Guide To Good Prescribing

WHO/DAP/94.
11 Distr:General Original:English
Guide to Good Prescribing
A practical manual
World Health Organization Action Programme on Essential Drugs Geneva
GuidetoGoodPrescribing
uthors
1
T.P.G.M.deVries R.H.Henning D.A.Fresle

2 1
H.V.Hogerzeil
WithcontributionsfromF.M.HaaijerRuskampandR.M.vanGilst
1
Department of Clinical Pharmacology, Faculty of Medicine, University of Groningen, The Netherlands (WHO Collaborating Centre for Pharmacotherapy TeachingandTraining)
2
WHOActionProgrammeonEssentialDrugs,Geneva,Switzerland
Acknowledgments
Thesupportofthefollowingpersonsinreviewingearlierdraftsofthisbookis gratefullyacknowledged:S.R.Ahmad(Pakistan),A.Alwan(WHO),F.S.Antezana (WHO),J.S.Bapna(India),W.Bender(Netherlands),L.Bero(USA),S.Berthoud (France),K.Besseghir(Iran),C.Boelen(WHO),P.BrudonJakobowicz(WHO), P.Bush(USA),M.R.Couper(WHO),M.Das(Malaysia),C.T.Dollery(United Kingdom),M.N.G.Dukes(Netherlands),J.F.Dunne(WHO),H.Fraser(Barbados), M.Gabir(Sudan),B.B.Gaitonde(India),W.Gardjito(Indonesia),M.Helling Borda(WHO),A.Herxheimer(UnitedKingdom),J.IdnpnHeikkil(WHO), K.K.Kafle(Nepal),Q.L.Kintanar(Philippines),M.M.Kochen(Germany),A.V. Kondrachine(WHO),C.Kunin(USA),R.Laing(Zimbabwe),C.D.J.deLangen (Netherlands),V.Lepakhin(USSR),A.Mabadeje(Nigeria),V.S.Mathur(Bahrain), E.Nangawe(Tanzania),J.Orley(WHO),M.Orme(UnitedKingdom),A.Pio (WHO),J.Quick(USA),A.Saleh(WHO),B.Santoso(Indonesia),E.Sanz(Spain), F.Savage(WHO),A.J.J.A.Scherpbier(Netherlands),F.SiemTjam(WHO), F.Sjqvist(Sweden),A.Sitsen(Netherlands),A.J.Smith(Australia),J.L.Tulloch (WHO),K.Weerasuriya(SriLanka),I.ZebrowskaLupina(Poland),Z.BenZvi (Israel). Thefollowingpersonsgaveinvaluableassistanceinfieldtestingthedraft,andtheir supportisgratefullyacknowledged:J.S.Bapna(India),L.Bero(USA),K.K.Kafle (Nepal),A.Mabadeje(Nigeria),B.Santoso(Indonesia),A.J.Smith(Australia). Illustrationsonp.56,72:B.Cornelius(withpermissionfromVademecum);p.7: P.tenHave;annexesandcartoononp.22:T.P.G.M.deVries.
Contents
T able of contents
W hyyouneedthisbook..............................................................................................................1 art1:Overview..................................................................................................................................5 hapter1.....................................................................................................................................6 Theprocessofrationaltreatment...........................................................................................6 art2:SelectingyourP(ersonal)drugs...........................................................................................15 hapter2....................................................................................................................................17 IntroductiontoPdrugs.........................................................................................................17 hapter3...................................................................................................................................19 ExampleofselectingaPdrug:anginapectoris..................................................................19 hapter4...................................................................................................................................28 GuidelinesforselectingPdrugs..........................................................................................28 hapter5...................................................................................................................................36 PdrugandPtreatment.........................................................................................................36 art3:Treatingyourpatients...........................................................................................................41 hapter6...................................................................................................................................43 STEP1:Definethepatient'sproblem...................................................................................43 hapter7....................................................................................................................................47 STEP2:Specifythetherapeuticobjective............................................................................47 hapter8...................................................................................................................................50 STEP3:VerifythesuitabilityofyourPdrug......................................................................50 hapter9...................................................................................................................................63 STEP4:Writeaprescription.................................................................................................63 hapter10.................................................................................................................................68 STEP5:Giveinformation,instructionsandwarnings.......................................................68 hapter11.................................................................................................................................75 STEP6:Monitor(andstop?)thetreatment.........................................................................75 art4:Keepinguptodate................................................................................................................80 i
hapter12.................................................................................................................................81 Howtokeepuptodateaboutdrugs...................................................................................81 nnexes................................................................................................................................................90 nnex1......................................................................................................................................92 Essentialsofpharmacologyindailypractice......................................................................92 nnex2......................................................................................................................................98 Essentialreferences................................................................................................................98 nnex3....................................................................................................................................101 Howtoexplaintheuseofsomedosageforms.................................................................101 nnex4....................................................................................................................................116 Theuseofinjections.............................................................................................................116
ii
Contents
L ist of patient examples
iii
Whyyouneedthisbook
hy you need this book
Atthestartofclinicaltrainingmostmedicalstudentsfindthattheydon'thavea veryclearideaofhowtoprescribeadrugfortheirpatientsorwhatinformation theyneedtoprovide.Thisisusuallybecausetheirearlierpharmacologytraining has concentrated more on theory than on practice. The material was probably 'drugcentred',andfocusedonindicationsandsideeffectsofdifferentdrugs.Butin clinicalpractice thereverseapproach hastobetaken,fromthediagnosis tothe drug.Moreover,patientsvaryinage,gender,sizeandsocioculturalcharacteristics, allofwhichmayaffecttreatmentchoices.Patientsalsohavetheirownperception ofappropriatetreatment,andshouldbefullyinformedpartnersintherapy.Allthis is not always taught in medical schools, and the number of hours spent on therapeuticsmaybelowcomparedtotraditionalpharmacologyteaching. Clinical training for undergraduate students often focuses on diagnostic rather than therapeutic skills. Sometimes students are only expected to copy the prescribing behaviour of their clinical teachers, or existing standard treatment guidelines, without explanation as to why certain treatments are chosen. Books maynotbemuchhelpeither.Pharmacologyreferenceworksandformulariesare drugcentred, and although clinical textbooks and treatment guidelines are diseasecentredandprovidetreatmentrecommendations,theyrarelydiscusswhy thesetherapiesarechosen.Differentsourcesmaygivecontradictoryadvice. The result of this approach to pharmacology teaching is that although pharmacologicalknowledgeisacquired,practicalprescribingskillsremainweak. Inonestudy,medicalgraduateschoseaninappropriateordoubtfuldruginabout halfofthecases,wroteonethirdofprescriptionsincorrectly,andintwothirdsof casesfailedtogivethepatientimportantinformation.Somestudentsmaythink thattheywillimprovetheirprescribingskills after finishingmedicalschool,but researchshowsthatdespitegainsingeneralexperience,prescribingskillsdonot improvemuchaftergraduation. Badprescribinghabitsleadtoineffectiveandunsafetreatment, exacerbation or prolongationofillness,distressandharmtothepatient,andhighercosts.They also make the prescriber vulnerable to influences which can cause irrational prescribing, such as patient pressure, bad example of colleagues and high poweredsalesmanship.Lateron,newgraduateswillcopythem,completingthe circle.Changingexistingprescribinghabitsisverydifficult.Sogoodtrainingis neededbeforepoorhabitsgetachancetodevelop. This book is primarily intended for undergraduate medical students who are abouttoentertheclinicalphaseoftheirstudies.Itprovidesstepbystepguidance totheprocessofrationalprescribing,togetherwithmanyillustrativeexamples.It teachesskillsthatarenecessarythroughoutaclinicalcareer.Postgraduatestudents
and practising doctors may also find it a source of new ideas and perhaps an incentiveforchange. Itscontentsarebasedontenyearsofexperiencewithpharmacotherapycoursesfor medical students in the Medical Faculty of the University of Groningen (Netherlands).Thedrafthasbeenreviewedbyalargebodyofinternationalexperts inpharmacotherapy teaching and has been further tested in medical schools in Australia,India,Indonesia,Nepal,Netherlands,NigeriaandtheUSA(seeBox1).
Box 1:
Field test of the Guide to Good Prescribing in seven universities
Theimpactofashortinteractivetrainingcourseinpharmacotherapy,usingtheGuidetoGood Prescribing,wasmeasuredinacontrolledstudywith219undergraduatemedicalstudentsin Groningen, Kathmandu, Lagos, Newcastle (Australia), New Delhi, San Francisco and Yogyakarta.Theimpactofthetrainingcoursewasmeasuredbythreetests,eachcontainingopen and structured questions on the drug treatment ofpain, using patient examples. Tests were takenbeforethetraining,immediatelyafter,andsixmonthslater. Afterthecourse,studentsfromthestudygroupperformedsignificantlybetterthancontrolsin allpatientproblemspresented(p<0.05).Thisappliedtoalloldandnewpatientproblemsinthe tests,andtoallsixstepsoftheproblemsolvingroutine.Thestudentsnotonlyrememberedhow tosolveapreviouslydiscussedpatientproblem(retentioneffect),buttheycouldalsoapplythis knowledge tootherpatientproblems (transfer effect).Atallsevenuniversitiesbothretention andtransfereffectsweremaintainedforatleastsixmonthsafterthetrainingsession.
Thismanualfocusesontheprocessofprescribing.Itgivesyouthetoolstothinkfor yourselfandnotblindlyfollowwhatotherpeoplethinkanddo.Italsoenablesyou tounderstandwhycertainnationalordepartmentalstandardtreatmentguidelines havebeenchosen,andteachesyouhowtomakethebestuseofsuchguidelines. Themanualcanbeusedforselfstudy,followingthesystematicapproachoutlined below,oraspartofaformaltrainingcourse. Part1:Theprocessofrationaltreatment Thisoverviewtakesyoustepbystepfromproblemtosolution.Rationaltreatment requiresalogicalapproachandcommonsense.Afterreadingthischapteryouwill know that prescribing a drug is part of a process that includes many other components, such as specifying your therapeutic objective, and informing the patient. Part2:SelectingyourPdrugs This section explains the principles of drug selection and how to use them in practice.Itteachesyouhowtochoosethedrugsthatyouaregoingtoprescribe regularlyandwithwhichyouwillbecomefamiliar,calledP(ersonal)drugs.Inthis selectionprocessyouwillhavetoconsultyourpharmacologytextbook,national
Whyyouneedthisbook
formulary, and available national and international treatment guidelines. After youhaveworkedyourwaythroughthissectionyouwillknowhowtoselecta drugforaparticulardiseaseorcomplaint.
Part3:Treatingyourpatients Thispartofthebookshowsyouhowtotreatapatient.Eachstepoftheprocessis described in separate chapters. Practical examples illustrate how to select, prescribe and monitor thetreatment, andhow tocommunicate effectivelywith yourpatients.Whenyouhavegonethroughthismaterialyouarereadytoputinto practicewhatyouhavelearned. Part4:Keepinguptodate Tobecomeagooddoctor,andremainone,youalsoneedtoknowhowtoacquire anddealwithnewinformationaboutdrugs.Thissectiondescribestheadvantages anddisadvantagesofdifferentsourcesofinformation. Annexes The annexes contain a brief refresher course on the basic principles of pharmacology in daily practice, a list of essential references, a set of patient informationsheetsandachecklistforgivinginjections.
A word of warning Evenifyoudonotalwaysagreewiththetreatmentchoicesinsomeofthe examples itisimportant toremember thatprescribing shouldbepart ofa logicaldeductiveprocess,basedoncomprehensiveandobjectiveinformation. Itshouldnotbeakneejerkreflex,arecipefroma 'cookbook',oraresponseto commercialpressure.
Drugnames Inviewoftheimportancethatmedicalstudentsbetaughttousegenericnames, theInternationalNonproprietaryNames(INNs)ofdrugsareusedthroughoutthe manual. Comments TheWHOActionProgrammeonEssentialDrugswouldbeverygladtoreceive commentsonthetextandexamplesinthismanual,aswellasreportsonitsuse. Pleasewriteto:TheDirector,ActionProgrammeonEssentialDrugs,WorldHealth Organization,1211Geneva27,Switzerland.Fax41227914167.
Part1
Overview
P art 1:
Overview
Asafirstintroductiontotherestofthebook,this section presents an overview of the logical prescribing process. A simple example of a taxi driverwithacough isfollowedbyananalysisof howthepatient'sproblemwassolved.Theprocess of choosing a firstchoice treatment is discussed first, followed by a step by step overview of the processofrationaltreatment.Detailsofthevarious stepsaregiveninsubsequentchapters.
Chapter 1
page Theprocessofrationaltreatment.................................................................................6 Whatisyourfirstchoicetreatmentfordrycough?.........................................7 Theprocessofrationalprescribing....................................................................9 Conclusionandsummary.................................................................................10
C hapter 1
The process of rational treatment
Thischapterpresentsafirstoverviewoftheprocessofchoosingadrugtreatment. Theprocess isillustratedusinganexampleofapatientwithadrycough.The chapterfocusesontheprinciplesofastepwiseapproachtochoosingadrug,andis not intended as a guideline for the treatment of dry cough. In fact, some prescriberswoulddisputetheneedforanydrugatall.Eachofthestepsinthe processisdiscussedindetailinsubsequentchapters. Agoodscientificexperimentfollowsaratherrigidmethodologywithadefinition of the problem, a hypothesis, an experiment, an outcome and a process of verification. This process, and especially the verification step, ensures that the outcomeisreliable.Thesameprinciplesapplywhenyoutreatapatient.Firstyou needtodefinecarefullythepatient'sproblem(thediagnosis).Afterthat,youhave tospecifythetherapeuticobjective,andtochooseatreatmentofprovenefficacy andsafety,fromdifferentalternatives.Youthen startthetreatment,forexample by writing an accurate prescription and providing the patient with clear information and instructions. After some time you monitor the results of the treatment;onlythenwillyouknowifithasbeensuccessful.Iftheproblemhas beensolved,thetreatmentcanbestopped.Ifnot,youwillneedtoreexamineall thesteps. Example:patient1 Yousitinwithageneralpractitionerandobservethefollowingcase.A 52year old taxidriver complains of a sore throat and cough which startedtwoweeksearlierwithacold.Hehasstoppedsneezingbutstill hasacough,especiallyatnight.Thepatientisaheavysmokerwhohas often been advised to stop. Further history and examination reveal nothing special, apart from a throat inflammation. The doctor again advisesthepatienttostopsmoking,andwritesaprescriptionforcodeine tablets15mg,1tablet3timesdailyfor3days. Letstakeacloserlookatthisexample.Whenyouobserveexperiencedphysicians, theprocessofchoosingatreatmentandwritingaprescriptionseemseasy.They reflectforashort timeandusuallydecidequicklywhattodo.But don'ttryto imitatesuchbehaviouratthispointinyourtraining!Choosingatreatmentismore difficult than it seems, and to gain experience you need to work very systematically. In fact, there are two important stages in choosing a treatment. You start by consideringyourfirstchoicetreatment,whichistheresultofaselectionprocess done earlier. The second stage is to verify that your firstchoice treatment is
Chapter1
Theprocessofrationaltreatment
What is your first-choice treatment for dry cough?
suitableforthisparticularpatient.So,inordertocontinue,weshoulddefineour firstchoicetreatmentfordrycough. Ratherthanreviewingallpossibledrugsforthetreatmentofdrycougheverytime you need one, you should decide, in advance, your firstchoice treatment. The generalapproachindoingthatistospecifyyourtherapeuticobjective,tomakean inventoryofpossibletreatments,andtochooseyourP(ersonal)treatment,onthe basisofacomparisonoftheirefficacy,safety,suitabilityandcost.Thisprocessof choosingyourPtreatmentissummarizedinthischapteranddiscussedinmore detailinPart2ofthismanual. Specifyyourtherapeuticobjective InthisexamplewearechoosingourPtreatmentforthesuppressionofdrycough. Makeaninventoryofpossibletreatments Ingeneral,therearefourpossibleapproachestotreatment:informationoradvice; treatmentwithoutdrugs;treatmentwithadrug;andreferral.Combinationsare alsopossible. Fordrycough, informationandadvicecanbegiven,explainingthatthemucous membrane will not heal because of the cough and advising a patient to avoid further irritation, such as smoking or traffic exhaust fumes. Specific nondrug treatmentforthisconditiondoesntexist,butthereareafewdrugstotreatadry cough.Youshouldmakeyourpersonalselectionwhilestillinmedicalschool,and then get to know these P(ersonal) drugs Cartoon1 thoroughly. In the case of dry cough an opioid cough suppressant or a sedative antihistamine could be considered as potential Pdrugs. The last therapeutic possibility is to refer the patient for further analysis and treatment. For an initial treatmentofdrycoughthisisnotnecessary. In summary, treatment of dry cough may consist of advice to avoid irritation of the lungs,and/orsuppressionofthecoughbya drug. Choose your Ptreatment on the basis of efficacy,safety,suitabilityandcost The next stage is to compare the various treatment alternatives. To do this in a scientific and objective manner you need to consider four criteria: efficacy, safety, suitabilityandcost.
If thepatient iswillingandabletofollow advice toavoid lungirritation from smoking or other causes, this will be therapeutically effective, since the inflammationofthemucousmembranewillsubsidewithinafewdays.Itisalso safe and cheap. However, the discomfort of nicotine withdrawal may cause habituatedsmokerstoignoresuchadvice. Opioid cough depressants, such as codeine, noscapine, pholcodine, dextromethorfan and the stronger opiates such as morphine, diamorphine and methadone, effectively suppress the cough reflex. This allows the mucous membranetoregenerate,althoughtheeffectwillbelessifthelungscontinuetobe irritated.Themostfrequentsideeffectsareconstipation,dizzinessandsedation.In highdosestheymayevendepresstherespiratorycentre.Whentakenforalong timetolerancemaydevelop.Sedativeantihistamines,suchasdiphenhydramine, are used as the cough depressant component of many compound cough preparations;alltendtocausedrowsinessandtheirefficacyisdisputed. Weighingthesefactsisthemostdifficultstep,andonewhereyoumustmakeyour owndecisions.Althoughtheimplicationsofmostdataarefairlyclear,prescribers workinvaryingsociocultural contextsandwithdifferenttreatment alternatives available.Sotheaimofthismanualistoteachyouhow,andnotwhat,tochoose, withinthepossibilitiesofyourhealthcaresystems. Inlookingatthesetwodruggroupsonehastoconcludethattherearenotmany alternativesavailablefortreatingdrycough.Infact,manyprescriberswouldargue thatthereishardlyanyneedforsuchdrugs.Thisisespeciallytrueforthemany coughandcoldpreparationsthatareonthemarket.However,forthesakeofthis example, we may conclude that an unproductive, dry cough can be very inconvenient, and that suppressing such a cough for a few days may have a beneficialeffect.Onthegroundsofbetterefficacywewouldthenpreferadrug fromthegroupofopioids. Withinthisgroup,codeineisprobablythebestchoice.Itisavailableastabletsand syrup.Noscapinemayhaveteratogenicsideeffects;itisnotincludedintheBritish NationalFormularybutisavailableinothercountries.Pholcodineisnotavailable astablets.NeitherofthetwodrugsareontheWHOModelListofEssentialDrugs. Thestrongeropiatesaremainlyindicatedinterminalcare. Onthebasisofthesedatawewouldproposethefollowingfirstchoicetreatment (yourPtreatment).Formostpatientswithadrycoughafteracold,advicewillbe effectiveifitispracticalandacceptableforthepatient'scircumstances.Adviceis certainlysaferandcheaperthan drugs, but ifthepatientisnotbetterwithina week,codeinecanbeprescribed.Ifthedrugtreatmentisnoteffectiveafterone week,thediagnosis shouldbereconsideredandpatientadherence totreatment verified. CodeineisourPdrugfordrycough.Thestandarddoseforadultswouldbe30 60mg 34 times daily (British National Formulary). Noscapine and pholcodine couldbeanalternative.
Chapter1
The process of rational prescribing

Now that we have defined our Ptreatment for dry cough, we can review the processofrationalprescribingasawhole.Thisprocessconsistsofsixsteps,eachof whichisdiscussedbriefly,usingtheexampleofourpatientwithadrycough.Each stepisexplainedindetailinPart3. Step1:Definethepatient'sproblem Thepatient'sproblemcanbedescribedasapersistentdrycoughandasorethroat. Thesearethesymptomsthatmattertothepatient;butfromthedoctor'sviewpoint there might be other dangers and concerns. The patient's problem could be translatedintoaworkingdiagnosisofpersistentdrycoughfortwoweeksaftera cold.Thereareatleastthreepossiblecauses.Themostlikelyisthatthemucous membrane of the bronchial tubes is affected by the cold and therefore easily irritated. A secondary bacterial infection is possible but unlikely (no fever, no greenoryellowishsputum).Itisevenlessprobablethatthecoughiscausedbya lungtumour,althoughthatshouldbeconsideredifthecoughpersists. Step2:Specifythetherapeuticobjective Continuous irritation ofthemucous membranes isthemostlikelycause of the cough. The first therapeutic objective is therefore to stop this irritation by suppressingthecough,toenablethemembranestorecover. Step3:VerifywhetheryourPtreatmentissuitableforthispatient YouhavealreadydeterminedyourP(ersonal)treatment,themosteffective,safe, suitableandcheaptreatmentfordrycoughingeneral.Butnowyouhavetoverify whether your Ptreatment is also suitable for this particular patient: is the treatmentalsoeffectiveandsafeinthiscase? Inthisexampletheremaybereasonswhythisadviceisunlikelytobefollowed. Thepatientwillprobablynotstopsmoking.Evenmoreimportant,heisataxi driverandcannotavoidtrafficfumesinthecourseofhiswork.Soalthoughadvice should still be given, your Pdrug should also be considered, and checked for suitability.Isiteffective,andisitsafe? Codeineiseffective,anditisnotinconvenient totakeafewtabletseveryday. However,thereisaproblemwithsafetybecausethepatientisataxidriverand codeinehasasedativeeffect.Forthisreasonitwouldbepreferabletolookfora coughdepressantwhichisnotsedative. Ourtwoalternativeswithinthegroupofopiates(noscapine,pholcodine)sharethe samesideeffect;thisisoftenthecase.Theantihistaminesareevenmoresedative andprobablynoteffective.Wemustthereforeconcludethatitisprobablybetter nottoprescribeanydrugatall.Ifwestillconsiderthatadrugisneeded,codeine remainsthebestchoicebutinaslowadosageaspossible,andforafewdaysonly.
10
Chapter1
11
Step4:Startthetreatment Theadviceshouldbegivenfirst,withanexplanationofwhyitisimportant.Be briefandusewordsthepatientcanunderstand.Thencodeinecanbeprescribed: R/codeine15mg;10tablets;1tablet3timesdaily;date;signature;name,address andageofthepatient,andtheinsurancenumber(ifapplicable).Writeclearly! Step5:Giveinformation,instructionsandwarnings Thepatientshouldbeinformedthatcodeinewillsuppressthecough,thatitworks within23hours,thatitmaycauseconstipation,andthatitwillmakehimsleepyif hetakestoomuchofitordrinksanyalcohol.Heshouldbeadvisedtocomebackif the cough does not go within one week, or if unacceptable side effects occur. Finallyheshouldbeadvisedtofollowthedosagescheduleandwarnednottotake alcohol. It's a good idea to ask him to summarize in his own words the key information,tobesurethatitisclearlyunderstood. Step6:Monitor(stop)thetreatment Ifthepatientdoesnotreturn,heisprobablybetter.Ifthereisnoimprovementand he does come back there are three possible reasons: (1) the treatment was not effective;(2)thetreatmentwasnotsafe,e.g.becauseofunacceptablesideeffects; or (3) the treatment was not convenient, e.g. the dosage schedule was hard to followorthetasteofthetabletswasunpleasant.Combinationsarealsopossible. If the patient's symptoms continue, you will need to consider whether the diagnosis,treatment,adherencetotreatmentandthemonitoringprocedurewere allcorrect.Infactthewholeprocessstartsagain.Sometimestheremaybenoend solutiontotheproblem. Forexample,inchronic diseasessuchashypertension, carefulmonitoringandimprovingpatientadherencetothetreatmentmaybeall thatyoucando.Insomecasesyouwillchangeatreatmentbecausethetherapeutic focusswitchesfromcurativetopalliativecare,asinterminalcancerorAIDS.
Conclusion
So,whatatfirstseemsjustasimpleconsultationofonlyafewminutes,infact requiresaquitecomplexprocessofprofessionalanalysis.Whatyoushouldnotdo iscopythedoctorandmemorizethatdrycoughshouldbetreatedwith15mg codeine3timesdailyforthreedayswhichisnotalwaystrue.Instead,buildyour clinicalpracticeonthecoreprinciplesofchoosingandgivingatreatment,which have been outlined. The process is summarized below and each step is fully describedinthefollowingchapters.
12
Chapter1
Summary
The process of rational treatment

