Nov., 1922.] THERAPEUTICS OF ALKALOIDS: CHOPRA. 401

and in the Himalayan range near Darjeeling. The cinchona trees are now so extensively culti- Original Articles. vated in Java, and to a lesser degree in India, that the world is entirely independent of South America The Dutch soon realised the great com- ~%HE THERAPEUTICS OF THE CIN- mercial possibilities of these plantations and devel- the cultivation of trees and CHONA ALKALOIDS. oped collection of the 1/ bark on a thoroughly scientific basis, thus making By R. N. CHOPRA, m.a., m.d. (Cantab.), Java the most important cinchona area in the world. Most of the bark at MAJOR, I.M.S., present is derived var. from C. calisaya ledgeriana, which grows Pharmacology, School island Professor of of Tropical luxuriously in that and has a very high Medicine, Calcutta. quinine yield. It contains 6 per cent, of this alkaloid and in exceptional cases 10 to 12 per PART 1. ? cent C. succirubra (red bark) yields 5 per cent of total alkaloids, of which 2 per cent, is I have written this as, a paper although great quinine ; C. calisaya (yellow bark) has 6 per cent, deal of work has been done the 3 recently-on of alkaloids, of which per cent, is quinine ; and .of cinchona bark, 1 have not been able alkaloids C officinalis contains 5 per cent, of total alka- to find a connected account of the modern views loids, of which 3^ per cent, is quinine. C. suc- of their action and from the therapeutics general ciruba has proved to be the hardiest and most of view. I have the practitioners' point Further, easily cultivated and is largely grown in India. of associated with H. W. privilege being Major It o-ives a high yield of total alkaloids 10 ? per Acton, whose classical researches on the i.m.sv cent. but the quinidine and cinchonine contents alkaloids are well in the :further cinchona known, predominate over that of quinine. The cultivation are now carried out in researches which being of C. ledgeriana is, therefore, now have had the of dis- being pushed this School and opportunity forward in India. The trees possess the with maxi- these alkaloids him, and this mum alkaloid cussing paper amount of yield when are embodies his views. they from 6 to 9 years old. The therapeutic effects of The Cinchona, from which this most vain- the bark are due to the alkaloids, of which is quinine able 'bark is obtained, indigenous to South is the best known : other alkaloids, quinidine, cin- embraces 36 America and of evergreen chonine and cinchonidine have until recently been shrubs. They are all restricted to the eastern little used in medicine. of the in slopes Andes, extending from Western The bark is collected the rainy season, when Peru to Venezuela through Bolivia. At an alti- it separates easily from the stem. The old method tude between to 10,000 trees of the trees and 3,000 feet, these felling stripping the bark was a warm and flourish in moist climate, generally very wasteful, and Maclvor suggested removal of or even not forming forests groups, but attaining longitudinal strips 4 to 5 cm. wide at intervals, as in a considerable size, 'being much as 100 feet the trunk afterwards being protected with a cover- The trees at a lower altitude of when a fresh height. growing ing moss, growth takes its place ; contain little alkaloids. 1 he natives of these this is richer in alkaloid contents. This " process " had only an imperfect of the is known as mossing and Shav- parts knowledge " renewing."" of the a bark, as, they ing is modification of as febiifuge properties " although only mossing," here name of Kinakina," or a bark is gave it the bark of barks, only portion of the removed by shaving, it. In 1639 the its the left they seldom used bark found remainder being behind to protect the soon " way to Spain ; its fame spread to Italy and trunk. Another method of collecting is coppic- were in in which the tree is cut the Jesuits probably chiefly instrumental ing," down to form a it into France and Gradu- stool, and from this shoots introducing England. arise which yield a ally the properties of the bark became more and very good quality of quill bark. use became as the more known, its extended and Composition of Cinchona Bark.?The finely of the bark at that time bark is made only method collecting powdered into a stiff paste fears were a was by felling the tree, entertained that with slaked lime, sufficient quantity of hark from South America would water added. The the supply of being paste is dried and ex- to cease altogether. Attempts were then made tracted with hot petroleum which dissolves all into the transplant some of the species other countries alkaloids, and from this they are recovered named was and a German botanist Hasskarl by shaking with successive quantities of dilute sul- Dutch on an commissioned by the Government phuric acid. The alkaloids are dissolved in acid and solvent and are expedition, and he successfully brought precipitated by adding excess of seeds which were started in caustic soda to neutralize by plantations Java. the acid, and this con- Robert was sent A few years later Sir Markham stitutes the cinchona febrifuge, which is manufac- on a the tured similar errand 'by Indian Government and issued by the Government of India in suc- the and he succeeded in introducing Cinchona form of tablets, each supposed to contain 3-1 some into cirubra, C. officinalis and other species grains of the alkaloids. According to MacGil- and were started in christ India, plantations the Nilgiris (1915), the average composition of 402 THE INDIAN MEDICAL GAZETTE. [Nov., 1922.

