hydroxylic carbon atom through a ·CH2· group: whilst in the latter the piperidine ring is substituted by a methyl group in addition to the vinyl group and the bridge is simply ·C(OH)·, with which connexion is made as before.
Medicine.—.The sulphate is still used in medicine, and the British Pharmacopeia has admitted two others, which are much more valuable-the hydrochloride and the acid hydrochloride-whilst the hydro bromide is also used. The hydrochloride—formerly known as the hydrochlorate—C20H24N2O2·HCl·2H2O, resembles the sulphate in appearance, the crystals being, however, somewhat larger. It is soluble in less than 40 parts of cold water, and in 3 parts of alcohol (90%). The doses are similar to those of the sulphate, but somewhat smaller, owing to its greater solubility. The acid hydrochloride is the most valuable of all salts of quinine. It is soluble in its own weight of water, and is the most rapidly and completely absorbed of all the salts of this alkaloid. It occurs in a colourless crystalline powder, having the formula C20H24N2O2·2HCl·3H2O,.
The sulphate of quinine used in medicine may contain up to 3% of cinchonidine, but should be free from cinchonine, quinidine and cupreine. There are four pharmacopeial preparations. The ferri et quininae citras, one of the “scale preparations” of iron, is given as a haematinic and tonic in doses of about 10 grains. It is very unpleasant to take. The pharmacopeial pilule quininae contains 5 parts of the sulphate in 6. The syrupus ferri phosphatis cum quinina et strychnine (Easton’s Syrup) contains 4ths of a grain of quinine in each drachm, that is, in each dose. Here the quinine acts as a bitter tonic. The tinctura quininae ammonia ta or “ammoniated quinine” is made by mixing 175 grains of quinine sulphate, 2 fluid oz. of liquor ammoniae (the pharmacopeial solution of ammonia), and 18 fluid oz. of a 60% solution of alcohol. The dose of 1 to 1 drachm contains little more than a grain of quinine, the antipyretic action of which is negligible. Its value in the early stages of a bronchitis or tracheitis is due to the ammonia. The small quantity of quinine it contains is conditioned by the solubility of the alkaloid, which is precipitated when this tincture is diluted with water. No particular value attaches to the pharmacopeial preparations of the hydrochloride.
Physiological Action.—Our knowledge of this subject is mainly due to Professor Binz of Bonn. Quinine has considerable powers as an antiseptic, this term defined for some time as indicating the power to kill bacteria. Whilst quinine possesses this power, however, it is far more potently lethal to a particular form of animal organism known as the plasmodium malariae. Against the bacteria quinine is not at all an exceptionally powerful antiseptic, though more powerful than carbolic acid. Many bacteria are killed by a .2% solution of the alkaloid. Quinine does not affect the unbroken skin, and cannot be absorbed from it, but it is slightly irritant to the pain-conducting nerves of a raw surface.
The first feature of the internal action of quinine is its intensely bitter taste. This induces a reflex secretion from the salivary and gastric glands, which is followed or accompanied by increased vascularity of the gastric mucous membrane, and by some degree of activity on the part of the muscular wall of the stomach. This means that the appetite is strengthened, and digestion rendered more rapid and complete. In this sense alone quinine is a tonic. The hydrochloric acid of the gastric juice is stated to convert any salt of quinine into a chloride, and it seems probable that the absorption of quinine takes place mainly from the stomach, for when the drug reaches the alkaline secretions of the duodenum it is precipitated, and probably none of it is thereafter absorbed. The greater part of a dose of quinine sulphate administered by the mouth may be recovered, as a rule, from the faeces, this being much the most wasteful method of giving quinine. The absorption of the acid hydrochloride is much more complete. Quinine hydrochloride circulates in the alkaline blood without precipitation, probably owing to the presence of carbonic acid in the blood.
The action of quinine on the blood itself-quite apart from its action on malarial blood—is of great complexity and importance. Whilst it is not a haematinic, in that it does not increase the number of the red blood corpuscles, it very markedly influences the stability of the compounds of the haemoglobin with oxygen. Like alcohol and prussic acid, quinine interferes with oxidation, so that oxyhaemoglobin is relatively unable to give up its oxygen to the tissues, the metabolism of which is therefore greatly modified. This property is doubtless partly—though not wholly—explanatory of the antipyretic action of quinine. The leukocytes or white blood corpuscles are very markedly affected by quinine, the characteristic “amoeboid” movements of the cells being arrested. Hence quinine stops the process of diapedesis or emigration of the leukocytes from the blood-vessels into the tissues, and if applied to the extra vascular spaces it arrests the leucocytic movements there. The explanation that this influence on the leukocytes explained the favourable action of quinine on certain inflammatory processes no longer holds, since we know that the inflammatory conditions are of microbic origin, and that the movements of the leukocytes are not objectionable, but highly desirable as a means of defence against bacteria and their products. Quinine, therefore, is not beneficial in inflammatory conditions as far as this particular property is concerned.
