Page:EB1911 - Volume 20.djvu/161

 Opium also contains a gum, pectin, a wax, sugar and similar substances, in addition to meconic and lactic acids.

The alkaloids fall into two chemical groups: (1) derivatives of isoquinoline, including papaverine, narcotine, gnoscopine (racemic narcotine), narceine, laudanosine, laudanine, cotarnine, hydrocotarnine (the last two do not occur in opium), and (2) derivatives of phenanthrene, including morphine, codeine, thebaine. The constitutions of the first series have been determined; of the second they are still uncertain.

Papaverine, C20H21NO4, was investigated by G. Goldschmiedt (Monats., 1883–1889), who determined its constitution (formula I., below) by a study of its oxidation products, showing that papaveraldine, which it gives with potassium permanganate, is a tetramethoxybenzoylisoquinoline. Its synthesis, and also that of laudanosine, C21H27NO4. which is N-methyltetrahydropapaverine, was effected in 1909 by F. L. Pyman (Jour. Chem. Soc., 95, p. 1610) and by A. Pictet and Mlle M. Finkelstein (Compt. rend., 1909, 148, p. 925). Laudanine, C20H26NO4, is very similar to laudanosine, differing in having three methoxy groups and one hydroxy instead of four methoxy.

Narcotine, C22H23NO7, has been principally investigated by A. Matthiessen and G. C. Foster, and by W. Roser (Ann., 1888, 249, p. 156; 1889, 254, p. 334.) By hydrolysis it yields opianic acid, C10H10O5, and hydrocotarnine, C12H15O3; reduction gives meconine, C10H10O4, and hydrocotarnine; whilst oxidation gives opianic acid and cotarnine, C12H16NO4. Narcotine was shown to be methoxyhydrastine (II.) (hydrastine, the alkaloid of Golden seal, Hydrastis canadensis, was solved by E. Schmidt, M. Freund, and P. Fritsch) and cotarnine to be III.; the latter has been synthesized by A. H. Salway (Jour. Chem. Soc., 1910, 97, p. 1208). Narceine, C23H27NO8, obtained by the action of potash on the methyl iodide of narcotine, is probably IV. (see Pyman, loc. cit. pp. 1266, 1738; M. Freund and P. Oppenheim, Ber., 1909, 42, p. 1084).

The proprietary drug “stypticin” is cotarnine hydrochloride, and “styptol” cotarnine phthalate; “antispasmin” is a sodium narceine combined with sodium salicylate, and “narcyl” narceine ethyl hydrochloride.

The chemistry of morphine, codeine and thebaine is exceedingly complicated, and the literature enormous. That these alkaloids are closely related may be suspected from their empirical formulae, viz. morphine＝C17H19NO3, codeine＝C18H21NO3, thebaine = C19H21NO3. As a matter of fact, Grimaux, in 1881, showed codeine to be a methylmorphine, and in 1903 Ach and L. Knorr (Ber., 36, p. 3067) obtained identical substances, viz. thebenine and morphothebaine, from both codeine and thebaine, thereby establishing their connexion. Our knowledge of the constitution of these alkaloids largely depends on the researches of M. Freund, E. Vongerichten, L. Knorr and R. Pschorr. The presence of the phenanthrene nucleus and the chain system CH3N·C·C· follows from the fact that these alkaloids, by appropriate treatment, yield a substituted phenanthrene and also dimethylaminoethanol (CH3)2N·CH2·CH2OH. Formulae have been proposed by Pschorr and Knorr explaining this and other decompositions (in Pschorr’s formula the morphine ring system is a fusion of a phenanthrene and pyridine nucleus); another formula, containing a fusion of a phenanthrene with a pyrrol ring, was proposed by Bucherer in 1907. The problem is discussed by Pschorr and Einbeck (Ber., 1907, 40, p. 1980), and by Knorr and Hörlein (ibid. p. 2042); see also ''Ann. Reps. Chem. Soc.''

Morphine, or morphia, crystallizes in prisms with one molecule of water; it is soluble in 1000 parts of cold water and in 160 of boiling water, and may be crystallized from alcohol; it is almost insoluble in ether and chloroform. It has an alkaline reaction and behaves as a tertiary, monacid base; its salts are soluble in water and alcohol. The official hydrochloride, C17H19NO3+HCl+3H2O, forms delicate needles. Distilled with zinc dust morphine yields phenanthrene, pyridine and quinoline; dehydration gives, under certain conditions, apomorphine, C17H17NO2, a white amorphous substance, readily soluble in alcohol, either and chloroform. The drug “heroin” is a diacetylmorphine hydrochloride. Codeine, or codeia, crystallizes in orthorhombic prisms with one molecule of water: it is readily soluble in alcohol, ether and chloroform. Thebaine forms silvery plates, melting at 193°.