Step1: Step2: Step3: Step4: Step5: Step6: Definethepatient'sproblem Specifythetherapeuticobjective Whatdoyouwanttoachievewiththetreatment? VerifythesuitabilityofyourPtreatment Checkeffectivenessandsafety Startthetreatment Giveinformation,instructionsandwarnings Monitor(andstop?)treatment
13
14
Part2
SelectingyourP(ersonal)drugs
art 2: Selecting your P(ersonal) drugs
This section teaches you how to choose your personal selection of drugs (called Pdrugs). It explainstheprinciplesofdrugselectionandhowto usetheminpractice.Chapter2explainswhyyou should develop your own list of Pdrugs. It also tellsyouhownottodoit.Chapter3givesadetailed example of selecting Pdrugs in a rational way. Chapter4providesthetheoreticalmodelwithsome criticalconsiderations,andsummarizestheprocess. Chapter5describesthedifferencebetweenPdrug and Ptreatment: not all health problems need treatmentwithdrugs. When selecting your Pdrugs you may need to revise some of the basic principles of pharmacology,whicharesummarizedinAnnex1.
Chapter 2 Chapter 3
page IntroductiontoPdrugs................................................................................................14
Example:anginapectoris.............................................................................................16
Chapter 4
GuidelinesforselectingPdrugs.................................................................................22 Stepi: Stepii: Stepiii: Stepiv: Stepv: Definethediagnosis.......................................................................................................22 Specifythetherapeuticobjective..........................................................................22 Makeaninventoryofeffectivegroupsofdrugs......................................23 Chooseaneffectivegroupaccordingtocriteria.......................................23 ChooseaPdrug.................................................................................................................26
Chapter 5
15
PdrugandPtreatment................................................................................................29
16
Chapter2
IntroductiontoPdrugs
C hapter 2
Introduction to P-drugs
As a doctor you may see 40 patients per day or more, many of whom need treatment with a drug. How do you manage to choose the right drug for each patientinarelativelyshorttime?ByusingPdrugs!Pdrugsarethedrugsyouhave chosentoprescriberegularly,andwithwhichyouhavebecomefamiliar.Theyare yourprioritychoiceforgivenindications. ThePdrugconceptismorethanjustthenameofapharmacologicalsubstance,it alsoincludesthedosageform,dosagescheduleanddurationoftreatment.Pdrugs will differ from country to country, and between doctors, because of varying availabilityandcostofdrugs,differentnationalformulariesandessentialdrugs lists,medicalculture,andindividualinterpretationofinformation.However,the principleisuniversallyvalid.Pdrugsenableyoutoavoidrepeatedsearchesfora gooddrugindailypractice.And,asyouuseyourPdrugsregularly,youwillget to know their effects and side effects thoroughly, with obvious benefits to the patient. Pdrugs,essentialdrugsandstandardtreatmentguidelines YoumaywonderwhattherelationisbetweenyoursetofPdrugsandtheWHO ModelListofEssentialDrugsorthenationallistofessentialdrugs,andexisting standardtreamentguidelines. Ingeneral,thelistofdrugsregisteredforuseinthecountryandthenationallistof essential drugs contain many more drugs than you are likely to use regularly. Mostdoctorsuseonly4060drugsroutinely. Itisthereforeusefultomakeyour ownselectionfromtheselists,andtomakethisselectioninarationalway.Infact, indoingsoyouarepreparingyourownessentialdrugslist.Chapter4contains detailedinformationontheprocessofselection. Institutional, national and international (including WHO) standard treatment guidelineshavebeendevelopedtodealwiththemostcommonconditions,suchas acute respiratory tract infections, diarrhoeal diseases and sexually transmitted diseases. They are based on good scientific evidence and consensus between experts.Forthesereasonstheyareavaluabletoolforrationalprescribingandyou shouldconsiderthemverycarefullywhenchoosingyourPdrugs.Inmostcases youwillwanttoincorporatetheminyourpractice. PdrugsandPtreatment
17
ThereisadifferencebetweenPdrugsandPtreatment.Thekeypointisthatnotall diseasesneedtobetreatedwithadrug.NoteveryPtreatmentincludesaPdrug! The concept of choosing a Ptreatment was already introduced in the previous chapter.TheprocessofchoosingaPdrugisverysimilarandwillbediscussedin thefollowingchapters. HownottocompileyourlistofPdrugs Insteadofcompilingyourownlist,oneofthemostpopularwaystomakealistof Pdrugsisjusttocopyitfromclinicalteachers,orfromexistingnationalorlocal treatmentguidelinesorformularies.Therearefourgoodreasonsnottodothis. 3 Youhavefinalresponsibilityforyourpatient'swellbeingandyoucannotpass this on to others. While you can and should draw on expert opinion and consensusguidelines,youshouldalwaysthinkforyourself.Forexample,ifa recommended drug is contraindicated for a particular patient, you have to prescribe another drug. If the standard dosage is inappropriate, you must adapt it. If you do not agree with a particular drug choice or treatment guideline in general, prepare your case and defend your choice with the committee that prepared it. Most guidelines and formularies are updated regularly. 3 ThroughdevelopingyourownsetofPdrugsyouwilllearnhowtohandle pharmacological concepts and data. This will enable you to discriminate betweenmajorandminorpharmacologicalfeaturesofadrug,makingitmuch easier foryou to determine its therapeutic value. It will also enable you to evaluateconflictinginformationfromvarioussources. 3 ThroughcompilingyourownsetofPdrugsyouwillknowthealternatives whenyourPdrugchoicecannotbeused,forexamplebecauseofseriousside effectsorcontraindications,orwhenyourPdrugisnotavailable.Thesame applies whenarecommended standard treatment cannot beused.With the experiencegainedinchoosingyourPdrugsyouwillmoreeasilybeableto selectanalternativedrug. 3 You willregularly receive information on new drugs, new side effects, new indications, etc. However, remember that the latest and the most expensive drug is not necessarily the best, the safest or the most costeffective. If you cannot effectively evaluate such information you will not be able to update yourlist,andyouwillendupprescribingdrugsthataredictatedtoyouby yourcolleaguesorbysalesrepresentatives.
18
Chapter3
ExampleofselectingaPdrug:anginapectoris
C hapter 3
Example of selecting a P-drug: angina pectoris
Example:patient2 Youareayoungdoctor,andoneofyourfirstpatientsisa60yearold man,withnopreviousmedicalhistory.Duringthelastmonthhehas had several attacks of suffocating chest pain, which began during physicallabouranddisappearedquicklyafterhe stopped.Hehasnot smoked for four years. His father and brother died of a heart attack. Apart from occasionally taking some aspirin he has not used any medicationinthepastyear.Auscultationrevealsamurmuroverthe rightcarotidarteryandtherightfemoralartery.Physicalexamination reveals no other abnormalities. Blood pressure is 130/85, pulse 78 regular,andbodyweightisnormal. Youarefairlysureofthediagnosis,anginapectoris,andexplainthe natureofthisdiseasetohim.Thepatientlistenscarefullyandasks:But, whatcanbedoneaboutit?.Youexplainthattheattacksareusually selflimiting,butthattheycanalsobestoppedbydrugs.Heresponds Well,that'sexactlywhatIneed.Youtendtoagreethathemightneed adrug,butwhich?Atenolol, glyceryltrinitrate,furosemide,metoprolol, verapamil, haloperidol (no, no that's something else) all cross your mind.Whattodonow?YouconsiderprescribingCordacor 1,because youhavereadsomethingaboutitinanadvertisement.Butwhichdose? Youhavetoadmitthatyouarenotverysure. Later at home you think about the case, and about your problem in finding the right drug for the patient. Angina pectoris is a common condition, and you decide to choose a Pdrug to help you in the treatmentoffuturecases.
ChoosingaPdrugisaprocessthatcanbedividedintofivesteps(Table1).Many ofthesearerathersimilartothestepsyouwentthroughintreatingthepatient withcoughinChapter1.However,thereisanimportantdifference.InChapter1 youhavechosenadrugforanindividualpatient;inthischapteryouwillchoosea drugoffirstchoiceforacommoncondition,withoutaspecificpatientinmind.
Afictitiousbrandname
19
Eachofthestepsisdiscussedindetailbelow,followinganexampleofchoosinga Pdrugforanginapectoris.
20
Chapter3
Table 1:
Steps in choosing a P-drug

i ii iii iv v Definethediagnosis Specifythetherapeuticobjective Makeaninventoryofeffectivegroupsofdrugs Chooseaneffectivegroupaccordingtocriteria ChooseaPdrug
Stepi:Definethediagnosis
Anginapectorisisasymptomratherthanadiagnosis. Itcanbesubdividedinto classicanginapectorisorvariantanginapectoris;itmayalsobedividedintostable andunstable.Bothaspectshaveimplicationsforthetreatment.Youcouldspecify the diagnosis of patient 2 as stable angina pectoris, caused by a partial (arteriosclerotic)occlusionofthecoronaryarteries.
Stepii:Specifythetherapeuticobjective
Anginapectoris canbepreventedandtreated,andpreventive measures canbe veryeffective.However,inthisexamplewelimitourselvestotreatmentonly. In thatcasethetherapeuticobjectiveistostopanattackassoonasitstarts.Asangina pectoris is caused by an imbalance in oxygen need and supply in the cardiac muscle,eitheroxygensupplyshouldbeincreasedoroxygendemandreduced.Itis difficulttoincreasetheoxygensupplyinthecaseofascleroticobstructioninthe coronaryartery,asastenosiscannotbedilatedwithdrugs.Thisleavesonlyone otherapproach:toreducetheoxygenneedofthecardiacmuscle.Sinceitisalife threateningsituationthisshouldbeachievedassoonaspossible. Thistherapeuticobjectivecanbeachievedinfourways:bydecreasingthepreload, thecontractility,theheartrateortheafterloadofthecardiacmuscle.Thesearethe fourpharmacologicalsitesofaction.2
Stepiii:Makeaninventoryofeffectivegroupsofdrugs
Thefirstselectioncriterionforanygroupofdrugsisefficacy.Inthiscasethedrugs mustdecreasepreload,contractility,frequencyand/orafterload.Therearethree groupswithsuchaneffect:nitrates,betablockersandcalciumchannelblockers. ThesitesofactionaresummarizedinTable2.
Ifyoudonotknowenoughaboutpathophysiologyofthediseaseorofthepharmacologicalsitesofaction,you needtoupdateyourknowledge.Youcouldstartbyreviewingyourpharmacologynotesortextbook;forthis exampleyoushouldprobablyalsoreadafewparagraphsonanginapectorisinamedicaltextbook.
21
Table 2:
Sites of action for drug groups used in angina pectoris

Preload Contractility ++ ++ Frequency ++ ++ Afterload ++ ++ ++
Nitrates Betablockers Calciumchannelblockers
++ + +
Stepiv:Chooseaneffectivegroupaccordingtocriteria
The pharmacological action of these three groups needs further comparison. Duringthisprocess,threeothercriteriashouldbeused:safety,suitabilityandcost oftreatment.TheeasiestapproachistolistthesecriteriainatableasinTable3.Of course,efficacyremainsoffirstimportance.Costoftreatmentisdiscussedlater. Efficacyisnotbasedonpharmacodynamicsalone.Thetherapeuticobjectiveisthat the drug should work as soon as possible. Pharmacokinetics are therefore importantaswell.Allgroupscontaindrugsordosageformswitharapideffect. Safety Alldruggroupshavesideeffects,mostofwhichareadirectconsequenceofthe workingmechanismofthedrug.Inthethreegroups,thesideeffectsaremoreor lessequallyserious,althoughatnormaldosagesfewseveresideeffectsaretobe expected. Suitability Thisisusuallylinkedtoanindividualpatientandsonotconsideredwhenyou makeyourlistofPdrugs.However,youneedtokeepsomepracticalaspectsin mind.Whenapatientsuffersanattackofanginapectoristhereisusuallynobody around to administer a drug by injection, so the patient should be able to administer the drug alone. Thus, the dosage form should be one that can be handledbythepatientandshouldguaranteearapideffect.Table3alsoliststhe availabledosageformswitharapideffectinthethreedruggroups.Allgroups containdrugs thatare available asinjectables,but nitrates are alsoavailable in sublingual forms (sublingual tablets and oromucosal sprays). These are equally effectiveandeasytohandle,andthereforehaveanadvantageintermsofpractical administrationbythepatient. Costoftreatment Pricesdifferbetweencountries,andaremorelinkedtoindividualdrugproducts thantodruggroups. InTable4,indicativepricesfordrugswithinthegroupof nitrates, as given in the British National Formulary of March 1994, have been
22
Chapter3
includedforthesake oftheexample. As youcanseefromthe table, thereare considerable price differences within the group. In general, nitrates are inexpensive drugs, available as generic products. You should checkwhetherin yourcountrynitratesaremoreexpensivethanbetablockersorcalciumchannel blockers,inwhichcasetheymaylosetheiradvantage.
Table 3:
Comparison between the three drug groups used in angina pectoris

Efficacy Safety Suitability Sideeffects Contraindications Contraindictions Cardiacfailure,hypotension, raisedintracranialpressure
Nitrates
Pharmacodynamics Peripheralvasodilatation Flushing,headaches, Cardiacfailure,hypo Tolerance(especiallywith constantbloodlevels) Nitratepoisoningdueto
Sideeffects Flushing,headaches, temporarytachycardia
Nitratepoisoningduetolong lastingoraldosage longlastingoraldosage Anaemia
Anaemia
Pharmacokinetics Highfirstpassmetabolism Varyingabsorptioninthe alimentarytract(lessin mononitrates) Fasteffectdosageforms:
Glyceryltrinitrateisvolatile: tabletscannotbekeptlong oromucosalspray Injection,sublingualtablet, Betablockers Sideeffects Contraindications
Fasteffectdosageforms: Injection,sublingualtablet, oromucosalspray
Hypotension,congestive Hypotension,congestive
23
GuidetoGoodPrescribing Pharmacodynamics Sideeffects Sinusbradycardia,AVblock sicksinussyndrome Reducedheartcontractility Reducedheartfrequency Provocationofasthma Asthma Bradycardia,AVblock, Hypotension,congestiveheart failure Sinusbradycardia,AVblock Coldhandandfeet Hypoglycaemia Raynaudsdisease Diabetes Bronchoconstriction,muscle vasoconstriction,inhibited glycogenolysis Lessvasodilatationinpenis Impotence Pharmacokinetics Lipophilicityincreasespassage throughbloodbrainbarrier Drowsiness,decreased Liverdysfunction reactions,nightmares Fasteffectdosageforms: Injection Calciumchannelblockers Pharmacodynamics Sideeffects Sideeffects Contraindications Coronaryvasodilatation Peripheralvasodilatation (afterload) Reducedheartcontractility Reducedheartfrequency Tachycardia,dizziness, Hypotension Tachycardia,dizziness, flushing,hypotension Congestiveheartfailure Sinusbradycardia,AVblock flushing,hypotension Hypotension Congestiveheartfailure AVblock,sicksinus syndrome Fasteffectdosageforms: Injection Congestiveheartfailure Congestiveheartfailure Contraindictions Fasteffectdosageforms: Injection Provocationofasthma Coldhandsandfeet Hypoglycaemia Impotence Asthma Raynaudsdisease Diabetes Hypotension,congestive heartfailure Bradycardia,AVblock,sick sinussyndrome Contraindications
Drowsiness,decreased reactions,nightmares
Liverdysfunction
Table 4:
Comparison between drugs within the group of nitrates
24
Chapter3 Efficacy NB:volatile 0.530min 0.57hours 124hours NB:tolerance 230min 0.54hours 0.510hours NB:tolerance 15hours 0.54hours 110hours NB:tolerance
ExampleofselectingaPdrug:anginapectoris Safety Nodifference between individual nitrates Suitability Nodifference between individual nitrates Cost/100 ()* 0.290.59 3.25428 42.0077.00
Glyceryltrinitrate Sublingualtab0.41mg Oraltab2.6mg,cap12.5mg Transdermalpatch1650mg Isosorbidedinitrate Sublingualtab5mg Oraltab1020mg Oraltab(retard)2040mg Pentaeritritoltetranitrate Oraltab30mg Isosorbidemononitrate Oraltab1040mg Oraltab/caps(retard)
1.451.51 1.102.15 9.5218.95
4.45 5.7013.30 25.0040.82
*Indicativepricesonly,basedonpricesgivenintheBritishNationalFormularyofMarch1994
Aftercomparingthethreegroupsyoumayconcludethatnitratesarethegroupof first choice because, with acceptable efficacy and equal safety, they offer the advantagesofanimmediateeffectandeasyhandlingbythepatient,atnoextra cost.
Stepv:ChooseaPdrug
Chooseanactivesubstanceandadosageform Notallnitratescanbeusedinacuteattacks,assomearemeantforprophylactic treatment.Ingeneral,threeactivesubstancesareavailableforthetreatmentofan acute attack: glyceryl trinitrate (nitroglycerin), isosorbide mononitrate and isosorbidedinitrate(Table4).Allthreeareavailableinsublingualtabletswitha rapid effect. In some countries an oromucosal spray of glyceryl trinitrate is availableaswell.Theadvantageofsuchspraysisthattheycanbekeptlonger;but theyaremoreexpensivethantablets. Thereisnoevidenceofadifferenceinefficacyandsafetybetweenthethreeactive substancesinthisgroup.Withregardtosuitability,thethreesubstanceshardly differincontraindicationsandpossibleinteractions.Thismeansthattheultimate choicedependsoncost.Costmaybeexpressedascostperunit,costperday,or costpertotaltreatment.AscanbeseenfromTable4,costsmayvaryconsiderably. Sincetabletsarecheapestinmostcountries,thesemightwellbeyourfirstchoice. InthiscasetheactivesubstanceforyourPdrugofchoiceforanattackofangina pectoriswouldbe:sublingualtabletsofglyceryltrinitrate1mg.
25
Chooseastandarddosageschedule As the drug is to be taken during an acute attack, there is no strict dosage schedule.Thedrugshouldberemovedfromthemouthassoonasthepainisgone. Ifthepainpersists,asecondtabletcanbetakenafter510minutes.Ifitcontinues even after a second tablet, the patient should be told to contact a doctor immediately. Chooseastandarddurationofthetreatment Thereisnowaytopredicthowlongthepatientwillsufferfromtheattacks,sothe duration of the treatment should be determined by the need for followup. In generalonlyasmallsupplyofglyceryltrinitratetabletsshouldbeprescribedas theactivesubstanceisrathervolatileandthetabletmaybecomeineffectiveafter sometime. Ifyouagreewiththischoice,glyceryltrinitratesublingualtabletswouldbethe first Pdrug of your personal formulary. If not, you should have enough informationtochooseanotherdruginstead.
Summary
Example of selecting a P-drug: angina pectoris

i. Definethediagnosis ii. Specifytherapeuticobjective Stable angina pectoris, caused by a partial occlusionofcoronaryartery Stopanattackassoonaspossible Reducemyocardialoxygenneedbydecreasing preload,contractility,heartrateorafterload
iii. Makeinventoryofeffectivegroups Nitrates blockers Calciumchannelblockers iv. Chooseagroupaccording tocriteria efficacy Nitrates(tablet) + Betablockers(injection) + Calciumchannelblockers(injection) + v. ChooseaPdrug Glyceryltrinitrate(tablet) (spray) Isosorbidedinitrate(tablet) Isosorbidemononitrate(tablet) Conclusion efficacy + + + +
safety safety
suitability ++ suitability + (+) + +
cost + cost +
26
Chapter3
Activesubstance,dosageform: Dosageschedule: Duration:
glyceryltrinitrate,sublingualtablet1mg 1tabletasneeded;secondtabletifpainpersists lengthofmonitoringinterval
27
C hapter 4
Guidelines for selecting P-drugs
The previous chapter gave an example of choosing a Pdrug for the treatment of acute angina pectoris, on the basis of efficacy, safety, suitability and cost. This chapter presents more general information on each of the five steps.
Cartoon2
Step i: Define the diagnosis

When selecting a Pdrug, it is important to remember that you arechoosingadrugoffirstchoice for a common condition. You are not choosing a drug for an individual patient (when actually treating a patient you will verify whetheryourPdrugissuitablefor thatparticularcaseseeChapter8). To be able to select the best drug for a given condition, you should study the pathophysiologyofthedisease. Themoreyouknowaboutthis,theeasieritisto choose a Pdrug. Sometimes the physiology of the disease is unknown, while treatmentispossibleandnecessary. Treatingsymptomswithoutreallytreatingthe underlyingdiseaseiscalledsymptomatictreatment. When treating an individual patient you should start by carefully defining the patientsproblem(seeChapter6).WhenselectingaPdrugyouonlyhavetochoose acommonproblemtostarttheprocess.
Step ii: Specify the therapeutic objective

It is very useful to define exactly what you want to achieve with a drug, for example, to decrease the diastolic blood pressure to a certain level, to cure an infectiousdisease,ortosuppressfeelingsofanxiety.Alwaysrememberthatthe (patho)physiology determines the possible site of action of your drug and the
28
Chapter4
GuidelinesforselectingPdrugs
maximum therapeutic effect that you can achieve. The better you define your therapeuticobjective,theeasieritistoselectyourPdrug.
Step iii: Make an inventory of effective groups of drugs

Inthisstepyoulinkthetherapeuticobjectivetovariousdrugs.Drugsthatarenot effectivearenotworthexamininganyfurther,soefficacyisthefirstcriterionfor selection. Initially, you should look at groups of drugs rather than individual drugs. There are tens of thousands of different drugs, but only about 70 pharmacologicalgroups!Alldrugswiththesameworkingmechanism(dynamics) andasimilarmolecularstructurebelongtoonegroup.Astheactivesubstancesin a drug group have the same working mechanism, their effects, side effects, contraindications and interactions are also similar. The benzodiazepines, beta blockersandpenicillinsareexamplesofdruggroups.Mostactivesubstancesina groupshareacommonstemintheirgenericname,suchasdiazepam,lorazepam and temazepam for benzodiazepines, and propranolol and atenolol for beta blockers. Therearetwowaystoidentifyeffectivegroupsofdrugs.Thefirstistolookat formularies or guidelines that exist in your hospital or health system, or at international guidelines, such as the WHO treatment guidelines for certain commondiseasegroups,ortheWHOModelListofEssentialDrugs.Anotherway istochecktheindexofagoodpharmacologyreferencebookanddeterminewhich groupsarelistedforyourdiagnosisortherapeuticobjective.Inmostcasesyouwill findonly24groupsofdrugswhichareeffective.InAnnex2varioussourcesof informationondrugsandtherapeuticsarelisted. Exercise Look at a number of advertisements for new drugs. You will be surprisedathowveryfewofthese'new'drugsarerealinnovations andbelongtoadruggroupthatisnotalreadyknown.
Step iv: Choose an effective group according to criteria

