-
138 Drug price reforms: the new F1–F2 bifurcation (Editorial) TFaunce&HLofgren
140 Letters
142 Top 10 drugs
143 Drugs for the doctor's bag ABaird
146 Dental notes Drugsforthedoctor'sbag
147 Abnormal laboratory results: Evaluation of adrenocortical function in adults JHo&DJTorpy
150 Relationships between health professionals and industry: maintaining a delicate balance PAKomesaroff
153 Dental notes Relationshipsbetweenhealthprofessionalsandindustry
153 Medicines Australia Code of Conduct: breaches
154 The story of one complaint
156 Treatment of myasthenia gravis SWReddel
160 Dental notes Treatmentofmyastheniagravis
160 Patient support organisation
161 Myasthenia gravis: a patient's perspective
162 Antipsychotic drugs in pregnancy and breastfeeding DKennedy
163 New drugsabatacept,exenatide,telbivudine
Fulltextwithsearchfacilityonlineatwww.australianprescriber.com
VoLuME 30 NuMbER 6 AN iNDEPENDENT REViEw DECEMbER 2007 C o n T E n T S
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138 | VoLuME 30 | NuMbER 6 | DECEMbER 2007
Editorial
in this issue…
Drug price reforms: the new F1–F2 bifurcationThomas Faunce, Senior Lecturer, College of Law and Medical School, Australian National University, Canberra; and Hans Lofgren, Senior Lecturer, School of International and Political Studies, Deakin University, Burwood, Victoria
Keywords:genericdrugs,PharmaceuticalBenefitsScheme,
referencepricing.
(Aust Prescr 2007;30:138–40)
SignificantchangestothePharmaceuticalBenefitsScheme
(PBS)areunderway.TheAustralianParliamentrecentlypassed
theNational Health Amendment (Pharmaceutical Benefits
Scheme) Act 2007.AtthecoreofthisActarenewsections
(85ABand85AC)totheNational Health Act 1953.Thesehadthe
effectofdividing,from1August2007,thePBSintotwoseparate
formularies–F1,whichmostlycontainssinglebrandmedicines,
andF2,whichmostlycontainsmultiplebrand,mainlygeneric,
medicines(seebox).
Thesecomplexchangesaimto'recognisetheimportanceof
world-classlife-enhancingdrugstopatients',protectpatients
fromhighercostsandgetbettervaluefrommarketcompetition
betweenmedicineswithmultiplebrands.1Thechangesmay
allowPBSandpatientsavingsthroughlowerpricedgenerics,
buttheirimpactonthepriceofpatentedsingle-brandmedicines
isuncertaininourview.Chieflythisisbecauseinfuturemost
newpatentedmedicineswillbelistedinF1withreduced
referencepricingthereafter.
InAustralia,overallpharmacyfeesvaryforproductspriced
belowthegeneralpatientco-payment($30.70),andaChoice
surveyinAugust2006foundawiderangeintheprices
pharmaciescharge.2Thiswasduetovariedapplicationof
permissiblefeesundertheFourthCommunityPharmacy
Agreement.Australianpricesforgenericdrugswerehigher
thanincountrieswithlargermarketsorprocessessuchas
competitivetender.InAustralia,thepriceapatientpaidfor
amedicinebelowthegeneralco-paymentdependedonthe
manufacturer'sprice,wholesaleandpharmacymarkups,and
dispensingfees.Manufacturerscouldoffergenericdrugsto
pharmacistsatlargediscountstothepricespaidbythePBS.
Thegovernmentthereforeconsideredthatithadbeenpaying
toomuchforthesemedicines.Inourview,thisconsideration
unfortunatelyoutweighedpolicyconcernsabouttheimportance
ofmaintainingthefullintegrityofPBSreferencepricing.1,3
PBSpriceswillnowbeinfluencedbywhichformularyadrugis
in(Table1).Toaddtothecomplexity,thecriteriadonotapply
tosinglebrandcombinationproducts,astheycouldhave
componentsindifferentformularies.
DrugswhichareinF2arecategorisedaccordingtothesize
ofthediscountstopharmacyasat1october2006.Whenthe
discountwaslessthan25%thedrugisinF2A.Drugswhich
wereheavilydiscountedbymorethan25%areinF2T.The
suppliersofdrugsinthesecategorieswillhavetodiscloseto
theDepartmentofHealthandAgeingtheactualpriceatwhich
theysellabrandtowholesalersorpharmacies.Thisrequirement
appliestonewbrandsofF2Amedicinesfrom1August2007and
tonewbrandsofF2Tmedicinesfrom1January2011.Theaimis
toensurethatthePBSpriceisbasedontheactualsupplierprice
towholesalersorpharmacy.
Apricereductionof12.5%atthetimeofPBSlistingofthe
firstgenericbrandofadrughasbeenrequiredsince2005,
andwillcontinuetoapply.From1August2008,therewillbe
F1containsdrugswithasinglebrand,howeveritdoesnot
containthosesinglebranddrugsthatareinterchangeable
onanindividualpatientbasiswithdrugsthathavemultiple
brandsorsinglebrandcombinationitems.
F2containsdrugswithmultiplebrandsandthosesingle
branddrugsthatareinterchangeableattheindividualpatient
levelwithdrugsthathavemultiplebrands.
Therearemanybalancesinmedicine.DebraKennedy
writesonbalancingtheuseofantipsychoticdrugsduring
pregnancywiththeriskofcongenitalabnormalities,
whileStephenReddeldescribeshowthebenefitsof
immunosuppressionformyastheniagravishavetobe
balancedagainsttheadverseeffects.
PaulKomesaroffdiscussesthedelicatebalancebetween
healthprofessionalsandthepharmaceuticalindustry.
Sometimesthisbalanceisupsetandcanresultinpromotional
activitybreachingtheMedicinesAustraliaCodeofConduct.
Governmentshavetobalancehealthbudgetsandthere
havebeenrecentreformsofthePharmaceuticalBenefits
Scheme.TomFaunceandHansLofgrengivetheirviewof
thechanges.
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| VoLuME 30 | NuMbER 6 | DECEMbER 2007 139
furthercompulsorypricereductionsforF2drugs:adropof
2%peryearforthreeyearsfordrugsinF2A,andaone-off
pricereductionof25%fordrugsinF2T(on1August2008).
TherearenomandatorypricecutsfordrugsinF1.Therewillbe
compensationforwholesalersandpharmacistsforthelossof
incomefromstatutoryF2pricereductions.Forexample,from
1August2008pharmacistswillreceive$1.50eachtimethey
dispenseasubstitutablebrandthatcoststhepatientnomore
thantheco-payment.
Manygenericdrugsarealreadypricedbelowthegeneral
patientco-payment,andthepricereductionstodrugsin
F2areexpectedtoresultinmoredrugsfallingunderthe
co-payment.ThePharmacyGuildofAustraliaestimatesthat
thepriceofmorethan400brands,belowthegeneralPBS
co-payment,willfall.4Completepriceandvolumedatawillnot
beavailablefordrugsoncetheyfallbelowthegeneralPBS
co-payment.AlthoughtheDrugUtilisationSub-Committee
ofthePharmaceuticalBenefitsAdvisoryCommittee(PBAC)
receivessomedata,prescriptionsforthesedrugsdonotappear
inofficialstatisticsofPBSexpenditure.
TheMinisterforHealthandAgeinghasstatedthattheroleof
thePBAC,inassessingcost-effectivenessandcostminimisation
andthenadvisingtheMinisteronthelistingofdrugsonthe
PBS,isnotaffectedbythelegislation.5Yettheresponsibilities
ofthePBACwillbeformallyextendedtoincludeadvicetothe
Ministeronexemptionsfrommandatorypricereductions.It
willalsoadviseonwhetherdrugsare'interchangeableonan
individualpatientbasis',astandardmoreuncertainthanthe
previous,moreevidence-based,'equivalence'testsusedto
determineTherapeuticGroupPremiumsforreferencepricing.
Drugsappearing'equivalent'onaverageeffectsmeasured
inclinicaltrials,forexample,maynotbe'interchangeable'
foranindividualpatient.3Forexample,whilecitalopram
andescitalopramwereinthesamereferencepricinggroup,
escitalopramwasinitiallyincludedinF1andcitalopramwas
inF2T.6
Theprincipleofreferencepricing,thatdrugswithidenticalor
similarclinicaloutcomesshouldhavesimilarprices,isintegral
tothearchitectureofthePBSandtherespectithasachieved
internationally.Inourview,theseparationoflisteddrugsinto
twogroups(F1andF2),howeverthisisimplemented,weakens
theroleandfiscalbenefitsofreferencingpricinginthePBS.
AlthoughtherewillbereferencepricingwithinF1,aneffectof
thechangesistoinsulatehighpricedsinglebrand(patented)
F1drugsfrompricecutsandfromthereferencepricingthat
appliedunderpreviousPBSprocesses.3onceanewdrugis
listedonthePBSasF1,itspricewillnotbelinkedtothepriceof
anysimilardruginF2.F1drugsarenotinterchangeableatthe
individualpatientlevelwithdrugsthathavemultiplebrands,
sothemanufacturersmaybeabletoretaintheiroriginalPBS
priceuntilthelistingofabioequivalentbrandsatisfiesthenew
standardsforashifttoF2.ReductionsinF2drugpriceswill
notaffectF1prices,evenwherethetherapeuticeffectofanF2
medicineissimilarthoughnotnecessarily'interchangeableat
theindividualpatientlevel'.
ItisouropinionthatthecreationoftheF1categorywill,over
time,resultinhigherpricesforsomepatenteddrugsthan
wouldhavebeenthecaseunderpreviousPBSarrangements.
Thegovernment'srationaleforthischangeappearstobethat
failuretomakesuchchangescouldresultinlarge'special
patientcontributions'orthewithdrawalofsingle-source
productsfromthePBS.5
Thegovernment,MedicinesAustralia,theConsumers'Health
ForumandseveralprofessionalgroupsviewtheF1–F2changes
asameansofachievinglowerpricesandgreatertransparency
inthegenericsmarket.6However,theexpectationofprice
reductionsflowingtoconsumersispremisedontrustineffective
competitionamongretailpharmacies.Ifdirectbenefitsto
Table 1
Examples of drugs in the new Pharmaceutical benefits Scheme formularies*
F1 F2A F2T
atorvastatin fluvastatin simvastatinbisoprolol carvedilol metoprolol
cefuroxime cephazolin cephalexin
celecoxib ketoprofen naproxen
doxorubicin(pegylatedliposomal) doxorubicin –
levobunolol betaxolol timolol
olanzapine clozapine –
reboxetine – citalopram,fluvoxamine
salmeterol – salbutamol
ticarcillinwithclavulanicacid – amoxycillinwithclavulanicacid
zolmitriptan sumatriptan –– oxazepam diazepam
* asat2007Sep11
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140 | VoLuME 30 | NuMbER 6 | DECEMbER 2007
LettersLetters,whichmaynotnecessarilybepublishedinfull,shouldberestrictedtonotmorethan250words.Whenrelevant,commentontheletterissoughtfromtheauthor.Duetoproductionschedules,itisnormallynotpossibletopublishlettersreceivedinresponsetomaterialappearinginaparticularissueearlierthanthesecondorthirdsubsequentissue.
patientsfromlowergenericmedicinespricesorgovernment
supportforanAustraliangenericsindustryhadbeentheprimary
policyobjectives,thenmorebroadlyframedlegislationcould
haveincludedpharmacyrewardsformeetinggenericdispensing
targets,anincentiveperiodofmarketexclusivityforthefirst
genericmarketentrant,andfinancialincentivesforpatientswho
electtobedispensedageneric,orforpatientswhosedoctors
arepreparedtoprescribegenericdrugs.Theroleofthepatented
pharmaceuticalindustryinpromotingandframingthese
changesisalsocontroversial7,particularlyifthenewsystem
allowspricereductionstobedeferredforsomeproducts.
