Atropine excretion

Atropine is weU absorbed orally and can be adrninistered parenteraHy. About 50% of an adrninistered dose is metabolized in the Hver, the rest is excreted in the urine unchanged. About 77—94% of an adrninistered dose is excreted in the urine. The pharmacological half-life of atropine is about 2—3 h... 

Although some steroids have been reported to reduce the toxic effects of some insecticides, the steroid ethylestrenol decreased the rate of recovery of depressed cholinesterase activity in disulfoton- pretreated rats (Robinson et al. 1978). The exact mechanism of this interaction was not determined. Ethylestrenol alone caused a small decrease in cholinesterase activity, and, therefore, resulted in an additive effect. Rats excreted less adrenaline and more noradrenaline when given simultaneous treatments of atropine and disulfoton compared with rats given disulfoton alone (Brzezinski 1973). The mechanism of action of disulfoton on catecholamine levels may depend on acetylcholine accumulation. In the presence of atropine, the acetylcholine effect on these receptors increases the ability of atropine to liberate catecholamines. 

Lactation Hyoscyamine is excreted in breast milk other anticholinergics (especially atropine) may be excreted in milk, causing infant toxicity, and may reduce milk production. 

Both atropine and scopolamine are tertiary amines that cross biological membranes readily. They are well absorbed from the gastrointestinal tract and conjunctiva and can cross the blood-brain barrier. After the intravenous injection of atropine (oL-hyoscyamine), the biologically inactive isomer, D-hyoscyamine, is excreted unchanged in the urine. The active isomer, however, can undergo dealkylation, oxidation, and hydrolysis. 

All the belladonna alkaloids are well absorbed from the GIT, from the site of injection and the mucous membrane. They are distributed throughout the body and cross the blood-brain barrier. About 50% of the atropine is metabolized in liver and remaining portion is excreted unchanged in urine. Atropine cross the placental barrier and is secreted in milk and saliva. 

After administration, the elimination of atropine from the blood occurs in two phases the t1/2 of the rapid phase is 2 hours and that of the slow phase is approximately 13 hours. About 50% of the dose is excreted unchanged in the urine. Most of the rest appears in the urine as hydrolysis and conjugation products. The drug s effect on parasympathetic function declines rapidly in all organs except the eye. Effects on the iris and ciliary muscle persist for s 72 hours. 

In lower mammals, scopolamine reduces the excitability of the motor areas as tested by electric shocks, and the reflex excitability in the frog is not increased as by atropine. Scopolamine appears to be excreted or destroyed in the tissues much more rapidly than atropine, for its effects last a shorter time. 

Pyrrolidine is the simple five-membered cyclic amine and pyrrolidine alkaloids contain this ring somewhere in their structure. Both nicotine and atropine contain a pyrrolidine ring as do hygrine and tropinone. All are made in nature from ornithine. Ornithine is an amino acid not usually found in proteins but most organisms use it, often in the excretion of toxic substances. If birds are fed benzoic acid (PI1CO2H) they excrete dibenzoyl ornithine. When dead animals decay, the decarboxylation of ornithine leads to putrescine which, as its name suggest, smells revolting. It is the smell of death . 

Disposition in the Body. Rapidly absorbed after oral administration but it is usually administered together with a small quantity of atropine and this may delay absorption, especially with high doses. It is extensively metabolised by hydrolysis, hydroxylation, and conjugation with glucuronic acid. The major metabolites are diphenoxylic acid (difenoxin), which is active, and hydroxy-diphenoxylic acid in both free and conjugated forms. About 14% and 50% of a dose, respectively, is excreted in the urine and faeces in 96 hours less than 0.1% of a dose is excreted in the urine as unchanged drug in 24 hours. 

The belladonna alkaloids are absorbed rapidly from the gastrointestinal tract. They also enter the circulation when applied locally to mucosal surfaces. Only limited absorption occurs from the intact skin. Atropine disappears rapidly from the blood and is distributed throughout the entire body. Most is excreted in the urine within the first 12 h, in part unchanged. Only about 1% of an oral dose of scopolamine is eliminated as such in the urine. Traces of atropine are found in various secretions, including milk. The total absorption of quaternary ammonium derivatives of the alkaloids after an oral dose is only about 10-25 percent (10,11) nevertheless, some of these compounds can cause mydriasis and cycloplegla if applied to the eye. 

The first part of the research to be reported was the study of the metabolic faces of labeled cropic acid and atropine In mice and rats (91,92). Mice and rats given Incraperlconeal Injections of alpha-[ C]tropic acid at 1 mg/kg excreted In their urine only a single labeled compound that had essentially the same chromatographic characteristics as authentic tropic acid. The excretion of administered in this form was complete within about 2.5 h In the mice and within slightly more than 3 h In the rats. 