Tocomparegroupsofeffectivedrugs,youneedinformationon efficacy, safety, suitabilityandcost(Tables3and4).Suchtablescanalsobeusedwhenyoustudy other diagnoses, or when looking for alternative Pdrugs. For example, beta blockers are used in hypertension, angina pectoris, migraine, glaucoma and arrhythmia. Benzodiazepines are used as hypnotic, anxiolytic and antiepileptic drugs. Althoughtherearemanydifferentsettingsinwhichdrugsareselected,thecriteria for selection are more or less universal. The WHO criteria for the selection of essentialdrugsaresummarizedinBox2. Efficacy This column in Table 3 (Chapter 3) shows data on pharmacodynamics and pharmacokinetics. In order to be effective, the drug has to reach a minimum
29
plasmaconcentrationandthekineticprofileofthedrugmustallowforthiswith aneasydosageschedule.Kineticdataonthedruggroupasawholemaynotbe availableastheyarerelatedtodosageformandproductformulation,butinmost casesgeneralfeaturescanbelisted.Kineticsshouldbecomparedonthegrounds of Absorption, Distribution, Metabolism and Excretion (ADME factors, see Annex1). Box 2: Criteria for the selection of essential drugs (WHO)
Priorityshouldbegiventodrugsofprovenefficacyandsafety,inordertomeettheneedsof the majority of the people. Unnecessary duplication of drugs and dosage forms should be avoided. Onlythosedrugsforwhichadequatescientificdataareavailablefromcontrolledclinicaltrials and/or epidemiologicalstudiesandforwhichevidence ofperformance ingeneraluse ina varietyofsettingshasbeenobtained,shouldbeselected.Newlyreleasedproductsshouldonly beincludediftheyhavedistinctadvantagesoverproductscurrentlyinuse. Eachdrugmustmeetadequatestandardsofquality,includingwhennecessarybioavailability, andstabilityundertheanticipatedconditionsofstorageanduse. Theinternationalnonproprietaryname(INN,genericname)ofthedrugshouldbeused.This istheshortenedscientificnamebasedontheactiveingredient.WHOhastheresponsibilityfor assigningandpublishingINNsinEnglish,French,Latin,RussianandSpanish. Thecostoftreatment,andespeciallythecost/benefitratioofadrugoradosageform,isa majorselectioncriterion. Wheretwoormoredrugsappeartobesimilar,preferenceshouldbegivento(1)drugswhich havebeenmostthoroughlyinvestigated;(2)drugswiththemostfavourablepharmacokinetic properties;and(3)drugsforwhichreliablelocalmanufacturingfacilitiesexist. Most essential drugs should be formulated as single compounds. Fixedratio combination productsareonlyacceptablewhenthedosageofeachingredientmeetstherequirementsofa defined population group and when the combination has a proven advantage over single compoundsadministeredseparatelyintherapeuticeffect,safety,complianceorcost.
Safety This column summarizes possible side effects and toxic effects. If possible, the incidenceoffrequentsideeffectsandthesafetymarginsshouldbelisted.Almost allsideeffectsaredirectlylinkedtotheworkingmechanismofthedrug,withthe exceptionofallergicreactions. Suitability Although the final check will only be made with the individual patient, some general aspects of suitability can be considered when selecting your Pdrugs. Contraindicationsarerelatedtopatientconditions,suchasotherillnesseswhich makeitimpossibletouseaPdrugthatisotherwiseeffectiveandsafe.Achangein 30
Chapter4
the physiology of your patient may influence the dynamics or kinetics of your Pdrug:therequiredplasmalevelsmaynotbereached,ortoxicsideeffectsmay occuratnormalplasmaconcentrations.Inpregnancyorlactation,thewellbeingof the child has to be considered. Interactions with food or other drugs can also strengthenordiminishtheeffectofadrug. Aconvenientdosageformordosage schedulecanhaveastrongimpactonpatientadherencetothetreatment. All these aspects should be taken into account when choosing a Pdrug. For example,intheelderlyandchildrendrugsshouldbeinconvenientdosageforms, suchastabletsorliquidformulations thatareeasytohandle. Forurinarytract infections,someofyourpatientswillbepregnantwomeninwhomsulfonamides apossiblePdrugarecontraindicatedinthethirdtrimester.Anticipatethisby choosingasecondPdrugforurinarytractinfectionsinthisgroupofpatients. Costoftreatment Thecostofthetreatmentisalwaysanimportantcriterion,inbothdevelopedand developing countries, and whether it is covered by the state, an insurance companyordirectlybythepatient.Costissometimesdifficulttodeterminefora group of drugs, but you should always keep it in mind. Certain groups are definitelymoreexpensivethanothers.Alwayslookatthetotalcostoftreatment ratherthanthecostperunit.Thecostargumentsreallystartcountingwhenyou choosebetweenindividualdrugs. Thefinalchoicebetweendruggroupsisyourown.Itneedspractice,butmaking thischoiceonthebasisofefficacy,safety,suitabilityandcostoftreatmentmakesit easier.Sometimesyouwillnotbeabletoselectonlyonegroup,andwillhaveto taketwoorthreegroupsontothenextstep.
Box 3:
Efficacy, safety and cost
Efficacy: Mostprescriberschoosedrugsonthegroundsofefficacy,whilesideeffectsare onlytakenintoconsiderationaftertheyhavebeenencountered.Thismeansthattoomany patientsaretreatedwithadrugthatisstrongerormoresophisticatedthannecessary(e.g.the useofwidespectrumantibioticsforsimpleinfections).AnotherproblemisthatyourPdrug may score favourably on an aspect that is of little clinical relevance. Sometimes kinetic characteristicswhichareclinicallyoflittleimportancearestressedtopromoteanexpensive drugwhilemanycheaperalternativesareavailable. Safety:Eachdrughassideeffects,evenyourPdrugs.Sideeffectsareamajorhazardinthe industrializedworld.Itisestimatedthatupto10%ofhospitaladmissionsareduetoadverse drugreactions.Notalldruginducedinjurycanbeprevented,butmuchofitiscausedby inappropriateselectionordosageofdrugs,andyoucanpreventthat.Formanysideeffects, highriskgroups canbe distinguished.Oftenthese areexactly the groupsofpatients you shouldalwaysbeverycarefulwith:theelderly,children,pregnantwomenandthosewith kidneyorliverdisease.
31
Cost:Youridealchoiceintermsofefficacyandsafetymayalsobethemostexpensivedrug, andincaseoflimitedresourcesthismaynotbepossible.Sometimesyouwillhavetochoose betweentreatingasmallnumberofpatientswithaveryexpensivedrug,andtreatingamuch largernumberofpatientswithadrugwhichislessidealbutstillacceptable.Thisisnotan easychoicetomake,butitisonewhichmostprescriberswillface.Theconditionsofhealth insurance and reimbursement schemes may also have tobe considered. The best drug in termsofefficacyandsafetymaynot(oronlypartially)bereimbursed;patientsmayrequest youtoprescribethereimburseddrug,ratherthanthebestone.Wherefreedistributionor reimbursementschemesdonotexist,thepatientwillhavetopurchasethedruginaprivate pharmacy.Whentoomanydrugsareprescribedthepatientmayonlybuysomeofthem,or insufficientquantities.Inthesecircumstancesyoushouldmakesurethatyouonlyprescribe drugsthatarereallynecessary,availableandaffordable.You,theprescriber,shoulddecide whichdrugsarethemostimportant,notthepatientorthepharmacist.
Step v: Choose a P-drug

ThereareseveralstepstotheprocessofchoosingaPdrug. Sometimesshortcuts are possible. Don't hesitate to look for them, but do not forget to collect and considerallessentialinformation,includingexistingtreatmentguidelines. Chooseanactivesubstanceandadosageform Choosinganactivesubstanceislikechoosingadruggroup,andtheinformation canbelistedinasimilarway.Inpracticeitisalmostimpossibletochooseanactive substancewithoutconsideringthedosageformaswell;soconsiderthemtogether. First,theactivesubstanceanditsdosageformhavetobeeffective.Thisismostlya matterofkinetics. Although active substances within one drug group share the same working mechanism,differencesmayexistinsafetyandsuitabilitybecauseofdifferencesin kinetics.Largedifferencesmayexistinconveniencetothepatientandthesewill haveastrong influenceonadherence totreatment. Different dosage forms will usuallyleadtodifferentdosageschedules,andthisshouldbetakenintoaccount whenchoosingyourPdrug.Last,butnotleast,costoftreatmentshouldalwaysbe considered. Price lists may be available from the hospital pharmacy or from a nationalformulary(seeTable4,Chapter3foranexample). Keepinmindthatdrugssoldundergeneric(nonproprietary)nameareusually cheaperthanpatentedbrandnameproducts.Iftwodrugsfromthesamegroup appear equal you could consider which drug has been longest on the market (indicatingwideexperienceandprobablysafety),orwhichdrugismanufactured inyourcountry.Whentwodrugsfromtwodifferentgroupsappearequalyoucan chooseboth.Thiswillgiveyouanalternativeifoneisnotsuitableforaparticular patient.Asafinalcheckyoushouldalwayscompareyourselectionwithexisting treatmentguidelines,thenationallistofessentialdrugs,andwiththeWHOModel ListofEssentialDrugs,whichisreviewedeverytwoyears. Chooseastandarddosageschedule
32
Chapter4
Arecommendeddosagescheduleisbasedonclinicalinvestigationsinagroupof patients. However,thisstatisticalaverageisnotnecessarilytheoptimalschedule foryourindividualpatient. Ifage,metabolism,absorptionandexcretioninyour patientareallaverage,andifnootherdiseasesorotherdrugsareinvolved,the average dosage is probably adequate. The more your patient varies from this average,themorelikelytheneedforanindividualizeddosageschedule. RecommendeddosageschedulesforallPdrugscanbefoundinformularies,desk referencesorpharmacologytextbooks.Inmostofthesereferencesyouwillfind rather vague statements such as 24 times 3090 mg per day. What will you chooseinpractice? The best solution is to copy the different dosage schedules into your own formulary. This willindicatetheminimumandmaximumlimitsofthedosage. When dealing with an individual patient you can make your definitive choice. Some drugs need an initial loading dose to quickly reach steady state plasma concentration.Othersrequireaslowlyrisingdosageschedule,usuallytoletthe patientadapttothesideeffects.Practicalaspectsofdosageschedulesarefurther discussedinChapter8.
33
Box 4:
General characteristics of dosage forms
Systemicdosageforms oral(mixture,syrup,tablet(coated,slowrelease),powder,capsule) sublingual(tablet,aerosol) rectal(suppository,rectiol) inhalation(gasses,vapour) injections(subcutaneous,intramuscular,intravenous,infusion) Localdosageforms skin(ointment,cream,lotion,paste) senseorgan(eyedrops/ointment,eardrops,nosedrops) oral/local(tablets,mixture) rectal/local(suppository,enema) vaginal(tablet,ovule,cream) inhalation/local(aerosol,powder) Oralforms efficacy: ()uncertainabsorptionandfirstpassmetabolism,(+)gradualeffect safety: ()lowpeakvalues,uncertainabsorption,gastricirritation convenience: ()?handling(children,elderly) Sublingualtabletsandaerosols efficacy: (+)actrapidly,nofirstpassmetabolism safety: ()easyoverdose convenience: ()aerosoldifficulttohandle,(+)tabletseasytouse Rectalpreparations efficacy: ()uncertainabsorption,(+)nofirstpassmetabolism,rectiolfasteffect safety: ()localirritation convenience: (+)incaseofnausea,vomitingandproblemswithswallowing Inhalationgassesandvapours efficacy: (+)fasteffect safety: ()localirritation convenience: ()needhandlingbytrainedstaff Injections efficacy: (+)fasteffect,nofirstpassmetabolism,accuratedosagepossible safety: ()overdosepossible,sterilityoftenaproblem convenience: ()painful,needtrainedstaff,morecostlythanoralforms Topicalpreparations efficacy: (+)highconcentrationspossible,limitedsystemicpenetration safety: ()sensitizationincaseofantibiotics,(+)fewsideeffects convenience: ()somevaginalformsdifficulttohandle
Chooseastandarddurationoftreatment WhenyouprescribeyourPdrugtoapatientyouneedtodecidethedurationof thetreatment.Byknowingthepathophysiologyandtheprognosisofthedisease youwillusuallyhaveagoodideaofhowlongthetreatmentshouldbecontinued. Somediseasesrequirelifelongtreatment(e.g.diabetesmellitus,congestivecardiac failure,Parkinson'sdisease).
34
Chapter4
Thetotalamountofadrugtobeprescribeddependsonthedosagescheduleand thedurationofthetreatment.Itcaneasilybecalculated.Forexample,inapatient withbronchitisyoumayprescribepenicillinforsevendays.Youwillonlyneedto seethepatientagainifthereisnoimprovementandsoyoucanprescribethetotal amountatonce. If the duration of treatment is not known, the monitoring interval becomes important. For example, you may request a patient with newly diagnosed hypertensiontocomebackintwoweekssothatyoucanmonitorbloodpressure andanysideeffectsofthetreatment. Inthiscaseyouwouldonlyprescribeforthe twoweek period. As you get to know the patient better you could extend the monitoring interval, say, to one month. Three months should be about the maximummonitoringintervalfordrugtreatmentofachronicdisease.
Summary
How to select a P-drug

i Definethediagnosis(pathophysiology) ii Specifythetherapeuticobjective iii Makeaninventoryofeffectivegroups iv Chooseagroupaccordingtocriteria efficacy safety suitability cost Group1 Group2 Group3 v ChooseaPdrug efficacy safety suitability cost Drug1 Drug2 Drug3 Conclusion: Activesubstance,dosageform: Standarddosageschedule: Standardduration:
35
C hapter 5
P-drug and P-treatment
Notallhealthproblemsneedtreatmentwithdrugs.AsexplainedinChapterl,the treatment can consist of advice and information, nondrug therapy, drug treatments,referralfortreatment,orcombinationsofthese.Makinganinventoryof effectivetreatmentalternativesisespeciallyimportantinordernottoforgetthat nondrugtreatmentisoftenpossibleanddesirable.Neverjumptotheconclusion thatyourPdrugshouldbeprescribed!AswithselectingyourPdrugs,thecriteria ofefficacy,safety,suitabilityandcostshouldbeusedwhencomparingtreatment alternatives.Theexamplesillustratehowthisworksinpractice. Exercise Makealistofpossibleeffectiveandsafetreatmentsforthefollowing common patient problems: constipation, acute diarrhoea with mild dehydrationinachild,andasuperficialopenwound.Thenchoose yourPtreatmentforeach.Theanswersarediscussedbelow. Constipation Constipationisusuallydefinedasafailuretopassstoolsforatleastaweek.The listofpossibleeffectivetreatmentsisasfollows. Adviceandinformation: Drinkalotoffluids,eatfruitandhighfibrefood.Only gotothetoiletwhentheneedisfelt.Donottrytopass stoolsbyforce.Reassurepatientthatnothingpointsto seriousdisease. Physicalexercise. Laxative(yourPdrug). Notindicated.
Nondrugtreatment: Drugtreatment: Referralfortreatment:
Inmanycasesadviceandnondrugtreatmentwillsolvetheproblem.Becauseof tolerance,laxativesareonlyeffectiveforashortperiodandmaythenleadtoabuse and eventually even to electrolyte disturbances. The first treatment plan, your Ptreatment,shouldtherefore beadvice; notdrugs! Iftheconstipation issevere (andtemporary)yourPdrugcouldbeprescribed,e.g.sennatabletsforafewdays. Ifitpersists,furtherexaminationisneededtoexcludeotherdiseases,e.g.acolon carcinoma. Acutewaterydiarrhoeawithmilddehydrationinachild
36
Chapter5
PdrugversusPtreatment
In acute diarrhoea with mild dehydration in a child, the main objective of the treatmentistopreventfurtherdehydration andtorehydrate;thegoalisnotto curetheinfection!Theinventoryofpossibleeffectivetreatmentsistherefore: Adviceandinformation: Nondrugtreatment: Drugtreatment: Referralfortreatment: Continue breast feeding and other regular feeding; carefulobservation. Additional fluids (rice water, fruit juice, homemade sugar/saltsolution). Oralrehydrationsolution(ORS),oralorbynasogastric tube. Notnecessary.
Youradvicewillpreventfurtherdehydration,butwillnotcureit,andextrafluids andORSwillbeneededtocorrectthelossofwaterandelectrolytes.Metronidazole andantibiotics,suchascotrimoxazoleorampicillin,arenotlistedintheinventory becausethesearenoteffectiveintreatingwaterydiarrhoea.Antibioticsareonly indicated for persistent bloody and/or slimy diarrhoea, which is much less common than watery diarrhoea; metronidazole is mainly used for proven amoebiasis.Antidiarrhoealdrugs,suchasloperamideanddiphenoxylate,arenot indicated,especiallyforchildren,astheymaskthecontinuinglossofbodyfluids into the intestines and may give the false impression that something is being done. YourPtreatmentistherefore:advicetocontinuefeedingandtogiveextrafluids (including home made solutions or ORS, depending on the national treatment guidelines),andtoobservethechildcarefully. Superficialopenwound Thetherapeuticobjectiveinthetreatmentofanopenwoundistopromotehealing andtopreventinfection.Theinventoryofpossibletreatmentsis: Adviceandinformation: Nondrugtreatment: Drugtreatment: Referralfortreatment: Regularlyinspectthewound;returnincaseofwound infectionorfever. Cleananddressthewound. Antitetanusprophylaxis. Antibiotics(local,systemic). Notnecessary.
The wound should be cleaned and dressed, and tetanus prophylaxis should probably be given. All patients with an open wound should be warned about possible signs of infection, and to return immediately if these occur. Local antibiotics are never indicated in wound infections because of their low penetrationandtheriskofsensibilization.Systemicantibioticsarerarelyindicated forprophylacticpurposes,exceptinsomedefinedcasessuchasintestinalsurgery. Theywillnotpreventinfection,aspermeabilityintothewoundtissueislow,but theycanhaveserioussideeffects(allergy,diarrhoea)andmaycauseresistance.
37
YourPtreatmentforasuperficialopenwoundisthereforetocleananddressthe wound,giveantitetanusprophylaxis,andadviceonregularwoundinspection.No drugs!
38
Chapter5
PdrugversusPtreatment
Conclusion
These three examples show that for common complaints the treatment of first choice often does not include any drugs. Advice and information are often sufficient, as in the case of constipation. Advice, fluids and rehydration are essentialinthetreatmentofacutewaterydiarrhoea,ratherthanantidiarrhoealsor antibiotics. Dressing and advice are essential in the case of open wounds, not antibiotics. Inmoreseriouscases,e.g.persistentconstipation,seriousdehydrationinasmall child or adeep open wound, referral may be the treatment of choice, and not stronger drugs. Referral can therefore also be your Ptreatment, e.g. when no facilitiesexistforfurtherexaminationortreatment.
39
40
Part3
Treatingyourpatients
art 3: Treating your patients
This part of the book shows you how to treat a patientwithyourPdrugs.Eachstepoftheprocess isdescribedinseparatechapters.Practicalexamples illustratehowtoselect,prescribeandmonitorthe treatment, and how to communicate effectively withyourpatients.When youhavegonethrough thismaterialyouarereadytoputintopracticewhat youhavelearned.
Chapter 6 Chapter 7
page Step1: Definethepatientsproblem......................................................................34
Step2: Specifythetherapeuticobjective...............................................................38
Chapter 8
Step3: VerifythesuitabilityofyourPdrug.........................................................40 3A: Aretheactivesubstanceanddosageformsuitable forthispatient?.......................................................................................41 3B: Isthestandarddosageschedulesuitableforthispatient?................43 3C: Isthestandarddurationoftreatmentsuitableforthispatient?.......47
Chapter 9
Step4: Writeaprescription.....................................................................................51
Chapter 10
Step5: Giveinformation,instructionsandwarnings.........................................56
Chapter 11
Step6: Monitor(andstop?)thetreatment............................................................62
41
42
Chapter7
Step2:Specifythetherapeuticobjective
C hapter 6
STEP 1: Define the patient's problem
A patient usually presents with a complaint or a problem. It is obvious that makingtherightdiagnosisisacrucialstepinstartingthecorrecttreatment. Makingtherightdiagnosisisbasedonintegratingmanypiecesofinformation:the complaint as describedbythe patient;adetailed history; physical examination; laboratory tests; Xrays and other investigations. A discussion on each of these components isoutside the scope ofthis manual. In thenextsectionson (drug) treatmentweshallthereforeassumethatthediagnosishasbeenmadecorrectly. Patients complaints are mostly linked to symptoms. A symptom is not a diagnosis,althoughitwillusuallyleadtoit.Thefollowingfivepatientsallhave thesamecomplaint,asorethroat.Butdotheyallhavethesamediagnosis?Let's lookattheminmoredetail. Exercise:patients37 Define the problem for each of the following patients. The cases are discussedbelow. Patient3: Man,54years.Complainsofaseveresorethroat.Nogeneralsymptoms, nofever,slightrednessinthethroat;nootherfindings. Patient4: Woman,23years.Complainsofasorethroatbutisalsoverytiredand hasenlargedlymphnodesinherneck.Slightfever.Shehascomeforthe resultsoflastweek'slaboratorytests. Patient5: Womanstudent,19years.Complainsofasorethroat.Slightrednessof thethroat;butnofeverandnootherfindings.Sheisalittleshyandhas neverconsultedyoubeforeforsuchaminorcomplaint. Patient6: Man43years.Complainsofasorethroat.Slightrednessofthethroat; nofeverandnootherfindings. Medicalrecordmentionsthathesuffers fromchronicdiarrhoea. Patient7: Woman, 32 years. Very sore throat, caused by a severe bacterial infection,despitepenicillinprescribedlastweek.
43
Patient3(sorethroat) Thesorethroatofpatient3probablyresultsfromaminorviralinfection. Perhaps heisafraidofamoreseriousdisease(throatcancer?). Heneedsreassuranceand advice,notdrugs. Hedoesnotneedantibiotics,becausetheywillnotcureaviral infection. Patient4(sorethroat) HerbloodtestconfirmsyourclinicaldiagnosisofAIDS.Herproblemiscompletely differentfromthepreviouscase,asthesorethroatisasymptomofunderlying disease. Patient5(sorethroat) Younoticedthatshewasrathershyandrememberedthatshehadneverconsulted youbeforeforsuchaminorcomplaint.Youaskhergentlywhattherealtroubleis, and after some hesitation she tells you that she is 3 months overdue. Her real concernhadnothingtodowithherthroat. Patient6(sorethroat) Inthiscase,informationfromthepatientsmedicalrecordisessentialforacorrect understanding of the problem. His sore throat is probably caused by the loperamidehetakesforhischronic diarrhoea. Thisdrugmayproducereduced salivationanddrymouthasasideeffect.Routinetreatmentofasorethroatwould not have solved his problem. You may have to investigate the reason for his chronicdiarrhoea,andconsiderAIDS. Patient7(sorethroat) A careful history of patient 7, whose bacterial infection persists despite the penicillin,revealsthatshestoppedtakingthedrugsafterthreedaysbecauseshe feltmuchbetter. Sheshould,ofcourse,havecompletedthecourse. Herproblem hascomebackbecauseofinadequatetreatment. These examples illustrate that one complaint may be related to many different problems:aneedforreassurance;asignofunderlyingdisease;ahiddenrequest forassistanceinsolvinganotherproblem;asideeffectofdrugtreatment;andnon adherencetotreatment.Sothelessonis:don'tjumptotherapeuticconclusions! Example:patient8 Man,67years.Hecomesforhismedicationforthenexttwomonths.He saysthatheisdoingverywellandhasnocomplaints. Heonlywantsa prescriptionfordigoxin0.25mg(60tablets),isosorbidedinitrate5mg (180 tablets), furosemide 40 mg (60 tablets), salbutamol 4 mg (180 tablets), cimetidine 200 mg (120 tablets), prednisolone 5 mg (120 tablets),andamoxicillin500mg(180tablets). Thispatientstatesthathehasnocomplaints.Butistherereallynoproblem? He may suffer from a heart condition, from asthma and from his stomach, but he definitelyhasoneotherproblem: polypharmacy!Itisunlikelythatheneedsall these drugs. Some may even have been prescribed to cure the side effects of another.Infactitisamiraclethathefeelswell.Thinkofallthepossiblesideeffects 44
Chapter7
and interactions between somany different drugs: hypokalemia by furosemide leadingtodigoxinintoxicationisonlyoneexample. Carefulanalysisandmonitoringwillrevealwhetherthepatientreallyneedsall thesedrugs. Thedigoxinisprobablyneededforhisheartcondition. Isosorbide dinitrateshouldbechangedtosublingualglyceryltrinitratetablets,onlytobeused whenneeded.Youcanprobablystopthefurosemide(whichisrarelyindicatedfor maintenance treatment), or change it to a milder diuretic such as hydrochloro thiazide. Salbutamol tablets could be changed toan inhaler, toreduce the side effectsassociatedwithcontinuoususe.Cimetidinemayhavebeenprescribedfor suspectedstomachulcer,whereasthestomachachewasprobablycausedbythe prednisolone,forwhichthedosecanprobablybereducedanyway. Itcanalsobe changedtoanaerosol.Soyoufirsthavetodiagnosewhetherhehasanulceror not,andifnot,stopthecimetidine.Andfinally,thelargequantityofamoxicillin hasprobablybeenprescribedasapreventionagainstrespiratorytractinfections. However, most microorganisms in his body will now be resistant to it and it should bestopped. If his respiratory problems become acute, ashort course of antibioticsshouldbesufficient.
Box 5:
Patient demand
Apatientmaydemandatreatment,orevenaspecificdrug,andthiscangiveyouahardtime. Somepatientsaredifficulttoconvincethatadiseaseisselflimitingormaynotbewillingto putupwithevenminorphysicaldiscomfort.Theremaybea'hidden'psychosocialproblem, e.g.longtermuseanddependenceonbenzodiazepine.Insomecasesitmaybedifficulttostop thetreatmentbecause psychologicalorphysicaldependenceonthedrugshasbeencreated. Patientdemandforspecificdrugsoccursmostfrequentlywithpainkillers,sleepingpillsand otherpsychotropicdrugs,antibiotics,nasaldecongestants,coughandcoldpreparations,and eye/earmedicines. Thepersonalcharacteristicsandattitudesofyourpatientsplayaveryimportantrole.Patients' expectationsareofteninfluencedbythepast(thepreviousdoctoralwaysgaveadrug),bythe family(thedrugthathelpedAuntSallysomuch),byadvertisementstothepublic,andmany otherfactors.Althoughpatientsdosometimesdemandadrug,physiciansoftenassumesucha demandevenwhenitdoesn'texist.Soaprescriptioniswrittenbecausethephysicianthinks thatthepatientthinks...Thisalsoappliestotheuseofinjections,orstrongdrugsingeneral. Patientdemandforadrugmayhaveseveralsymbolicfunctions.Aprescriptionlegitimizesa patient's complaint as an illness. It may also fulfill the need that something be done, and symbolizethecareofthephysician.Itisimportanttorealizethatthedemandforadrugis muchmorethanademandforachemicalsubstance. Therearenoabsoluterulesabouthowtodealwithpatientdemand,withtheexceptionofone: ensurethatthereisarealdialoguewiththepatientandgiveacarefulexplanation.Youneed goodcommunicationskillstobeagoodphysician.Findoutwhythepatientthinksas(s)he does. Make sure you have understood the patient's arguments, and that the patient has understoodyou.Neverforgetthatpatientsarepartnersintherapy;alwaystaketheirpointof
45
viewseriouslyanddiscusstherationaleofyourtreatmentchoice.Validargumentsareusually convincing,providedtheyaredescribedinunderstandableterms. Your enemy when dealing with patient demand is time, i.e. the lack of it. Dialogue and explanation take time and youoften will feel pressed for it.However, inthe long run the investmentisworthwhile.
Conclusion
Patientsmaycometoyouwitharequest,acomplaintoraquestion. Allmaybe relatedtodifferentproblems:aneedforreassurance;asignofunderlyingdisease; ahiddenrequestforassistanceinsolvinganotherproblem;asideeffectofdrug treatment;nonadherencetotreatment;or(psychological)dependenceondrugs. Throughcarefulobservation,structuredhistorytaking,physicalexaminationand other examinations, you should try to define the patient's real problem. Your definition(yourworkingdiagnosis)maydifferfromhowthepatientperceivesthe problem. Choosingtheappropriatetreatmentwilldependuponthiscriticalstep. Inmanycasesyouwillnotneedtoprescribeadrugatall.
Summary
STEP 1: Define the patient's problem