cinchona febrifuge prepared from C. succirubra The quinine derivatives are formed by alterations bark at Mungpoo, is as follows :? in the three groups, methoxy, hydroxyl and vinyl For ... 16*58% groups. example, cinchonidine differs from ld'n6 quinine in the absence of the methoxy group, Quinine 7*40% O. and if the is Quinidine ... 23 83% CH3 methoxy group replaced Amorphous alkaloids ...{Cinchonine Grouped under by an (OH) radicle, we get cupreidine. Quinoidin ... 29*12% A number of insoluble esters of Refuse, Moisture, Ash, etc...... 16*12% large quinine are prepared the II of the The bark also contains, in addition, certain by substituting (OH) group by another group. Such compounds are acids, neutral a volatile gums, principles, oil, insoluble and therefore tasteless and can be and matter.. easily starches, colouring less side Since Pelletiere and Dumas first isolated administered, produce actions, though quinine are not devoid of cinchonism. In and cinchonine, fourteen alkaloids have been dis- they altogether the stomach they remain unchanged, and 011 reach- covered to be present in the bark, but most of ing the duodenum, split up into quinine base, these occur in very small quantities and from a producing in this way a gradual and somewhat therapeutic point of view one need only consider weaker action. To this group aristochin alkaloids which can be in two belong eight grouped carbonic series :? (diquinine ester), eu-quinine (quinine carbonic sali- A. The cinchonine series which include cincho- ethyl ester), soloquinine (quinine cylic ester), and chenophenin (phenetidin quinine nine and its isomeri'de cinchonidine and the hydro- carbonic ester). The last two compounds exhibit alkaloids of the same, hydro-cinchonine and the action of both the constituents, i.e., of quinine hydro-cinchonidine. and acid and and These alkaloids occur in cinchona and salicylic quinine phenecetin. cuprea Hydro-quinine, from which most of the valuable barks, though the amount present shows great hydro-derivatives are obtained, is formed by con- variations. They can easily be separated from version of the vinyl CH : CH2 group into : the associated alkaloids, are diacid bases and form CH2 In the they are prepared pass- two series of salts, i.e., neutral and acid. CH;i. laboratory by gas solutions of natural alka- B. cinchonine or series ing hydrogen through Methoxy quinine loids in the of This which includes and its isomeride presence platinum. change quinine quinidine makes the alkaloids much more stable to the action and the and hydro-alkaloids, hydro-quinine hydro- of and to MacGilchrist Like the cinchonine series also oxidising agents according quinidine. they act more in the as are form a mono- and bi-series of salts. they efficiently body, they not so readily acted on by the tissues. Two closely related alkaloids cuprein and its The interesting point in connection with the isomeride and hydro-cuprein and cupreidine pharmacological action of the cinchona alkaloids have also to be considered, which hydro-cupreidine and their derivatives is that from the piperidine are found in cuprea bark?Remijia pedunculata? ring they come close to nicotine, and their antisep- along with other cinchona alkaloids. Both these tic are attributable to the pre- alkaloids are derivatives of cinchonine. properties mainly hydroxy sence of a in the molecule. Chemical constitution the cinchona alkaloids. quinoline ring of to have so far met ?To understand the between Attempts synthesize quinine relationship with but success. first N. the different alkaloids found in cinchona partial By preparing bromotoxins, then with alkali to produce a brief reference to the constitutional heating bark, ketones and reducing them, substances resembling formula will be necessary. This has been now cinchona alkaloids in constitution and having a established by the laborious researches of Konig, toxic action on infusoria were synthetically pre- Skraup and Rabe and is as follows:? pared. Their toxicity on man is, however, very C2> slight, and much more research is needed in this N CI- direction before success can be expected. CO the cinchona alkaloids.? AA Ch2 CH CH:ch2 Stereo-isomerism of VINYL GROUP The researches of Major H. W. Acton, i.m.s., (4) (3) have shown the definite relationship which exists CH,0.. ?CHOH?CH CH CH? between the optical activities of cinchona alkaloids v and their action and it will not METHOXY GROUPw HYDROXYL GROUP N pharmacological 'be out of place to say a few words about tjhe Quinoline ring. Quinuclidine (Second half) stereo-isomeric relationship of the different QUININE alkaloids. Where R = H in cinchonine and cinchonidine OH in their hydroxy derivatives?Cupreidine and From the formula of quinine cupreine. graphic given CH30CH3O in their methoxy derivatives?quinidine and above, it is evident that there are four asymmeteric quinine. = carbon atoms in the molecule and it R' CH : CHj the vinyl group of the natural alkaloids. (marked 1-4) in CH2. CHjCH3 in the hydro-alkaloids. is also obvious that any substance with this formula The alkaloidal molecule- is composed of two should have 16 optically active isomerides, 8 of which would be or mirror portions, the quinoline ring on the left and enantimorphic image forms other 8. The number of the quinuclidine nucleus on the right, generally of the those called the second half of the molecule. The two actually known is very limited. Acton has out that since is and portions are connected by an alcoholic grouping. pointed quinine laevo-rotatory Nov., 1922.] THERAPEUTICS OF CINCHONA ALKALOIDS: CHOPRA. 