References1. DepartmentofHealthandAgeing.Strengtheningyour
PBS–preparingforthefuture.Canberra;2007.http://www.health.gov.au/internet/wcms/publishing.nsf/Content/A2F23E7630B8F9F3CA257227007F1EC7/$File/strengthening-your-PBS161106.pdf[cited2007nov12]
2. Choice.Prescriptionprices:surveyresultssummary.2006nov.http://www.choice.com.au/viewArticle.aspx?id=105514&catId=100231&tid=100008&p=2&title=Prescription+prices[cited2007nov12]
3. SearlesA,JefferysS,DoranE,HenryDA.Referencepricing,genericdrugsandproposedchangestothePharmaceuticalBenefitsScheme.MedJAust2007;187:236-9.
4. PharmacyGuildofAustralia.SubmissiontoInquiryintonationalHealthAmendment(PharmaceuticalBenefitsScheme)Bill2007.http://www.aph.gov.au/Senate/committee/clac_ctte/nat_hth_pbs_07/submissions/sub07.pdf[cited2007nov12]
5. ParliamentofAustraliaSenateCommunityAffairsCommittee.InquiryintonationalHealthAmendment(PharmaceuticalBenefitsScheme)Bill2007.Submissionsindex.http://www.aph.gov.au/Senate/committee/clac_ctte/nat_hth_pbs_07/submissions/sublist.htm[cited2007nov12]
6. PharmaceuticalBenefitsScheme(PBS)reform.PBSfactsheet.http://www.health.gov.au/internet/wcms/publishing.nsf/Content/pbs_reform_02feb07.htm[cited2007nov12]
7. FaunceTA.Referencepricingforpharmaceuticals:istheAustralia-UnitedStatesFreeTradeAgreementaffectingAustralia'sPharmaceuticalBenefitsScheme?.MedJAust2007;187:240-2.
Conflict of interest: none declared
Managing chronic obstructive pulmonary disease
Editor,–Iwonderwhyalpha-1antitrypsindeficiencywasnot
mentionedinthearticleon'Managingchronicobstructive
pulmonarydisease'(AustPrescr2007;30:59–63).Thereis
worldwideevidencethatthisgeneticproblemismuchmore
commonthanitwasthoughtinthepast.InfacttheWorld
Healthorganizationadvisesthateverybodywithchronic
obstructivepulmonarydiseaseshouldbetestedforalpha-1
antitrypsindeficiency,especiallysincethereistreatmentfor
it,thoughnocure.
MichaelAKennedy
Generalpractitioner,retired
Vaucluse,nSW
Professor Michael Abramson, Associate Professor Christine
McDonald and Professor Nicholas Glasgow, authors of the
article, comment:
WethankDrKennedyfordrawingattentiontotherole
ofalpha-1antitrypsindeficiencyinchronicobstructive
pulmonarydisease(CoPD).Thisgeneticdisorderisevidence
fortheelastase–antielastasehypothesisofemphysema.The
prevalenceofseverehomozygous(ZZ)alpha-1antitrypsin
deficiencyhasbeenestimatedataround1/4,727inEuropean
populations.1Although75–85%ofsuchindividualswill
developemphysema,tobaccosmokingisstillthemost
importantriskfactorforCoPDeveninthisgroup.Targeted
screeningsuggests1–4.5%ofpatientswithCoPDhave
underlyingseverealpha-1antitrypsindeficiency.2The
indexofsuspicionshouldbehighinyoungerpatients
withpredominantlybasaldiseaseandafamilyhistory.The
diagnosiscanbemadebymeasuringserumlevelsofalpha-1
trypsin.Iftheyarereduced,genotypingshouldbeperformed.
Whetherpeoplewhoareheterozygous(MZ,MS)arealsoat
anincreasedriskofCoPDremainscontroversial.
Althoughreplacementtherapyisavailable,trialsconducted
todatehavebeenunderpoweredtoconfirmbeneficial
effectsontherateofdeclineinlungfunctionoronsurvival.
oneplacebo-controlledrandomisedtrialsuggestedsome
reductioninthelossoflungtissueasassessedbyCT
scan.3Therapyinvolvesintravenousadministrationof
alpha-1trypsinconcentratepurifiedbyfractionationof
normalhumanplasmaorrecombinantalpha-1trypsin.
Theseproductscanrestorealpha-1trypsinlevelsabovethe
protectivethresholdforsomeweeks.Replacementtherapy
isavailablethroughtheSpecialAccessScheme.Anational
patientsupportgroupcanbecontactedathttp://health.
groups.yahoo.com/group/Alpha1-AnZ.
References
1. BlancoI,deSerresFJ,Fernandez-BustilloE,LaraB,MiravitllesM.EstimatednumbersandprevalenceofPI*SandPI*Zallelesofalpha1-antitrypsindeficiencyinEuropeancountries.EurRespirJ2006;27:77-84.
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| VoLuME 30 | NuMbER 6 | DECEMbER 2007 141
2. AmericanThoracicSociety/EuropeanRespiratorySocietystatement:standardsforthediagnosisandmanagementofindividualswithalpha-1antitrypsindeficiency.AmJRespirCritCareMed2003;168:818-900.
3. DirksenA,DijkmanJH,MadsenF,StoelB,HutchisonDC,UlrikCS,etal.Arandomizedclinicaltrialofalpha(1)-antitrypsinaugmentationtherapy.AmJRespirCritCareMed1999;160:1468-72.
A century of concern about complementary medicines
Editor,–ThecommentinAustralian Prescriber(2007;30:91)
drawsunhelpfulandmisleadingparallelsbetween
complementarymedicinestodayand'dangerousanduseless
medicines'available100yearsago.
Theauthorisrighttopointtotheestablishmentofthe
TherapeuticGoodsAdministration(TGA)asanimportant
landmarkfortheregulationofpharmaceuticalsand
complementarymedicines.TheComplementaryHealthcare
Council(CHC)fullysupportsaregulatoryprocessthat
safeguardsconsumerinterests.However,tosuggest
thatcomplementarymedicinesastherapeuticgoodsare
somehowcompromisedbyfalseormisleadingadvertisingor
thatbarriersexisttounderstandingthembecausesponsors
hidebehind'commercial-in-confidence'isinaccurate.
Alladvertisementsfortherapeuticgoodsaresubjectto
theTherapeuticGoods,TradePracticesandotherrelevant
laws.TheTherapeuticGoodsAdvertisingCode,which
appliestoadvertisementsdirectedtoconsumersandwhere
sanctionsapplyforbreaches,requiresmaterialtobetruthful,
balanced,notcontainmisleadingorexaggeratedclaims,and
alldescriptions,claimsandcomparisonsmustbeabletobe
substantiated.
Withregardto'commercial-in-confidence',itishardtosee
howconcernsregardingtransparencywouldnotequally
applytopharmaceuticalcompanies.Companiesresponsible
formarketingproductsareobligedtomakeavailableall
evidenceregardingclaimsinrelationtotheirproducts,
shouldtheybeaskedtodosobytheTGA.
WhatdoesconcerntheCHC,istheoutdatedattitudes
demonstratedtowardscomplementarymedicines,despite
repeatedandcompellingevidencedemonstratingtheir
healthbenefits.Let'simagineforonemomenttheimplication
forpregnantwomenglobally,iffolatesupplementationin
preventingneuraltubedefectshadnotbecomeaccepted
mainstreampractice.
TonyLewis
ExecutiveDirector
ComplementaryHealthcareCouncil
Canberra
Dr JS Dowden, the author of the comment, responds:
ThereisLevel1evidencetosupporttheuseoffolate
supplementsbywomenplanningpregnancy.Itisdoubtful
thatsuchstrongevidenceexistsformanycomplementary
products.Giventheplethoraofcomplementarymedicines
itisunlikelythattheTGAhastheresourcestoassessthe
evidenceformanyoftheseproducts.Evidenceofaproduct's
safetyandefficacyshouldnotbe'commercial-in-confidence'
irrespectiveofwhetheritisaprescriptionoranon-
prescriptiondrug.
Despitethesomewhatconfusingregulatorysystem,
thereareplentyofcomplaintsabouttheadvertisingof
complementarymedicines.1Theusualsanctionforan
unacceptableadvertisementseemstobearequestfor
theadvertisementtobewithdrawn,butitisunclearhow
effectivelythisisenforced.2
octaviusBealewasconcernedabouttheoutrageousclaims
beingmadebymedicinesmanufacturersintheearly
20thcentury.3Thenumberofjustifiedcomplaintsin2007
suggeststhatthereisstillaproblem.1
References
1. http://www.tgacrp.com.au/index.cfm?pageID=13[cited2007oct30]
2. http://www.medreach.com.au/Downloads/SPH_Complementary_Medicines.pdf[cited2007oct30]
3. ReportbyRoyalCommissiononSecretDrugs,CuresandFoods.BealeoC.Parliament,Australia.Sydney:CommonwealthofAustralia;1907.
Magnesium
Editor,–InthearticleonmagnesiumbyDrWuandDrCarter
(AustPrescr2007;30:102–5)thereislittleattempttoaddress
theissueofcrampsandmagnesiumingestionbythepublic.
Myclinicalexperiencehasbeenthateveryagedpatient
whohasanyproblemwithcramping,haseithertried,oris
on,oralmagnesiumusuallyfromthesupermarketorhealth
store.Thisisoftenmagnesiumphosphate.
Couldtheauthorscommentontheissueofcrampingand
adultsovertheageoffiftyyears?Isthereanyevidencethat
lackofmagnesiumcausesthis,orthatoralmagnesiumisof
anybenefit?