The action of quinine on the circulatory apparatus is not marked. It is only in very large doses that it weakens the intracardiac nervous ganglia, slows and weakens the pulse, and dangerously lowers the blood pressure. Similarly the depressant action on the respiratory centre in the medulla oblongata occurs only after the administration of enormous doses.
The action of quinine on the temperature is important, for it is the safest of all known antipyretics. Its action on the normal temperature is nil. The drug is not an antithermal. But when the temperature is raised, quinine will frequently lower it. The action is not due to any influence on the thermic centres, nor to any production of diaphoresis, but to the influence of quinine upon the stability of oxyhaemoglobin. Quinine was the first antipyretic used, and after the introduction of such preparations as antipyrin and acetanilide it may still be said to be the safest, though it is much less powerful. The maximum dose of the sulphate is about 40 grains, and of the acid hydrochloride about 25 grains. The temperature usually”begins to fall in about two hours. The influence of quinine upon a malarial temperature is due to an entirely different cause (see below).
In some of the lower vertebrates quinine reduces the activity of the spinal cord, but in the human species it appears to stimulate the nervous mechanism of the uterus under certain conditions, and it is therefore included under the class of oxytocic or ecbolic drugs.
Quinine is excreted in some degree by nearly all the glands of the body, but mainly by the kidneys. Traces of it may be detected in the urine within an hour of its administration, and most of it is eliminated within eight or ten hours. The study of the urine is highly interesting in correlation with that of the influence of quinine upon the oxidising power of the blood, and upon the movements of the leukocytes. The amount of urea, creatin, creatinin, sulphates and phosphates in the urine is diminished, clearly showing that quinine exerts an inhibitory influence over the metabolic processes of the body. This conclusion is further confirmed by the observation that the amount of carbonic acid excreted by the lungs is also diminished. The uric acid excreted in the urine (mostly in the form of urates) is markedly diminished. This product is largely derived from the nuclei of the leukocytes, which contain large quantities of the nucleo-proteids, of which uric acid is a decomposition product. It is therefore plain that the diminution of leucocytic movement is to be regarded as a sign of diminished metabolism within the cells.
Therapeutics.—The supreme value of quinine is as a specific antidote to malaria, against which it also possesses a powerful prophylactic action. Ten or fifteen grains of the sulphate are often given three times a day for this latter purpose, and smaller doses of the much more efficacious acid hydrochloride will be found to convey even more certain immunity. In treating malaria (including ague, remit tent fever, intermittent fever, and all its other forms) with this drug certain important facts are to be observed. Quinine administered by the mouth or by any other means will soon enter the blood, and will then kill the haematozoon malariae, whether it be free in the blood-plasma, in the leukocytes or in the red blood corpuscles. There is one exception, however. Quinine is apparently powerless to kill the organism when it is in its reproductive phase. This phase corresponds to the pyretic attack. There is therefore no purpose to be served by administering quinine during a malarial paroxysm. Two successful methods may be adopted. The quinine may be given in a single large dose—30 grains of the sulphate, or 20 of the acid hydrochloride—an hour or two before the attack is due, i.e. just before the parent organism in the red blood corpuscles is about to discharge the new generation of young parasites into the blood-plasma. An equally effective method, which may be combined with the above, is to give the quinine in Io-grain doses of the acid hydrochloride every four hours between the attacks. Whichever method be adopted, the paroxysm that was expected will probably not appear. After a single full dose of quinine no parasites can as a rule be observed in the blood for several days. In beginning treatment, it is well to clear the hepatic and alimentary passages by a preliminary dose of calomel combined with a secretory cholagogue, such as enonymin or iridin. The quinine treatment may be begun with success on the day following an attack. Quinine is much less efficacious in the treatment of post-malarial symptoms, such as neuralgia and haematuria, when no parasites can be detected in the blood. In such cases quinine is often inferior to arsenic.
Quinine is largely used as a bitter tonic in doses of about half a grain. The acid hydrochloride is the best salt to employ.
Quinine has some analgesic power, and is a safe and often efficient drug in the treatment of neuralgia, even when the patient has not had malaria. Somewhat smaller doses than those given in pyrexia should be employed.