When the labeled atropine was administered to both mice and rats by both Intravenous and Intraperltoneal Injections, the cumulative excretion of In the urine by the mouse was always considerably greater than that by the rat. The label from alpha-[ C]acroplne Injected intravenously Into mice appeared In their urine slightly more promptly and to a somewhat greater extent chan chat from labeled atropine that had been Injected Intraperltoneally or subcutaneously or Chat had been administered by gavage. The curve for the clearance of from the body of the mouse with time elapsed after subcutaneous Injection of the labeled alkaloid required three simultaneous exponential equations to represent the observations after a period of latency of about 45 min, during which excretion of followed none of the three exponential relationships. In addition to atropine itself, at least three other substances containing appeared In the urine of the mouse. 

The failure to find C02 In the expired air of the mice Indicates that the tropic acid moiety in the atropine molecule Is not metabollzed ln accord with the finding that labeled tropic acid Itself was excreted without loss In the urine. The finding of atropine but no tropic acid In the urine of the mice Indicates that hydrolysis of the ester did not occur rapidly. The latter finding was somewhat unexpected because an esterase capable of hydrolysing atropine is present In the livers of many vertebrate species, although It or a similar enzyme appears In the sera of only a few species (93-95). This enzyme Is also able to hydrolyze L hyoscyamine, troplnyl benzoate, and caramlphen (95). 

Despite the quantitative differences In excretion of labeled atropine by different routes In the mouse and the rat, Gabourel and Gosselln (97) proposed that atropine... 

Isolated, perfused livers of rats exposed to [ C]atropine Injected into the perfusion fluid excreted about 60Z of the into the bile during 4 h (101) ... 

Two fairly recent papers on the metabolic face of atropine In man have been published (104,105) an excellent summary of the work was presented by Kaiser (106). The two subjects In the first of these papers excreted within 24 h 85% of an Intramuscularly Injected dose of 2 mg of alpha-[ C]atroplne. A urine saaq>le collected from one of the subjects between 1.5 and 4 h after injection contained substances that produced four small. Interconnected peaks of radioactivity on a paper chromatogram that were apparently removed by Incubation of the urine with bacterial beta-glucuronldase. Only three clear peaks of radioactivity appeared on the paper chromatograms of this urine after It had been exposed to glucuronidase. Two of these had Rfs chat agreed with those for atropine (the major peak) and for tropic acid (a small peak). The Identity of the third peak, with an Rf below that for atropine, was not determined. After alkaline hydrolysis of this sample of urine, the only radioactive substance detected In the chromatogram had an Rf similar to that of tropic acid thus, the tropic acid... 

Kaiser and McLain (105) found that glucuronldation was an important metabolic pathway in the early excretion of atropine from the body but that this type of reaction seemed not to be particularly Important after 4 b from the time of injection of atropine. Referring to the work of Fhilllpson (98), one may suppose that... 

The two labeled atropines used by Kaiser and McLain (105) yielded the same chromatographically distinguishable C-contalnlng substances in the urine excreted by their subjects. There were four principal peaks of radioactivity, all of which appeared to consist, at least in part, of glucuronldes at the early times of collection of urine. Peaks of radioactivity with Rfs similar to chose of labeled atropine and tropine were the most prominent ones in the paper chromatograms of the... 

Evertsbusch, V., Gelling, E.H.K. 1953 Distribution and Excretion of Radioactivity in Mice Following the Administration of C -Labeled Atropine. Fed. Proc. 12 319. 

Radioactive Atropine. I. Distribution and Excretion Patterns In the Mouse. Arch. Internat. Fharmacodyn. Therap. 105 175-192. 

Pharmacokinetics. Atropine is readily absorbed from the gastrointestinal tract and may also be injected by the usual routes. The occasional cases of atropine poisoning following use of eye drops are due to the solution rurming down the lacrimal ducts into the nose and being swallowed. Atropine is in part destroyed in the liver and in part excreted unchanged by the kidney (t 2 h). 

Molecular Factors in the Absorption, Fate, and Excretion of Atropine and... 

The belladonna alkaloids are absorbed rapidly after oral administration (75). They enter the circulation when applied locally to the mucosal surfaces of the body. Atropine absorbed from inhaled smoke of medicated cigarettes can abolish the effects of intravenous infusion of methacholine in humans. The transconjunctival absorption of atropine is considerable. About 95% of radioactive atropine is absorbed and excreted followingsubconjunctival injection in the rabbit. The total absorption of quaternary ammonium derivatives (Section 3.5) of the alkaloids after an oral dose is only about 25%. The liver, kidney, lung, and pancreas are the most important organs that take up the labeled atropine. The liver probably excretes metabolic products of atropine by way of bile into the intestine (in mice and rats). 

At least four types of molecular modificationb occur for the urinary excretion of atropine (Fig. 3.2). Cleavage of the ester bond takes place in the rabbit and the guinea pig (84), whereas para and meta hydroxylation of the benzene ring of tropic acid occurs in the mouse and the rat (80, 82). The tropine moiety of atropine is also chemically modified for excretion in man and mouse and, though unidentified, tropine-modified atropines are excreted in humans and in mouse (83). Tropic acid itself does not undergo metabolic alteration for urinary excretion in all species mentioned above. The metabolic conversions of tropine itself are not fully investigated. However, demethylation of atropine- (or... 

After intravenous injection of atropine, approximately 25% of the dose is excreted in mouse urine as atropine, more than 50% as... 

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