ChrisCommens
Dermatologist
PennantHills,nSW
Dr J Wu and Dr A Carter, authors of the article, comment:
InresponsetoProfessorCommens,aliteraturesearch
performedinconsultationwithourpharmacologyunit
failedtoraiseanyconclusiveevidencethatmagnesium
phosphateisusefulinpreventingcrampsintheelderly.This
isnottosaythatbiochemicallyprovenhypomagnesaemia
wouldnotrespondtosupplementation,inthesamewayas
hypocalcaemiaorhypokalaemiawouldrequirecalciumor
potassiumsupplementationrespectively.
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142 | VoLuME 30 | NuMbER 6 | DECEMbER 2007
Top 10 drugsThesetablesshowthetop10subsidiseddrugsin2006–07.Thetablesdonotincludeprivateprescriptions.
Table 1
Top 10 drugs supplied by DDD*/1000 pop/day †
Drug PbS/RPbS ‡
1. atorvastatin 131.7992. simvastatin 58.0723. ramipril 30.4514. perindopril 21.6815. aspirin 18.016. omeprazole 17.9967. frusemide 17.9848. irbesartan 17.289. salbutamol 17.11610. esomeprazole 16.802
Table 2
Top 10 drugs by prescription counts †
Drug PbS/RPbS ‡
1. atorvastatin 100004952. simvastatin 62312123. esomeprazole 44285304. omeprazole 38823595. paracetamol 37541406. perindopril 36335367. atenolol 32171518. irbesartan 29893599. pantoprazole 292272410.metforminhydrochloride 2822776
Table 3
Top 10 drugs by cost to Government †
Drug Cost to Government DDD/1000/day Prescriptions ($A) PbS/RPbS ‡ PbS/RPbS ‡
1. atorvastatin 562234406 131.799 100004952. simvastatin 309227367 58.072 62312123. clopidogrel 179983732 9.219 24043614. esomeprazole 161102420 16.802 44285305. olanzapine 157471533 3.073 7754756. salmeterolandfluticasone 157239113 –§ 27898147. omeprazole 114030881 17.996 38823598. pravastatin 93389809 13.537 18708799. venlafaxine 93329210 11.987 231853110. tiotropiumbromide 91223529 5.289 1303682
* Thedefineddailydose(DDD)/thousandpopulation/dayisamoreusefulmeasureofdrugutilisationthanprescriptioncounts.Itshowshowmanypeople,ineverythousandAustralians,aretakingthestandarddoseofadrugeveryday.
† Basedondateofsupply‡ PBSPharmaceuticalBenefitsScheme,RPBSRepatriationPharmaceuticalBenefitsScheme§ CombinationdrugsdonothaveaDDDallocated
Source:DrugUtilisationSub-Committee(DUSC)DrugUtilisationDatabase,asat11october2007.©CommonwealthofAustralia.
NPS RADAR December 2007
Strontiumranelate:ThePBSlistingfortheosteoporosisdrug
strontiumranelatehasbeenextendedtoallowtreatmentof
postmenopausalwomenwithoutanexistingfractureanda
bonemineraldensityT-score≤–3.0(primaryprevention).The
latestissueofNPS RADAR describestheplaceintherapyof
strontiumrelativetootheranti-resorptiveagents.
Italsocontainsinformationon:
n thelistingoftheanticonvulsantdrugtopiramateasan
alternativetreatmentformigraineprevention,foradults
unabletotoleratebetablockersorpizotifen
n updatedsafetyinformationfortheglitazones–rosiglitazone
andpioglitazone.
Seethecompletereviewsatwww.npsradar.org.au
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| VoLuME 30 | NuMbER 6 | DECEMbER 2007 143
Drugs for the doctor's bagAndrew Baird, General Practitioner, Brighton, Victoria
Summary
The doctor's bag should contain drugs for medical emergencies that may occur in the community. Most of these drugs are provided under the Pharmaceutical benefits Scheme and can be ordered free of charge through a pharmacist. General practice accreditation now requires that clinics have appropriate emergency drugs as well as oxygen and a bag-valve-mask system. Practices should also have an up-to-date logbook detailing the emergency drug stocks and a system for checking that the drugs have not expired.
Keywords:medicalemergencies,PharmaceuticalBenefits
Scheme.
(Aust Prescr 2007;30:143–6)
introductionTraditionallythedoctor'sbagcontainsdrugsandequipment
formanagingmedicalemergenciesthatpresentintheclinicor
inthecommunity.1,2,3Thefrequencyandtypeofemergencies
thatoccurdependonthelocationandnatureofthepractice.
WiththeincreasingavailabilityofskilledMobileIntensiveCare
Ambulance(MICA)paramedicsas'firstresponders',manygeneralpractitionershavebecomelessinvolvedinmanaging
emergencies.However,inruralandremoteareasthedoctorwill
oftenbethe'firstresponder'andmaybeworkingwithvolunteer
ambulancecrews.
what to carryDoctorsshouldconsiderthemedicalemergenciesthatthey
mayencounterintheirpracticeandselectappropriatedrugsfor
theirdoctor'sbag(Table1).Manyofthesedrugsareprovided
underthePharmaceuticalBenefitsScheme(PBS)asEmergency
drug(Doctor'sbag)supplies.4Mostofthemareinjectable.
However,therearesomenon-injectabledrugswhichareuseful
inemergencies,suchassolubleaspirin,glyceryltrinitrate
(sublingualspray)andsalbutamolaerosol.
Doctorscansubmitamonthlyorderform*toapharmacistfor
thesupplyofPBSdoctor'sbagemergencydrugsatnocost.
SomePBSdrugsaresuppliedaspairedalternatives.These
includehydrocortisoneordexamethasoneandmetoclopramide
orprochlorperazine.Agrouppracticecanhaveallofthesedrugs
availableifdoctorsagreetoorderoneorotheritemineachpair.
Adrugcanonlyberequestedifthedoctorholdslessthanthe
maximumquantityprovidedunderthePBS,ortoreplace
date-expireddrugs.
Somedrugswhichareusefulforemergenciesarenotprovided
underthePBS(Table1).Doctorsmayobtaintheseasprivate
itemsbysubmittingawrittenordertoapharmacist.These
drugsinclude:
n oraldrugssuchasaspirin,analgesics,diazepam,antibiotics,
prednisolone
n non-steroidalanti-inflammatorydrugs(nSAIDs)forrectalor
intramuscularuse
n glucose50%
n ceftriaxone
n midazolam
n ergometrine.
Itisalsousefultocarryatleastone1Lbagofnormalsaline,
andasupplyofnormalsalineandwaterforinjections.
Current practice guidelinesEmergencydrugsavailablethroughthePBSsometimesdiffer
fromthoserecommendedbyAustraliantreatmentguidelines.
Forexample,theuseofparenteralchlorpromazineisnot
recommendedbytheTherapeuticGuidelinesbecauseitcan
causeserioushypotension.Instead,oralpreparationsof
risperidone,olanzapineorhaloperidolarerecommendedfor
behaviouralemergenciesiforaldiazepamisnoteffective.5
onlyinjectableformsofdiazepamandhaloperidolare
providedasemergencydrugsbythePBS.
LignocaineisaPBSdoctor'sbagitem.However,other
treatmentsforsustainedventriculartachycardiamaybe
preferred.5
Precautions with emergency drugsWithsedatingdrugs,thereisariskofdeathfromrespiratory
depression,especiallywhengivenintravenously.Itis
thereforeimportanttokeepthepatientunderobservationafter
administrationofthesedrugs.
Pethidineisnolongersuppliedasadoctor'sbagitem.6Instead,
aninjectableformoftramadolisnowavailablethroughthePBS.
Tramadolshouldnotbeusedinpatientstakingaserotonergic
antidepressantbecauseoftheriskofserotoninsyndrome.
Doctorsshouldbeawarethatketorolacshouldnotbegivento
patientswithrenalimpairment.* orderformsareobtainablefromMedicareAustralia,
phone132290.
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144 | VoLuME 30 | NuMbER 6 | DECEMbER 2007
Table 1
useful drugs for the doctor's bag
Drug (form) indications Contraindications Cautions
Adrenaline(1mgin1mLinjection)
Cardiacarrest,anaphylaxis7 noneincardiacarrestoranaphylaxis
Maycausearrhythmiaandmyocardialorcerebrovascularischaemia
†Aspirin,soluble,300mgtablet
Acutecoronarysyndrome,migraine
Pepticulcer,bleedingdisorders none
Atropinesulfate(600microgramin1mLinjection)
Bradycardia,asystole noneincardiacarrestorhypotensivebradycardia
Maycausetachycardia,confusionandnausea
Benztropinemesylate(2mgin2mLinjection)
Acutedystonicreactions Children<3years Maycausetachycardiaandconfusion
Benzylpenicillin(600mgor3gofpowder)
Severeinfections(meningococcaemia,pneumonia,septicaemia)
Allergy none
†Ceftriaxone(2gpowder)
Severeinfections(meningococcaemia,pneumonia,septicaemia)
Allergy none
Dexamethasonesodiumphosphate(4mgin1mLinjection)
Acuteallergicreactions(anaphylaxis,severeasthma),severecroup,acuteAddisoniancrisis.Palliativecareemergencies8
noneinemergency none
Diazepam(10mgin2mLinjection)
Acuteanxiety,convulsions(canbegivenrectally)
Cardiorespiratoryfailure,
CnSdepression
Maycausedrowsiness,confusionandrespiratorydepression
Dihydroergotaminemesylate(1mgin1mLinjection)
Migraine Hemiplegicmigraine,useofsumatriptan
Vasospasmsyndromescanoccurbutarerare
Diphtheriaandtetanusvaccine(0.5mLinjection)
Tetanusanddiphtheriaprophylaxisfollowinginjury
Children<8years Maycausepainandswellinglocallyandfeverandmalaise
†Ergometrinemaleate(500microgramin1mL)
Postpartumhaemorrhageandincompleteabortion
Threatenedabortion,severehypertension
Maycausehypertension,headacheandnausea
Frusemide(20mgin2mLinjection)
Acutepulmonaryoedema Sulfonamideallergy none
Glucagonhydrochloride(1mgin1mLinjection)
Hypoglycaemia none none
†Glucose50%(500mg/mLin50mL)
Hypoglycaemia Diabeticcoma Maycausephlebitis
Glyceryltrinitrate(400microgramdoseperspray)
Acutecoronarysyndrome,angina,acutepulmonaryoedema
Cardiogenicshock(SBP<90mmHg)
Maycauseheadacheandhypotension
Haloperidol(5mgin1mLinjection)
Acutepsychosis,acutemania,nauseaandvomiting
CardiovascularcollapseandCnSdepression
Maycauseextrapyramidalsymptoms,confusionandhypotension
Hydrocortisonesodiumsuccinate(100mgor250mgin2mLinjection)
Anaphylaxis,severeasthma noneinemergency none
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| VoLuME 30 | NuMbER 6 | DECEMbER 2007 145
†Ketorolac(10mgin1mLinjection)
Pain Renalimpairment,anticoagulation,asthma,treatmentwithprobenecid
Maycausenausea
Metoclopramidehydrochloride(10mgin2mLinjection)
nauseaandvomiting,migraine Acutecompletebowelobstruction
Extrapyramidalsymptomswithincreasedriskofdystonicreactionsinchildren
†Midazolam(5mgin1mLor15mgin3mLinjection)
Convulsions,severeagitation CardiorespiratoryfailureandCnSdepression
Maycausedrowsiness,confusionandrespiratorydepression
Morphinesulphate(15mgor30mgin1mLinjection)
Severepain,acutecoronarysyndrome,acutepulmonaryoedema
RespiratoryorCnSdepression.Avoidusingininfants.