403 cinchonine is dextro-rotatory, quinine is not a Iso-octyl-hydro-cupreine or vuzin was ex- derivative of cinchonine. The true relationship tensively employed by the Germans during the cases of is 'between cinchonidine, cupreine and quinine war ;for disinfecting suppurating gun- to its bactericidal action on their hydro-alkaloids), which are all lrevo- shot wounds, owing (with dilutions in rotatory ; and cinchonine, cupreidine and quini- streptococci in very high (1 80,000). of 0.1 in a litre of dine (with hydro-derivatives), which-are all It was used in a strength gm. be efficacious. dextro-rotatory. The action of these groups is water and proved to highly has been to more marked in certain directions ; for instance, found Iso-amyl-hydro-cupreinein Vincent's and it the dextro-rotatory alkaloid quinidine has been have a specific effect angina a in other forms of ulceration of shown by him to have greater destructive action may be useful on the benign tertian parasite than has quinine. spirochetal origin, such as Naga Sore. We are Pharmacological action of the cinchona investigating the antiseptic properties of the and it is alkaloids.?To apprehend the rationale of the dextro-rotatory cupreildine compounds, therapeutic action of these alkaloids, it is import- possible that this series, being more active us the to have a clear idea of their general pharma- pharmacologically, may ultimately give I will view with these different infections. cological action, and it briefly, taking means of coping the of quinine as a typical example. The type of action Ferments.?Interference with activity of is the same in case of all the alkaloids. .ferments is a well marked property quinine on the in blood The action of quinine on undifferentiated and its inhibiting action oxydases the metabolic in protoplasm is quite characteristic. Very dilute is well known. All processes anabolic or katabolic solutions such as 1 in 20,000 to 50,000 destroy the body, whether of nature, and tissue waste and amoebae and paramsecia in a few hours; the activity are decidedly inhibited aie both retarded. of certain forms of non-pathogenic spiro- energy production are affected to chsetae, spermatozoa and ova is inhibited at first Various digestive enzymes vary- to the of concentra- and finally stops. Certain protozoa are, however, in

of the intestinal muscle, such dilutions were to the toxic effects of quinine salts on the red impossible to attain in the body. The diarrhoea blood cells. Quinine circulates in the blood as is very probably due to an interference with quinine base and Acton has demonstrated that digestion both in the stomach and intestine. strong solutions of quinine and quinidine base Uterus.?Quinine has often been employed to such as 1 in 2,000 of normal saline produce no increase the force of contractions in the second haemolysis of washed red corpuscles in vitro stage of labour under the belief that it favours incubated 'for twenty-four hours. In case of the contractions of uterine muscle ; it is also be- the acid salts, such as the bisulphate, there is lieved that given in large doses it has an ecbolic faint haemolysis in 1 in 8,000 solution, but none effect. It should be remembered that the high whatever in 1 in 11,000. temperature, which often accompanies malaria Intravenous injections of strong solutions of against which quinine is employed, may produce acid salts are, therefore, highly undesirable and death of the foetus and evacuation of this organ. there is no doubt that the rigors which are often Acton performed some- very interesting observed after such injections, are due to the experiments on the pregnant uterus of rats and haemolysis which is produced. As a matter of guinea-pigs, by rapidly excising this organ and fact injection of acid salts of quinine and other placing it in a bath of Ringer's solution (with cinchona alkaloids, whether intravenous or intra- traces of MgCl2) and recording the contractions muscular, is not correct from a physiological on a moving drum. The drug to be tested was point of view, as they always circulate in the put in the bath and allowed to act directly on blood as bases. They are preferred because they the excised organ. He found that such dilute are very soluble and, therefore, convenient to solutions as 1 in 300,000 were without any effect, administer. 