Diseaseordisorder Signofunderlyingdisease Psychologicalorsocialproblems,anxiety Sideeffectofdrugs Refillrequest(polypharmacy) Nonadherencetotreatment Requestforpreventivetreatment Combinationsoftheabove
46
Chapter7
C hapter 7
STEP 2: Specify the therapeutic objective
Before choosing a treatment it is essential to specify your therapeutic objective. Whatdoyouwanttoachievewiththetreatment?Thefollowingexercisesenable youtopracticethiscrucialstep. Exercise:patients912 Foreachofthesepatientstrytodefinethetherapeuticobjective.The casesarediscussedbelow. Patient9: Girl, 4 years, slightly undernourished. Watery diarrhoea without vomiting for three days. She has not urinated for 24 hours. On examination she has no fever (36.8 C), but a rapid pulse and low elasticityoftheskin. Patient10: Womanstudent,19years.Complainsofasorethroat.Slightrednessof thethroat,nootherfindings.Aftersomehesitationshetellsyouthatshe isthreemonthsoverdue.Onexamination,sheisthreemonthspregnant. Patient11: Man,44years.Sleeplessnessduringsixmonths,andcomesforarefillof diazepamtablets,5mg,1tabletbeforesleeping.Hewants60tablets. Patient12: Woman,24years.Consultedyou3weeksago,complainingofconstant tiredness after delivery of her second child. Slightly pale sclerae, but normalHb.Youhadalreadyadvisedhertoavoidstrenuousexercise. Shehasnowreturnedbecausethetirednesspersistsandafriendtoldher thatavitamininjectionwoulddohergood.Thisiswhatshewants. Patient9(diarrhoea) Inthispatientthediarrhoeaisprobablycausedbyaviralinfection,asitiswatery (not slimy or bloody) and there is no fever. She has signs of dehydration (listlessness,littleurineanddecreasedskinturgor).Thisdehydrationisthemost worrying problem, as she is already slightly undernourished. The therapeutic objective in this case is therefore (1) to prevent further dehydration and (2) to rehydrate.Not:tocuretheinfection!Antibioticswouldbeineffectiveanyway. Patient10(pregnancy)
o
47
InPatient10youwillhaverecognizedPatient5whocomplainedofasorethroat while her real problem was the suspected pregnancy. You will not solve her problem by prescribing something for her throat. The therapeutic objective depends on her attitude towards the pregnancy and she will probably need counsellingmorethananythingelse.Thetherapeuticobjectiveisthentoassisther toplanforthefuture.Thiswillprobablynotinvolvedrugtreatmentforhersore throat. Moreover, the factthat she isin early pregnancy should stopyou from prescribinganydrugatall,unlessitisabsolutelyessential. Patient11(sleeplessness) In Patient 11 the problem is not which drugs to prescribe, but how to stop prescribing them. Diazepam is not indicated for long term treatment of sleeplessness as tolerance quickly develops. It should only be used for short periods,whenstrictlynecessary.Thetherapeutic objectiveinthiscaseisnotto treatthepatient'ssleeplessnessbuttoavoidapossibledependenceondiazepam. Thiscouldbeachievedthroughagradualandcarefullymonitoredloweringofthe dose to diminish withdrawal symptoms, coupled with more appropriate behaviouraltechniquesforinsomnia,whichshouldleadtoeventualcessationof thedrug. Patient12(tiredness) InPatient12thereisnoclearcauseforthetirednessanditisthereforedifficultto makearationaltreatmentplan.Havingexcludedanaemiayoumayguessthatasa young mother with small children and perhaps a job outside the home, she is chronicallyoverworked.Thetherapeuticobjectiveisthereforetohelpherreduce physicalandemotionaloverload.Toachievethisitmaybenecessarytoinvolve othermembers ofthefamily.Thisisagoodexample oftheneedfornondrug therapy. Vitamins willnothelp,andwould onlyactasa placebo. Infact,they wouldprobablyactasaplaceboforyourselfaswell,creatingthefalseimpression thatsomethingisbeingdone.
Conclusion
Asyoucansee,insomecasesthetherapeuticobjectivewillbestraightforward:the treatmentofaninfectionoracondition.Sometimesthepicturewillbelessclear,as inthepatientwithunexplainedtiredness. Itmayevenbemisleading,asinthe studentwiththesorethroat.Youwillhavenoticedthatspecifyingthetherapeutic objectiveisagoodwaytostructureyourthinking.Itforcesyoutoconcentrateon therealproblem,whichlimitsthenumberoftreatmentpossibilitiesandsomakes yourfinalchoicemucheasier. Specifyingyourtherapeuticobjectivewillpreventalotofunnecessarydruguse.It shouldstopyoufromtreatingtwodiseasesatthesametimeifyoucannotchoose betweenthem,likeprescribingantimalarialdrugsandantibioticsincaseoffever, orantifungalandcorticosteroidskinointmentwhenyoucannotchoosebetweena fungusandeczema.
48
Chapter7
Specifying your therapeutic objective will also help you avoid unnecessary prophylactic prescribing, for example, the use of antibiotics to prevent wound infection,whichisaverycommoncauseofirrationaldruguse. Itisagoodideatodiscussyourtherapeuticobjectivewiththepatientbeforeyou start the treatment. This may reveal that (s)he has quite different views about illnesscausation,diagnosisandtreatment. Italsomakesthepatientaninformed partnerinthetherapyandimprovesadherencetotreatment.
49
C hapter 8
STEP 3: P-drug Verify the suitability of your
After defining your therapeutic objective you should now verify whether your Pdrug issuitablefortheindividual patient. You will rememberthatyouhave chosenyourPdrugsforanimaginary,standardpatientwithacertaincondition, usingthecriteriaofefficacy,safety,convenienceandcost.However,youcannot assume that this firstchoice treatment will always be suitable for everyone. Cookbook medicine does not make for good clinical practice! You should thereforealwaysverifywhetheryourPdrugissuitableforthisindividualpatient. The same applies when you practice within the limits of national treatment guidelines,ahospitalformularyordepartmentalprescribingpolicies. Chapter5explainedtherelationshipbetweenPdrugandPtreatment.Infact,you shoulddefinePtreatments forthemostcommonproblemsyouwillencounterin practice;suchPtreatmentswillfrequentlyincludenondrugtreatment.However, asthismanualisprimarilyconcernedwiththedevelopmentofprescribingskills, fromnowonthefocuswillbeondrugtreatment,basedontheuseofPdrugs. Alwayskeepinmindthatmanypatientsdonotneeddrugsatall! ThestartingpointforthisstepistolookupyourPdrugs(describedinPart2),or thetreatmentguidelinethatisavailabletoyou.Inallcasesyouwillneedtocheck threeaspects:(1)aretheactivesubstanceandthedosageformsuitable forthis patient? (2)is the standard dosage schedule suitable? and (3) is the standard durationoftreatment suitable?Foreachaspect,youhavetocheckwhetherthe proposed treatment is effective and safe. A check on effectiveness includes a review of the drug indication and the convenience of the dosage form. Safety relatestocontraindicationsandpossibleinteractions.Becarefulwithcertainhigh riskgroups.
Verify the suitability of your P-drug A Activesubstanceanddosageform B Standarddosageschedule C Standarddurationoftreatment Foreachofthese,check: Effectiveness(indication,convenience) Safety(contraindications,interactions,highriskgroups)
50
Chapter8
Step3:VerifythesuitabilityofyourPdrug
Step 3A: Are the active substance and dosage form suitable for this patient?
Effectiveness We assume that all your Pdrugs have already been selected on the basis of efficacy.However,youshouldnowverifythatthedrugwillalsobe effective in thisindividualpatient.Forthispurposeyouhavetoreviewwhethertheactive substanceislikelytoachievethetherapeutic objective,andwhetherthedosage formisconvenientforthepatient. Convenience contributestopatientadherence to the treatment, and therefore to effectiveness. Complicated dosage forms or packages and special storage requirements can be major obstacles for some patients. Safety Table 5: Highrisk factors/ groups Pregnancy Lactation Children Elderly Renalfailure Hepaticfailure Historyofdrug allergy Otherdiseases Othermedication Thesafetyofadrugfortheindividual patientdependson contraindications and interactions; these may occur more frequentlyincertainhighriskgroups.Contraindicationsare determinedbythemechanismofactionofthedrugandthe characteristics of the individual patient. Drugs in the same groupusuallyhavethesamecontraindications.Somepatients willfallintocertainhighriskgroups(seeTable5)andany otherillnessesshouldalsobeconsidered. Somesideeffects areseriousforcategoriesofpatientsonly,suchasdrowsiness for drivers. Interactions can occur between the drug and nearly every other substance taken by the patient. Best knownareinteractionswithotherprescribeddrugs,butyou mustalsothinkofoverthecounterdrugsthepatientmight be taking. Interactions may also occur with food or drinks (especially alcohol). Some drugs interact chemically with othersubstancesandbecomeineffective(e.g.tetracyclineand milk). Fortunately, in practice only a few interactions are clinicallyrelevant.
Exercise:patients1316 Verifyineachofthesecaseswhethertheactivesubstanceanddosage form of your Pdrug is suitable (effective, safe) for this patient. Examplesarediscussedbelow. Patient13: Man,45years.Suffersfromasthma.Usessalbutamolinhaler.Afew weeks ago you diagnosed essential hypertension (145/100 on various occasions).Youadvisedalowsaltdiet,butbloodpressureremainshigh. You decide to add a drug to your treatment. Your Pdrug for hypertensioninpatientsunder50isatenololtablets,50mgaday. Patient14:
51
Girl,3years.Broughtinwithasevereacuteasthmaticattack,probably precipitatedbyaviralinfection.Shehasgreatdifficultyinbreathing (expiratory wheeze, no viscid sputum), little coughing and a slight temperature(38.2 C).Furtherhistoryandphysicalexaminationreveal nothing.Apartfromminorchildhoodinfectionsshehasneverbeenill before and she takes no drugs. Your Pdrug for such a case is a salbutamolinhaler. Patient15: Woman, 22 years, 2 months pregnant. Large abscess on her right forearm. You conclude that she will need surgery fast, but in the meantimeyouwanttorelievethepain.YourPdrugforcommonpainis acetylsalicylicacid(aspirin)tablets. Patient16: Boy,4years.Coughandfeverof39.5 C.Diagnosis:pneumonia.Oneof yourPdrugsforpneumoniaistetracyclinetablets. Patient13(hypertension) AtenololisagoodPdrugforthetreatmentofessentialhypertensioninpatients below50yearsofage,anditisveryconvenient.However,likeallbetablockers,it isrelativelycontraindicatedinasthma.Despitethefactthatitisaselectivebeta blocker, it can induce asthmatic problems, especially in higher doses because selectivity then diminishes. If the asthma is not very severe, atenolol can be prescribed in a low dose. In severe asthma you should probably switch to diuretics;almostanythiazideisagoodchoice. Patient14(childwithacuteasthma) Inthischildafasteffectisneeded,andtabletsworktooslowlyforthat.Inhalers onlyworkwhenthepatientknowshowtousethemandcanstillbreatheenough to inhale. In the case of a severe asthma attack this is usually not possible; moreover,somechildrenbelowtheageoffivemayexperiencedifficultieswithan inhaler.Intravenousinjectioninyoungchildrencanbeverydifficult.Ifaninhaler cannot be used, the best alternative is to give salbutamol by subcutaneous or intramuscularinjection,whichiseasyandonlybrieflypainful. Patient15(abscess) Thispatientispregnantandwillsoonbeoperatedon.Inthiscaseacetylsalicylic acidiscontraindicatedasitaffectsthebloodclottingmechanismandalsopasses the placenta. You should switch to another drug that does not interfere with clotting.Paracetamolisagoodchoiceandthereisnoevidencethatithasanyeffect onthefetuswhenitisgivenforashorttime. Patient16(pneumonia) Tetracyclineisnotagooddrugforchildrenbelow12yearsofage,becauseitcan causediscolourationoftheteeth.Thedrugmayinteractwithmilkandthechild mayhaveproblemsswallowingthelarge tablets.Thedrugand,ifpossible,the dosage form, will therefore have to be changed. Good alternatives are cotrimoxazole andamoxicillin. Tablets orparts oftabletscouldbecrushed and
o o
52
Chapter8
dissolvedinwater,whichiscosteffectiveifyoucanclearlyexplaintheprocedure totheparents.3Youcouldalsoprescribeamoreconvenientdosageform,suchasa syrup,althoughthisismoreexpensive. InallthesepatientsyourPdrugwasnotsuitable,andineachcaseyouhadto change either the active substance or the dosage form, or both. Atenolol was contraindicatedbecauseofanotherdisease(asthma);aninhalerwasnotsuitable because the child was too young to handle it; acetylsalicylic acid was contraindicatedbecauseitaffectsthebloodclottingmechanismandbecausethe patient is pregnant; and tetracycline tablets were contraindicated because of serious side effects in young children, possible interactions with milk, and inconvenienceasadosageform.
Step 3B: Is the standard dosage schedule suitable for this patient?
Theaimofadosagescheduleistomaintaintheplasmalevelofthedrugwithinthe therapeutic window. As in the previous step, the dosage schedule should be effective and safe fortheindividualpatient.Therearetwomainreasonswhya standarddosageschedulemayhavetobeadapted.Thewindowand/orplasma curvemayhavechanged,orthedosagescheduleisinconvenienttothepatient.If youarenotfamiliarwiththeconceptofthetherapeuticwindowandtheplasma concentrationtimecurve,readAnnex1. Exercise:patients1720 Reviewforeachofthefollowingcaseswhetherthedosageschedule issuitable(effective,safe)forthepatient.Adapttheschedulewhere necessary.Thecasesarediscussedbelow. Patient17: Woman,43years.Historyofinsulindependentdiabetesfor26years. Stableontreatmentwithtwodailydosesofneutralinsulin,20IUand 30IU.Recentlymildhypertensionwasdiagnosed,anddietandgeneral advicehavenotbeensufficientlyeffective.Youwouldliketotreatthis conditionwithabetablocker.YourPdrugisatenolol50mgoncedaily. Patient18: Man,45years.Terminallungcancer.Hehaslost3kgduringthelast week. YouhavebeentreatinghispainsuccessfullywithyourP drug, oralmorphinesolution,10mgtwicedaily.Nowhecomplainsthatthe painisgettingworse. Patient19: Woman,50years.Chronicrheumaticdisease,treatedwithyourP drug, indometacin,3times50mgdailyplusa50mgsuppositoryatnight. Shecomplainsofpainearlyinthemorning. Patient18again,afteroneweek: Hehaslostanother6kg,andlooksveryill. Hewasonoralmorphine solution,15mgtwicedaily,towhichhehadrespondedwell.However,
3
Thisisacheapandconvenientwayofgivingadrugtoasmallchild.However,itshouldnotbedonewith capsulesnorwithspecialtabletssuchassugarcoatedorslowreleasepreparations.
53
hehasbecomeverydrowsyandhastobewokenuptohearwhatyou say.Hehasnopain. Patient20: Man,73years.Hassufferedfromdepressionfortwoyears,afterthe deathofhiswife.Youwanttoprescribeanantidepressantdrug.YourP drugisamitriptyline,25mgdailyinitially,followedbyaslowlyrising dosetillthedrugiseffective(withamaximumof150mgperday).
54
Chapter8
Changesintherapeuticwindow
Figure1:Shiftintherapeuticwindow
For a variety of reasons (e.g. age, pregnancy, disturbed organ functions) individual patients may differ from the standard. Thesedifferencesmayinfluencethepharmaco dynamicsorpharmacokineticsofyourPdrug.Achangein pharmacodynamicsmayaffectthelevel(position)orwidth ofthetherapeuticwindow(Figure1;seealsoAnnex1).The therapeuticwindowreflectsthesensitivityofthepatientto theactionofthedrug.Changesinthetherapeuticwindow aresometimesexpressedasthepatientbeingresistantor hypersensitive. The only way to determine the therapeutic window in the individual patient is by trial, carefulmonitoringandlogicalthinking.
InPatient17(diabetes)itisimportanttonotethatblockerscounteracttheeffect of insulin. This means that higher concentrations of insulin are needed for the sameeffect:thetherapeuticwindowforinsulinshiftsupwards.Theplasmacurve nolongermatchesthewindow,andthedailydoseofinsulinmustberaised. blockersmayalsomaskanysignsofhypoglycemia. Forthesetworeasons you maydecidetochangetoanotherdruggroupthatdoesnotaffectglucosetolerance, e.g.calciumchannelblockers. Patient 18 (lung cancer) has probably become tolerant to morphine, as he respondedwelltothedrugbefore.Tolerancetoeffectandalsotosideeffects,is commoninopiates.Thetherapeuticwindowisshiftedupwardsandthedosehas toberaised,forexampleto15mgtwicedaily.Interminalpatientsdrugabsorption andmetabolismmaybesodisturbedthatevenlargerdosages(e.g.10timesthe normaldose)maybenecessary. Changesinplasmaconcentrationtimecurve The plasma concentrationtime curve may be lowered or raised, or the concentrationmayfluctuateoutsidethetherapeuticwindow.Thiseffectdepends onthepharmacokineticsofthedruginthatpatient.
Figure2: Slow fall in plasma concentration late at nightinpatient19
In Patient19(painatnight) theplasmaconcentrationof indometacinprobablyfallsbelowthetherapeuticwindow early in the morning (see Figure 2). Any change in medicationshouldthereforeaimatincreasingtheplasma level in that period. You could advise her to take the eveningdoselater,ortosetthealarminthenighttotake anextratablet.Youcouldalsoincreasethestrengthofthe eveningsuppositoryto100mg,whiledecreasingherfirst morningtabletto25mg. The second visit of Patient 18 (lung cancer) presents a complicated problem. He has probably been overdosed, becausehismetabolismisimpairedbytheterminalcancer, decreasing the elimination of the drug and therefore
Figure3: Plasmaconcentrationrising abovetherapeuticwindowin patient18
55
lengtheningitshalflife.Inaddition,thedistributionvolumeofhisbodyisreducedbecause ofemaciation.Thecurvethereforeprobablyliesabovethewindow,implyingthatthedaily doseshouldbereduced.Rememberthatittakesaboutfourhalflivestolowertheplasma concentrationtoanewsteadystate.Ifyouwanttospeedupthisprocessyoucanstopthe morphineforoneday,afterwhichyoucanstartwiththenewdose.Thisisthereverse processofaloadingdose. Fourfactorsdeterminethecourseofthe concentration curve,usuallycalled ADMEfactors: Absorption, Distribution, Metabolism and Excretion. You always have to check whether ADMEfactorsinyourpatientaredifferentcomparedtoaveragepatients.Ifso,youhaveto determinewhatthiswilldotothe plasmacurve. Anychangein ADMEfactorsinfluences plasmaconcentration(seeTable6). Howcanyoudefinethepositionoftheplasmacurveinan individual patient? The plasma concentration can be measured by laboratory investigations, but in many settingsthisisnotpossibleanditmaybeexpensive.More important,eachmeasurementrepresentsonlyonepointof the curve and is difficult to interpret without special training and experience. More measurements are expensiveandmaybestressfultothepatient,especiallyin anoutpatientsetting.Itissimplertolookforclinicalsigns oftoxiceffects.Theseareofteneasytodetectbyhistory takingandclinicalinvestigation. Changesinwindowandcurve Changesinbothwindowandcurvearealsopossible,as illustrated in Patient 20 (depression) (see Figure 4). Elderlypeopleareoneofseveralcategories ofhighrisk patients.Dosageschedulesforantidepressantdrugsinthe elderly usually recommend that the dose be reduced to halftheadultdose,fortworeasons.First,intheelderly the therapeutic window of antidepressant drugs shifts downwards (a lower plasma concentration will suffice). Atafulladultdosetheplasmacurvemayriseabovethe therapeutic window, leading to side effects, especially anticholinergic and cardiac effects. Secondly, metabolism andrenalclearanceofthedruganditsactivemetabolites maybereducedintheelderly,alsoincreasingtheplasma curve. Thus,inprescribingthenormaladultdosageyour patient will be exposed to unnecessary and possibly harmfulsideeffects. Convenience A dosage schedule should be convenient. The morecomplextheschedule,thelessconvenientit is.Forexample,twotabletsoncedailyaremuch more convenient than half a tablet four times daily.Complexdosageschedulesdecreasepatient 56
Table 6: Relation between ADME factors and plasma concentration

