The final stage in the transformation of drugs into inert substances consists in the formation of acidic substances from the products of oxidation, reduction, etc., by means of the previously mentioned syntheses with sulphuric acid, glycuronic acid, etc. Other synthetic processes sometimes met with are the formation of urea derivatives and sulphocyanides, and more rarely, the introduction of acetyl or methyl groups, and the production of cystine derivatives. Usually no single synthetic process takes place to the exclusion of all others, but, on the contrary, a substance is usually excreted in more than one way, for example, as a glycuronic acid derivative, and also as a sulphonic ester. Sulphonic Esters.-The sulphuric acid required for these syntheses may be formed by the oxidation of albuminous bodies containing sulphur. It has already been pointed out that phenolic substances are often formed by the oxidation of aromatic compounds, and most of these phenolic compounds are excreted primarily combined with sulphuric acid as alkali salts, and secondarily combined with glycuronic acid. Phenol itself is found in the urine as the sodium salt of phenylsulphuric acid, CH5. O. SO2. ONa, a perfectly non-toxic substance. Similar syntheses take place with other hydroxyl derivatives, but if these themselves are non-toxic, they are excreted unchanged without undergoing a synthesis with sulphuric or glycuronic acids. For example, homogentisinic which is toxic, is eliminated partly as the non-toxic sulphuric acid derivative.1 The entrance of acid groups into phenols, with the corresponding loss of toxicity, destroys the property of combining with sulphuric or glycuronic acids, as in the case of salicylic acid, which is eliminated in combination with amino-acetic acid in the same way as benzoic acid (i.e. it forms a compound analogous to hippuric acid).2 Loss of acid 1 Likhatscheff, Zeit. physiol. Chem., 21 (1896), 422. character causes this property of combining with sulphuric acid to reappear, and methyl salicylate, COOCH,, and acid derivatives. он are found in the urine as sulphuric Introduction of more hydroxyl groups also causes this property to reappear, as in the case of gentisinic acid, and also protocatechuic and vanillic acids; but veratric HOOCOOH Vanillic acid. CH2O COOH CH,O Veratric acid. acid, which contains no free hydroxyl, does not unite with sulphuric acid. Aromatic ketones are usually oxidized to acids, but if they contain an hydroxyl group the formation of esters with sulphuric or glycuronic acids takes place, to the exclusion of the oxidation of the ketone to the corresponding acid. For example, acetophenone, CH. CO. CH,, is oxidized to benzoic acid, but paeonol, gallacetophenone, and resacetophenone are found in the urine as sulphuric and glycuronic acid derivatives.3 Glycuronic Acid Derivatives.-This acid, which has the constitution CHO-(CH.OH)-COOH, is of great interest, as a very large number of poisonous substances are found in the urine as derivatives of it. It seems likely that in the first instance combination takes place between the drug and glucose, the -CH2OH group of which is then oxidized to COOH, with the formation of glycuronic acid. In the case of aliphatic 1 Baumann and Herter, Zeit. physiol. Chem., 1 (1878), 255. 2 Nencki, Journ. prakt. Chem., 18 (1878), 288. 3 Nencki, Ber., 27 (1894), 2737. compounds, the resulting compounds are formed with elimination of water, and are probably analogous in structure to the single glucosides. For example, chloral is reduced to trichlorethyl alcohol, which then combines with glycuronic acid in the following In the case of some aromatic compounds, combination can occur without the elimination of water. For example, it has been shown that vanillin is oxidized to vanillic acid, which then combines with glycuronic acid-1 Thymol and carbostyril have been shown to behave in a similar manner. Derivatives of Amino-Acetic Acid.-Combination between 1 Kotake, Zeit. physiol. Chem., 45 (1905), 320. glycine, NH. CH2. COOH, and benzoic acid takes place in the kidney, with formation of hippuric acid—1 This synthesis is of great importance, as so many compounds are oxidized in the body to benzoic acid, and it is also typical of a large number of precisely similar syntheses undergone by other carboxylic acids, such as salicylic acid, para-hydroxy-benzoic acid, chloro-, nitro-, and bromo-benzoic acids, anisic acid, naphthoic acid, and many others. Other synthetic processes that may be mentioned are the formation of the less toxic sulphocyanides from the toxic nitriles, the transformation of pyridine into methyl pyridyl ammonium hydroxide,3 2 and the introduction of an acetyl group into a compound, as in the previously mentioned case of meta-nitro-benzaldehyde, which is transformed into meta-acetyl-amino-benzoic acid. 112. 1 Boucis and Ure, Berzelius Jahresb., 22 (1843), 567. 2 A. e. P. P., 84 (1894), 247, 281. 3 His, A. e. P. P., 22 (1887), 253; R. Cohn, Zeit. physiol. Chem., 18, (1894), CHAPTER IV NARCOTICS AND GENERAL ANÆSTHETICS GENERAL THEORIES OF THE ACTION OF NARCOTIC DRUGS Up to within quite recent times, the only narcotics in use were the various preparations of opium, and all of these suffered from the great drawback of being dangerous in the doses that were necessary to produce certain sleep, and of sometimes causing unpleasant by-effects. The discovery of many synthetic substances having a powerful narcotic action, and almost free from the dangers and other drawbacks of preparations containing morphine, is one of the great triumphs of the application of synthetic chemistry to pharmacology. Still more important are those substances which are used as general anæsthetics. These compounds do not differ fundamentally from the other narcotics in their physiological action or chemical constitution, but they are usually volatile substances which are administered by inhalation, so that their effect can be rapidly produced, and the duration easily regulated. On the other hand, for use as a narcotic it is more convenient to employ non-volatile substances capable of offering resistance to oxidation by the organism, and which are therefore slower and more prolonged in their action. The aliphatic hydrocarbons possess narcotic properties, and these are increased by the introduction of an hydroxyl group to form alcohols. The introduction of more hydroxyl groups, as in glycerol, causes the narcotic action to disappear, the hydroxyl merely playing the part of an "anchoring" group. On the other hand, the narcotic action of many different substances is associated with the presence of alkyl groups, especially ethyl groups. It therefore appears that in the alcohols, the alkyl group, and not the hydroxyl group, is the active portion of the molecule. Replacement of hydrogen |