PT THEE . 9Tli - -MEDCAL(JouRAL VOL. V. OCTOBER, 1929. No. 49. CONTENTS PAGE A CONSIDERATrION OF THE VARIOUS METHODS OF DRUG ADMIINISTRATION ... I By S. H. DAUKES, O.B.E., M.D., D.P.H. SOME CLINICAL ASPECTS OF ARTERIAL PRESSURE ... ... ... -.. ... 7 By J. F. HALLS DALLY, M.A., M.D.CANTAB., M.R.C.P.LOND. TUBERCULOSIS; THE SUBJECT FOR TEACHING MEDICINE ... ... ... ... 14 By S. VERE PEARSON, M.D.CAMB., M.R.C.P.LOND. E-DITORIAI.L ... . ... ... ... ... ... ... ... .. ... 17. POST-GRADUATE NEws ... ... ... ... ... ... ... 17 FELLOWSHIP OF MEDICINE AND POST-GRADUATE MEDICAL ASSOCIATION.- SPECIAI, COURSES ... ... ... ... ... ... ... ... ... I9 A CONSIDERATION OF THE VARIOUS METHODS OF DRUG ADMINISTRATION. OSTr-GRADUATE LECTURE D)ELIVEREL) AT THE \NVELCOME MIUSEUM OF MEDICAL SCIENCE. By S. H. DAUKES, O.B.E., M.D., D.P.H., I-r has occasionally been fashionable in the past to belittle the value of " dr-ug treat- ment." A famous physiciani once said that he could well dispense with all the drugs in the British Phai-macopceia, provided that he could keep magnesium sulphate. This was a suirprising statemenit, for even in those days the value of mercutr-y in the treatment of syphilis and of quinine in "ague" was acknowledged by all. It is possible that his attitude was mot-e iri the nature of a protest against that blind faith *in a bottle of mnedicine which was tending to sinik the reputationi of the physician' in the mystic potency of his bottled prescription. At the present time such anl attitude would be inconceivable in. the light of recenit advances in medicinal treatment.' We have onily to think of the prognostic revolution vhich has been brought about in such diseases as kala-azar, the, black death of India; in bilharziasis, the curse of Egypt; in syphilis, in diabetes, in pernicious anaemia, in diphtheria, in cretinism, and a host of other diseases. We even find drug treatments waging warfare with the surgeon in his stronghold of the upper abdomen, and triumphantly proclaiming their victories over gastric and duodenal ulceration, It is whispered that the exponents of radical by copyright. on November 13, 2020 by guest. Protected http://pmj.bmj.com/ Postgrad Med J: first published as 10.1136/pgmj.5.49.1 on 1 October 1929. Downloaded from
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PT THEE .9Tli
- -MEDCAL(JouRALVOL. V. OCTOBER, 1929. No. 49.
CONTENTSPAGE
A CONSIDERATrION OF THE VARIOUS METHODS OF DRUG ADMIINISTRATION ... I
By S. H. DAUKES, O.B.E., M.D., D.P.H.
SOME CLINICAL ASPECTS OF ARTERIAL PRESSURE ... ... ... -.. ... 7
By J. F. HALLS DALLY, M.A., M.D.CANTAB., M.R.C.P.LOND.
TUBERCULOSIS; THE SUBJECT FOR TEACHING MEDICINE ... ... ... ... 14
FELLOWSHIP OF MEDICINE AND POST-GRADUATE MEDICAL ASSOCIATION.-SPECIAI, COURSES ... ... ... ... ... ... ... ... ... I9
ACONSIDERATION OF THEVARIOUS METHODS OFDRUG ADMINISTRATION.
OSTr-GRADUATE LECTURE D)ELIVEREL) AT THE \NVELCOME
MIUSEUM OF MEDICAL SCIENCE.