1 in 150,000 only produced contractions under Blood pressure is definitely lowered after certain circumstances and 1 in 44,000, a concen- intravenous injections and Acton has pointed tration which can never be attained in the blood out that this depression is much more marked unless the patient was literally poisoned with with the dextro-rotatory cinchonine series, quini- quinine, produced a tonic spasm of both the cir- dine being the worst offender in this respect. cular and longitudinal fibres, which, if maintained, Experiments show that it is ten times more toxic would kill the foetus. Concentrations of 1 in than quinine : and its effects are more prolonged 150,000, such as occur in the blood normally after and it should never be given by this route. ingestion of quinine in moderately large doses, The action of quinidine on the heart has lately stimulate the intermittent contractions; if now been the subject of much study owing to the some exciting cause is present, e.g., weak mem- beneficial effects it produces in auricular fibril- brances or a patulous os, the membranes may lation and arhythmia and it is generally believed rupture and labour be brought on in this manner. that this action is produced by its depressant In the treatment of pregnant women suffering effect on the heart muscle, which reduces its from malaria, the temperature should not be excitability to a point below that at which fibril- allowed to go beyond 103? F., and quinine should lation is possible and also possibly an atropine-like be given in divided doses of 3 to 5 grains action on the vagus. It is usually given by the every two or three hours, till twenty grains are mouth in form of sulphate, 0.2 gm. being given given. General measures to prevent abortion on the first day and, if it is well borne, the dose should foe adopted. is increased to 0.4 gm. two or three times a day, Cases of abortion from large doses of quinine and this can he kept up for 5 to 8 days. In are not infrequent in the first month of preg- about 50 per cent, of cases the medication has nancy. though in a large majority of cases no no effect and these' are generally advanced cases ill-effects seem to be produced, as it is given of heart disease with extensive changes in the indiscriminately by practitioners in this country. rhyocandum. As the drug has a paralysing effect Effects on the blood and blood pressure.?If on the heart muscle, it should be given with quinine in large doses is given intravenously to caution and after a course of digitalis in cases of an animal, certain changes are noticed to take place failure of compensation. in the blootd corpuscles. The leucocytes loose Nervous system.?On the cerebrum quinine their amoeboid movements, become round and has a tendency, though not so marked as other granular and diapedesis through the capillary antipyretics, to allay pain. In ordinary thera- walls ceases. Such concentration, however, can- peutic doses, it has no effect either on the medulla not be attained in man with ordinary therapeutic or on the cord; but large doses depress these doses, but the same type of effect is noticeable structures and the respiratory centre is especially in the white corpuscles. Their number is also attacked. reduced to half the normal per c. mm. of blood On the peripheral nerves, the cinchona alka- or even less, lymphocytes being chiefly affected. loids and their derivatives produce a slow and This leucopccnia is often preceded by a preli- prolonged abolition of sensation by direct effects minary leucocytosis and lasts for several hours. on sensory nerve endings. Lately a good deal of On the erythrocytes, the acid salts of quinine attention has been paid to their local anaesthetic have a decidedly hsemolytic action in vitro and properties and their potencv can be judged from blackwater fever has been attributed by some the fact that whilst a 1 in 50 solution of cocaine Nov., 1922.] THERAPEUTICS OF CINCHONA ALKALOIDS: CHOPRA. 405

break down o-f which occurs hydrochloride will produce anaesthesia on the the excessive proteins same can be in these diseases. cornea of a rabbit, the effects distribution and in the by 1 in 60 hydrochloride, 1 in Absorption, fate body.? produced quinine the salts are dissolved 100 1 hi 1,000 et hyl-hydro- In the stomach quinine hydro-quinine, the and into the cupreine (optochin), and 1 in 1,200 of iso-amyl- by the HC1 of gastric juice pass from which they are taken up into the hydro-cupreine. duodenum, blood and circulate as quinine base. If excess with urea and is Quinine is often combined of alkali is present here, quinine is precipitated used as a This combination local anaesthetic. the bile salts and may pass out into the fceces and its by increases its solubility power of penetra- unabsorbed. The soluble salts of the alkaloid tion into