Maycausesedation,nauseaandvomiting
naloxonehydrochloride(2mgin5mL)
opioid-inducedrespiratorydepression
none Peoplewithopioiddependencemayexperienceacutewithdrawalsyndrome
Procainepenicillin(1.5gforinjection)
Severeinfections(meningococcaemia,pneumonia,septicaemia)
Allergy none
Prochlorperazine(12.5mgin1mL)
nauseaandvomiting,vertigo CirculatorycollapseandCnSdepression
Maycausedrowsinessandextrapyramidalsymptoms
Promethazinehydrochloride(50mgin2mLinjection)
nauseaandvomiting,allergicreactions
Children<2years(exceptonadvice)
Maycausedrowsiness
Salbutamolsulfate(inhaler100microgram/doseornebulisersolution2.5mgor5mgin2.5mL)
Asthma,bronchospasm none Maycausetachycardiaortremor
Tramadolhydrochloride(100mgin2mLinjection)
Pain Children,treatmentwithserotonergicantidepressantsorMAoIs,respiratoryorCnSdepression
Maycausenausea,vomitinganddizziness
Verapamilhydrochloride(5mgin2mLinjection)
Supraventriculartachycardia Cardiogenicshock,heartblock,hypotension,useofbetablockersandsomeSSRIs
Maycausenausea,heartblock,bradycardiaandhypotension
† notsuppliedunderPBSdoctor'sbagemergencydrugsCnS centralnervoussystemSBP systolicbloodpressureMAoI monoamineoxidaseinhibitorSSRI selectiveserotoninreuptakeinhibitor
oxygenoxygencylinderscanberentedandrefilledfromamedicalgas
supplier(forexampleBoC(BritishoxygenCorporation)).A490L
(sizeC)willlastfor55minutesat8L/min.Usehigh-flowoxygen
withcautioninpatientsathighriskofcarbondioxideretention.
Storage of drugsDrugsmustbestoredinalockedbagoralockedcupboardat
below25°C.Doctor'sbagsshouldnotbeleftincarswhere
thetemperaturewilleasilyexceed25°Conevenamildday.
Diphtheriaandtetanusvaccineisstoredinarefrigerator.
Aregisterisrequiredtologdrugsreceivedanddrugsused
(includingtherecipient'sname).Schedule8drugs(opioids)
mustbestoredinalocked,fixed,steelsafe,althoughampoules
maybeputinalockedbagforuseawayfromtheclinic.A
separatebook(availablefromtheRoyalAustralianCollegeof
GeneralPractitioners)isrequiredtologSchedule8drugsthat
arereceivedandused.
Drug (form) indications Contraindications Cautions
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146 | VoLuME 30 | NuMbER 6 | DECEMbER 2007
General practice accreditationTomeetaccreditationstandards,generalpracticesmusthave
oxygen,abag-valve-masksystem,andappropriateemergency
drugs.Allgeneralpractitionersmusthaveaccesstoadoctor's
bag(whichmaybesharedbetweentwoormoregeneral
practitioners).Thereshouldbeasystemforcheckingemergency
drugstocksandexpirydates–forexample,amonthlyinventory
byapracticenurse.Doctor'sbagsshouldhaveasharps
container,disposablegloves,anddressingpacks.Safety
intravenouscannulasandneedlelesssystemsreducetherisk
ofneedlestickinjury.3
ConclusionAppropriatedrugsinthedoctor'sbagareanessentialpartof
generalpractice.Thecontentsofthebagwillbetailoredtosuit
theneedsofeachpractice.
References1. MurtaghJ.Drugsforthedoctor'sbag.AustPrescr
1996;19:89-92.2. MurtaghJ.Thedoctor'sbag–whatdoyoureallyneed?
AustFamPhysician2000;29:2509.3. Hiramanekn,o'SheaC,LeeC,SpeechlyC,CavanaghK.
What'sinthedoctor'sbag?AustFamPhysician2004;33:714-20.
4. PharmaceuticalBenefitsScheme:Doctor'sbagitemlist.http://www.pbs.gov.au/html/healthpro/browseby/doctorsbag[cited2007nov12]
Dental notes
Prepared by Dr M McCullough of the Australian Dental Association
Drugs for the doctor's bag
Dentistsdonotneedtostockasmanyemergencydrugsas
generalpractitioners,howeverwearerequiredtohavefully
equippedandwellmaintainedemergencyequipmentinour
surgery.
AsstatedintherecentlypublishedTherapeuticGuidelines:
oralandDental1,theminimumrequirementsforemergency
situationsinthedentalsurgeryareoxygen,adisposableairway,
andadrenaline.Fordentalpracticesperformingmoreextensive
procedures,orwithanincreasedproportionofmedically
compromisedpatients,thenmoreequipmentandmedications
arerequired.
Medicalemergenciesindentalsurgeriesareuncommonso
thereisariskthatmedicationswillexpirebeforetheyare
needed.Itisincumbentondentiststoensurethatthedrugsin
theiremergencyequipmentarenotoutofdate.Ideally,there
shouldbeasystemforcheckingemergencydrugstocksand
expirydates,perhapsbyamonthlyinventory.Manydental
practicesprobablyalreadyhavesuchaninventoryanditcanbe
easilyforeseenthatsuchdocumentationmaywellbecomepart
ofanypotentialpracticeaudit.
EmergencydrugsarenotavailableunderthePharmaceutical
BenefitsSchemefordentistsandmustbepurchasedatfullcost.
Thisanomalyshouldberedressed.
Reference1. TherapeuticGuidelines:oralandDental.Version1.
Melbourne:TherapeuticGuidelinesLimited;2007.
5. eTGcomplete.TherapeuticGuidelines.2006oct.http://www.tg.com.au[cited2007nov12]
6. MolloyA.Doespethidinestillhaveaplaceintherapy?AustPrescr2002;25:12-13.
7. Emergencymanagementofanaphylaxisinthecommunity.Wallchart[insert].AustPrescr2007;30(5).
8. SeidelR,SandersonC,MitchellG,CurrowDC.Untilthechemistopens–palliationfromthedoctor'sbag.AustFamPhysician2006;35:225-31.
Further readingAustralianResuscitationCouncilguidelines.http://www.resus.org.au[cited2007nov12]
Adultcardiorespiratoryarrestflowchart.http://www.resus.org.au/public/arc_adult_cardiorespiratory_arrest.pdf[cited2007nov12]
Paediatriccardiorespiratoryarrestflowchart.http://www.resus.org.au/public/arc_paediatric_cardiorespiratory_arrest.pdf[cited2007nov12]
nationalAsthmaCouncil.Emergencymanagementofasthma.http://www.nationalasthma.org.au/html/emergency/print/EMAC.pdf[cited2007nov12]
nationalHeartFoundation.Emergencydepartment/CCUguidelinesforthemanagementofacutecoronarysyndrome.ACStherapyalgorithm.http://www.heartfoundation.org.au/document/nHF/acs_chart0506.pdf[cited2007nov12]
Conflict of interest: none declared
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| VoLuME 30 | NuMbER 6 | DECEMbER 2007 147
Evaluation of adrenocortical function in adultsJui Ho, Endocrinologist, and David J Torpy, Associate Professor, Discipline of Medicine, University of Adelaide, and Endocrine and Metabolic Unit, Royal Adelaide Hospital, and Hanson Institute, Adelaide
Abnormallaboratoryresults
Summary
Cushing's syndrome is caused by increased
concentrations of cortisol. Most cases can be
detected by measuring the free cortisol in a urine
sample collected over 24 hours. in Cushing's
syndrome the increased secretion of cortisol is
not reduced during a dexamethasone suppression
test. Addison's disease is caused by a decreased
secretion of cortisol that does not respond to
an injection of synthetic adrenocorticotrophic
hormone. Concentrations of adrenocorticotrophic
hormone are raised in primary, and low or normal
in secondary adrenal insufficiency. Some patients
with hypertension have primary aldosteronism.
They have a high ratio of aldosterone to plasma
renin activity. when investigating adrenal function
it is important to consider the patient's diet and
drugs as well as the timing of the sample.
Keywords:Addison'sdisease,aldosterone,Conn'ssyndrome,
cortisol,Cushing'ssyndrome.
(Aust Prescr 2007;30:147–9)
introduction
Theadrenalcortexconsistsofthreefunctionallyseparate
layers.Theouterzonaglomerulosaproducesaldosterone
underthestimulatorycontroloftherenin-angiotensinsystem
andpotassium.Aldosteroneincreasessodiumreabsorption
andpotassiumexcretioninthekidneyandgut.Thezona
fasciculataproducescortisolunderthecontrolofpituitary
adrenocorticotrophichormone(ACTH).ACTHisprincipally
regulatedbyhypothalamiccorticotrophin-releasinghormone.
ThesecretionofACTHrespondstoadiurnalrhythm,stressand
negativefeedbackfromcirculatingcortisol.Cortisolregulates
metabolism,andduringstressitrestrainsandredirectsthe
immunesystemandaccentuatescardiovascularresponses.
Theinnerzonareticularisproducestheadrenalandrogens
dehydroepiandrosteroneandandrostenedione.
Clinicalevaluationdetermineswhichtestsofadrenalfunction
areneeded.Theprinciplesoftestinginclude:
n usingbasalhormoneconcentrationsforscreening
n usingsuppressionorstimulationteststodefinitively
diagnosehormoneexcessordeficiency
n measuringtrophichormonestodiagnosethesite
ofendocrinelesions(forexample,measuringACTH
todistinguishanadrenalfromapituitarylesionin
hypocortisolism).
Testing for hypercortisolism (Cushing's syndrome)MildCushing'ssyndromeisnotoriouslydifficulttodiagnose,
butearlydiagnosisavoidsdisabilityandreducesmortality.