By S. H. DAUKES,O.B.E., M.D., D.P.H.,
I-r has occasionally been fashionable inthe past to belittle the value of " dr-ug treat-ment." A famous physiciani once said thathe could well dispense with all the drugs inthe British Phai-macopceia, provided thathe could keep magnesium sulphate. Thiswas a suirprising statemenit, for even in thosedays the value of mercutr-y in the treatmentof syphilis and of quinine in "ague" wasacknowledged by all. It is possible that his
attitude was mot-e iri the nature of a protestagainst that blind faith *in a bottle ofmnedicine which was tending to sinik thereputationi of the physician' in the mysticpotency of his bottled prescription.At the present time such anl attitude
would be inconceivable in. the light of recenitadvances in medicinal treatment.' We haveonily to think of the prognostic revolutionvhich has been brought about in such
diseases as kala-azar, the, black death ofIndia; in bilharziasis, the curse of Egypt;in syphilis, in diabetes, in perniciousanaemia, in diphtheria, in cretinism, and ahost of other diseases. We even find drugtreatments waging warfare with the surgeonin his stronghold of the upper abdomen,and triumphantly proclaiming their victoriesover gastric and duodenal ulceration, It iswhispered that the exponents of radical
treatment have given a-not unwilling ear tosuch blandishments when called upon tomake the great decision on their own behalf.There must be an explanation for such pro-gress, and it seems to me that we can find itin the greater care that is now taken withregard to a correct technique of administra-tion. Cushny says: " The effect of a remedyis often determined, verv lai-gely, by themethod in which it is administer-ed. Asu'bstance may be quite inactive when givenby one route, and fatal when administeredby some otlher method."'
Let me give somie illustrations of this mostimportant therapeutic truth. I n the firstplace, the wise physician has realized theimportant part played by suggestion iInsuccessful treatment. 1 think of a physicianof the old school-some called him ahomoeopathist-who was famouis through-out London for the results he obtained. Ican hear him now: " I will give you some-thing that- will do you good, it will...."anid then the patient knew exactly whatwould happen. Many have objected tosuch methods, but surely they constituteone of the techniques of successful admini-stration-suggestion combinied with thecorrect remedy.We must: leave, -hovever, this side of the
problemn and pass to more obvious examples.Adrentalin, if given by the mouth, is oxidizedand rendered useless. If given hypodermi-cally, it constricts blood-vessels and is onlyslowly absorbed. It is, however, usedsuccessfully by this route in the treatmentof asthma. For shock, it must be givenintravenously in order to induce conitractionof the abdominal blood-vessels and raise theblood-pressure. If applied locally it pro-duces ischxemia and, when given with atoxic substanice may act as a safeguard byreducing-absorption.
Insulin is another good example. Thissubstance is destroyed by the enzymes ofthe stomach and must be given by inrjection.There would be a manifest advantage in
oral administration. in such a case,- and a
drug, synthalin, has been tried, but hasproved to be slow in actioni and relativelyineffective. It is for this reason thatephedrine has become so popular. Peoplewith chronic diseases, such as diabetes andlasthma, do not want to depend upon repeatedinjections. The asthmatics are mor-e fortu-nate than the diabetics, for in ephedrinethey have a substance which can be takenby the mouth and which is effective in acertain number of cases. It is an alkaloidwhich is obtained from a Chiniese drug, MaHuang, and is closely related to adrenalin.It is more stable, however, and its activityis not destroyed by boiling.Among our examples xve can include
salvarsan and the various allied drugs usedin the treatment of syphilis and yaws. Herewe have a trivalent organic arsenic com-pound, which is not available for or-aladministration owing to the fact that, ifgiven by the mouth, it becomes organicarsenioxide, the cause of many of the trouiblesthat arose in early days with imiipure pre-parations. As a result, injection into themnuscles was tried, but the drutg was de-posited locally, caused pain and swelliniganid was very slowly absorbed. The intra-venous method is now used; it acts veryrapidly-a few hours-and the drug ismnostly excreted in tlhree days. It is for thisr-eason that, in syphilis, mercury is used asvell, the insoluble salts being injected intr-a-muscularly so that the action of the mercuryis prolonged. Here we have anl excellentexample of how the different methods ofadministration may be used to accomplishdefinite objects; a prognostic revolutionhas occurred, we have salvation withoutsalivation.Once again, a preparation which could be
used by the mouth would be invaluable.Stovarsol has been tried, and merits furthertr-ial. It is said to have prophylactic valuein syphilis, and has been proved to be ofvalue in chr-onic malaria.The neo-compounds, neosalvarsan, neo-
excreted, inore easily prepared for injectioni,and can be given intramuscularly, buit theintravenous route is generally preferred.