Plasmaconcentrationcurve willdropif: Absorptionislow Distributionishigh Metabolismishigh Excretionishigh Plasmaconcentrationcurve willriseif: Absorptionishigh Distributionislow Metabolismislow Excretionislow
Figure4: Downward shifted window and upward shiftedcurveinpatient20
Chapter8
adherence totreatment, especiallywhen more than onedrug isused,andthus decreaseeffectiveness. Trytoadjustadosagescheduletootherschedulesofthe patient. Inpatients1720thestandarddosagescheduleofyourPdrugwasnotsuitable.If youhadnotadapted theschedule, thePdrug treatment would have been less effective,orunsafe.Youcanpreventthisbycarefullycheckingthesuitabilityofthe standarddosageschedulebeforewritingtheprescription.Youmayhavetomodify theschedule,orchangetoacompletelydifferentPdrug. Howtoadaptadosageschedule
Figure5: Relationbetween frequencyandfluctuations inplasmaconcentration
There are three ways to restore the mismatch between curveandwindow:changethedose,changethefrequency of administration, or both. Changing dose or frequency havedifferenteffects.Thedailydosedeterminesthemean plasma concentration, while the frequency of administrationdefinesthefluctuationsintheplasmacurve. Forexample,twicedaily200mgwillgivethesamemean plasmaconcentrationasfourtimesdaily100mg,butwith more fluctuations in plasma level. The minimum fluctuationwouldbeobtainedbydelivering400mgin24 hoursbymeansofacontinuousinfusion(Figure5).
Decreasingthedailydoseisusuallyeasy.Youcanreducethenumberoftablets,or dividethemintohalves.Bewareofantibiotics,becausesomemayneedhighpeaks in plasma concentration to be effective. In that case you should reduce the frequency,notthedose. Increasingthedailydose isalittlemore complicated. Doubling the dose while maintainingthesamefrequencynotonlydoublesthemeanplasmalevel,butalso increasesthefluctuationsonbothsidesofthecurve.Indrugswithanarrowsafety marginthecurvemaynowfluctuateoutsidethetherapeuticwindow.Thesafest waytopreventthisistoraisethefrequencyofdosage.However,fewpatientslike taking drugs 12 times a day and a compromise has to be found to maintain adherencetotreatment.Afterchangingthedailydoseittakesfourtimesthehalf lifeofthedrugtoreachthenewsteadystate.Table7liststhosedrugsforwhichit isadvisabletostarttreatmentwithaslowlyrisingdosageschedule.
57
Table 7:
Drugs in which slowly raising the dose is advisable

o o o o o o o o o Tricyclicantidepressants(anticholinergiceffects) Someantiepileptics(carbamazepine,valproicacid) DopabasedantiParkinsondrugs ACEinhibitorsinpatientsusingdiuretics Alphareceptorblockingagentsinhypertension(orthostasis) Somehormonaldrugtherapies(corticosteroids,levothyroxin) Goldsaltsinrheumatism Mixturesfordesensitization Opiatesincancer
Step 3C: Is the standard duration of treatment suitable for this patient?
Many doctors not only prescribe too much of a drug for too long, but also frequentlytoolittleofadrugfortooshortaperiod.Inonestudyabout10%of patientsonbenzodiazepines received themforayear orlonger. Another study showed that 16% of outpatients with cancer still suffered from pain because doctors were afraid to prescribe morphine for a long period. They mistook toleranceforaddiction.Thedurationofthetreatmentandthequantityofdrugs prescribedshouldalsobeeffectiveandsafefortheindividualpatient. Overprescribingleadstomanyundesiredeffects.Thepatientreceivesunnecessary treatment,ordrugsmaylosesomeoftheirpotency.Unnecessarysideeffectsmay occur. The quantity available may enable the patient to overdose. Drug dependence and addiction may occur. Some reconstituted drugs, such as eye drops and antibiotic syrups, may become contaminated. It may be very inconvenientforthepatienttotakesomanydrugs. Last,butnotleast,valuable andoftenscarceresourcesarewasted. Underprescribing is also serious. The treatment is not effective, and more aggressive or expensive treatment may be needed later. Prophylaxis may be ineffective, resulting in serious disease, e.g. malaria. Most patients will find it inconvenienttoreturnforfurthertreatment.Moneyspentonineffectivetreatment ismoneywasted. Exercise:patients2128 For each of the following cases verify whether the duration of treatmentandtotalquantityofthedrugsaresuitable(effective,safe). InallcasesyoumayassumethatthedrugsareyourPdrugs. Patient21: Woman,56years.Newlydiagnoseddepression.R/amitriptyline25mg, onetabletdailyatnight,give30tablets. Patient22:
58
Chapter8
Child, 6 years. Giardiasis with persistent diarrhoea. R/metronidazole 200mg/5mloralsuspension,5mlthreetimesdaily,give105ml. Patient23: Man,18years.Drycoughafteracold.R/codeine30mg,1tabletthree timesdaily,give60tablets. Patient24: Woman,62years.Anginapectoris,waitingforreferraltoaspecialist. R/glyceryl trinitrate 5 mg, as necessary 1 tablet sublingual, give 60 tablets. Patient25: Man,44years. Sleeplessness. Comesforarefill, R/diazepam5mg,1 tabletbeforesleeping,give60tablets. Patient26: Girl,15years.NeedsmalariaprophylaxisforatwoweektriptoGhana. R/mefloquine 250mg,1tabletweekly,give7 tablets;startoneweek beforedepartureandcontinuefourweeksafterreturn. Patient27: Boy,14years.Acuteconjunctivitis.R/tetracycline0.5%eyedrops,first 3dayseveryhour1drop,then2dropseverysixhours,give10ml. Patient28: Woman,24years.Feelsweakandlooksabitanaemic.NoHbresult available.R/ferroussulfate60mgtablets,1tabletthreetimesdaily,give 30tablets. Patient21(depression) Adoseof25mgperdayisprobablyinsufficienttotreatherdepression.Although shecanstartwithsuchalowdoseforafewdaysoraweek,mainlytogetusedto sideeffectsofthedrug,shemayfinallyneed100150mgperday.With30tablets thequantityissufficientforonemonth,ifthedosageisnotchangedbeforethat time. Butisitsafe? Atthebeginningofthetreatmenttheeffectandsideeffects cannotbeforeseen.Andifthetreatmenthastobestopped,theremainingdrugs arewasted. Theriskofsuicidealsohastobeconsidered:depressivepatientsare moreliabletocommitsuicideintheinitialstagesoftreatmentwhentheybecome more active because of the drug, but still feel depressed. For these reasons 30 tabletsarenotsuitable.Itwouldbebettertostartwith10tablets,forthefirstweek orso.Ifshereactswellyoushouldincreasethedose. Patient22(giardiasis) Withmostinfectionstimeisneededtokillthemicrobes,andshorttreatmentsmay not be effective. However, after prolonged treatment the microorganisms may developresistanceandmoresideeffectswilloccur.Inthispatientthetreatmentis botheffectiveandsafe.Giardiasiswithpersistentdiarrhoeaneedstobetreatedfor oneweek,and105mlisexactlyenoughforthatperiod.Maybeitiseventooexact. Mostpharmacistsdonotwanttodispensequantitiessuchas105mlor49tablets. Theypreferroundedfigures,suchas100mlor50tablets,becausecalculatingis easieranddrugsareusuallystockedorpackedinsuchquantities. 59
Patient23(drycough) Thequantityoftabletsismuchtoohighforthispatient.Thepersistentdrycough preventshealingoftheirritatedbronchialtissue.Sincetissuecanregeneratewithin threedaysthecoughneedstobesuppressedforfivedaysatmost,so1015tablets will be sufficient. Although a larger quantity will not harm the patient, it is unnecessary, inconvenient and needlessly expensive. Many prescribers would arguethatnodrugisneededatall(seep.8). Patient24(angina) Forthispatientthequantityisexcessive. Shewillnotuse60tabletsbeforeher appointmentwiththespecialist.Anddidyourememberthatthedrugisvolatile? Aftersometimetheremainingtabletswillnolongerbeeffective. Patient25(sleeplessness) Thediazepamrefillforpatient25isworrying. Yousuddenlyrememberthathe cameforasimilarrefillrecentlyandcheckthemedicalrecord.Itwastwoweeks ago!Lookingmorecloselyyoufindthathehasuseddiazepamfourtimesdailyfor thelastthreeyears. Thistreatmenthasbeenexpensive,probablyineffectiveand hasresultedinaseveredependency.Youshouldtalktothepatientatthenextvisit anddiscusswithhimhowhecangraduallycomeoffthedrug.
Box 6:
Repeat prescriptions in practice
Inlongtermtreatment,patient adherence totreatment canbeaproblem.Oftenthe patient stops taking the drug when the symptoms have disappeared or if side effects occur. For patientswithchronicconditionsrepeatprescriptionsareoftenpreparedbythereceptionistor assistantandjustsignedbythephysician.Thismaybeconvenientfordoctorandpatientbutit has certainrisks,as the process ofrenewal becomes aroutine,ratherthanaconscious act. Automaticrefillsareoneofthemainreasonsforoverprescribinginindustrializedcountries, especially in chronic conditions. When patients live far away, convenience may lead to prescriptionsforlongerperiods.Thismayalsoresultinoverprescribing.Youshouldseeyour patientsonlongtermtreatmentatleastfourtimesperyear.
Patient26(malariaprophylaxis) ThereisnothingwrongwiththisprescriptionwhichfollowstheWHOguidelines onmalariaprophylaxisfortravellerstoGhana. Thedosagescheduleiscorrect,and shereceivedenoughtabletsforthetripplusfourweeksafterwards. Apartfroma smallriskofdrugresistancethisdrugtreatmentiseffectiveandsafe. Patient27(acuteconjunctivitis) Theprescriptionof10mleyedropsseemsadequate,atfirstsight.Infact,eyedrops areusuallyprescribedinbottlesof10ml. Butdidyouevercheckhowmanydrops thereareinabottleof10ml? Onemlisabout20drops,so10mlisabout200 drops. Onedropeveryhourforthefirstthreedaysmeans3x24=72drops. That
60
Chapter8
leaves about 128 drops in the bottle. Two drops four times per day for the remainingperiodis8dropsaday.Thatisforanother130/8=16days. Thetotal treatmenttherefore covers 3+16=19days! Yet,sevendaystreatment atmost shouldbeenoughforbacterialconjunctivitis. Aftersomearithmetic(72+(4x8)= 104drops=104x0.05=5.2ml)youconcludethat5mlwillbeenoughinfuture. This will also prevent any leftovers from being used again without a proper diagnosis. Even more important, eyedrops become contaminated after a few weeks,especiallyiftheyarenotkeptcool,andcancausesevereeyeinfections. Patient28(weakness) Did you notice that this is a typical example of a prescription without a clear therapeuticobjective? Ifthediagnosisisuncertain,theHbshouldbemeasured. If thepatientisreallyanaemicshewillneedmuchmoreironthanthetendaysgiven here. Shewillprobablyneedtreatmentforseveralweeksormonths,withregular Hbmeasurementsinbetween.
Conclusion
VerifyingwhetheryourPdrugisalsosuitablefortheindividualpatientinfrontof youisprobablythemostimportantstepintheprocessofrationalprescribing.It alsoappliesifyouareworkinginanenvironmentinwhichessentialdrugslists, formulariesandtreatmentguidelinesexist.Indailypractice,adaptingthedosage scheduletotheindividualpatientisprobablythemostcommonchangethatyou willmake.
Summary
STEP 3:
Verify that your P-drug is suitable for this patient
3A
Aretheactivesubstanceanddosageformsuitable? Effective: Indication(drugreallyneeded)? Convenience(easytohandle,cost)? Safe: Contraindications(highriskgroups,otherdiseases)? Interactions(drugs,food,alcohol)? Isthedosageschedulesuitable? Effective: Adequatedosage(curvewithinwindow)? Convenience(easytomemorize,easytodo)? Safe: Contraindications(highriskgroups,otherdiseases)? Interactions(drugs,food,alcohol)? Isthedurationsuitable? Effective: Adequateduration(infections,prophylaxis,leadtime)? Convenience(easytostore,cost)?
3B
3C
61
Safe:
Contraindications(sideeffects,dependence,suicide)? Quantitytoolarge(lossofquality,useofleftovers)?
Ifnecessary,changethedosageform,thedosagescheduleorthedurationof treatment. InsomecasesitisbettertochangetoanotherPdrug.
62
Chapter9
Step4:Writeaprescription
C
hapter 9
Cartoon3
STEP 4: Write a prescription

A prescription is an instruction from a prescribertoadispenser.Theprescriberis not always a doctor but can also be a paramedical worker, such as a medical assistant, a midwife or a nurse. The dispenserisnotalwaysapharmacist,but canbeapharmacytechnician,anassistant or a nurse. Every country has its own standards for the minimum information required for a prescription, and its own laws and regulations to define which drugs require a prescription and who is entitledtowriteit.Manycountries have separate regulations for opiate
prescriptions.
Information on a prescription
There is no global standard for prescriptions and every country has its own regulations.Doyouknowthelegalrequirementsinyourowncountry?Themost importantrequirementisthattheprescriptionbeclear.Itshouldbelegibleand indicate precisely what should be given. Few prescriptions are still written in Latin;thelocallanguageispreferred.Ifyouincludethefollowinginformation,not muchcangowrong. Nameandaddressoftheprescriber,withtelephonenumber(ifpossible) Thisisusuallypreprintedontheform. Ifthepharmacisthasanyquestionsabout theprescription(s)hecaneasilycontacttheprescriber. Dateoftheprescription Inmanycountries thevalidityofa prescription hasnotime limit, but insome countriespharmacistsdonotgiveoutdrugsonprescriptionsolderthanthreeto sixmonths.Youshouldchecktherulesinyourowncountry.
63
Nameandstrengthofthedrug R/(notRx)isderivedfromRecipe (Latinfortake). AfterR/youshouldwritethe nameofthedrugandthestrength. Itisstronglyrecommendedtousethegeneric (nonproprietary)name. Thisfacilitateseducationandinformation. Itmeansthat youdonotexpressanopinionaboutaparticularbrandofthedrug,whichmaybe unnecessarilyexpensiveforthepatient.Italsoenablesthepharmacisttomaintain amorelimitedstockofdrugs,ordispensethecheapestdrug. However,ifthereisa particularreasontoprescribeaspecialbrand,thetradenamecanbeadded.Some countries allowgeneric substitution bythepharmacist andrequire theaddition Do not substitute or Dispense as written if that brand, and no other, is to be dispensed. Thestrengthofthedrugindicateshowmanymilligramseachtablet,suppository, ormilliliteroffluidshouldcontain. Internationallyacceptedabbreviationsshould beused:gforgram,mlformilliliter. Trytoavoiddecimalsand,wherenecessary, writewordsinfulltoavoidmisunderstanding.Forexample,writelevothyroxin50 micrograms,not0.050milligramsor50ug. Badlyhandwrittenprescriptionscan leadtomistakes,anditisthelegaldutyofthedoctortowritelegibly(Box7). In prescriptionsforcontrolleddrugsorthosewithapotentialforabuseitissaferto writethestrengthandtotalamountinwords,topreventtampering. Instructions forusemustbeclearandthemaximumdailydosementioned.Useindelibleink.
Box 7:
Legal obligation to write clearly
Doctorsarelegallyobligedtowriteclearly,asemphasizedintheUKCourtofAppealruling inthefollowingcase.AdoctorhadwrittenaprescriptionforAmoxiltablets(amoxicillin). ThepharmacistmisreadthisanddispensedDaonil(glibenclamide)instead.Thepatientwas notadiabeticandsufferedpermanentbraindamageasaresultoftakingthedrug. Thecourtindicatedthatadoctorowedadutyofcaretoapatienttowriteaprescription clearlyandwithsufficientlegibilitytoallowforpossiblemistakesbyabusypharmacist.The courtconcludedthatthewordAmoxilontheprescriptioncouldhavebeenreadasDaonil.It foundthatthedoctorhadbeeninbreachofhisdutytowriteclearlyandhadbeennegligent. The courtconcludedthatthedoctor'snegligence hadcontributedtothenegligenceofthe pharmacist, although the greater proportion of the responsibility (75%) lay with the pharmacist. Onappealthedoctorarguedthatthewordontheprescriptionstandingonitsowncould reasonably have been read incorrectly but that various other aspects of the prescription shouldhavealertedthepharmacist.ThestrengthprescribedwasappropriateforAmoxilbut notforDaonil;theprescriptionwasforAmoxiltobetakenthreetimesadaywhileDaonil wasusuallytakenonceaday;theprescriptionwasforonlysevendays'treatment,whichwas unlikelyforDaonil;andfinally,allprescriptionsofdrugsfordiabeteswerefreeunderthe NationalHealthServicebutthepatientdidnotclaimfreetreatmentforthedrug.Allofthese factorsshouldhaveraiseddoubtsinthemindofthepharmacistandasaresultheshould
64
Chapter9
have contacted the doctor. Therefore, the chain of causation from the doctor's bad handwritingtotheeventualinjurywasbroken. ThisargumentwasrejectedintheCourtofAppeal.Theimplicationsofthisrulingarethat doctorsareunderalegaldutyofcaretowriteclearly,thatiswithsufficientlegibilitytoallow formistakesbyothers.Whenillegiblehandwritingresultsinabreachofthatduty,causing personalinjury,thenthecourtswillbepreparedtopunishthecarelessbyawardingsufficient damages.Liabilitydoesnotendwhentheprescriptionleavesthedoctor'sconsultingroom.It mayalsobeacauseofthenegligenceofothers.
Source:JRCollGenPract,1989:3478
Dosageformandtotalamount Onlyusestandardabbreviationsthatwillbeknowntothepharmacist. Informationforthepackagelabel SstandsforSigna(Latinforwrite).AllinformationfollowingtheSortheword Labelshould be copied by thepharmacist ontothe label of thepackage. This includes how much of the drug is to be taken, how often, and any specific instructions and warnings. These should be given in lay language. Do not use abbreviations or statements like as before or as directed. When stating as required, themaximumdose andminimum doseinterval shouldbeindicated. Certaininstructionsforthepharmacist,suchasAdd5mlmeasuringspoonare writtenhere,butofcoursearenotcopiedontothelabel. Prescriber'sinitialsorsignature Nameandaddressofthepatient;age(forchildrenandelderly)
Box 8:
Incomplete labels
The label on the drug package is very important for the patient as a reminder of the instructions for use. In many cases, however, labels are incomplete. An analysis of 1533 (=100%)labelsshowed: Nolabelorillegible Quantitynotrecorded Nodirections,oronlyasbefore/asdirected Nodate 1.% 50.% 26.% 14.%
Thedatalistedabovearethecoreofeveryprescription. Additionalinformation maybeadded,suchasthetypeofhealthinsurancethepatienthas.Thelayoutof theprescriptionformandtheperiodofvaliditymayvarybetweencountries.The number of drugs per prescription may be restricted. Some countries require prescriptions for opiates on a separate sheet. Hospitals often have their own
65
standardprescriptionforms.Asyoucancheckforyourself,allprescriptionsinthis chapterincludethebasicinformationgivenabove. Exercise:Patients2932 Writeaprescriptionforeachofthefollowingpatients.Prescriptions arediscussedbelow. Patient29: Boy, 5 years. Pneumonia with greenish sputum. Your Pdrug is amoxicillinsyrup. Patient30: Woman,70years.Moderatecongestivecardiacfailure.Forseveralyears on digoxin 0.25 mg 1 tablet daily. She phones to ask for a repeat prescription.Asyouhavenotseenherforsometimeyouaskhertocall. Duringthevisitshecomplainsofslightnauseaandlossofappetite.No vomitingordiarrhoea.Yoususpectsideeffectsofdigoxin,andcallher cardiologist.Asshehasanappointmentwithhimnextweek,andheis verybusy,headvisesyoutohalvethedoseuntilthen. Patient31: Woman,22years.New patient. Migraine with increasingly frequent vomiting.Paracetamolnolongereffectiveduringattacks.Youexplainto her that the paracetamol does not work because she vomits the drug before it is absorbed. You prescribe paracetamol plus an antiemetic suppository,metoclopramide,whichsheshouldtakefirst,andwait20 30minutesbeforetakingtheparacetamol. Patient32: Man,53years.Terminalstageofpancreaticcancer,confinedtobedat home.Youvisithimonceaweek.Todayhiswifecallsandasksyouto comeearlierbecauseheisinconsiderablepain.Yougoimmediately.He has slept badly over the weekend and regular painkillers are not working.Togetheryoudecidetotrymorphineforaweek.Makingsure nottounderdosehim,youstartwith10mgeverysixhours,with20mg atnight.Healsohasnoninsulindependentdiabetes,soyouaddarefill forhistolbutamide.
Thereisnothingwrongwithanyofthefourprescriptions(Figures6,7,8and9). However,afewremarkscanbemade. Repeatprescriptions,suchastheonefor patient30,arepermitted.Manyprescriptionsarelikethat.Buttheyalsoneedyour fullattention.Donotwritearepeatprescriptionautomatically!Checkhowmany timesithasbeenrepeated.Isitstilleffective?Itisstillsafe?Doesitstillmeetthe originalneeds? Fortheopiateforpatient32,thestrengthandthetotalamounthavebeenwritten inwordssotheycannoteasilybealtered.Theinstructionsaredetailedandthe maximumdailydoseismentioned.Insomecountriesitismandatorytowritean opiateprescriptiononaseparateprescriptionsheet.
66
Chapter9
Summary
DrB.Who Farmstreet12 Kirkville tel.3876 R/
date
DrB.Who Farmstreet12 Kirkville tel.3876 R/
date
Ms/Mr address: age:
Ms/Mr address: age:
A prescription should include:

*Name,address,telephoneofprescriber *Date *Genericnameofthedrug,strength *Dosageform,totalamount *Label:instructions,warnings *Name,address,ageofpatient *Signatureorinitialsofprescriber
Figure6:Prescriptionforpatient29
67
C hapter 10
STEP 5: Give information, instructions and warnings
Cartoon4 Example:patient33 Woman, 59 years. She is taking drugs for congestiveheartfailureandhypertension.Shealso hasanewlydiagnosedgastriculcer,forwhichshe hasbeenprescribedanotherdrug.Asthedoctoris explaining why sheneeds thenewdrug and how sheshouldtakeit,herthoughtsaredriftingaway. Thedoctor'svoicesinksintothebackgroundasshe startsworryingaboutthenewillness,afraidofthe consequencesandhowshewillremembertotakeall these drugs. The doctor doesn't notice the loss of attention, doesn't encourage a dialogue but just keepsontalkingandtalking.Inthepharmacyher thoughts are still wandering off even when the pharmacist is explaining how to take the drug. Whenshegetshomeshefindsherdaughterwaiting toheartheresultsofhervisittothedoctor.Without tellingherthediagnosisshetalksaboutherworry: howtocopewithallthesedifferentdrugs.Finally herdaughter reassuresherandsaysthatshewill helphertotakethedrugscorrectly.
On average, 50% of patients do not take prescribed drugs correctly, take them irregularly,ornotatall.Themostcommonreasonsarethatsymptomshaveceased, side effectshave occurred, thedrugisnot perceived aseffective,orthedosage schedule is complicated for patients, particularly the elderly. Non adherence to treatment mayhave noserious consequences. Forexample,irregular dosesofa thiazidestillgivethesameresult,asthedrughasalonghalflifeandaflatdose response curve. But drugs with a short halflife (e.g. fenytoin) or a narrow therapeutic margin (e.g. theophylline) may become ineffective or toxic if taken irregularly. Patientadherencetotreatmentcanbeimprovedinthreeways:prescribeawell chosendrugtreatment;createagooddoctorpatientrelationship;taketimetogive thenecessaryinformation,instructionsandwarnings.Anumberofpatientaidsare discussed in Box 9. A well chosen drug treatment consists of as few drugs as possible (preferably only one), with rapid action, with as few side effects as
68
Chapter10
Step5:Giveinformation,instructionsandwarnings
possible,inanappropriatedosageform,withasimpledosageschedule(oneor twotimesdaily),andfortheshortestpossibleduration.
How to improve patient adherence to treatment *Prescribeawellchosentreatment *Createagooddoctorpatientrelationship *Takethetimetogiveinformation,instructionsandwarnings Agooddoctorpatientrelationshipisestablishedthroughrespectforthepatient's feelingsandviewpoint,understanding,andwillingnesstoenterintoadialogue whichempowersthepatientasapartnerintherapy.Patientsneedinformation, instructions and warnings to provide them with the knowledge to accept and follow the treatment and to acquire the necessary skills to take the drugs appropriately. Insomestudieslessthan60%ofpatientshadunderstoodhowto takethedrugstheyhadreceived.Informationshouldbegiveninclear,common languageanditishelpfultoaskpatientstorepeatintheirownwordssomeofthe coreinformation,tobesurethatithasbeenunderstood.Afunctionalname,such asaheartpillisofteneasiertorememberandclearerintermsofindication.
Box 9:
Aids to improving patient adherence to treatment
Patientleaflets Patientleafletsreinforcetheinformationgivenbytheprescriber andpharmacist.Thetext shouldbeinclear,commonlanguageandineasilylegibleprint. Pictorialsandshortdescriptions Ifthepatientcannotread,trypictorials.Iftheyarenotavailable,makepictorialsorshort descriptionsforyourownPdrugs,andphotocopythem. Daycalendar Adaycalendarindicateswhichdrugshouldbetakenatdifferenttimesoftheday.Itcanuse wordsorpictorials:alowsunontheleftformorning,ahighsunformidday,asinkingsun fortheendofthedayandamoonforthenight. Drugpassport Asmallbookorleaflet with anoverviewofthe different drugsthat the patient isusing, includingrecommendeddosages. Dosagebox Thedosageboxisbecomingpopularinindustrializedcountries.Itisespeciallyhelpfulwhen manydifferentdrugsareusedatdifferenttimesduringtheday.Theboxhascompartments forthedifferenttimesperday(usuallyfour),spreadoversevendays.Itcanthenberefilled
69
each week. Ifcost isaproblem, the box can be made locally from cardboard. Intropical countriesacoolandcleanplacetostoretheboxwillbenecessary. Evenifthepatientaidsdescribedheredon'texistinyourcountry,withcreativityyoucan oftenfindyourownsolutions.Theimportantthingistogiveyourpatientstheinformation andtoolstheyneedtousedrugsappropriately.
Thesixpointslistedbelowsummarizethe minimum informationthatshouldbe giventothepatient.
1.
Effectsofthedrug Whythedrugisneeded Whichsymptomswilldisappear,andwhichwillnot Whentheeffectisexpectedtostart Whatwillhappenifthedrugistakenincorrectlyornotatall Sideeffects Whichsideeffectsmayoccur Howtorecognizethem Howlongtheywillcontinue Howserioustheyare Whatactiontotake Instructions Howthedrugshouldbetaken Whenitshouldbetaken Howlongthetreatmentshouldcontinue Howthedrugshouldbestored Whattodowithleftoverdrugs Warnings Whenthedrugshouldnotbetaken Whatisthemaximumdose Whythefulltreatmentcourseshouldbetaken Futureconsultations Whentocomeback(ornot) Inwhatcircumstancestocomeearlier Whatinformationthedoctorwillneedatthenextappointment Everythingclear? Askthepatientwhethereverythingisunderstood Askthepatienttorepeatthemostimportantinformation Askwhetherthepatienthasanymorequestions
2.
3.
4.
5.
6.
70
Chapter10
Thismayseemalonglisttogothroughwitheachpatient. Youmaythinkthat thereisnot enough time;thatthe patientcan readthepackage insert withthe medicine;thatthepharmacistordispensershouldgivethisinformation;orthat toomuchinformationonsideeffectscouldevendecreaseadherencetotreatment. Yet it is the prime responsibility of the doctor to ensure that the treatment is understood by the patient, and this responsibility cannot be shifted to the pharmacistorapackageinsert. Maybenotallsideeffectshavetobementioned, butyoushouldatleastwarnyourpatientsofthemostdangerousorinconvenient sideeffects. Havingtoomanypatientsisneveracceptedbyacourtoflawasa validexcusefornotinformingandinstructingapatientcorrectly. Exercise:Patients3438 Review the following prescriptions and list the most important instructionsandwarningsthatshouldbegiventothepatient.You mayconsultyourpharmacologybooks.Casesarediscussedbelow. Patient34: Man,56years. Newlydiagnoseddepression. R/amitriptyline25mg,1 tabletdailyatnightforoneweek. Patient35: Woman,28years.Vaginaltrichomonasinfection.R/metronidazole500 mg,1vaginaltabletdailyfor10days. Patient36: Man,45years.Newlydiagnosedessentialhypertension.R/atenolol50 mg,1tabletdaily. Patient37: Boy,5years.Pneumonia.R/amoxicillinsyrup,5ml(=250mg)three timesdaily. Patient38: Woman,22years.Migraine.R/paracetamol500mg,2tablets20min. afterR/metoclopramide10mg1suppository,attheonsetofanattack. Patient34(depression) Itwilltakeapproximatelytwotothreeweeksbeforethepatientstartstofeelbetter, but side effects, such as dry mouth, blurred vision, difficulty in urinating and sedation, may occur quickly. Because of this many patients think that the treatmentisworsethanthediseaseandstoptakingthedrug.Iftheyarenottold thatthismayhappenandthattheseeffectsdisappearaftersometime,adherence to treatment will be poor. For this reason a slowly rising dosage schedule is usuallychosen,withthetabletstakenbeforebedtime. Thisshouldbeexplained carefully to the patient. Older people, especially, may not remember difficult dosageschedules.Writethemdown,orgiveamedicationbox. Youcanalsoask thepharmacisttoexplainitagain(writethisontheprescription).Instructionsare tofollow thedosage schedule,totakethedrugatbedtime andnottostopthe treatment. Warnings are that the drug may slow reactions, especially in combinationwithalcohol. Patient35(vaginaltrichomonas) 71
Asinanyinfectionthepatientshouldbetoldwhythecoursehastobefinished completely, even when the symptoms disappear after two days. The patient shouldalsobeinformedthattreatmentisuselessifthepartnerisnottreatedas well. Careful and clear instructions are needed for vaginal tablets. If possible, pictures or leaflets should be used to show the procedure (see Annex 3). Side effectsofmetronidazoleareametaltaste,diarrhoeaorvomiting,especiallywith alcohol,anddarkurine.Giveaclearwarningagainsttheuseofalcohol. Patient36(essentialhypertension) Theproblemwiththetreatmentofhypertensionisthatpatientsrarelyexperience any positive effect of the drugs, yet they have to take them for a long time. Adherencetotreatmentmaybeverypooriftheyarenottoldwhytheyshould takethedrug,andiftreatmentisnotmonitoredregularly.Thepatientshouldbe toldthatthedrugpreventscomplicationsofhighbloodpressure(angina,heart attack, cerebral problems). You can also say that you will try to decrease the dosage after three months, or even stop the drug entirely. Remember to check whetherthepatienthasahistoryofasthma. Patient37(boywithpneumonia) Thepatientsmothershouldbetoldthatthepenicillinwillneedsometimetokill thebacteria.Ifthecourseoftreatmentisstoppedtoosoon,thestrongeroneswill survive,andcauseasecond,possiblymoreseriousinfection.Inthiswayshewill understandwhyitisnecessarytofinishthecourse.Knowingthatanysideeffects will disappear soon will increase the likelihood of adherence to treatment. She shouldalsobetoldtocontactyouimmediatelyifarash,itchingorrisingfever occur. Patient38(migraine) Inadditiontootherinformation theimportantinstruction hereisthatthedrug (preferably a suppository) should be taken 20 minutes before the analgesic, to preventvomiting.Becauseofpossiblesedationandlossofcoordinationsheshould bewarnednottodriveacarorhandledangerousmachinery.
Sample page of a personal formulary
Tablet50,100mg
Betablocker
ATENOLOL
*DOSAGE Hypertension:startwith50mginthemorning.Average:50100mgperday. Anginapectoris:100mgperdayin12doses Adjusttoeachpatientindividually,startaslowaspossible.Raisethedoseafter2 weeks,ifneeded. *WHATTOTELLTHEPATIENT Information
72
Chapter10
Hypertension: drug decreases blood pressure, patient will usually not notice any effect.Drugwillpreventcomplicationsofhighbloodpressure(angina,heartattack, cerebrovascularaccident). Anginapectoris:decreasesbloodpressure,preventstheheartfromworkingtoohard, preventingchestpain. Sideeffects:hardlyany,sometimesslightsedation. Instructions Takethedrug..timesperday,for..days Warnings Anginapectoris:donotsuddenlystoptakingthedrug. Nextappointment Hypertension:oneweek. Angina pectoris: within one month, earlier if attacks occur more frequently, or becomemoresevere. *FOLLOWUP Hypertension:duringfirstfewmonthspulseandbloodpressureshouldbechecked weekly.Trytodecreasedosageafterthreemonths.Higherdosagesdonotincrease therapeuticeffect,butmayincreasesideeffects.Trytostoptreatmentfromtimeto time. Anginapectoris:incasefrequencyorseverityoftheattacksincrease,morediagnostic testsorothertreatmentareneeded.Trytostopdrugtreatmentfromtimetotime.
Your personal formulary

Duringyourmedicalstudiesyoushouldcontinuetoexpandyourlistofcommon complaintsanddiseases,withyourPdrugsandPtreatments.However,verysoon youwillnoticethatmanydrugsareusedformorethanoneindication.Examples areanalgesics,certainantibiotics,andevenmorespecificdrugslikebetablockers (used for hypertension and angina pectoris). You can, of course, repeat the necessarydruginformationwitheachdiseaseorcomplaint,butitmaybeeasierto make a separate section in your personal formulary where you collect the necessary information for each of your Pdrugs. This way you write down or updatethedruginformationonlyonce. Youcanalsofindtheinformationmore easilywhenyouneedit. ItisgoodadvicetonotetheessentialinstructionsandwarningswitheachPdrug inyourpersonalformulary.Ifyoudothisforeverynewdrugyoulearntouse,the formularywillbereasonablycompleteandreadyforusebythetimeyoufinish yourmedicalstudies.Anexampleofthecontentsofsuchapersonalformularyis givenonthepreviouspage.Pleasenotethatthisisnotapublishedtext,butshould beyourpersonal(handwritten?)summaryofimportantinformation.
Summary
STEP 5:
Give information, instruction and warnings
73
1.
Effectsofthedrug Whichsymptomswilldisappear;andwhen;howimportantisittotake thedrug;whathappensifitisnottaken; Sideeffects Whichsideeffectsmayoccur;howtorecognize them;howlongwill theyremain;howserioustheyare;whattodoiftheyoccur; Instructions When to take; how to take; how to store; how long to continue the treatment;whattodoincaseofproblems; Warnings Whatnottodo(driving,machinery);maximumdose(toxicdrugs);need tocontinuetreatment(antibiotics); Nextappointment Whentocomeback(ornot);whentocomeearlier;whattodowithleft overdrugs;whatinformationwillbeneeded; Everythingclear? Everythingunderstood;repeattheinformation;anymorequestions.
2.
3.
4.
5.
6.
74
Chapter11
Step6:Monitor(andstop?)thetreatment
C hapter 11
STEP 6: Monitor (and stop?) the treatment
Youhavenowlearnedhowtochoosearationaldrugtreatment,howtowritethe prescriptionandwhattotellyourpatient.Yetevenawellchosentreatmentmay notalwayshelpthepatient. Monitoringthetreatmentenablesyoutodetermine whetherithasbeensuccessfulorwhetheradditionalactionisneeded.Todothis youneedtokeepintouchwithyourpatient,andthiscanbedoneintwoways. Passive monitoring means that you explain to the patient what to do if the treatmentisnoteffective,isinconvenientoriftoomanysideeffectsoccur.Inthis casemonitoringisdonebythepatient. Activemonitoring meansthatyoumakeanappointmenttodetermineyourself whetherthetreatmenthasbeeneffective.Youwillneedtodetermineamonitoring interval,whichdependsonthetypeofillness,thedurationoftreatment,andthe maximumquantityofdrugstoprescribe. Atthestartoftreatmenttheintervalis usuallyshort;itmaygraduallybecomelonger,ifneeded.Threemonthsshouldbe the maximum for any patient on longterm drug therapy. Even with active monitoringthepatientwillstillneedtheinformationdiscussedinChapter10. The purpose of monitoring is to check whether the treatment has solved the patient's problem. You chose the treatment on the basis of efficacy, safety, suitabilityandcost.Youshouldusethesamecriteriaformonitoringtheeffect,but inpracticetheycanbecondensedintotwoquestions:isthetreatmenteffective? Arethereanysideeffects? Historytaking,physicalexaminationandlaboratorytestswillusuallyprovidethe informationyouneedtodeterminetheeffectivenessoftreatment. Insomecases moreinvestigationsmaybeneeded. Treatmentiseffective Ifthediseaseiscured,thetreatmentcanbestopped. 4Ifthediseaseisnotyetcured or chronic, and the treatment is effective and without side effects, it can be continued. If serious side effects have occurred you should reconsider your selecteddruganddosageschedule,andcheckwhetherthepatientwascorrectly instructed.Manysideeffectsaredosedependent,soyoumaytrytolowerthedose beforechangingtoanotherdrug.
Exceptincasesinwhichastandarddurationoftreatmentiscrucial,suchaswithmostantibiotics.
75
Table 8: Some examples of drugs in which a slow reduction in dose should be considered
Treatmentisnoteffective
If the treatment is not effective, with or without side effects, you should reconsider the diagnosis, the treatment Amphetamines which wasprescribed, whetherthedose Antiepileptics was too low, whether the patient was Antidepressants correctly instructed, whether the patient Antipsychotics actuallytookthedrug,andwhetheryour Cardiovasculardrugs monitoring is correct. When you have clonidine determined the reason for the treatment methyldopa failureyoushouldlookfor solutions. So betablockers thebestadviceistogoagainthroughthe vasodilators process of diagnosis, definition of Corticosteroids therapeutic objective, verification of the Hypnotics/sedatives suitability ofthePdrug forthis patient, benzodiazepines instructions and warnings, andmonitor barbiturates ing.Sometimesyouwillfindthatthereis Opiates norealalternativetoatreatmentthathas not been effective or has serious side effects.Youshoulddiscussthiswiththe patient. When you cannot determine why the treatment was not effective you shouldseriouslyconsiderstoppingit. Ifyoudecidetostopdrugtreatmentyoushouldrememberthatnotalldrugscan bestoppedatonce.Somedrugs(Table8)havetobetailedoff,withadecreasing dosageschedule. Exercise:patients3942 In the following cases, tryto decide whether the treatment can be stoppedornot.Casesarediscussedbelow. Patient39: Man, 40 years. Review visit after pneumonia, treated with oral ampicillin (2 grams daily) for one week. No symptoms remain, only slightunproductivecough.Examinationnormal. Patient40: Man,55years.Severemyalgiaandundefinedarthritisformanyyears. Hasbeenonprednisolone(50mgdaily)andindometacin(10mgdaily) foralongtime.Epigastricpainandpyrosisoverseveralmonths,for whichhetakesaluminumhydroxidetabletsfromtimetotime.During theconsultationhecomplainsthattheepigastricpainandpyrosishave notdisappeared;infacttheyhavebecomeworse. Patient41: Woman,52years.Mildhypertensionforthepasttwoyears.Responded well to a thiazide diuretic (25 mg daily). The maintenance dose has
76
Chapter11
alreadybeendecreasedtwicebecauseherbloodpressurehaddroppedto aroundnormal.Sheregularlyforgetstotakethedrug.
Patient42: Man,75years.Hadbeenprescribedtemazepamforoneweek,(10mg daily)becauseofsleeplessnessafterhiswifediedsixmonthsago.Heasks formore,becauseheisafraidhewillstillnotbeabletosleep.
Patient39(pneumonia) Thecourseoftreatmentwasdefinedinadvance.Itwaseffectiveandwithoutside effects.Theampicillincanbestopped. Patient40(epigastricpain) Inthiscasethetreatmenthasnotbeeneffectivebecausetheepigastricpainisaside effectofthedrugsusedformyalgia.Thetreatmentthatreallyneedsmonitoringis theantiinflammatorydrugs,notthealuminiumhydroxide. Theproblemcanbe solvedbyfindingoutwhetherthepainoccursatcertaintimes,ratherthanbeing continuous. In this case the dosage schedule could be adjusted to reach peak plasmaconcentrationsatthosetimes,andthetotaldailydosecouldbelowered. The lesson to be learned from this patient is that it is better to reconsider the originaltherapyratherthantotreatitssideeffectswithanotherdrug. Patient41(mildhypertension) Thistreatmentseemseffectiveandwithoutsideeffects.Thepatientisnolonger hypertensiveandmaynotneedcontinuedtherapy,especiallysincesheregularly forgetstotakethedrug.Youcanstopthetreatmentforassessmentbutyoumust continuetomonitorthepatient. Patient42(insomnia) As the patient wants to continue the treatment it was obviously effective. However,benzodiazepines canproduce psychological andphysical dependence whentakenregularlyformorethanafewweeks.Inaddition,tolerancedevelops quicklyandthiscanleadpatientstotakemorethantherecommendeddose.You shouldexplainthistothepatient andalsotellhimthatthenature ofthesleep induced by such drugs is not the same as normal sleep, but the result of suppressedbrainactivity.Encouragehimtotrytoreturntonaturalsleeppatterns; possiblyawarmbathorahotmilkdrinkwillhelptopromoterelaxationbefore bedtime.Itmayalsohelptoencouragehimtoexpresshisfeelingsabouthisloss; actingasasympatheticlistenerisprobablyyourmajortherapeuticroleinthiscase, ratherthanprescribingmoredrugs. Inthiscasethedrugcanbestoppedatonce becauseitwasonlyusedforoneweek.Thiscannotbedonewhenpatientshave takenbenzodiazepinesforlongerperiodsoftime.
77
Summary
STEP 6:
Monitor (and stop?) the treatment
Wasthetreatmenteffective? a.Yes,anddiseasecured: b.Yes,butnotyetcompleted: Stopthetreatment Anyserioussideeffects? No:treatmentcanbecontinued Yes:reconsiderdosageordrugchoice
c.No,diseasenotcured:
Verifyallsteps: Diagnosiscorrect? Therapeuticobjectivecorrect? Pdrugsuitableforthispatient? Drugprescribedcorrectly? Patientinstructedcorrectly? Effectmonitoredcorrectly?
78
Chapter11
79
art 4: Keeping up-todate
In this section various sources of drug and therapeutic information are discussed, together withtheirrelativeadvantagesanddisadvantages.It also includes practical advice on how to read scientific papers in general, and clinical trials in particular.
Chapter 12
page Howtokeepuptodateaboutdrugs........................................................................68 Makeaninventoryofavailableinformation..................................................68 Choosebetweensourcesofinformation.........................................................74 Efficientreading.................................................................................................74 Conclusion..........................................................................................................75
80
Chapter12
Howtokeepuptodateaboutdrugs
C hapter 12
How to keep up-to-date about drugs
Knowledgeandideasaboutdrugsareconstantlychanging.Newdrugscomeon themarketandexperiencewithexistingdrugsexpands.Sideeffectsbecomebetter known and new indications or ways of using existingdrugs are developed. In generalaphysicianisexpectedtoknowaboutdevelopmentsindrugtherapy.For example,ifadruginducedillnessoccurswhichthephysiciancouldhaveknown andprevented, courts inmany countries would hold thedoctor liable.Lack of knowledgeisnotanexcuse. Howcanyoukeepuptodate?Thisproblemcanbesolvedintheusualway:make an inventory of available types of information; compare their advantages and disadvantages;andchooseyourownsource(s)ofinformation.
Make an inventory of available sources of information

Therearenumeroussourcesofdruginformation,rangingfrominternationaldata bases, journals and reference books, to national or regional drug information centres,andlocallyproducedformulariesandbulletins.Annex2providesalistof essential references. Some sources are commercial and independent, others are noncommercial.Informationisavailableverballyorinwrittenform,ontapeor video,online(interactiveconnectionwithacentralcomputerdatabase)oron CDROM(CompactDiskReadOnlyMemory,acompactdiskwithinformation, readbypersonalcomputer). Referencebooks Reference books can cover general or clinical pharmacology, or specialize in a particularaspect.ExamplesofgeneralpharmacologicalreferencebooksinEnglish areGoodmanandGilmans ThePharmacologicalBasisofTherpautics andLaurence andBennettsClinicalPharmacology(seeAnnex2).Goodequivalentsexistinother languages.Animportantcriterioninchoosingreferencebooksisthefrequencyof new editions. Only publications that are revised every two to five years can provideuptodateknowledge. Martindales TheExtraPharmacopoeia isanexcellentreferencebookwithdetailed druginformationonmostactivesubstancesandchemicals.However,itdoesnot distinghuish between essential and nonessential drugs and does not contain comparativetherapeuticinformation.AverysDrugTreatmentisamorespecialized book,appropriateforprescriberswithaspecialinterestinclinicalpharmacology.
81
AnotherexampleofaspecializedtextbookisMeyler'sSideEffectsofDrugs,which provides an annually updated assessment of side effects of drugs reported worldwide.Itis,however,expensive.Otherspecializedbooksaddresssuchareas aspsychotropicdrugs,orspecificriskgroupssuchasdrugsinlactation,drugsfor children,ordrugsfortheelderly. Drugcompendia In many countries there are publications that list the drugs available on the market.Thesecompendiavaryintypeandscopebutusuallyincludegenericand brand names; chemical composition; clinical indications and contraindications; warnings, precautions and interactions; side effects; administration and dosage recommendations. Some are based on the official labelling information for the product as approved by the national regulatory authority. An example is the annualPhysician'sDeskReference,whichisavailablefreeofchargetophysiciansin theUnitedStates. Commercially sponsored drug compendia may have additional limitations. For example, thedruglistingmay be incomplete, andcomparative assessmentsare usually lacking. An example is the Monthly Index of Medical Specialities (MIMS) whichispublishedindifferentpartsoftheworld. However,comprehensiveandobjectivecompendiaareavailablewhichdoinclude comparative assessmentsand/or provide criteria forchoice withinwelldefined therapeutic drug categories. Examples are the United States Pharmacopeia Dispensing Information (USP DI), which is not available free of charge, and the British National Formulary (BNF), which is free to all UK prescribers. The latter includesinformationoncost,whichisnotoftenincludedinothercompendia.The frequentrevisionsofbothpublicationscontributetotheirvalue.Infact,theyare issuedsofrequentlythatoldcopies,whichmaybeavailableatverylowcostor freeofcharge,remainusefulforquitesometime. Nationallistsofessentialdrugsandtreatmentguidelines Inmanydevelopingcountriesanationallistofessentialdrugsexists.Itusually indicates the essential drugs chosen for each level of care (dispensary, health centre, district hospital, referral hospital). It is based on a consensus on the treatmentofchoiceforthemostcommondiseasesandcomplaints,anddefinesthe rangeofdrugsthatisavailabletoprescribers.Ifnonationallistofessentialdrugs exists,youmayconsulttheWHOmodellist(seeAnnex2).Veryoftennational treatmentguidelines,whichincludethemostimportantclinicalinformationforthe prescriber (treatment of choice, recommended dosage schedule, side effects, contraindications,alternativedrugs,etc.)areavailable.Youshouldverifywhether suchguidelinesexistinyourcountry.Trytoobtainthemostrecentedition. Drugformularies Formulariescontainalistofpharmaceuticalproducts,togetherwithinformation on each drug. They can be national, regional or institutional. They are usually
82
Chapter12
developedbytherapeuticcommitteesandtheylistthedrugsthatareapprovedfor useinthatcountry,region,districtorhospital.Inmanycountriesdrugformularies arealsodevelopedforhealthinsuranceprogrammes,listingtheproductsthatare reimbursed.Drugformulariesareusuallydrugcentred.Theirvalueisenhancedif theycontaincomparisons betweendrugs, evaluations andcostinformation, but thatisoftennotthecase.TheexcellentBNFhasalreadybeenmentioned.Trytoget yourowncopy,evenifitisnotthemostrecentone.Itfitswellinyourpocket. Drugbulletins Theseperiodicalspromoterationaldrugtherapyandappearatfrequentintervals, rangingfromweeklytoquarterly.Independentdrugbulletins,i.e.nonindustry sponsored, provide impartial assessments of drugs and practical recommend ations,basedonacomparisonbetweentreatmentalternatives. Drug bulletins can be a critical source of information in helping prescribers to determine the relative merits of new drugs and in keeping uptodate. Drug bulletinscanhaveavarietyofsponsors,suchasgovernmentagencies,professional bodies, university departments, philanthropic foundations and consumer organizations.Theyarepublishedinmanycountries,areoftenfreeofcharge,and arehighlyrespectedbecauseoftheirunbiasedinformation.ExamplesinEnglish are: Drug and Therapeutics Bulletin (UK), Medical Letter (USA) and Australian Prescriber(Australia).AgoodindependentdrugbulletininFrenchisPrescrire;itis notfreeofcharge. National drug bulletins are appearing in an increasing number of developing countries, which include Bolivia, Cameroon, Malawi, the Philippines and Zimbabwe.Themainadvantagesofnationaldrugbulletinsarethattheycanselect topicsofnationalrelevanceandusethenationallanguage. Medicaljournals Somemedicaljournalsaregeneral,suchasTheLancet,theNewEnglandJournalof MedicineortheBritishMedicalJournal;othersaremorespecialized.Mostcountries have their own national equivalents. Both types contain much information of relevancetoprescribers.Thegeneraljournalsregularlypublishreviewarticleson treatment. The specialized journals include more detailed information on drug therapyforspecificdiseases. Good medical journals are 'peer reviewed', that is, all articles are sent for independentexpertreviewpriortopublication.Youcanusuallycheckwhether journals meet thisimportant criterion byreading thepublished instructions for submissionofarticles. Some journals are not independent. They are usually glossy and often present informationinaneasilydigestibleformat.Theycanbecharacterizedas:freeof charge, carrying more advertisements than text, not published by professional bodies,notpublishingoriginalwork,variablysubjecttopeerreview,anddeficient in critical editorials and correspondence. In the industrialized world they are
83
promotedtothephysicianasa'waytosavetime'.Infactreadingthemisalossof time,whichiswhytheyarecommonlyreferredtoas'throwaways'.Alsobecareful with journal supplements. They sometimes report on commercially sponsored conferences;infact,thewholesupplementmaybesponsored. Sodon'tassumethatbecauseareviewarticleorresearchstudyappearsinprint thatitisnecessarilygoodscience.Thousandsof 'medical' journalsarepublished andtheyvaryenormouslyinquality.Onlyarelativelysmallproportionpublish scientificallyvalidated,peerreviewedarticles.Ifindoubtaboutthescientificvalue ofajournal,verifyitssponsors,consultseniorcolleagues,andcheckwhetheritis includedintheIndexMedicus,whichcoversallmajorreputablejournals. Verbalinformation Anotherwaytokeepuptodateisbydrawingontheknowledgeofspecialists, colleagues, pharmacists or pharmacologists, informally or in a more structured way through postgraduate training courses or participation in therapeutic committees. Community based committees typically consist of general practitionersandoneormorepharmacists.Inahospitalsettingtheymayinclude several specialists, a clinical pharmacologist and/or a clinical pharmacist. Such committeesmeetregularlytodiscussaspectsofdrugtreatment.Insomecasesthey establishlocalformulariesandfollowupontheiruse.Usingaclinicalspecialistas thefirstsourceofinformationmaynotbeidealwhenyouareaprimaryhealth carephysician.Inmanyinstancestheknowledgeofspecialistsmaynotreallybe applicable toyour patients. Some of the diagnostic tools or more sophisticated drugsmaynotbeavailable,orneeded,atthatlevelofcare. Druginformationcentres Somecountrieshavedruginformationcentres,oftenlinkedtopoisoninformation centres.Healthworkers,andsometimesthegeneralpublic,cancallandgethelp withquestionsconcerningdruguse,intoxications,etc.Moderninformatics,such asonlinecomputersandCDROM,havedramaticallyimprovedaccesstolarge volumesofdata.Manymajorreferencedatabases,suchasMartindaleandMeylers SideEffectsofDrugs,arenowdirectlyaccessiblethrough internationalelectronic networks. When drug information centres are run by the pharmaceutical department of the ministry of health, the information is usually drug focused. Centreslocatedinteachinghospitalsoruniversitiesmaybemoredrugproblemor clinicallyoriented. Computerizedinformation Computerized drug information systems that maintain medication profiles for everypatienthavebeendeveloped.Someofthesesystemsarequitesophisticated and include modules to identify drug interactions or contraindications. Some systemsincludeaformularyforeverydiagnosis,presentingtheprescriberwitha numberofindicateddrugsfromwhichtochoose,includingdosagescheduleand quantity.Prescriberscanalsostoretheirownformularyinthecomputer.Ifthisis done,regularupdatingisneededusingthesourcesofinformationdescribedhere.
84
Chapter12
Cartoon5
In many parts of the world access to the hardware and software needed for this technology will remain beyond the reach of individual prescribers. In countries where such technology is easily accessible it can make a useful contribution to prescribing practice. However, such systems cannot replaceinformedprescriberchoice,tailoredto meettheneedsofindividualpatients.
Pharmaceutical industry sources of information Informationfromthepharmaceuticalindustry is usually readily available through all channels of communication: verbal, written and computerized. Industry promotionbudgetsarelargeandtheinformationproducedisinvariablyattractive andeasytodigest.However,commercialsourcesofinformationoftenemphasize onlythepositiveaspectsofproductsandoverlookorgivelittlecoveragetothe negative aspects. This should be no surprise, as the primary goal of the informationistopromoteaparticularproduct.Commercialinformationisoften tailoredtotheprescriber'sspecificsituation:informationonanantinauseantgiven toagynaecologistinauniversityhospitalmaydifferfromthatgiventoageneral practitionerinruralpractice. Usuallythepharmaceuticalindustryusesa'multitrack'approach.Thismeansthat theinformationisprovidedthroughanumberofmedia:medicalrepresentatives (detailmen/women),standsatprofessionalmeetings,advertisinginjournalsand directmailing. Fromindustry'spointofview,medicalrepresentativesareusuallyveryeffectivein promoting drug products, and much more effective than mailings alone. Often over50%ofthepromotionalbudgetofpharmaceuticalcompaniesinindustrialized countries is spent onrepresentatives. Studies from a number of countries have shown that over 90% of physicians see representatives, and a substantial percentage rely heavily on them as sources of information about therapeutics. However,theliteraturealsoshowsthatthemorereliantdoctorsareoncommercial sourcesofinformationonly,thelessadequatetheyareasprescribers. Indecidingwhetherornottousetheservicesofdrugrepresentativestoupdate yourknowledgeondrugs,youshouldcomparethepotentialbenefitswiththoseof spendingthesametimereadingobjectivecomparativeinformation. Ifyoudodecidetoseerepresentatives,therearewaystooptimizethetimeyou spendwiththem.Takecontrolofthediscussionattheoutsetsothatyougetthe information you need about the drug, including its cost. If your country has a health insurance scheme, check whether the drug is included in the list of
85
reimbursableproducts.Earlyoninthediscussionasktherepresentativetogive youacopyoftheofficiallyregistereddruginformation(datasheet)ontheproduct underdiscussion,andduringthepresentationcomparetheverbalstatementswith thoseintheofficialtext.Inparticularlookatsideeffectsandcontraindications. Thisapproachwillalsohelpyoutomemorizekeyinformationaboutthedrug. Always ask forcopies of the published references on efficacy and safety. Even beforereadingthese,thequalityofthejournals inwhichtheyappearwillbea strong indication of the likely quality of the study. You should know that the majorityofnewlymarketeddrugsdonotrepresenttruetherapeuticadvancesbut arewhatisknownasmetooproducts.Inotherwords,theyareverysimilarin chemicalcompositionandactiontootherproductsonthemarket.Thedifferenceis usuallyinprice;themostrecentlymarketeddrugisusuallythemostexpensive! Seeing medical representatives can be useful to learn what is new, but the informationshouldalwaysbeverifiedandcomparedwithimpartial,comparative sources. Druginformationfromcommercialsourcesisalsoissuedasnewsreports,andas scientific articles in professional journals. Industry is also a major sponsor of scientificconferencesandsymposia.Thelinebetweenobjectiveandpromotional information is not always clear. A number of countries and professional associationsaretighteningregulations controllingdrugpromotion totacklethis problem. Some journals now require that any sponsorship from the pharmaceuticalindustryshouldbementionedinthearticle. As mentioned above and as studies show, it is not good practice to use only commercialinformationtokeepuptodate.Althoughitmayseemaneasywayto gather information, this source is often biased towards certain products and is likely to result in irrational prescribing. This is particularly true for countries withoutaneffectiveregulatoryagency,becausemoredrugsofsometimesdoubtful efficacymaybeavailableandtheremaybelittlecontrolonthecontentsofdata sheetsandadvertisements. WHOhasissuedEthicalCriteriaforMedicinalDrugPromotionwhichcontainglobal guidelines for promotional activities. The International Federation of Pharmaceutical Manufacturers Associations also has a code of pharmaceutical marketing practices. Inseveral countries national guidelines existaswell.Most guidelinesspecifythatthepromotionalinformationshouldbeaccurate,complete and in good taste. It is a very good exercise to compare a number of drug advertisementswiththenationalorglobalcriteria.Mostguidelinesalsocoverthe use of samples and gifts, participation in promotional conferences and clinical trials,etc. Ifyoudousecommercialinformationfollowthesegroundrules.First,lookfor moreinformationthanadvertisementscontain.Second,lookoraskforreferences, andchecktheirquality.Onlyreferencesinwellestablishedpeerreviewedjournals shouldbetakenseriously.Thencheckthequalityoftheresearchmethodologyon which the conclusions are based. Third, check what your colleagues, and preferablyaspecialistinthefield,knowaboutthedrug.Finally,alwayscollect 86
Chapter12
datafromunbiasedsourcesbeforeactuallyusingthedrug.Donotstartbyusing free samples on a few patients or family members, and do not base your conclusionsonthetreatmentofafewpatients! Yetcommercialinformationissometimeshelpfulinageneralsense,especiallyto know of new developments. However, comparative information from drug bulletinsortherapeutic reviews isabsolutelyessential tohelpyouevaluate the newdruginrelationtoexistingtreatments,andtodecidewhetheryouwishto includeitinyourpersonalformulary.
Choose between sources of information