CortisolconcentrationsincreaseinCushing'ssyndrome,but
therearetwomajorconfounders.oneisthatsomepatients
haveincreasedcortisolproductionratesthatremainwithinthe
statisticallynormalrange.Furthermore,thisoverproduction
maybeintermittentorcyclic.Secondly,someindividualsmay
havetransienthypercortisolismandfeaturesconsistentwith
earlyCushing'ssyndrome,butwithouttheprogressivecatabolic
effects.Theseindividualshave'pseudo-Cushing's'.Insome
casesthisisassociatedwithalcoholabuseordepression.no
singletestisinfallibleinCushing'ssyndromeandvaluesclose
tothelimitsofnormalmustberegardedwithsuspicion.1
Screening tests for Cushing's syndromeMostcasescanbereadilydiagnosedbyanelevationofthefree
cortisolina24-hourcollectionofurine,howeverinupto15%
ofnewcasestheresultmaybenormal.Thedexamethasone
suppressiontestalsohasasubstantialfalsepositiveandfalse
negativerate.Thediagnosiscanbemadewithplasmacortisol,
butthebloodsamplehastobetakenatmidnightandthis
isoftenimpractical.Amidnightvaluelessthan120nmol/L
virtuallyexcludesCushing'ssyndrome.
Urinary free cortisolover24hoursthefreecortisolprovidesanintegrated
assessmentofcortisolsecretion.Thisavoidsthepitfallsof
bloodtestsincludingcircadianrhythm,pulsatilecortisolrelease
andalteredlevelsofcorticosteroid-bindingglobulin.However,
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148 | VoLuME 30 | NuMbER 6 | DECEMbER 2007
urinevolumesabovefourlitresperdaymayresultinfalse
positivetests.
Cortisolexcretionratesvarydiurnallybuturinecreatinine
excretiondoesnot.Hence,itisnotpossibletocorrectan
incompleteorover-collectionwiththe24-hoururinecreatinine.
Urinarycreatinineisusefulindeterminingiftheurinecollection
wasadequate,forexamplealow24-hoururinecreatininein
alargepersonmaysuggestunder-collection.Inaddition,in
sequentialmeasurementsthe24-hoururinecreatinineshould
notvarybymorethan10%.
Falsepositiveresultscanoccurinpatientswithhighurine
volumes,chronicalcoholism,depression,idiopathicpseudo-
Cushing's,orseriousillness.Falsenegativesmayoccurin
patientswithearlyormildCushing'ssyndrome,orinthosewith
cyclichypercortisolismwhichoccursin10%ormoreofcases
dependingonhowcyclicisdefined.
Midnight plasma cortisolCortisolpeaksaroundthetimeofwaking,decreasesrapidly
throughthemorningandreachesanadiraroundmidnight.Most
patientswithCushing'ssyndromehaveearlymorningplasma
cortisolconcentrationswithinorslightlyabovethenormalrange.
Incontrast,midnightplasmacortisolconcentrationsarealmost
alwayshigh(greaterthan207nmol/L).
Midnight salivary cortisolSalivarycortisolconcentrationsreflectplasmafreecortisol,but
appropriateassay-specificnormativevaluesmustbeusedfor
itsinterpretation.Internationally,cut-offshaverangedwidely.
Wehavefoundacut-offof13nmol/Ltoreliablydistinguish
Cushing'sfromnon-Cushing'spatients.
Low-dose dexamethasone suppression testingAlowdoseofdexamethasoneshouldsuppressplasmacortisol.
ThisiscommonlyusedasascreeningtestforCushing's
syndrome.Dexamethasone,1mgorally,isgivenat11pmand
plasmacortisolismeasuredat8–9amthenextdaytoseeifit
hasbeensuppressed.Thedexamethasonesuppressiontesthas
beenvariouslyvalidatedinthepast,oftenwithinappropriate
controls,suchasnormalvolunteers.Lowcut-offvalues
(50nmol/Lorless)tendtoover-diagnose,whilehighcut-off
values(140nmol/Lorabove)tendtomisscasesofCushing's
syndrome.Falsepositiveresultscanoccurinacuteillness,
depression,anxiety,alcoholism,highoestrogenstatesand
withdrugsthatacceleratedexamethasonemetabolism.Ifalow
dosedoesnotsuppresscortisol,ahigh-dosedexamethasone
suppressiontestisindicated.
Testing for primary hypoadrenalism (Addison's disease) and ACTH deficiencyHypoadrenalismmaybecausedbyabnormalitiesintheadrenal
glandoralackofACTH.Adrenalsuppressionisalsoanadverse
effectofcorticosteroids.
Althoughfatigueisakeysymptomofhypoadrenalism,most
fatiguedpeoplehavenormaladrenalfunction.Thereisnosingle
cheapandconvenienttestforevaluatinghypoadrenalism.2Testing
includesanACTHstimulationtest,andmeasurementsofsodium,
potassium,ACTH,plasmacortisol,aldosteroneandreninactivity.
Plasma cortisolAnearlymorningplasmacortisol,measuredwithinone
hourofwaking,below200nmol/Lstronglysuggestsadrenal
insufficiency.Conversely,aplasmacortisolgreaterthan
500nmol/Lexcludesthediagnosisandobviatestheneedforan
ACTHstimulationtest.Intermediatecortisolconcentrationsmay
requireinvestigationwithanACTHstimulationtest.
ACTH stimulation testingInmostcasesofsuspectedhypoadrenalism,astimulationtest
isneededtodiagnosecortisoldeficiency.Anormalresponseto
intravenousACTH(250microgram)isacortisolpeakvalueat
either30or60minutesofgreaterthan500nmol/L.Thepreviously
recommendedadditionalcriterionofacortisolincrementgreater
than200nmol/Lrarelycontributestothediagnosis.
Therearecasesofmissedadrenalinsufficiencyafteranormal
ACTHtest.Thereproducibilityoftestingisimperfect.Thetest
hasnotbeenvalidatedagainstclinicalendpoints,buthasbeen
validatedagainstthenowrarelyusedinsulinhypoglycaemiatest.
Plasma ACTHMeasurementofplasmaACTHhelpslocalisethecauseof
adrenalinsufficiency–adrenal(primaryorAddison's)versus
pituitary(secondary)orhypothalamic(tertiary).Inprimary
adrenalinsufficiency,plasmaACTHisgreatlyelevatedduetoa
lackofthenegativefeedbackofcortisolonthehypothalamic-
pituitaryaxis.Insecondaryortertiaryadrenalinsufficiency,
ACTHisloworinappropriatelynormal.
Corticotrophin-releasing hormone testTheuseofcorticotrophin-releasinghormonetotestACTHand
cortisolreservedirectlyassessespituitaryandadrenalfunction.
otherthanminorflushing,corticotrophin-releasinghormone
(1microgram/kgintravenously)rarelyproducesadverseeffects.
Thetestisexpensiveandcorticotrophin-releasinghormoneis
notwidelyavailable.
Testing for primary aldosteronismConn'ssyndromeishypertensionandhypokalaemiaduetoan
aldosterone-secretingadrenaltumour,howevermanycasesare
normokalaemic.Screeningforprimaryaldosteronismmaybe
indicatedinpatientswithhypertensionwhohavespontaneous
orthiazide-inducedhypokalaemia.3
Plasma aldosterone concentration:plasma renin activity ratioAmid-morningbloodsampleistakenfromaseatedpatient.
Inprimaryaldosteronism,theplasmareninactivityisreduced
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| VoLuME 30 | NuMbER 6 | DECEMbER 2007 149
andtheplasmaaldosteroneconcentrationsarehigh,resulting
inaplasmaaldosteroneconcentration(pmol/L):plasmarenin
activity(ng/mL/hr)ratioofgreaterthan700.Afalsepositive
mayoccurwithlowaldosteroneconcentrationsiftheplasma
reninactivityisverylow,forexampleinpatientstakingahigh
saltdiet.Hence,anelevatedratiomaynotsuggestprimary
aldosteronismiftheplasmaaldosteroneconcentrationisless
than270nmol/L.
Serumpotassiumshouldbemeasuredsimultaneouslyas
alowserumpotassiumwillreducetheplasmaaldosterone
concentrationandindicatearequirementtoreplacepotassium
beforetestingagain.Antihypertensivedrugs,exceptfor
hydralazine,prazosinandverapamil,canalsointerferewith
theplasmaaldosteroneconcentration:plasmareninactivity
ratio.Diureticsandaldosteronereceptorblockerssuchas
spironolactoneneedtobestoppedforsixweeksbeforetesting.
Betablockerssuppresstheplasmareninactivitybutthey
canbestoppedfor24–48hoursbeforetesting.Theeffectsof
angiotensinconvertingenzyme(ACE)inhibitorsandangiotensin
receptorantagonistsaregenerallyminor,butinapatienttreated
withthesedrugsadetectableplasmareninactivitylevelora
lowplasmaaldosteroneconcentration:plasmareninactivity
ratiodoesnotexcludethediagnosisofprimaryaldosteronism.
Dihydropyridinecalciumantagonistssuchasnifedipineand
amlodipinecanreducetheplasmaaldosteroneconcentration
inpatientswithanaldosteronesecretingadenoma.Renal
impairmentmayelevatetheratioasincreasedpotassium
elevatesaldosteronesecretionwhilesaltandwaterretention
suppressestheplasmareninactivity.
Confirming primary hyperaldosteronismConfirmatorytestingaimstodemonstratealdosterone
secretoryautonomy,usingmeasurementsofplasmaorurine
aldosteroneundersaltloadingconditions,withorwithout
fludrocortisone.Thefinalstepistodetermineifoneorboth
adrenalsarethesourceofaldosterone,generallyrequiring
adrenalveinsampling.
Adrenal incidentalomaAnunanticipatedadrenalmass(incidentaloma)isfoundin
approximately4%ofupperabdominalcomputedCTscans.
Clinical,imagingandbiochemicalevaluationisnecessaryto
excludemalignancyandhormoneexcess.4Theriskof
adrenocorticalcancerisverylow,butadrenalmetastasesare
commonandneedtobeconsideredinpatientswithahistory
ofcancer.
ConclusionDisordersofadrenocorticalfunctionareuncommonandthe
symptomsoftennon-specific.Applicationofasmallnumberof
biochemicalscreeningtestscanseparatethosepatientswhodo
nothaveadisorderofadrenalfunctionfromthosewhorequire
specialisedassessmentandmorecomplextesting.
References1. newell-PriceJ,BertagnaX,GrossmanAB,niemanLK.
Cushing'ssyndrome.Lancet2006;367:1605-17.2. niemanLK.Dynamicevaluationofadrenalhypofunction.
JEndocrinolInvest2003;26(7Suppl):74-82.3. MulateroP,DluhyRG,GiacchettiG,BoscaroM,VeglioF,
StewartPM.Diagnosisofprimaryaldosteronism:fromscreeningtosubtypedifferentiation.TrendsEndocrinolMetab2005;16:114-19.
4. nationalInstitutesofHealth.nIHstate-of-the-sciencestatementonmanagementoftheclinicallyinapparentadrenalmass('incidentaloma').nIHConsensStateSciStatements2002;19:1-25.
Conflict of interest: none declared
Self-test questionsThe following statements are either true or false
(answers on page 167)
1. Mostpatientswithprimaryhyperaldosteronismhave
hyperkalaemia.
2. Anormal24-hoururinefreecortisolexcludesCushing's
syndrome.