the but the combination is decided- cells, are absorbed a little more quickly than the insolu- weaker and has to be used in twice the ly ble ones, for compounds like eu-quinine have when is used. strength necessary, quinine alone first to be by the alkali of the duode- cent, hydrolysed As a rule 0.25 per solutions are can the wall. quite num before they pass through gut effective. The rate of absorption varies, but there appears a soluble salt is absorbed with Quinidine and cupreidine compounds also to be no doubt that crreat the whole of the quinine possess anesthetic properties, though their action rapidity, being as none is to be found in the faeces. is somewhat weaker ; these are still under taken up, investigation. It can be detected in the urine very soon after it is ingested. According to Ramsden and Lipkin The of all the cinchona deriva- disadvantage does not circulate in the blood for a long tives over cocaine and its allied is quinine compounds time, if injected intravenously; 90 per cent, dis- that the induction takes and are more longer a time. they appears in about minute's In the various and in stronger solutions cause irritating may tissues it is distributed rapidly, only a fraction infiltration of the tissues and sloughing may of from 23 to 60 cent, in the urine the per appearing result. also irritate conjunctiva and their now no They as base ; till other recognisable action is not quinine deep seated, otherwise they would derivatives have been detected. There has been for be excellent anaesthetics ophthalmic as opera- a difference of opinion regards the distribu- tions. tion of quinine among the constituents of the Spccial senses.?Eyes. In toxic doses quinine blood, but recent researches by King and Acton produces contraction of the visual fields, diminu- (1921), show an approximately uniform distri- tion in acuity, colour blindness, amblyopia and bution in corpuscles and serum. A certain amaurosis. Ophthalmoscopic examination in proportion of quinine ingested is metabolised. these cases shows contraction of the choroidal The liver has been known to destroy morphine, vessels and the retina looks pale and cedematous. nicotine and other alkaloids and probably deals In therapeutic doses it has little effect ? most with quinine in the same way. of the visual disturbances in patients taking ordi- Excretion.?In the faces the excretion is so nary doses of quinine in malaria being due to small as to be negligible. By the kidneys it is parasitic emboli in the retinal vessels. excreted unchanged and if this organ is healthy the is very rapid, in Ear.?The common process quinine appearing accompaniments, ringing urine within 15 minutes of administration the in the ears and deafness appear to be due by chiefly mouth stomach). The excretion continues to congestion of this organ. In animals, such (empty for 41 hours after a single dose by the mouth and effects can be produced experimentally by giving after a succession of doses it may be found in the large doses of quinine. Degenerative changes urine for a^ long as seven days. After a have also been noticed in the cochlear ; single ganglia dose orally the acme of excretion occurs after chronic otitis media may be set up by stand- long 4 to 8 hours. Never less than 23 per cent., or ing congestion producing permanent deafness. greater than 60 per cent., is eliminated from the When giving quinine to patients with middle ear body, the balance being either stored up in the disease, the possibility of its a quiescent activating tissues or is destroyed. Probably the latter view condition may be borne in mind. is correct, as estimation of the total quinine in Metabolism.?This is affected by quinine in the body will not account for all that is missing. most very small doses in a remarkable manner. A fact of great clinical interest is that when There is a slight transient increase in the nitro- more than eleven grains of quinine base per litre genous constituents of the urine, followed by a are passed through the kidneys, temporary albu- marked decrease especially in urea and uric acid. minuria is produced. This should be remembered This is probably due to its effect on the digestive when prescribing a heroic dose of quinine. enzymes, which decreases the formation of Quinine idiosyncrasy.?Some individuals show amino-acids and, therefore, diminished protein very peculiar susceptibilities in regard to quinine This even assimilation results. would by itself when such minute quantities as 1116th decrease the katabolism of proteins in the tissues grain are given. The symptoms which and lead to decreased heat formation : antipyretic manifest themselves are urticaria, erythematous effect. The use of quinine, therefore, in wasting or bullous eruptious, dyspncca, fever, nausea diseases has a rational basis, as it tends to check and vomiting. A case has been recorded in 406 THE INDIAN MEDICAL GAZETTE. [Nov., 1922.