Theadvantagesanddisadvantagesofvariousdruginformationsourceshavebeen outlined. Possible information sources will vary according tocountry and your ownpersonalsituation.Yourjobisnowtodecidehowbesttokeepuptodate,by makingalistofallthepossibleresourcestowhichyouhaveaccess.Trytofindat least one each of the following: (1) medical journals; (2) drug bulletins; (3) pharmacology or clinical reference books; (4) therapeutic committees or consultantsorapostgraduatetrainingcourse. Althoughyourprimarysource of prescribing information in your dailyclinical work should be your personal formulary, you will sometimes face a difficult problem, which calls for an additional source of information. This could be a pharmacologyorclinicalreferencebook,adrugbulletin,consultants(pharmacist, specialist,colleagues),adrugcompendiumoraformulary. The limitations of commercial information have been clearly described. If you decide,nevertheless,that ithas arole toplay, follow theground rules already outlined. But do not use commercial information in isolation from other more objectivesources.
Efficient reading
Articles Many prescribers have a problem in reading everything they would like. The reasonsarelackoftimeandinindustrializedcountriesthesheervolumeof materials mailed to them. It's wise to adopt a strategy to use your time as efficientlyaspossible. Youcansavetimewhenreadingclinicaljournalsbyidentifyingatanearlystage articleswhichareworthreading,throughthestepslistedbelow. 1. Lookatthe title todetermineifitappearsinterestingorusefultoyou.Ifnot, moveontothenextarticle. 2. Review the authors. The experienced reader will know of many authors whethertheygenerallyprovidevaluableinformationornot.Ifnot,rejectthe article.Iftheauthorsareunknown,givethemthebenefitofthedoubt. 87
3. Readthe abstract.Themainpointhereistodecidewhethertheconclusionis importanttoyou.Ifnot,rejectthearticle. 4. Considerthesitetoseeifitissufficientlysimilartoyourownsituation,and decidewhethertheconclusionmaybeapplicabletoyourwork.Forexample,a conclusionfromresearchinahospitalmaynotberelevantforprimarycare.If thesitedifferstoomuchfromyourownsituation,rejectthearticle. 5. Checkthematerialsandmethodssection.Onlybyknowingandacceptingthe researchmethodcanyoudecidewhethertheconclusionisvalid. 6. Check the references. If you know the subject you will probably be able to judge whether the authors have included the key references in that field. If thesearemissing,becareful. Clinicaltrials Itisbeyondthescopeofthisbooktogointothedetailsofhowreportsonclinical trialsshouldbeassessed,butafewgeneralprinciplesaregivenhere.Generally, only randomized, doubleblind clinical trials give valid information about the effectivenessofatreatment.Conclusionsdrawnfromstudiesofotherdesignmay bebiased. Second,acompletedescriptionofaclinicaltrialshouldinclude(1)thepatientsin the trial, with number, age, sex, criteria for inclusion and exclusion; (2) administrationofthedrug(s):dose,route,frequency,checksonnonadherenceto treatment,duration;(3)methodsofdatacollectionandassessmentoftherapeutic effects;and(4)adescriptionofstatisticaltestsandmeasurestocontrolforbias. Finallyyou shouldlookat theclinical relevance ofthe conclusion, not onlyits statistical significance. Many statistical differences are too small to be clinically relevant. Sometimesconflictingevidenceispresentedbydifferentsources.Ifindoubt,first checkonthemethodology,becausedifferentmethodsmaygivedifferentresults. Thenlookatthepopulation studiedtoseewhich oneismore relevant toyour situation.Ifdoubtsremain,itisbettertowaitandtopostponeadecisiononyour Pdrugchoiceuntilmoreevidencehasemerged.
Conclusion
Keeping uptodate should not be too difficult for prescribers in developed countries; it can be far from easy in some parts of the world where access to independentsourcesofdruginformationisverylimited.Butwhereveryoulive andworkitisimportanttodevelopastrategytomaximizeyouraccesstothekey informationyouneedforoptimalbenefitofthedrugsyouprescribe.Beawareof thelimitationsofsometypesofinformation,andspendyourtimeoninformation thatisworthit.
88
Chapter12
89
nnexes
Annex 1:
page
Essentialsofpharmacologyindailypractice..................................................79
Annex 2:
Essentialreferences............................................................................................85
Annex 3:
Howtoexplaintheuseofsomedosageforms...............................................87
Annex 4:
Theuseofinjections.........................................................................................101
90
Annex1
91
A nnex 1
Essentials of pharmacology in daily practice
Contents
Introduction................................................................................................................79 Pharmacodynamics....................................................................................................80 TheCp/responsecurve.................................................................................80 Pharmacokinetics.......................................................................................................80 TheCp/timecurvewithatherapeuticwindow........................................81 Drugtreatment...........................................................................................................82 Startingdrugtreatment.................................................................................82 Steadystatedrugtreatment.........................................................................82 Stoppingdrugtreatment...............................................................................83 Specialfeaturesofthecurve....................................................................................83 Loadingdose...................................................................................................83 Slowlyraisinginitialdose.............................................................................84 Taperingthedose...........................................................................................84
Introduction Pharmacology describes the interaction between drugs and organisms. In this interactiontwofeaturesareespeciallyimportant. Pharmacodynamics dealswith theeffectsofadrugonthebody;howadrugactsanditssideeffects,inwhich tissues,atwhichreceptorsites,atwhichconcentration,etc.Theeffectsofdrugs maybealteredbyotherdrugsordiseasestates.Antagonism,synergism,addition and other phenomena are also described by pharmacodynamics. Pharmacokinetics deals with the effects of the body on the drug, through Absorption,Distribution,MetabolismandExcretion(ADME). The dynamics and kinetics of a drug determine its therapeutic usefulness. The pharmacodynamics ofadrugdetermineitseffectivenessandwhichsideeffects mayoccur,andatwhatconcentration. Theprescriberhasverylittleinfluenceon this.The pharmacokineticsofadrugdeterminehowoften,inwhatquantityand dosageformandforhowlongthedrugshouldbegiventoreachandmaintainthe
92
Annex1
Pharmacodynamics
required plasma concentration. As the prescriber can actively influence the process,thefollowingsectionconcentrateson Figure10:Doseresponsecurve thisaspect. Theeffectsofadrugareusuallypresentedin adoseresponsecurve.Theeffectofthedrug isplottedontheYaxisandthedoseonthe Xaxis(Figure10).Thedoseisusuallyplotted onalogarithmic scale. The higher the dose thestrongertheeffect,untiltheeffectlevels off to a maximum. The effect is usually expressedasapercentageofthemaximum. Themaximumeffectofonedrugmaybemorethanthatofanother.Desiredand sideeffectscanbothbeplottedindoseresponsecurves. Thedoseisusuallyexpressedperkilogrambodyweightorperm bodysurface area.However,themostaccuratewayistousetheplasmaconcentration,because itexcludesdifferencesinabsorptionandeliminationofthedrug.Inthefollowing texttheplasmaconcentrationresponsecurve(Cp/responsecurve)isused.
2
TheCp/responsecurve TheshapeoftheCp/responsecurveisdeterminedbypharmacodynamicfactors. Cp/responsecurvesreflecttheresultinanumberofindividuals,referredtoasa population.Iftheplasmaconcentrationislowerthanwherethecurvebegins,0% ofthepopulationwillexperienceaneffect.Aneffectof50%meansthattheaverage effectinthetotalpopulationis50%ofthemaximum(andnota50%effectinone individual)(Figure10). Unfortunately,mostdrugshaveaCp/responsecurveforsideeffectsaswell.This curve should be interpreted in the same way as Cp/response curves. The two curvestogetherdefinetheminimumandmaximumplasmaconcentrations.The concentrationthatgivestheminimumusefuleffectisthe therapeuticthreshold, whiletheplasmaconcentrationatwhichthemaximumtoleratedsideeffectsoccur iscalledthetherapeuticceiling.RememberthatCp/responsecurvesrepresentthe dynamicsinagroupofpatients,andcanonlyofferaguidelinewhenthinkingin termsofanindividualpatient.
Pharmacokinetics
Adose isusually repeatedover acertain period. Theplasmaconcentrationinoneormorepatients duringacertainperiodisdepictedinasocalled plasmaconcentration/timecurve(Cp/timecurve). Figure 11showstheCp/timecurve ofthefirst7 daysafterstartingtreatment.
Figure11:Cp/timecurve
93
The shape of the Cp/time curves is defined by Figure12: Cp/timecurve,dose doubled pharmacokinetic factors. The relationship between dose and plasma concentration is linear. This impliesthatifthedoseisdoubled,thesteadystate plasmaconcentrationisalsodoubled(Figure12). TheCp/timecurvewithatherapeuticwindow TwohorizontallinescanbeplacedovertheCp/time curve,indicatingtherapeuticthresholdandceiling. The space between these two lines is called the therapeutic window (Figure 13). Drug treatment aims at plasma concentrations within this Figure13: Cp/timecurveand therapeutic window. The possible variables to be therapeuticwindow considered are therefore (1) the position and the widthofthewindow,and(2)theprofileofthecurve. Therapeuticwindow The position and the width of the window are determinedbypharmacodynamicfactors(Figure14). The position of the window may shift upwards in case of resistance by the patient or competitive antagonism by another drug: a higher plasma concentrationisneededtoexertthesameeffect.The window can shift downwards in case of Figure14: Placeandwidthof therapeuticwindow hypersensitizationorsynergismbyanotherdrug: a lowerplasmaconcentrationisneeded. The width of the window may also vary. It may become narrower in case of a decreased safety margin. For example, the therapeutic window of theophylline is narrower in small children than in adults. A broader window usually has no consequences. Curve Theprofileofthecurveisdeterminedbyfourfactors: Absorption, Distribution, Metabolism and Excretion. These are usually referred to as ADME factors. Although most treatments consist of more than one dose of a drug, some pharmacokineticparameterscanbestbeexplainedbylookingattheeffectofone doseonly. Oneofthemostimportantparametersisthehalf life of a drug (Figure 15). Most drugs are eliminatedbymeansofafirstorderprocess.This meansthatperunitoftimethesamepercentageof drugiseliminated,forexample6%perhour.The Figure15: Halflifeofadrug
94
Annex1
halflifeofadrugisthetimeittakestodecreasetheplasmaconcentrationtohalfof itsinitialvalue.With6%perhourthehalflifeisabout11hours(ifnomoreofthe drugisgiveninthemeantime).After2halflives(22hours)itwillbe25%;after3 halflives12.5%;andafter4halflives6.25%.Iftheoriginalplasmaconcentration fallswithinthetherapeuticwindow,adeclineto6.25%willusuallybefarbelow thetherapeuticthreshold.Forthisreasonitisusuallysaidthatdrugsnolonger haveapharmacologicaleffect4halflivesafterthelastdose.
Drug treatment
ThetotalCp/timecurveisinfluencedbythreeactionsbytheprescriber:starting the drugtreatment; steady state treatment; stopping the treatment. All have a distincteffectonthecurve. Startingdrugtreatment Themostimportantissueinstartingtreatmentis thespeedatwhichthecurvereachessteadystate, withinthetherapeuticwindow.Ifyougiveafixed dose per unit of time, this speed is only determinedbythehalflifeofthedrug.Onafixed dosage schedule, steady state is reached after about4halflives(Figure16).Incaseofalonghalf lifeitmaythereforetakesometimeforthedrugto reachatherapeutic concentration. Ifyouwant to reachthewindowquicker,youcanusealoading dose(seebelow). Steadystatedrugtreatment In steady state drug treatment two aspects are important.First,themeanplasmaconcentrationis determined by the dose per day. The relation betweendoseandplasmaconcentration islinear: atdoubledosethemeanplasmaconcentrationalso doubles.
Figure17:Dosedependent fluctuationsinthe Cp/timecurve Figure16: Steadystateisreached after4halflives
Second, fluctuations in the curve are determined bythefrequencyofadministration.Withthesame total dose per day, a higher frequency of administration gives fewer fluctuations in the curve(Figure17).Withacontinuousinfusionthere arenofluctuationsatall. Ifyoudecidetoraisethedoseitwillagaintakeabout4halflivesbeforeyoureach thenewsteadystate.Thesameapplieswhenyoudecreaseitbygivingalower dose.
95
Stoppingdrugtreatment Fordrugswithfirstorderelimination kineticsthe plasmaconcentrationdecreasesby50%eachhalf lifeperiod,ifnomoreofthedrugistaken(Figure 18). The effect of the drug stops when the concentrationfallsbelowthetherapeuticthreshold. Forexample,iftheinitialplasma concentration is 300ug/ml,thetherapeuticthreshold75ug/mland thehalflife8hours,thiswilltake16hours(2half lives).Thisprincipleappliesequallytodrugstaken inoverdose.
Figure18: Stoppingdrugtreatment
Somedrugsareeliminatedbyzeroordereliminationprocess.Thismeansthatthe same amount of drug is eliminated per period of time. For example, 100 mg is eliminatedperday,regardlessofwhetherthetotalamountinthebodyis600mg or20grams.Suchdrugsdonothaveahalflife.ThisalsomeansthattheCp/time curveneverlevelsofftoacertain maximum:theplasma concentration canrise forever if more of the drug is administered than the body can eliminate. To maintainasteadystateyouwillhavetoadministerexactlytheamountthatthe bodyeliminates.Thedosageofdrugsinthiscategoryrequiresgreatcarebecause ofthe increased riskof accumulation. Fortunately only a few such drugs exist. Examplesarephenytoin,dicoumarolandprobenicid.Acetylsalicylicacidinhigh dosage(gramsperday)alsobehaveslikethis.Andsodoesalcohol!
Special features of the curve

In commonly used dosage schedules with identical doses taken at regular intervals, the required steady state is reached after 4 halflives, and plasma concentrationdropstozerowhenthetreatmentisstopped. Loadingdose Theremaybereasonstouseanotherschedule.In steadystatethetotalamountofdruginthebody remains constant. If you want to reach this state quickly you can administer at once the total amount of drug which is present in the body in steady state (Figure 19). What quantity is then needed? Theoretically you will need the mean plasma concentration, multiplied by the distributionvolume.Inthemajorityofcasesthese figures can be found in pharmacology books, or may be obtained from the pharmacist or the manufacturer. For several drugs fixed schedules exist,e.g.fordigoxin. Slowlyraisinginitialdose
Figure19:Loadingdose
96
Annex1
Somedrugscannotbeusedinfulldosageatonce.Therearethreepossiblereasons forthis.Thefirstreasoniswhenadrughasanarrowtherapeuticwindowora largevariationinlocationofthetherapeuticwindowinindividuals.Theaimisto getslowlywithinthewindow,withoutanovershoot.Thisiscalleddosefinding. Asecondreason isvariation in kinetics among different patients. Athird is to inducetoleranceofsideeffects.Theruleisgolow,goslow. Asmentionedearlier,ittakesabout4halflivestoreachasteadystate.Thismeans that you should not raise the dose before this time has elapsed and you have verifiedthatnounwantedeffectshaveoccurred.Table7inChapter8listsdrugsin whichslowlyraisingthedoseisusuallyrecommended. Taperingthedose Sometimes the human body gets used to the presence of a certain drug and physiologicalsystemsareadjustedtoitspresence.Topreventreboundsymptoms thetreatmentcannotbeabruptlystoppedbutmustbetailedofftoenablethebody toreadjust.Todothisthedoseshouldbeloweredinsmallstepseachtimeanew steadystateisreached.Table8inChapter11liststhemostimportantdrugsfor whichthedosageshouldbedecreasedslowly.
97
A nnex 2
Essential references
Practical low-cost books on drugs and prescribing
National essential drugs list, national formulary, hospital formulary, institutionalandnationaltreatmentguidelines.Theseareessentialtoolsinyour prescribing,astheyindicatewhichdrugsarerecommendedandavailableinthe healthsystem.Ifthesereferencesdonotexist: WHOModelListofEssentialDrugs.See:Theuseofessentialdrugs(containing thelatestmodellist)underWHOpublicationsonp.86.Intheabsenceofanational list,theWHOmodellistoffersagoodindicationofeffective,safeandrelatively cheapessentialdrugswithineachtherapeuticcategory. WHOtreatmentguidelinesforcommondiseases,suchasacuterespiratorytract infections, diarrhoeal diseases, malaria and other parasitic diseases, sexually transmitted diseases, tuberculosis, leprosy and others. These are very useful references,basedoninternationalexpertconsensus.Inmanycasestheyareused bycountrieswhendevelopingtheirnationaltreatmentguidelines. British National Formulary. London: British Medical Association & The PharmaceuticalSocietyofGreatBritain.Thisisahighlyrespectedreferencework containing essential information on a selection of drugs available on the UK market, with price indication. There are short evaluative statements for each therapeutic group. Although revised every six months, old issues remain a valuablesourceofinformationandmaybeavailabletoyouatnoorverylowcost. ClinicalGuidelines Diagnostic andTreatment Manual.Paris: Mdecins sans Frontires.Editions Hatier,1990.This isaverypractical book,whichislargely basedonWHOtreatmentguidelinesforcommondiseases.
Major reference works