In this group also we have tryparsamnide-a penitavalent arseniical compound-wlhichhas little action in syphilis, but has provedinivaluable in the treatment of sleepingsicktness.
In antinony we have another outstandinigexample of the importance of the mode ofadministrationi. A ntimony may be regardedas a drug with a past and a future. It haseaten husks in a far country and returnedto become a useftul citizen. In the seven-teenth centtury it was much prescribed anddid harm ; so much so, that the graduatesof Heidelberg were requlir-ecl to take an oathnever to use it. When taken by the mouthit is an emetic, expectorant and very depres-sing. If it is rLubbed into the skin a cropof pustules occurs. This does not seemmtuch recommendation, but antimoniy oint-ment applied in this way has been usedwitlh success in the treatment of lumbago,anid also in the treatment of oriental sore.As the inor-ganic antimony preparationscause vomiting anid the organic may be de-composed in the stomnach, injection wastried. Hypodermic and intramuscular in-jectionis are impossible, owing to the intensepain, suppuration and sloughing which mayoccur. lntravenous injection is safe andeffective provided care is taken that all thesolution passes into the vein. So we hiaveworked, by devious routes, to a state of greatreliance on this druLg ill two very importanitdiseases-bilharziasis and kala-azar.The pentavalent organic compounds are
chiefly used for kala-azar-stibamine gluco-side, urea stibamine and v. Heydeii 693.1One could go on indefinitely illustrating
this statement of Cushny's with regard tothe importance of the method of adminis-tration.
I Antitnosan (trivalent) cani be administeredintramuscularly; also Neostibosan (v. Heyden 693b).
Iodinie applied to the skin is antiseptic;tlken internlally it can stop vomiting.Chloroform by the lungs is anaesthetic;
in small doses, by the mouth, it is a car-mi-native.
Olive oil, by the rectum, opetns the bowelsanid, by the mouth, reduces gastric acidity.
Certain substances taken by one route maybe intactive, whereas by aniother route theyinay be fatal. Peptonie is a good example,anid in snake venom we have a practicalanid dramatic demnonstration of this fact.Adult animals can swallow many timies thefatal injection dose. We have all readstories of the hero sucking venom fromthe heroine's arm, with no ill-effects beyondthose incidental to matrimony. A rabbitcan swallow 6oo times as much poison as itcani tolerate when injected. The ptyalin ofthe digestive juice destroys venom in vitroand evidently has a similar action int vivo.We must always remember the possibilityof the hydrochloric acid ot digestive juicesof the stomach altering the action of a drug.We can now rapidly survey the various
miethods of driug administration in use at thepresent time. Roughly speakinig, the drugmay gaini admissioni through the unbrokenskin or mucous membrane, through thealveoli of the lungs, oY- by injection into anlyselected organ or tissuie.We give drugs by the mouth-local appli-
cation, ingestion, inhalation; by the rectum;by the skin-inunction, ionic medication;by subcutaneous injection; by intramuscularinijection ; by intravenous injection; by deepinjection-lungs, liver, spine, &c. And eachof these methods has its appropriate indica-tions and mode of applicationl. To enterinto the technique of these various methodsis beyond the scope of the lecture, buLt eachwill niow be reviewed in somewhat greaterdetail.By the Mouth. Ingestion.-Medicinal
preparations are taken by the mouth, eitherfor their- direct action upoIl the alimentarysystem, upon some parasite which hasinvaded that system;. or for their genieral
action after absorption. The modernmethod is to administer a drug in the mostpleasant manner possible, and it is well toremember that insoluble salts have verylittle taste, hence the use of quinine tannateand euquinine. In the bad old days ofGregory's powder nobody studied the tasteof the victim, and children were expected toswallow half a pint of the nauseous stuffwithout complaint. Now we have flown tothe other extreime, anid aperients are dis-pensed so attractively that it is only abenevolent Providence which preventsserious accidents. The story of a greedyIndian colonel who, before the very eyesof his horrified hostess, gorged himself onTamar Indiens in a full appreciation of theirdelectable properties and ignorance of theirmedicinal action, may rank with thecautionary tales of Hilaire Belloc.