Therapeutic Advice and information Service (TAiS)A telephone service for health professionals Telephone 1300 138 677 (local call charge)
ThenationalPrescribingServiceTherapeuticAdviceand
InformationService(TAIS)isanationaltelephoneservice
forgeneralpractitioners,communitypharmacistsandother
healthprofessionals.Forthecostofalocalcall,TAIS
providesindependentdrugandtherapeuticsinformation
ontopicssuchasnewdrugs,useofdrugsforunlicensed
indications,interactionsbetweendrugs,foodsor
complemetarytherapies,adverseeffects,andthesafetyof
drugsinpregnancyandlactation.
Contact: officehours MondaytoFriday,exceptnational
publicholidays
Telephone: 1300138677(localcallcharge)Fax: (03)94594546Email: [email protected]: AustinHealthDrugInformation PharmacyDepartment AustinHospital 145StudleyRoad
HEIDELBERGVIC3084
Fornon-urgentenquiriesyoucanalsousetheTAISonlineenquiryformonthenPSwebsite.
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150 | VoLuME 30 | NuMbER 6 | DECEMbER 2007
Relationships between health professionals and industry: maintaining a delicate balancePaul A Komesaroff, Professor of Medicine, Director, Centre for the Study of Ethics in Medicine and Society, Monash University Department of Medicine, Alfred Hospital, Melbourne, and Ethics Convener, Royal Australasian College of Physicians
Summary
The power and influence of the pharmaceutical industry has raised concerns among health professionals and the wider community and led to calls for increased regulation. overwhelming evidence that advertising, contact with company representatives, gift giving, sponsorship of meetings and other forms of promotion influence prescribing behaviour, has drawn particular attention to drug promotion. in answer to these concerns a range of responses has developed, including rules set by government, processes for the review and management of research, industry codes of conduct, community responses, and guidelines generated by practitioner associations. The various forms of regulation taken together strike a delicate balance that aims to protect the interests of the community and individual patients, foster research and the development of new products, maintain public confidence in pharmaceuticals and medicine, and facilitate ethical decision making among the various participants. Although guidelines for health professionals provide some advice, they cannot cover all situations where conflicts and dualities may arise in practice.
Keywords:drugpromotion,drugregulation,ethics.
(Aust Prescr 2007;30:150–3)
introductionDespiteimprovementsachievedinthemanagementofcomplex
medicalconditionsinrecentyearsandwidespreadand
increasinguseofpharmaceuticals,thepharmaceuticalindustry
hasbeenincreasinglyportrayedinboththeacademicliterature
andthepopularmediainanunfavourablelight.Whileitmay
betruethattheindustry'snegativereputationisnotcompletely
justified,itisnotdifficulttounderstandthesourceofthe
concerns.
Generalpractitionersandotherhealthprofessionalssuch
aspharmacistsarefrequentlyvisitedbyrepresentativesof
pharmaceuticalcompanies.Thepurposeofthesevisitsisto
promotethecompany'sdrugsandtobuildarelationship.In
dealingwithsuchencounters,situationsmayarisewherethere
isanethicaldilemmaorconflictofinterest.Itisimportant
forhealthprofessionalstobeawareoftheseandtorespond
appropriately.
Drug promotionInAustraliatheprimarytargetsofdrugpromotionaredoctors,
whomaybeprovidedwithgifts,offersoftravel,andother
inducementstoprescribe.1Moresubtlepromotionmayinclude
educationalactivities,drugsamplesanddrugfamiliarisation
schemes,andsupportforthepracticesuchasprovidinganurse
tocollectdata.
Eventhoughdoctorsgenerallydenythattheyareinfluenced
bysuchapproaches2,3,thereisoverwhelmingevidencethat
advertisinginfluencesprescribingbehaviour.Physicians
whoattendpharmaceuticaleventsaremorelikelytousethe
productsofthesponsors,evenintheabsenceofreliableand
credibleevidenceintheirfavour.4,5Promotionalactivitiesin
generalleadtoincreasedprescribingofdrugs,acceptanceof
commercialratherthanscientificviews,apropensitytoengage
innon-rationalprescribingbehaviour6,7,8,andbiasesinfavourof
acompany'sdrugs.9,10
Whileresearchundertakenbyindustryisoftenrigorousand
wellconducted,itmaybedrivenbycommercialimperatives
leadingtobiasedpresentationandinterpretationofresults.11,12
Protocolsandmethodologiesmayreflectandsupportintended
outcomesratherthandisinterestedinquiry.13
Perhapsofevengreaterconcernisthewelldocumentedfact
thatindustryinterestssubstantiallyinfluencethesocialagenda
relatingtotheunderstandingofhealthanddisease,sexuality,
bodyimageandlifestyles.14,15
What is special about drug promotion?Concernabouttheroleandinfluenceofthepharmaceutical
industryisheightenedbecauseofthespecialfeaturesof
medicinescomparedtoothercommercialproducts.The
consumersofmedicationsareoftenextremelyvulnerable,for
theobviousreasonthattheirhealthmaybeatstakeinusinga
product.Decisionsaboutwhatdrugstouseareoftentaken
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| VoLuME 30 | NuMbER 6 | DECEMbER 2007 151
notbythemalonebutbytheirmedicalpractitioners,whose
interestsarenotalwaysidenticaltothoseoftheirpatients.
Forprescriptiondrugs,medicalpractitionershavegreat
influenceandarechargedwiththeresponsibilityofbalancing
patients'needsandthepublicinterest.Theyhaveknowledge
andexpertisetoassessthescientificevidence,andaccesstothe
specificcontextualdetailsofmedicalneedinparticularcases.
Forover-the-counterproducts,pharmacistsadvisepatientsand
directlybenefitfrommakingasale.Theymayalsobeoffered
incentivestostockparticularbrands.
Theongoingdebatesabouttheroleandpowerofthedrug
industryinthepopularmedia16,17,18havenodoubtinfluenced
communityattitudes,althoughitisdifficulttodeterminejust
whatimpactthesemayhavehad.Whilesomeconsumer
groupshaveexpressedsuspicionandhostilitytotheindustry,
othergroupshaveemphasisedtheimportanceofimproved
co-operationanddevelopmentofactivecollaborations.19Public
scepticismmayhelptocontroldoctors'dealingswithindustry,
butmayalsodamagethedoctor–patientrelationship.
Physiciansneedtobeawareoftheevidenceabouttheimpact
ofadvertisingonbehaviourandcommunityperceptions.While
bansontheprovisionofinformationbydrugcompaniesare
inappropriate,highlevelsofcriticalawareness,supportedby
educationalprograms,areneededbyclinicians.
Inmanycountries,includingAustralia,thepurchaseof
medicationsisheavilysubsidisedfrompublicfunds.The
prescriberthereforedoesnotdirectlybearthecostoftheir
decisions.
Conflicts of interestsoneofthekeyrequirementsofahealthprofessionalinvolved
ininteractionswithindustryistobeabletodistinguishdualities
andconflictsofinterests.Adualityexistswheretherearetwoor
moresocialrolesthatoverlap,eachofwhichisassociatedwith
amoralimperative.Aconflictexistswheretheseimperatives
arecontradictoryandthreatentocompromisetheprimarygoal
ofoneofthem.
Adualityofinterestwouldexistwhenageneralpractitioner
involvedinresearchisconsideringrecruitingtheirownpatients
forastudy,orwhenadoctorconsidersacceptingtravel
assistancefromapharmaceuticalcompanytoattendameeting
withundisputedscientificcontentatapleasantresortlocation.
Theprinciplesforrespondingtoadualityarestraightforward.
Itneedstobeidentifiedanddisclosedpubliclytotherelevant
community.Thiscommunityshoulddecidewhetherit
constitutesaconflictand,ifso,thisneedstobemanaged,
usuallybydisengagingthetwoconflictingroles.
Sometimesthisprocessofdisengagementisstraightforward
–forexample,ifresearchersproposetoincludetheirown
patientsinaresearchprojecttheyshouldingeneralnot
approachthepatientthemselvesbutleavetheconsentprocess
tothirdparties.onotheroccasions,suchaswherearesearcher
hasdirectpecuniaryinterestsinaproductbeingtested,more
elaboratemechanisms,suchasanarm'slengthcommitteeor
divestmentofshareholdings,maybenecessary.
Regulation of drug promotionInresponsetotherealorperceivedrisksassociatedwiththe
pharmaceuticalindustry'sinfluenceandpower,anarrayof
formalandinformalmechanismsforregulatingtheindustry
hasdeveloped.Theseincluderulessetbygovernment,
industrycodesofconduct,guidelinesgeneratedbypractitioner
associations,processesforthereviewandmanagement
ofresearch,andcommunityresponses.Together,they
seektoensureawiderangeofgoals,includingprotection
oftheinterestsofthecommunityandindividualpatients,
responsivenesstospecificclinicalcontexts,fosteringofresearch
anddevelopmentofnewproducts,maintenanceofpublic
confidenceinpharmaceuticalsandmedicine,facilitationof
ethicaldecisionmakingamongthevariousparticipants,and
enhancementofoptionsandfreedomtoact.
GovernmentAlthoughgovernmentregulationundoubtedlyplaysakey
role,itisabluntinstrumentthatmaynotbeabletoprovide
specificguidanceforallcircumstancesthatoccurinaclinical
setting.Statutoryregulatoryregimesarealsocumbersomeand
bureaucraticandrequireelaborateandexpensivesystemsof
enforcement.
IndustryTheindustryitselfhasdevelopedacodeofconduct,which
isadministeredthroughtheindustrypeakbody,Medicines
Australia.20ThisCodehasbeencriticised,forexample,on
thebasisthatmembershipofMedicinesAustralia,andthus
allegiancetoitspolicies,isvoluntaryanddoesnotincludeall
manufacturers.Areasofconcern,suchasthecollectionand
controlofdata,areomittedaltogether.EnforcementoftheCode
isincompleteandmostlyreliesoncomplaints.Sanctionsfor
breachesaregenerallymodest.21nonetheless,itisbelievedthat
theCoderepresentsasubstantialachievementandthatithas
contributedtosignificantchangeinthecommercialbehaviour
ofthepharmaceuticalindustryinAustralia.Forexample,a
recentamendmenttotheCodenowrequirespharmaceutical
companiestopubliclydisclosethecostofeventsorganisedfor
doctors.
Guidelines for health professionalsAnumberofprofessionalassociationshavedeveloped
guidelinesabouttheethicalrelationshipsbetweenhealth
professionalsandthepharmaceuticalindustry.22,23Amongthese
aretheRoyalAustralasianCollegeofPhysicians(RACP)24,the
RoyalAustralianCollegeofGeneralPractitioners(RACGP)25,and
thePharmaceuticalSocietyofAustralia.26
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152 | VoLuME 30 | NuMbER 6 | DECEMbER 2007
RACP recommendationsTheseguidelinesseektodemonstratehowdualitiesmay
bemanagedinspecificcircumstancesthatariseincommon
practice.Theyrecommendthatgiftsshouldberejected,even
itemsoftrivialvalue.Ingeneral,acceptanceoftravelexpensesis
discouraged.However,whereapractitionerismakingaformal
contributiontoameetingitmaybeacceptablefortheorganising
committeetoofferassistancewithtravelandothercosts.