Medicine.—Of the opium alkaloids only morphine and codeine are used to any extent in medicine. Thebaine is not so used, but is an important and sometimes very dangerous constituent of the various opium preparations, which are still largely employed, despite the complexity and inconstant composition of the drug. Of the other alkaloids narceine is hypnotic, like morphine and codeine, whilst thebaine, papaverine and narcotine have an action which resembles that of strychnine, and is, generally speaking, undesirable or dangerous if at all well marked. A drug of so complex a composition as opium is necessarily incompatible with a large number of substances. Tannic acid, for instance, precipitates codeine as a tannate, salts of many of the heavy metals form precipitates of meconates and sulphates, whilst the various alkalis, alkaline carbonates and ammonia precipitate the important alkaloids.

The pharmacology of opium differs from that of (q.v.) in a few particulars. The chief difference between the action of opium and morphine is due to the presence in the former of thebaine, which readily affects the more irritable spinal cord of very young children. In infants especially opium acts markedly upon the spinal cord, and, just as strychnine is dangerous when given to young children, so opium, because of the strychnine-like alkaloid it contains, should never be administered, under any circumstances or in any dose, to children under one year of age.

When given by the mouth, opium has a somewhat different action from that of morphine. It often relieves hunger, by arresting the secretion of gastric juice and the movements of the stomach and bowel, and it frequently upsets digestion from the same cause. Often it relieves vomiting, though in a few persons it may cause vomiting, but in far less degree than apomorphine, which is a powerful emetic. Opium has a more marked diaphoretic action than morphine, and is much less certain as a hypnotic and analgesic.

There are a few therapeutic indications for the use of opium rather than morphine, but they are far less important than those which make the opposite demand. In some abdominal conditions, for instance, opium is still preferred by the majority of practitioners, though certainly not in gastric cases, where morphine gives the relief for which opium often increases the need, owing to the irritant action of some of its constituents. Opium is often preferred to morphine in cases of diabetes, where prolonged administration is required. In such cases the soporific action is not that which is sought, and so opium is preferable. A Dover’s powder, also, is hardly to be surpassed in the early stages of a bad cold in the head or bronchitis. Ten grains taken at bedtime will often give sleep, cause free diaphoresis and quieten the entire nervous system in such cases. The tincture often known as “paregoric” is also largely used in bronchial conditions, and morphine shows no sign of displacing it in favour. Opium rather than morphine is also usually employed to relieve the pain of haemorrhoids or fissure of the rectum. This practice is, however, obsolescent.

The alkaloid thebaine may here be referred to, as it is not used separately in medicine. Crum Brown and Fraser of Edinburgh showed that, whilst thebaine acts like strychnine, methyl and ethyl thebaine act like curara, paralysing the terminals of motor nerves. At present we say of such a substance as thebaine, “it acts on the anterior cornua of grey matter in the spinal cord,” but why on them and not elsewhere we do not know.

Toxicology.—Under this heading must be considered acute poisoning by opium, and the chronic poisoning seen in those who eat or smoke the drug. Chronic opium poisoning by the taking of laudanum—as in the familiar case of De Quincey—need not be considered here, as the hypodermic injection of morphine has almost entirely supplanted it.

The acute poisoning presents a series of symptoms which are only with difficulty to be distinguished from those produced by alcohol, by cerebral haemorrhage and by several other morbid conditions. The differential diagnosis is of the highest importance, but very frequently time alone will furnish a sufficient criterion. The patient who has swallowed a toxic or lethal dose of laudanum, for instance, usually passes at once into the narcotic state, without any prior excitement. Intense drowsiness yields to sleep and coma which ends in death from failure of the respiration. This last is the cardinal fact in determining treatment. The comatose patient has a cold and clammy skin, livid lips and ear-tips—a grave sign—and “pin-point pupils.” The heart’s action is feeble, the pulse being small, irregular and often abnormally slow. The action on the circulation is largely secondary, however, to the all-important action of opium on the respiratory centre in the medulla oblongata. The centre is directly poisoned by the circulation through it of opium-containing blood, and the patient’s breathing becomes progressively slower, shallower and more irregular until finally it ceases altogether.

In treating acute opium poisoning the first proceeding is to empty the stomach. For this purpose the best emetic is apomorphine, which may be injected subcutaneously in a dose of about one-tenth of a grain. But apomorphine is not always to be obtained, and even if it be administered it may fail, since the gastric wall is often paralysed in opium poisoning, so that no emetic can act. It is therefore better to wash out the stomach, and this should be done, if possible, with a solution containing about ten grains of salt to each ounce of water. This must be repeated at intervals of about