For convenience of dosage, administrationand transport, medicinal preparatioons arefrequently sold in some compact form,either compressed or otherwise. Suchpreparations may be ready to be swallowed,or may require to be crushed or dissolvedbefore administration. Full directions aresupplied by the manufacturers of such pro-ducts, and it is important to follow carefullythese directions. The're can be no questionthat for convenience of dosage-and transportsuch a metlhod has manifest advantages.When, however, we come to the questionof administration it is not quite so simple.During the war a physician who was treatingcases of malaria with quinine found one ofhis patientswhorefused to respond; it wasob-viously a case of a quinine-resistant parasite.Being young and enthusiastic, the physicianseized pen and paper to record his experiencefor the benefit of posterity. The hospitalorderly, being a plain man and withoutguile, examined the patient's stools, wherehe found most of the quinine exactly as ithad been swallowed. The tablets had neverbeen dissolved; they were evidently unl-suitable for administration to that particularpatient in that particular way.
This danger does not exist if the drug isof good quality, properly- prepared andadministered according to directions. Theadvantages of taking medicine in such a formare many, quite apart from palatability-ironcan be swallowed without effect on theteeth, special coatings can be used to ensurepassage through the stomach when neces-sary, accuracy of dosage is secured.
Having got the substance down, it eitherhas to be absorbed or not to be absorbed.It is obvious that such remedies as aperientsalts, anthelminthics, astringents, amroebi-cides, &c., must reach their objective in thesmall bowel. Some do so without anyhelp; for example, the aperient sulphates.Others need some protective coating, keratin,salol or wax, which will pass through thestomaclh unharmed. Others need specialprecautions for them to achieve their object,as, for example, thymol or male fern. Herespecial aperient treatment, both before andafter, is required, and certain substanceswhich enicourage absorption must beavoided, as, for example, fats and alcoholwith thymol. In using alkalis in the treat-ment of gastric or duodenal ulcers we needlocal not general action, and sodium bicar-bonate, which is readily absorbed, shouldbe used sparingly, giving place to themagnesium and calcium salts.
Rectal medicationl may have one of fourobjects in view:
(i) General action.(2) Local action.(3) To wash out the bowel.(4) Anaesthesia.
With regard to the last group, ether inolive oil has been used, anid recently a sub-stance, "avertin," a tri-brom-ethyl alcohol,has been introduced. For a man of i i stone,io gmi. is said to be readily absorbed anidto produce anxsthesia in ten minutes,lasting for two hours or more. There isthen thirty-six hours' sleep, after the opera-tion, owing to the production of sodiumbromide. To hasten elimination, 5 to iogm. of common salt, well diluted, may be
injected into the rectum. This method, inspite of obvious advantages, seems open tothe grave objection that it is not readilycontrolled, and there may be danger ofacidosis.For local action suppositories may be of
great use. The late Mr. Harold Barnardused to say, " When in dotubt about a rectalcondition, try a 2 gr. calomel suppository."Mlany have had reason to be thankful forthat advice.
For general action, quinine may be givento children by this route.
Inthalation.-Here we have a mode ofadministration which is rapid and can becontr-olled with moderate accuracy. Wehave the various anesthetics-chloroform,ether, nitrous oxide, ethyl chloride, &c. Weknow that nicotine can act powerfully wheninhaled in large quantities. The variousasthma inhalations, containing stramo-nium, &c., are well-known examples, andadrenialin has been administered by thismethod with success. Oxygen is used as atherapeutic agent under various conditions,more especially in pneumonia. To dilatethe blood-vessels and relieve an anginalattack, amyl niitrite is valuable.To what extent other routes might be
substituted is an interesting problem. Therapidity of action required in angina andasthma offers a cleat indication as to route.Anaesthetics are never administered by thestomach, though in the old days alcoholwas given before operationis with a similarobject. There is, however, a story whichbears uponl this question. Chloroform isCHCI3, and carbon tetrachloride, used todestroy hookworms, is closely allied, CCI4.All the inmates of a hospital in India, staffand patients, were treated for hookwormswith car-bon tetrachloride. That night thehospital was visited by burglars, who foundeverybody fast asleep as the result of theirCCI4.- It is obvious, however, that the degreeof ainaesthesia could never be controlledwith equal accuracy by this method.