Forscientificmeetingsorprofessionaldevelopmentevents,itis
importantthatprogramsaredevelopedbycommitteesatarm's
lengthfromsponsorsandthatsponsorshipisnotnegotiatedon
thebasisofconditionsrelatingtospeakersorcontent.
TheRACPguidelinescovermanyissuesregardingresearch,
includingdesignofexperiments,managementand
interpretationofdata,andpublicationofresults,whichraise
thepossibilityofconflictsofinterests.Researchershavespecial
responsibilitiestoensurethattheconductandoutcomesof
researcharenotinfluencedbypecuniaryornon-pecuniary
interestsandthatthepubliccanhavefullconfidenceinthe
integrityofanydatathataredisseminated.
RACGP recommendationsTheRACGPmakessimilarrecommendationstogeneral
practitionersbutismorerelaxedaboutdoctorsaccepting
gifts.Agiftmaybeacceptedbutthepatientshouldbethe
primarybeneficiaryandthegiftshouldberelatedtothegeneral
practitioner'swork.So,forinstance,giftssuchasastethoscope
oratextbookareacceptable,whereasgiftsofaholiday,
frequentflyerpoints,acomputerorcashpaymentsarenot
acceptable.
Theguidelinesalsorecommendthatifageneralpractitioner
isinvolvedinpostmarketingsurveillancestudies,theyshould
makeitcleartothepatientthatthepatient'swelfareisnot
dependentonparticipationinthestudyandtheycanwithdraw
atanytimeandstartanalternativetreatmentiftheywish.
The Pharmaceutical Society of Australia CodeAlthoughverybrief,theCodeobligatespharmaciststoavoid
situationsthatmaypresentaconflictofinterest.Accepting
inappropriategiftsisalsocontrarytotheCode.
Conclusionopinionsdifferandcontroversiescontinueabouttheinfluence
ofthepharmaceuticalindustryandtheproperresponses
toit.ThesystemofregulationthathasevolvedinAustralia
iscomplexandheterogeneous,incorporatingcomponents
fromgovernment,industry,communityandtheprofessions.
Althougheachwouldonitsownbeinsufficient,together
theseelementsconstituteadelicatelybalancedequilibrium
thatgoesatleastsomewaytowardsensuringthatthediverse
tasksandgoalssetbythevariousstakeholdersareaddressed
andacknowledged.Whetherthebalanceshouldshiftmorein
thedirectionofregulation,whetheramorepunitiveapproach
wouldbemoreorlesseffective,howbesttomaintainboth
economicincentivesandpublicresponsibility–orevenifitis
possibletodoso–remainsuncertain.
References1. McneillPM,KerridgeIH,HenryDA,StokesB,HillSR,
newbyD,etal.GivingandreceivingofgiftsbetweenpharmaceuticalcompaniesandmedicalspecialistsinAustralia.InternMedJ2006;36:571-8.
2. BrettAS,BurrW,MolooJ.Aregiftsfrompharmaceuticalcompaniesethicallyproblematic?Asurveyofphysicians.ArchInternMed2003;163:2213-8.
3. HalperinEC,HutchisonP,BarrierRCJr.Apopulation-basedstudyoftheprevalenceandinfluenceofgiftstoradiationoncologistsfrompharmaceuticalcompaniesandmedicalequipmentmanufacturers. IntJRadiatoncolBiolPhys2004;59:1477-83.
4. HaayerF.Rationalprescribingandsourcesofinformation.SocSciMed1982;16:2017-23.
5. LexchinJ.Interactionsbetweenphysiciansandthepharmaceuticalindustry:whatdoestheliteraturesay?CMAJ1993;149:1401-7.
6. WazanaA.Physiciansandthepharmaceuticalindustry:isagifteverjustagift?JAMA2000;283:373-80.
7. PeayMY,PeayER.Theroleofcommercialsourcesintheadoptionofanewdrug.SocSciMed1988;26:1183-9.
8. ChrenMM,LandefeldCS.Physicians'behaviorandtheirinteractionswithdrugcompanies.Acontrolledstudyofphysicianswhorequestedadditionstoahospitaldrugformulary.JAMA1994;271:684-9.
9. RutledgeP,CrookesD,McKinstryB,MaxwellSR.Dodoctorsrelyonpharmaceuticalindustryfundingtoattendconferencesanddotheyperceivethatthiscreatesabiasintheirdrugselection?Resultsfromaquestionnairesurvey.PharmacoepidemiolDrugSaf2003;12:663-7.
10. AgrawalS.Pharmaceuticalindustryandsponsorshipofdelegatesfornationalconferences.IndianPediatr2002;39:445-8.
11. HenryDA,KerridgeIH,HillSR,McneillPM,DoranE,newbyDA,etal.Medicalspecialistsandpharmaceuticalindustry-sponsoredresearch:asurveyoftheAustralianexperience.MedJAust2005;182:557-60.
12. HenryD,DoranE,KerridgeI,HillS,McneillPM,DayR.Tiesthatbind:multiplerelationshipsbetweenclinicalresearchersandthepharmaceuticalindustry.ArchInternMed2005;165:2493-6.
13. BeroLA,RennieD.Influencesonthequalityofpublisheddrugstudies.IntJTechnolAssessHealthCare1996;12:209-37.
14. IllichI.Limitstomedicine.London:MarionBoyars;1977.
15. MoynihanR.Themakingofadisease:femalesexualdysfunction.BMJ2003;326:45-7.
16. AngellM.Thetruthaboutthedrugcompanies:howtheydeceiveusandwhattodoaboutit.newYork:RandomHouse;2004.
17. MoynihanR,CassellsA.Sellingsickness:howthedrugcompaniesareturningusallintopatients.Sydney:Allen&Unwin;2005.
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| VoLuME 30 | NuMbER 6 | DECEMbER 2007 153
18. JohnleCarre.Theconstantgardener.newYork:SimonandSchuster;2001.
19. Workingtogether.Theguide.Aguidetorelationshipsbetweenhealthconsumerorganisationsandpharmaceuticalcompanies.Consumers'HealthForumofAustraliaandMedicinesAustralia.2005.http://www.chf.org.au/Docs/Downloads/360_guide_for_relationships.pdf[cited2007nov12]
20. MedicinesAustralia.CodeofConduct.15thed.2006.AmendedAug2007.http://www.medicinesaustralia.com.au[cited2007nov12]
21. MedicinesAustraliaCodeofConduct:breaches.AustPrescr2007;30:151-3.
22. BickerstaffeR,BrockP,HussonJM,RubinI,BragmanK,PatersonK,etal.Ethicsandpharmaceuticalmedicine–thefullreportoftheEthicalIssuesCommitteeoftheFacultyofPharmaceuticalMedicineoftheRoyalCollegesofPhysiciansoftheUK.IntJClinPract2006;60:242-52.
23. KomesaroffPA,BachMA,DanoffA,GrumbachMM,KaplanS,LakoskiJM,etal.TheEndocrineSocietyEthicsAdvisoryCommittee:ethicalaspectsofconflictsofinterests,october2003.Endocrinology2004;145:3032-41.
24. KomesaroffP,CarneyS,LaBrooyJ,TattersallM,GreenbergP.Guidelinesforethicalrelationshipsbetweenphysiciansandindustry.3rded.Sydney:RoyalAustralasianCollegeofPhysicians;2006.http://www.racp.edu.au[cited2007nov12]
25. RoyalAustralianCollegeofGeneralPractitioners.Generalpractitionersandcommercialsponsorship.http://www.racgp.org.au/guidelines[cited2007nov12]
26. PharmaceuticalSocietyofAustralia.Giftsfrompharmaceuticalcompanies.http://www.psa.org.au[cited2007nov12]
Conflict of interest: none declared
Dental notesPrepared by Dr M McCullough of the Australian Dental Association
Relationships between health professionals and industry: maintaining a delicate balanceThelevelofprescribingthatoccursintheaveragedentalpractice
isnotusuallysuchthatitattractstheattentionofpharmaceutical
companies'marketingdepartments.However,wearelarge
consumersofrestorativematerials,medicamentsandother
products.Werelyonagoodworkingrelationshipwithdental
supplycompanieswhonotonlyofferaccesstotheseproducts,
butarealsoofteninvolvedinresearchrelatedtothem.Itismost
likelythatdentistsarenotawareoftheinfluencethatadvertising,
'specialoffers',personalvisitsbycompanyrepresentatives,
endorsementsandtradeshowshaveonourpurchasinghabits.
Whatdentalpractitionerspurchaseorprescribeshouldalways
bedoneonthebasisofavailablescientificevidencewith
patients'interestutmostinourminds.Infact,inthemajority
ofpracticesitisnotthedentistswhopurchasetheseitems,but
ratherthepracticemanagerontheadviceofthedentist,advice
thatmaynotbeconsistentlyavailable.Situationsofconflict
anddualityofinterestmaywellberelativelycommoninthe
dentalprofession,andtheseshouldbeacknowledgedand
dealtwithinanopenmanner.Currently,theAustralianDental
Associationisdevelopingapolicytoadviseitsmemberswhere
theseconflictsanddualitiesofinterestsarise.
MedicinesAustraliahasaCodeofConducttoguidethe
promotionofprescriptiondrugsbypharmaceuticalcompanies
inAustralia.AneweditionoftheCodehasrecentlybeen
approved.1ComplaintsareconsideredbytheCodeofConduct
Committeeandtheresultsarepublishedinitsannualreport.
Thereportfor2006–07isavailableontheMedicinesAustralia
website.2
Thisyear'sreportcontainsdetailedinformationabout41
complaints.InfourteencasesnobreachoftheCodewasfound.
Table1showsthe27complaintsinwhichatleastonebreach
oftheCodewasfound.Asusual,mostofthecomplaintswere
madebyrivalpharmaceuticalcompanies,but12weremadeby
healthprofessionals.
Mostofthebreacheswereforusingmisleadinginformationin
promotionalmaterial.Someofthelargerfineswereimposed
oncompaniesthathadallowedthepublictobeexposed
totheirpromotions.Twocomplaintsrelatedtoacompany
whichsponsoredthenationalconferenceofapatientsupport
Medicines Australia Code of Conduct: breaches
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154 | VoLuME 30 | NuMbER 6 | DECEMbER 2007
group.Anarticle,originallydraftedforhealthprofessionals,
butpublishedinReader'sDigest,clearlybreachedtheCode.
