of reactions affords a complete synthesis of tropine and of the tropeines. Combining the formula given above for tropine with that of tropic acid, atropine and hyoscyamine are represented as follows ... 

Oxidation of ecgonine (2) by means of chromium trioxide was found to afford a keto acid (3). This was formulated as shown based on the fact that the compound undergoes ready themnal decarboxylation to tropinone (4)The latter had been obtained earlier from degradative studies in connection with the structural determination of atropine (5) and its structure established independently. Confirmation for the structure came from the finding that carbonation of the enolate of tropinone does in fact lead back to ecgonine. Reduction, esterification with methanol followed by benzoylation then affords cocaine. 

About scaritoxin, the following results were reported. This toxin was found to depress the oxidative metabolic process in the rat brain (20) and to have a depolarizing action on excitable membranes (38). In the guinea-pig atria, scaritoxin caused a marked potentiation of the acetylcholine negative inotropic and chronotropic effects (39). In rat atria, we observed biphasic inotropic and chronotropic effects similar to those of ciguatoxin. Negative inotropic and chronotropic effects were antagonized by atropine. 

Aspirin does not alter the normal body temperature, which is maintained by a balance between heat production and dissipation. In a fever associated with infection, increased oxidative processes enhance heat production. Aspirin acts by causing cutaneous vasodilation, which prompts perspiration and enhances heat dissipation. This effect is mediated via the hypothalamic nuclei, as proved by the fact that a lesion in the preoptic area suppresses the mechanism through which aspirin exerts its antipyretic effects. The antipyretic effects of aspirin may be due to its inhibition of hypothalamic prostaglandin synthesis. Although aspirin-induced diaphoresis contributes to its antipyretic effects, it is not an absolutely necessary process, because antipyresis takes place in the presence of atropine. 

A new method for the rapid separation of alkaloids, inter alia atropine, has been elaborated, using chromatography on paper that is impregnated with zirconium oxide.57 Cation-exchange h.p.l.c. analysis of tropane alkaloids has been developed,58 followed by post-column derivatization using the fluorimetric ion-pair technique.58,59 Gas chromatography of tropanes has been reviewed.60... 

Proton61 and carbon-1362 n.m.r. spectroscopy have recently been used extensively for the analysis of tropane alkaloids. The non-equivalence of H-6 and H-7 on the one hand and of H-2 and H-4 on the other in atropine and scopolamine is due to the non-symmetrical shielding by the tropic acid moiety. The configuration of A-substituents, e.g. N-oxides, has been determined by studying the deshielding of the 6- and 7/3-hydrogens. All of these results should be useful for the identification of new tropane alkaloids and other related systems in the future. 

CL systems other than luminol have also been used, such as the Ru(bpy)2+ (or TBR) system. Chemical reaction of TBR has been achieved by oxidation using cerium(IV) sulfate [283,722] or lead oxide [722]. The addition of a nonionic surfactant (Triton X-45) strongly enhanced the CL emission [722]. The TBR system has been applied on a glass chip for the determination of alkaloids, such as codeine [722], or atropine and pethidine [283]. 

The metabolism of atropine (227) by rat and guinea pig liver microsomes has been studied (197-199). French workers noted the formation of nora-tropine (229), apoatropine (233), and a phenolic metabolite formulated as the ortho-phenol 230 (197, 198) by liver microsomes from the rat, and they reported that hydrolysis of the ester function of 227 did not occur with enzymes from this source (197, 198). The structure of 229 was determined by TLC comparisons of the metabolite with an authentic sample and by correlation of the formation of the metabolite with the release of formaldehyde in the incubation mixture. The structure of 233 was deduced by TLC and UV spectral comparisons of isolated metabolite with authentic sample, and the phenol 230 was identified by TLC color reactions and by comparison with a phenolic sample obtained by Udenfried oxidation of atropine. In the absence of more definitive data on the phenolic products of this reaction, the structure 230 proposed for the phenolic metabolite of atropine... 

Chen et al. used MeOH for precipitation of rat plasma in a 3 1 volume ratio to investigate a broad spectrum of biotransformation products generated from ani-sodine [5], anisodamine [6], atropine [52] and scopolamine [87], Biotransformation products covered a broad spectrum of polarity including sulfo- and glucuronide conjugates, oxidized, hydroxylated, methoxylated and demethylated metabolites of the parent drug as well as its hydrolysis products. Unfortunately, recoveries were not reported (Table 2). 

Scopolamine (42), an optically active, viscous liquid, also isolated from Solanaceae, eg, Datura metelY,., decomposes on standing and is thus usually both used and stored as its hydrobromide salt. The salt is employed as a sedative or, less commonly, as a prophylactic for motion sickness. It also has some history of use in conjunction with narcotics as it appears to enhance their analgesic effects. Biogenetically, scopolamine is clearly an oxidation product of atropine, or, more precisely, because it is optically active, of (—)-hyoscyanune. 

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