Cutaneouis Adminishtation.-This is gener-
ally used for its local effect; very few drugshave been administered through the skin fortheir action after absorption. Mercurialinunction is quite effective, but a very dirtymethod. Cod-liver oil and insulin haveboth been tried, but without any usefulresuilt. Perhaps of greatest interest is thefact that the ergosterol in a child's skin canbe inactivated by sunlight, and thus ricketsmay be treated or prevented by autogenousmedication.The attempt has repeatedly been made
to introduce druigs into the body by ioniza-tion. It is probably of little value for tissuesmore than a few mm. below the surface.Ions migrate slowly, encounter blood-vesselsand are carried away, or form compoundswith tissue proteins and pass no further.The treatment is mainly restricted to theuse of zinc sulphate, iodine, &c., for surfacelesions.Hypodermic admninistration is used wlhere
rapidity of action is indicated as, for ex-ample, where morphia is used to allay pain.The benefits of this method of administrationareAvoidance of local action on the stomachi.Rapid absorption.Whole remedy used (if soluble and not
precipitated at the point of injectioni).Occasionally this method is used for local
action, as with cocaine, novocain, and otherlocal anaesthetics..
If the substance is irritant it must beinjected into the less sensitive musculartissue; hence, we have intrantuscutlar inijec-tion. Two familiar examples of the use ofthis methodc will occur at once:-
(i) Mercury. Soluble salts are absorbedtoo rapidly and cause pain. The insolublesalts and metallic mercury are thereforeused. These are absorbed slowly.
(2) Quinine, injected into the glutealmuscles. A stout platinum iridium needle isused. The solution is freshly prepared andboiled. Strict asepsis is essential, becausethere is always some muscle necrosis and agood focus for infection is formed. In the
Sixteentth Annuiiial Report of the MedicalDepartmciit of the United Fru1it Comnpanty,de la Torre states that he has given 9,ooointramulscular injections of qulinine withexcellent therapeutic results (I gm. dailyfor four to six days, then twice a week forthl-ee weeks). As Manison-Balhr says, "Thereis no need to make a pin-cuishion of yourpatient." De la Torre recommends amassage ride oni horseback after eachinijection, and states that in his series onllyfour abscesses were seeni.There has been some talk of danger of
tetanius from quinine injections. It is wellto remember that in tryinig to sterilize asyrinige, (i) cold alcohol does not kill spores;(2) boilinig water does not kill spores;(3) boiling oil does not kill spores; thougheach of these methods will probably killmost of the common organisms. To killspores the syringe should be boiled in 5 percent. carbolic acid for ten minutes, orsuspenided in a plugged test tube and auto-claved.
Deep intjections ar-e occasionally of use.Emetinie may be inijected for liver abscess;inijections into the spinal columinii are usedto produce anwsthesia for major operations;injections may be made inlto luing cavities ;iodized oil into the trachea for diagnosticpurposes; and alcohol inlto the ganglion ofthe trigeminal nerve. In every case of deepinjection the action is primarily a local one.
Initravenious injections are more and moreemployed at the present time. This methodof administering drugs was first tried bySir Christopher Wren in the spare momentsleft over from architecture and astronomy.It is scarcely strange that it never becamereally popular in pre-antiseptic days. Ithas the advantage of exact dosage, rapidaction, and complete utilization. Pharma-cologists always employ it, when possible,for it is the method of precision. Ift has thegreat advantage of producing a maximumconcentration in the blood-stream at once;in other methods there., may be a delayextending even to twenity-four hours. On
the other hanid, it is a minor surgical pro-cedure witlh definiite requirements as toasepsis and techniique.
It is therefore essenitial to have some clearviews with regard to the inidicationis forintravenous injections. These may besummarized' as follows:-
(i) As an emnergenicy ineasutre where rapidaction is essential. In such conIditions asshock, toxzemia and haemorrhage-the in-jection of saline solution, glucose infusionis,&c.To combat severe acidosis-salinie sodium
bicarbonate solution.In diabetic coma-intravenious insulin.In very severe tetany-calcium chloride.In acute circulatory collapse-slow inljec-
tion of weak solutions of epinephr-ine inphysiological saline solutioni.