which three grains caused fever, bloody stools always be resorted to when stronger concentra- and severe prostration which disappeared on the tions are required. following day, but reappeared some weeks later I believe there is a form of cachetic condition when the dose was repeated. which occurs in patients taking large doses of for In These idiosyncrasies are not commonly met quinine prolonged periods. military where men with in the tropics, where large doses, such as practice who have suffered from malarial fever are on to for 30 to 60 grains are given, and the case appears put quinine periods to be similar to that of /Potasium Iodide and ranging from I to 3 months, this condition is not met with. The only seen with small doses. infrequently patient looks' and is listless, has no inclination for Cinchonism.?This name is to the toxic pale anaemic, given exertion and has no for food. There effects, chiefly connected with the central nervous appetite is generally a jaundiced tinge about the con- system, when quinine or other cinchona alkaloids junctivae and the temperature is usually sub- are given in large doses and should be differen- normal. All these are put down as tiated from idiocyncrasy, which is a condition symptoms being after effects of malaria, but are probably of increased susceptibility and is brought on by due to the action of quinine on digestive and very small doses. The of toxicity of the degree other as of the or decrease different alkaloids varies, cinchonine the organs, stoppage drug being of dose rapidly improves 'the condition. most toxic, next comes quinine, then cinchonidine and lastly quinidine. The association between the That quinine has toxic effects on the liver has symptoms of intoxication and high concentration been experimentally proved. Intravenous injec- of in of the alkaloid circulating in the blood is very tions moderate doses rabbits produce striking. The early symptoms are nausea, head- progressive degeneration of liver cells, which ache (due to cerebral congestion), vomiting, increases with the increase of dosage and it is ringing in ears, giddiness and disturbed vision possible that some such factor comes into play in (due to selective changes in the vessels). Photo- these cases. The toxic effects of quinine have been phobia. deafness, blindness?at first partial and attributed by some to the formation of a body then complete?appear later. Apathy, mental called quinotoxin which is formed by action of free on and it is depression and general muscular weakness 4super- organic'acids quinine suggested vene that such conditions arise in the and with very high doses somnolence and gut. It is, how- loss of consciousness, delirium and finally death ever, found that this substance has a very low from collapse. Large doses paralyse first the toxicity and cannot be responsible for these brain and respiratory centre and later the heart. effects. Quinine amblyopia and amaurosis have already be been referred to. (To continued.) I saw twenty cases of quinine poisoning in East Africa, where a large dose had been given by mistake to a group of men taking it for prophy- lactic purposes. The exact amount given could not be determined, but judging from the symp- toms which developed, must have been fairly large. All these men suffered from very severe symptoms of cinchonism starting within a few minutes of ingestion; four were unconscious, or rather semi-conscious for a few hours, -all suffered from amblyopia, amaurosis and deafness for 1 to 7 days, but they all recovered by promptly washing out the stomach, and administration of salines and stimulants. One case developed optic atrophy. The grave effects of cinchonism are only met with when the dose is increased beyond 40-to 60 (grains a day. These large doses are sometimes prescribed by practitioners in this country and are often continued for long periods, but it is certain that they do harm. In my experience I have found that a maximum of thirty grains in twenty-four hours is as much as is needed ; in most cases twenty grains are quite sufficient. Such doses are quite safe and effective ; they cause no symptoms of cerebral congestion and should not be exceeded. There is no particular point in giving very big doses by the mouth, as the intravenous and intramuscular methods can