AveryGS.DrugTreatment.2nded.Sydney:ADISPress,1987. LaurenceDR,BennettPN. ClinicalPharmacology.7thed.Edinburgh:Churchill Livingstone,1992. Goodman&Gilman. ThePharmacologicalBasisofTherapeutics.8thed.New York:McMillanPublicationsCo,1992. Martindale. The Extra Pharmacopoeia. 30th Ed. London: Pharmaceutical Press, 1993
98
Annex2
USP DI, Vol. 1.: Drug Information for the Health Care Provider, Vol. 2.: InformationforthePatient.UnderauthorityoftheUnitedStatesPharmacopeial ConventionInc.,12601TwinbrookParkway,Rockville,Maryland20832,USA.
Drug bulletins
DrugandTherapeuticsBulletin,ConsumersAssociation,14BuckinghamStreet, LondonWC2N6DS,UK.Publishedfortnightly;offerscomparativeassessmentsof therapeuticvalueofdifferentdrugsandtreatments. PrescrireInternational,AssociationMieuxPrescrire,BP459,75527ParisCedexll, France.Publishedquarterly;providesEnglishtranslationsofselectedarticleson clinicalpharmacology,ethicalandlegalaspectsofdrugs,whichhaveappearedin LaRevuePrescrire. TheMedicalLetter,TheMedicalLetterInc.56HarrisonStreet,NewRochelle,NY 10801,USA.Publishedfortnightly;providescomparativedrugprofilesandadvice onthechoiceofdrugsforspecificproblems. Ifyouwanttocheckwhetheranindependentdrugbulletinispublishedinyour countrycontact:TheInternationalSocietyofDrugBulletins,l03HertfordRoad, LondonN29BX,UK,ortheWHOActionProgrammeonEssentialDrugs.
WHO publications
TheUseofEssentialDrugs(includingthe8thModelListofEssentialDrugs). Geneva: World Health Organization, 1995. Technical Report Series 850. This bookletalsocontainsthecriteriafortheselectionofessentialdrugsandinformation onapplicationsofthemodellist.Thebookisupdatedeverytwoyears. WHO Model Prescribing Information. Geneva: World Health Organization. A seriesofauthoritativebookletswithunbiaseddruginformationfortheprescriber, includingmostdrugsontheWHOModel ListofEssentialDrugs.Eachmodule dealswithonetherapeuticgroup.Theseriesisnotyetcomplete. WHO Ethical Criteria for Medicinal Drug Promotion. Geneva: World Health Organization, 1988.This isthetextofa WHOstatementadoptedbytheWorld HealthAssemblyof1988,settingoutgeneralprincipleswhichcouldbeadaptedby governmentstonationalcircumstances.ReprintedinEssentialDrugsMonitor17. WHODrugInformation.Geneva:WorldHealthOrganization.Aquarterlyjournal thatprovidesanoverviewoftopicsrelatingtodrugdevelopmentandregulation.It seekstorelateregulatoryactivitytotherapeuticpractice. International Nonproprietary Names (INN) for Pharmaceutical Substances. Geneva: World Health Organization, 1992. This book contains an updated cumulative list of officially approved generic names in Latin, English, French, RussianandSpanish.
99
EssentialDrugsMonitor,Geneva:WorldHealthOrganization,ActionProgramme onEssentialDrugs. Freeofcharge andpublishedthreetimesperyear;contains regular features on issues related to the rational use of drugs, including drug policy,research,educationandtraining,andareviewofnewpublications.
100
Annex3
A nnex 3
How to explain the use of some dosage forms
Information,insimplelanguage,onhowtoadministereyedropstoachildorhow touseanaerosolinhalerisnotalwayseasilyavailable.Thisannexcontainsstepby stepguidance onhowtoadministerdifferent dosage forms.Thisinformation is included because, as a doctor, you are ultimately responsible for your patients treatment,evenifthattreatmentisactuallyadministeredbyacolleague,suchasa nurse,orbypatientsthemselves.Youwilloftenneedtoexplaintopatientshowto administeratreatmentcorrectly.Youmayalsoneedtoteachotherhealthworkers. Theinstructionshavebeenpresentedinsuchawaythattheycanbeusedasaself standinginformationsheetforpatients.Ifyouhaveaccesstoaphotocopymachine youmightconsidermakingcopiesofthemastheyare.Youmightalsowishto adaptthemtoyourownsituationortranslatethemintoanationallanguage.
Table of contents
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
page
Eyedrops....................................................................................................................88 Eyeointment...............................................................................................................89 Eardrops.....................................................................................................................90 Nasaldrops.................................................................................................................91 Nasalspray.................................................................................................................92 Transdermalpatch.....................................................................................................93 Aerosol........................................................................................................................94 Inhalerwithcapsules.................................................................................................95 Suppositories..............................................................................................................96 Vaginaltabletwithapplicator..................................................................................97 Vaginaltabletwithoutapplicator............................................................................98 Vaginalcream,ointmentandgel.............................................................................99
101
CHECKLIST 1 Eye drops

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Washyourhands. Donottouchthedropperopening. Lookupward. Pullthelowereyeliddowntomakeagutter. Bringthedropperasclosetothe`gutter'aspossiblewithouttouchingitor theeye. Applytheprescribedamountofdropsinthegutter. Closetheeyeforabouttwominutes.Donotshuttheeyetootight. Excessfluidcanberemovedwithatissue. Ifmorethanonekindofeyedropisusedwaitatleastfiveminutesbefore applyingthenextdrops. Eyedropsmaycauseaburningfeelingbutthisshouldnotlastformorethan afewminutes.Ifitdoeslastlongerconsultadoctororpharmacist.
Steps4and5
When giving eye-drops to children:

1. 2. 3. 4. 5. Letthechildliebackwithheadstraight. Thechild'seyesshouldbeclosed. Driptheamountofdropsprescribedintothecorneroftheeye. Keeptheheadstraight. Removeexcessfluid.
102
Annex3
103
CHECKLIST 2 Eye ointment

1. 2. 3. 4. 5. 6. 7. 8. 9. Washyourhands. Donottouchanythingwiththetipofthetube. Tilttheheadbackwardsalittle. Takethetubeinonehand,andpulldownthelowereyelidwiththeother hand,tomakeagutter. Bringthetipofthetubeasclosetothegutteraspossible. Applytheamountofointmentprescribed. Closetheeyefortwominutes. Removeexcessointmentwithatissue. Cleanthetipofthetubewithanothertissue.
Steps4and5
104
Annex3
CHECKLIST 3 Ear drops

1. 2. 3. 4. 5. 6. 7. Warmtheeardropsbykeepingtheminthehandorthearmpitforseveral minutes.Donotusehotwatertap,notemperaturecontrol! Tiltheadsidewaysorlieononesidewiththeearupward. Gentlypullthelobetoexposetheearcanal. Applytheamountofdropsprescribed. Waitfiveminutesbeforeturningtotheotherear. UsecottonwooltoclosetheearcanalafterapplyingthedropsONLYifthe manufacturerexplicitlyrecommendsthis. Eardropsshouldnotburnorstinglongerthanafewminutes.
Step1
Steps2and3
Step6
105
CHECKLIST 4 Nasal drops

1. 2. 3. 4. 5. 6. 7. 8. Blowthenose. Sitdownandtiltheadbackwardstronglyorliedownwithapillowunderthe shoulders;keepheadstraight. Insertthedropperonecentimeterintothenostril. Applytheamountofdropsprescribed. Immediatelyafterwardtiltheadforwardstrongly(headbetweenknees). Situpafterafewseconds,thedropswillthendripintothepharynx. Repeattheprocedurefortheothernostril,ifnecessary. Rinsethedropperwithboiledwater.
Steps2and3
Step5
106
Annex3
CHECKLIST 5 Nasal spray

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Blowthenose. Sitwiththeheadslightlytiltedforward. Shakethespray. Insertthetipinonenostril. Closetheothernostrilandmouth. Spraybysqueezingthevial(flask,container)andsniffslowly. Remove the tip from the nose and bend the head forward strongly (head betweentheknees). Situpafterafewseconds;thespraywilldripdownthepharynx. Breathethroughthemouth. Repeattheprocedurefortheothernostril,ifnecessary. Rinsethetipwithboiledwater.
Steps4and5
Step7
107
CHECKLIST 6 Transdermal patch

1. 2. 3. 4. 6. 7. 8. 9. For patchsite see instructions included with the drug or checkwith your pharmacist. Donotapplyoverbruisedordamagedskin. Do not wear over skin folds or under tight clothing and change spots regularly. Applywithclean,dryhands. Cleananddrytheareaofapplicationcompletely. Removepatchfrompackage,donottouchdrugside. Placeonskinandpressfirmly.Rubtheedgestoseal. Removeandreplaceaccordingtoinstructions.
Step7
Step8
108
Annex3
CHECKLIST 7 Aerosol
1. 2. 3. 4. 5. 6. 8. 9. 10. 11. Coughupasmuchsputumaspossible. Shaketheaerosolbeforeuse. Hold the aerosol as indicated in the manufacturer's instructions (this is usuallyupsidedown). Placethelipstightlyaroundthemouthpiece. Tilttheheadbackwardslightly. Breatheoutslowly,emptyingthelungsofasmuchairaspossible. Breatheindeeplyandactivatetheaerosol,keepingthetonguedown. Holdthebreathfortentofifteenseconds. Breatheoutthroughthenose. Rinsethemouthwithwarmwater.
Steps4and5
Step8
109
CHECKLIST 8 Inhaler with capsules

1. 2. 3. 4. 5. 6. 7. 8. 9. Coughupasmuchsputumaspossible. Placethecapsule(s)intheinhaleraccordingtomanufacturer'sinstructions. Breatheoutslowlyandemptylungsofasmuchairaspossible. Placelipstightlyaroundthemouthpiece. Tiltheadbackwardslightly. Takeadeepbreaththroughtheinhaler. Holdthebreathfortentofifteenseconds. Breatheoutthroughthenose. Rinsethemouthwithwarmwater.
Step4
Step5
110
Annex3
CHECKLIST 9 Suppository
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Washyourhands. Removethecovering(unlesstoosoft). Ifthesuppositoryistoosoftletithardenfirstbycoolingit(fridgeorhold undercoldrunningwater,stillpacked!)thenremovecovering. Removepossiblesharprimsbywarminginthehand. Moistenthesuppositorywithcoldwater. Lieonyoursideandpullupyourknees. Gentlyinsertthesuppository,roundedendfirst,intothebackpassage. Remainlyingdownforseveralminutes. Washyourhands. Trynottohaveabowelmovementduringthefirsthour.
Step6
111
CHECKLIST 10 Vaginal tablet with applicator

1. 2 3. 4. 5. 6. 7. 8. 9. 10. Washyourhands. Removethewrapperfromthetablet. Placethetabletintotheopenendoftheapplicator. Lieonyourback,drawyourkneesupalittleandspreadthemapart. Gentlyinserttheapplicatorwiththetabletinfrontintothevaginaasfaras possible,doNOTuseforce! Depresstheplungersothatthetabletisreleased. Withdrawtheapplicator. Discardtheapplicator(ifdisposable). Clean both parts of the applicator thoroughly with soap and boiled, lukewarmwater(ifnotdisposable). Washyourhands.
Steps4and5
Step6
112
Annex3
CHECKLIST 11 Vaginal tablet without applicator

1. 2. 3. 4. 5. 6. Washyourhands. Removethewrapperfromthetablet. Dipthetabletinlukewarmwaterjusttomoistenit. Lieonyourback,drawyourkneesupandspreadthemapart. Gentlyinsertthetabletintothevaginaashighaspossible,doNOTuseforce! Washyourhands.
Steps4and5
113
CHECKLIST 12 Applying vaginal creams, ointments and gels

(mostofthesedrugscomewithanapplicator)
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Washyourhands. Removethecapfromthetubecontainingthedrug. Screwtheapplicatortothetube. Squeezethetubeuntiltherequiredamountisintheapplicator. Removetheapplicatorfromthetube(holdthecylinder). Applyasmallamountofcreamtotheoutsideoftheapplicator. Lieonyourback,drawyourkneesupandspreadthemapart. Gentlyinserttheapplicatorintothevaginaasfaraspossible,doNOTuse force. Hold the cylinder and with the other hand push the plunger down thus insertingthedrugintothevagina. Withdrawtheapplicatorfromthevagina. Discardtheapplicatorifdisposableorcleanthoroughly(boiledwater)ifnot. Washyourhands.
Steps4and5
Steps7and8
114
Annex3
115
A nnex 4
The use of injections
Therearetwomainreasons toprescribeaninjection.Thefirstisbecauseafast effectisneeded,andthesecondisbecausetheinjectionistheonlydosageform available that has the required effect. A prescriber should know how to give injections,notonlyforemergencyandothersituationswhereitmightbenecessary, butalsobecauseitwillsometimesbenecessarytoinstructotherhealthworkers (e.g.anurse)orthepatientsthemselves. Many injections are prescribed which are unnecessarily dangerous and inconvenient.Nearlyalwaystheyaremuchmoreexpensivethantablets,capsules andotherdosageforms.Foreveryinjectiontheprescribershouldstrikeabalance between the medical need on the one hand and the risk of side effects, inconvenienceandcostontheother. Whenadrugisinjectedcertaineffectsareexpected,andalsosomesideeffects.The persongivingtheinjectionmustknowwhattheseeffectsare,andmustalsoknow how to react if something goes wrong. This means that if you do not give the injectionyourselfyoumustmakesurethatitisdonebysomeonewhoisqualified. Aprescriberisalsoresponsibleforhowwasteisdisposedofaftertheinjection.The needleandsometimesthesyringearecontaminatedwasteandspecialmeasures areneededfortheirdisposal.Apatientwhoinjectsathomemustalsobeawareof thisproblem.
Table of contents
page
Generalpracticalaspectsofinjecting............................................................................102 1. 2. 3. 4. 5. 6. Aspiratingfromampoules(glass,plastic)............................................................103 Aspiratingfromavial.............................................................................................104 Dissolvingdrymedicine.........................................................................................105 Subcutaneousinjection............................................................................................106 Intramuscularinjection...........................................................................................107 Intravenousinjection...............................................................................................108
116
Annex4
General practical aspects of injecting

Apartfromthespecifictechniqueofinjecting,thereareafewgeneralrulesthatyou shouldkeepinmind. l. Expirydates Checktheexpirydatesofeachitemincludingthedrug. If youmake housecalls, checkthe drugs in your medical bagregularly to makesurethattheyhavenotpassedtheexpirydate. Drug Make sure that the vial or ampoule contains the right drug in the right strength. Sterility Duringthewholepreparationprocedure,materialshouldbekeptsterile. Washyourhandsbeforestartingtopreparetheinjection. Disinfecttheskinovertheinjectionsite. Nobubbles Makesurethattherearenoairbubblesleftinthesyringe. Thisismoreimportantinintravenousinjections. Prudence Oncetheprotectivecoveroftheneedleisremovedextracareisneeded. Donottouchanythingwiththeunprotectedneedle. Oncetheinjectionhasbeengiventakecarenottoprickyourselforsomebody else. Waste Makesurethatcontaminatedwasteisdisposedofsafely.
2.
3.
4.
5.
6.
117
CHECKLIST 1 Aspirating from ampoules

(glass,plastic) Materialsneeded Syringeofappropriatesize,needleofrequiredsize,ampoulewithrequireddrugor solution,gauze. Technique 1. Washyourhands. 2. Puttheneedleonthesyringe. 3. Removetheliquidfromtheneckoftheampoulebyflickingitorswingingit fastinadownwardspirallingmovement. 4. Filearoundtheneckoftheampoule. 5. Protectyourfingerswithgauzeifampouleismadeofglass. 6. Carefullybreakoffthetopoftheampoule(foraplasticampouletwistthe top). 7. Aspiratethefluidfromtheampoule. 8. Removeanyairfromthesyringe. 9. Cleanup;disposeofworkingneedlesafely;washyourhands.
Step4
Step5
Step6
118
Annex4
CHECKLIST 2 Aspirating from a vial

Materialsneeded Vialwithrequireddrugorsolution,syringeoftheappropriatesize,needleofright size(im,sc,oriv)onsyringe,disinfectant,gauze. Technique 1. Washyourhands. 2. Disinfectthetopofthevial. 3. Useasyringewithavolumeoftwicetherequiredamountofdrugorsolution andaddtheneedle. 4. Suckupasmuchairastheamountofsolutionneededtoaspirate. 5. Insertneedleinto(topof)vialandturnupsidedown. 6. Pumpairintovial(creatingpressure). 7. Aspiratetherequiredamountofsolutionand0.1mlextra.Makesurethetip oftheneedleisbelowthefluidsurface. 8. Pulltheneedleoutofthevial. 9. Removepossibleairfromthesyringe. 10. Cleanup;disposeofwastesafely;washyourhands.
Step4
Step6
Step7
119
CHECKLIST 3 Dissolving dry medicine

Materialsneeded Vialwithdrymedicinetobedissolved,syringewiththerightamountofsolvent, needleofrightsize(iv,scoriv)onsyringe,disinfectant,injectionneedle,gauze. Technique 1. Washhands. 2. Disinfecttherubbercap(top)ofthevialcontainingthedrymedicine. 3. Inserttheneedleintothevial,holdthewholeupright. 4. Suckupasmuchairastheamountofsolventalreadyinthesyringe. 5. Injectonlythefluidintothevial,nottheair! 6. Shake. 7. Turnthevialupsidedown. 8. Injecttheairintothevial(creatingpressure). 9. Aspiratethetotalamountofsolution(noair). 10. Removeanyairfromthesyringe. 11. Cleanup;disposeofwastesafely;washhands.
Step4
Step5
Step8
120
Annex4
CHECKLIST 4 Subcutaneous injection

Materialsneeded Syringewiththedrugtobeadministered(withoutair),needle(Gauss25,shortand thin;onsyringe),liquiddisinfectant,cottonwool,adhesivetape. Technique 1. Washhands. 2. Reassurethepatientandexplaintheprocedure. 3. Uncovertheareatobeinjected(upperarm,upperleg,abdomen). 4. Disinfectskin. 5. Pinchfoldoftheskin. 6. Insertneedleinthebaseoftheskinfoldatanangleof20to30degrees. 7. Releaseskin. 8. Aspirate briefly; if bloodappears: withdraw needle,replace itwith anew one,ifpossible,andstartagainfrompoint4. 9. Injectslowly(0.52minutes!). 10. Withdrawneedlequickly. 11. Presssterilecottonwoolontotheopening.Fixwithadhesivetape. 12. Checkthepatient'sreactionandgiveadditionalreassurance,ifnecessary. 13. Cleanup;disposeofwastesafely;washhands.
Step3
Step5
Step6
121
CHECKLIST 5 Intramuscular injection

Materialsneeded Syringewiththedrugtobeadministered(withoutair),needle(Gauss22,longand mediumthickness;onsyringe),liquiddisinfectant,cottonwool,adhesivetape. Technique 1. Washhands. 2. Reassurethepatientandexplaintheprocedure. 3. Uncovertheareatobeinjected(lateralupperquadrantmajorglutealmuscle, lateralsideofupperleg,deltoidmuscle). 4. Disinfecttheskin. 5. Tellthepatienttorelaxthemuscle. 6. Inserttheneedleswiftlyatanangleof90degrees(watchdepth!). 7. Aspiratebriefly;ifbloodappears,withdrawneedle.Replaceitwithanew one,ifpossible,andstartagainfrompoint4. 8. Injectslowly(lesspainful). 9. Withdrawneedleswiftly. 10. Presssterilecottonwoolontotheopening.Fixwithadhesivetape. 11. Checkthepatient'sreactionandgiveadditionalreassurance,ifnecessary. 12. Cleanup;disposeofwastesafely;washyourhands.
Step4
Step5
Step6
122
Annex4
CHECKLIST 6 Intravenous injection

Materialsneeded Syringewiththedrugtobeadministered(withoutair),needle(Gauss20,longand medium thickness; on syringe), liquid disinfectant, cotton wool, adhesive tape, tourniquet. Technique 1. Washyourhands. 2. Reassurethepatientandexplaintheprocedure. 3. Uncoverarmcompletely. 4. Havethepatientrelaxandsupporthisarmbelowtheveintobeused. 5. Applytourniquetandlookforasuitablevein. 6. Waitfortheveintoswell. 7. Disinfectskin. 8. Stabilizetheveinbypullingtheskintautinthelongitudinaldirectionofthe vein.Dothiswiththehandyouarenotgoingtouseforinsertingtheneedle. 9. Inserttheneedleatanangleofaround35degrees. 10. Puncturetheskinandmovetheneedleslightlyintothevein(35mm). 11. Holdthesyringeandneedlesteady. 12. Aspirate.Ifbloodappearsholdthesyringesteady,youareinthevein.Ifit doesnotcome,tryagain. 13. Loosentourniquet. 14. Inject(very)slowly.Checkforpain,swelling,hematoma;ifindoubtwhether youarestillintheveinaspirateagain! 15. Withdrawneedleswiftly.Presssterilecottonwoolontotheopening.Secure withadhesivetape. 16. Checkthepatient'sreactionsandgiveadditionalreassurance,ifnecessary. 17. Cleanup;disposeofwastesafely;washyourhands.
Step8
Step9
Steps11to14
123
124
Annex4
125

Guide To Good Prescribing

Diunggah oleh

Informasi Dokumen

Deskripsi Asli:

Judul Asli

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

Guide To Good Prescribing

Diunggah oleh

Hak Cipta:

Format Tersedia

WHO/DAP/94.

Guide to Good Prescribing

World Health Organization Action Programme on Essential Drugs Geneva

T.P.G.M.deVries R.H.Henning D.A.Fresle

L ist of patient examples

hy you need this book

Field test of the Guide to Good Prescribing in seven universities

What is your first-choice treatment for dry cough?

The process of rational prescribing

The process of rational treatment

art 2: Selecting your P(ersonal) drugs

Steps in choosing a P-drug

Ifyoudonotknowenoughaboutpathophysiologyofthediseaseorofthepharmacologicalsitesofaction,you needtoupdateyourknowledge.Youcouldstartbyreviewingyourpharmacologynotesortextbook;forthis exampleyoushouldprobablyalsoreadafewparagraphsonanginapectorisinamedicaltextbook.

Sites of action for drug groups used in angina pectoris

Nitrates Betablockers Calciumchannelblockers

Comparison between the three drug groups used in angina pectoris

Pharmacodynamics Peripheralvasodilatation Flushing,headaches, Cardiacfailure,hypo Tolerance(especiallywith constantbloodlevels) Nitratepoisoningdueto

Sideeffects Flushing,headaches, temporarytachycardia

Nitratepoisoningduetolong lastingoraldosage longlastingoraldosage Anaemia

Pharmacokinetics Highfirstpassmetabolism Varyingabsorptioninthe alimentarytract(lessin mononitrates) Fasteffectdosageforms:

Glyceryltrinitrateisvolatile: tabletscannotbekeptlong oromucosalspray Injection,sublingualtablet, Betablockers Sideeffects Contraindications

Fasteffectdosageforms: Injection,sublingualtablet, oromucosalspray

Comparison between drugs within the group of nitrates

1.451.51 1.102.15 9.5218.95

4.45 5.7013.30 25.0040.82

Example of selecting a P-drug: angina pectoris

suitability ++ suitability + (+) + +

Activesubstance,dosageform: Dosageschedule: Duration:

glyceryltrinitrate,sublingualtablet1mg 1tabletasneeded;secondtabletifpainpersists lengthofmonitoringinterval

Step i: Define the diagnosis

Step ii: Specify the therapeutic objective

Step iii: Make an inventory of effective groups of drugs

Step iv: Choose an effective group according to criteria

Efficacy, safety and cost

Step v: Choose a P-drug

General characteristics of dosage forms

How to select a P-drug

Nondrugtreatment: Drugtreatment: Referralfortreatment:

YourPtreatmentforasuperficialopenwoundisthereforetocleananddressthe wound,giveantitetanusprophylaxis,andadviceonregularwoundinspection.No drugs!

art 3: Treating your patients

page Step1: Definethepatientsproblem......................................................................34

STEP 1: Define the patient's problem

Figure3: Plasmaconcentrationrising abovetherapeuticwindowin patient18

Table 6: Relation between ADME factors and plasma concentration

Figure4: Downward shifted window and upward shiftedcurveinpatient20

Drugs in which slowly raising the dose is advisable

Repeat prescriptions in practice

Verify that your P-drug is suitable for this patient

Ifnecessary,changethedosageform,thedosagescheduleorthedurationof treatment. InsomecasesitisbettertochangetoanotherPdrug.

STEP 4: Write a prescription

Legal obligation to write clearly

DrB.Who Farmstreet12 Kirkville tel.3876 R/

DrB.Who Farmstreet12 Kirkville tel.3876 R/

Ms/Mr address: age:

Ms/Mr address: age:

A prescription should include:

Aids to improving patient adherence to treatment

Thesixpointslistedbelowsummarizethe minimum informationthatshouldbe giventothepatient.

Sample page of a personal formulary

*DOSAGE Hypertension:startwith50mginthemorning.Average:50100mgperday. Anginapectoris:100mgperdayin12doses Adjusttoeachpatientindividually,startaslowaspossible.Raisethedoseafter2 weeks,ifneeded. *WHATTOTELLTHEPATIENT Information

Your personal formulary

Give information, instruction and warnings

DOSAGE Hypertension:startwith50mginthemorning.Average:50100mgperday. Anginapectoris:100mgperdayin12doses Adjusttoeachpatientindividually,startaslowaspossible.Raisethedoseafter2 weeks,ifneeded. WHATTOTELLTHEPATIENT Information