In severe heart failure-strophanithin.In malignant malaria-quininle.In very severe diphtheria-antidiphtlhe-
iritic seruIn.(2) When greater intensity of action is
r-equired than can be obtained by othermethods. Many toxic sera, &c., ar-e veryslowly absorbed if given subcutaneouisly orintramusctular-ly-anitistreptococcic serum,antipneumococcic serum, or noni-specificpr-oteins to induce proteini shock.
(3) When the volume of the dosage is large.More tlhan OO c.c.-sali ne,glucoses,oIlutions,&C.
(4) To avoid irritation or destruction oftissue at the site of injection. Arsphena-mine, antimony, dye-stuffs, colloidal metals,alkalis, &c.
(5) To secure direct actionI within theblood-stream against invading organisms.This is the most obvious indicationi, andprobably the most fallacious. Most agentsleave the blood-str-eam very rapidly.
In this connectioni the intravenous useof mercurochrome is of special importance.
1 From the Report of the Special Committeeappointed by the American Therapeutic ResearchCommittee of the Council on Pharmacy andChemistry.
Here we have a drug which has beeni highlypraised, and, with equal force, condemined-as useless, for the purpose of fighting blood-infections. Dixon says -
" Experiments made on animals,inoculated with pneumococcus oranthrax, have shown that mercuro-clhrome produces a considerable pro-portion of cures-5o per cent. or more.These experiments have, however, beendisputed. Clinical rieports are moredefinite and impressive. They showthat in a large proportion of cases ofsepticeiiia, in which a pure culture ofstreptococci could be obtained from theblood, intravenous injections of mer-curochronie were followed by cure.
Yotung reports I73 cases ofsepticiemia treated with mercuro-chrome, with a cure in 63 per cent. ofcases."
I once asked an author-ity on the subjectwhat he thouglht of this group, i.e., directaction oni organisms in the blood-stream.His answer was short anid to the point, butit was not encouraging.
In these five groups we have certaindefinite indications which may guide us inour selection of the method of adminis-tration.From this summary you will, I tlhink, be
able to appreciate the enormous importancewhich attaches to a correct method of drugadminiistration.
SOME CLINICAL ASPECTSOF ARTERIAL PRESSURE.
Jy J. F. HALLS DALLY,M.A., M.D.CANTAB, M.R.C.P.LOND.,
Physician to Mount Vernon Hospital for Diseases ofthe Heart anid Lungs; Senior Physician to the
St. Marylebone General Dispensary.
I ESTEEM it a great privilege to have beenasked to give a short address oni " ArterialPressure," a subject which, by reason of its
widespread ramifications and( recent develop-ments, becomes of ever-increasing interestand importance, and I trust that you willprefer a practical issue, such as that which Ihave chosen, to a more profound or abstracttheme. The more we study arterial pressure,the more we find it of the greatest service indaily practice. The aspects of it are, how-ever, so manifold that I catinot do morethani to attempt a brief synopsis of the mostsalient features.
DEFINITIONS OF BLOOD PRESSURE.At the outset it is essential to have a clear
understanding of the terms that we employ.What, then, do we meanvwhen we speak of" blood-pressure'" ? In the physiologicalsense not only does this term include arterialpressure, but also pressures which are intra-auricular, intra-ventricular, capillary andvenous. In the physical sense blood-pres-sure is that pressure which the blood exertsat a given instant upon a given poinlt inlthe circulatory system. In the clinical sense"blood-pressure" is loosely uised in every-day language as implyinig solely arterialpressure, and sphygmomanometric read-ings, expressed as a set of figures repre-senting the height in millimiietres of acolumn of mhercury or the equivalent ininstruments calibrated from that source,constitute the generally accepted measure.In the pathological sense we have to dealwith arterial pressures which may be eitherabnormially high or abnormally low.
MEASUREMENTS OF ARTERIAL PRESSURE.We measure arterial pressure with instru-
ments, primarily to assess the efficiency orotherwise of the circulation, so as to gain anestimate of the nature of each problem withwhich we have to deal, and secondarily toglean other indications which are bothpsychical and physical. Personally, I findno instrument so reliable as an accurately-constructed mercurial manometer, such asthe " Baumanometer," though general prac-