Anotherbreach,identifiedbyseveralcomplaints,wasoffering
a'money-backguarantee'topatientsbeingtreatedforerectile
dysfunction.
Theinformationinthereportrevealssomeofthesophisticated
strategiescompaniescanuse.onecompanyhadusedapublic
relationsconsultanttomanageacampaignaboutamedicine
whichhadyettobeapprovedinAustralia.Thisincluded
sponsoringajournalisttoattendanoverseasconferenceabout
thedrug.Issuingamediareleaseonanunapproveddrugwas
consideredtobepromotionalactivitywhichbreachedtheCode.
TheCommitteehadtograpplewithwhatconstitutesexcessive
The story of one complaintJohn S Dowden, Editor
Anadvertisingcampaignforvardenafilencouragedmen
witherectiondifficultiestoseektreatment.Theadvertisement
includedtheproductlogoandthenameofthecompany.
Theimagery,ofanuprightbanana,wasalsousedinthe
advertisingtohealthprofessionals.Aspartofthisparallel
campaign,doctorsandpharmacistswereinformedthatthe
companywouldofferamoney-backguaranteetopatients.
ImadeacomplainttoMedicinesAustraliaasIbelievedthat
theadvertisingtothepublicwouldstimulatedemandfora
particularproductandthemoney-backguaranteecouldbe
seenasaninducement.Complaintswerealsomadebytwo
pharmacistsandtheAustralianConsumers'Association.
TheCodeofConductCommitteeconsideredmycomplaint
withinamonthandsentmeitsdecisionwithinsixweeks.The
rulingwasinanextractoftheminutesoftheCommittee's
meeting.Thisshowedthattherehadbeenaseverebreach
oftheCodeofConduct,butIwasaskedtokeeptheruling
confidentialincasetherewasanappeal.Astherewasno
hospitality.onecompanywasfinedforprovidingafunction
thatwasnot'simpleormodest',whileafunctionattheCrown
TowersinMelbournewasruledtobe'notextravagant'.Perhaps
thenewrequirementforcompaniestodisclosethecostoftheir
promotionalfunctionswillhelptheCodeofConductCommittee
decidewhatisappropriate.
References1. MedicinesAustralia.CodeofConduct.15thed.2006.
AmendedAug2007.http://www.medicinesaustralia.com.au[cited2007nov12]
2. MedicinesAustraliaCodeofConductAnnualReport2006/2007.Canberra:MedicinesAustralia;2007.http://www.medicinesaustralia.com.au[cited2007nov12]
appealthecomplaintwasfinalisedanddetailsappearinthe
CodeofConductAnnualReport.1
TheCodeofConductCommitteeconsideredthatthe
advertisingcampaigncouldhavebreachedninesectionsofthe
Code,howeveronlyonebreachwasconfirmed.Amajorityof
theCommitteeconsideredthatthecampaignbroughtdiscredit
totheindustry.Thiswasnotbecausethebananaimages
wereinpoortaste,butbecauseamoney-backguaranteewas
consideredtodecreasethevalueofprescriptionmedicines.
TheCodeofConductCommitteedidnotfinethecompany
fortheseverebreach,butorderedittoimmediatelycease
thepromotionofferingthemoney-backguarantee.Corrective
lettershadtobesenttoallhealthprofessionalswhoreceived
thepromotionandcorrectiveadvertisementshadtobe
placedinhealthprofessionaljournalswhichhadpublished
advertisementsaboutthemoney-backguarantee.
Reference1. MedicinesAustraliaCodeofConductAnnualReport
2006/2007.Canberra:MedicinesAustralia;2007.http://www.medicinesaustralia.com.au[cited2007nov12]
Table 1
breaches of the Code of Conduct July 2006 – June 2007
Company Drug Sanction imposed by Code of Conduct Committee
brand name generic name
AbbottAustralasia Lucrin leuprorelin WithdrawmaterialCorrectiveletter$10000fine
AlconLaboratories DuoTrav timololmaleate/travoprost
Ceaseprogram$10000fine
AllerganAustralia Lumigan bimatoprost WithdrawmaterialCorrectiveletter$15000fine
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| VoLuME 30 | NuMbER 6 | DECEMbER 2007 155
AstraZeneca Crestor rosuvastatin WithdrawpromotionalmaterialsCorrectiveletter$75000finereducedonappealto$40000
nexium esomeprazole Withdrawmaterials$75000fine
BayerHealthcare Levitra
(fourcomplaints)
vardenafil Withdrawmoney-backguaranteeofferCorrectivelettersCorrectiveadvertisement
BoehringerIngelheim Buscopan hyoscine Withdrawmaterial$25000finereducedonappealto$10000
Mobic meloxicam WithdrawmaterialsCorrectiveletter$25000fine
CSLLimited Biostate factorVIII $5000finedroppedonappeal
Behaviourofcompanyrepresentative Withdrawtrainingmaterial$15000fine
GlaxoSmithKlineAustralia
Rotarix rotavirusvaccine WithdrawmaterialsCorrectiveletter$25000fine
Tykerb lapatinib Providenomediareleasesuntilmedicineregistered$40000fine
Janssen-Cilag Pariet rabeprazole Withdrawmaterial$100000fine
Pariet rabeprazole Withdrawmaterialothersanctionscoveredinpreviousbreach
MerckSharp&Dohme FosamaxPlus alendronate Withdrawmaterials
octapharma octanate factorVIII WithdrawmaterialsCorrectiveletter$100000finereducedonappealto$10000
PfizerAustralia Celebrex celecoxib Withdrawmaterials$100000fine
Celebrex celecoxib Articlenottobepublishedagainforgeneralpublic$100000fine
Xalacom latanoprost/timololmaleate
WithdrawmaterialCorrectiveletter$50000fine
RocheProducts Hospitality $75000fine
Sanofi-Aventis Stilnox zolpidem Withdrawmaterials
$5000fine
Schering Betaferon interferonbeta-1b Withdrawmaterials
Correctiveletters
$150000fine
Betaferon interferonbeta-1b Withdrawmaterials
LettertoMultipleSclerosisSociety
$100000fine
Angeliq drospirenone/oestradiol
Ceasedistributionoftradepacks
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156 | VoLuME 30 | NuMbER 6 | DECEMbER 2007
Treatment of myasthenia gravisStephen W Reddel, Sydney Neurology, Brain and Mind Research Institute, The University of Sydney, and Departments of Neurology and Molecular Medicine, Concord Repatriation General Hospital, Sydney
Summary
Myasthenia gravis is a syndrome of weakness and fatigue due to dysfunction of the neuromuscular junction. it is an antibody-mediated autoimmune condition with a range of moderately effective treatments. occasionally patients go into remission spontaneously, but most require treatment. Mild disease, such as that confined to the ocular muscles, can often be treated with pyridostigmine alone. More significant or generalised weakness requires immunosuppression, principally with prednisone and azathioprine. The response to immunosuppression is slow, ranging from several months to 1–2 years for a full response. Short-term use of antibody-based therapy such as plasma exchange or intravenous immunoglobulin is warranted for more severely affected patients. Thymectomy offers the hope of drug-free remission but as yet remains unproven. Treatment-related morbidity is considerable, but partly preventable.
Keywords:azathioprine,immunosuppression,prednisone,
pyridostigmine,thymectomy.
(Aust Prescr 2007;30:156–60)
introductionMyastheniagravisisanautoimmunediseasewhichcauses
muscularweaknessduetodysfunctionoftheneuromuscular
junction(Fig.1).Autoantibodiesdirectedagainstantigenic
proteinsonthepostsynapticsideoftheneuromuscularjunction
resultinbothblockadeoftransmissionanddamagetothe
postsynapticstructure.Asaresultthemotorneuronisunable
to'talk'tothemusclefibreandweaknessresults.Theknown
antigenstowhichtheautoantibodiesbindaretheacetylcholine
receptorand,lesscommonly,muscle-specifictyrosinekinase.
Theprevalenceofmyastheniagravisisabout1in10000.The
genderratioisapproximatelyequal,withapeakincidenceof
onsetinthe20sforwomenandthe60sformen.Around10%
ofpatientswithapositiveacetylcholinereceptorantibodytest
haveanassociatedthymoma.
DiagnosisTherearearangeofdiagnostictestsformyasthenia
gravis.Theseincludedynamictestsformeasuringmuscle
weakness(forexample,responsetoedrophoniumorice
pack),electricaltestssuchasrepetitivestimulationorsingle
fibreelectromyography,andmeasurementofantibodiesto
acetylcholinereceptorandtomuscle-specifictyrosinekinase.
Clinical manifestationsMyastheniagravisaffectssomeregionalmusclesmorethan
others.Mostcommonlytheorbitalmusclesareaffectedfirst,
witheitherdiplopiaorptosis.However,myastheniagravismay
firstaffectthebulbarmuscles(speechandswallowing),the
neckmuscles(headdrops)andproximalorrarelydistallimbor
respiratorymuscles.Involvementisfairlysymmetricalexcept
intheeyes.Symptomsmaygetworsetowardstheendofthe
dayorafterafewminutesofcontinuoususe–forinstance
speechmaybecomeslurredoverafewminutes.Moresevere
myastheniagravisaffectsmultiplemuscularregionsandmay
besufficientlyseveretocauserespiratoryfailureanddeathif
untreated.
Natural history of myasthenia gravisGenerally,myastheniagravisisapersistentdiseaserequiring
chronictreatment.Fluctuationsoverthelongtermarethenorm.
Somepatientsgointolong-termremissionspontaneously–
approximately15–25%afterfiveyearsforthosepresentingwith
generaliseddiseaseandsomewhatmoreforthosepresenting
withoculardiseaseonly.Laterelapseaftersustainedremission
alsooccurs,thelongestreportedexamplebeingafter32years.
Itshouldbenotedthattheneuromuscularjunctioncanbe
reformed,unlikemanypartsofthenervoussystem.Muscle
strengththathasbeenaffectedbymyastheniagravisforalong
timeoftenrecoverswithtreatment.Thismeansthattheintensity
oftreatmentformyastheniagraviscanbemodulatedtothe
currentseverityofthedisease.
overtime,patientswithclinicallyisolatedocularmyasthenia
gravisoftenprogresstogeneralisedmyastheniagravis.
Treatmentwithcorticosteroidscanreducethelikelihoodof
progression,andcontrolbothocularandgeneralisedweakness
completelyinmanycases.Itisnotknownifthisaltersthe
naturalhistoryortheneedforlong-termtreatment.Itis
thereforeunclearwhethertreatmentshouldbecommencedfor
oculardiseaseorjust'asrequired'tocontrolsymptomsthat
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| VoLuME 30 | NuMbER 6 | DECEMbER 2007 157
arecausingsufficientdisabilitytojustifytheadverseeffectsof
treatment.Long-standingocularmisalignmentmaynotrecover
despitegeneralisedremission.
Treatment Thediagnosismustbeconfirmedbeforetreatment,becausethe
mainstayoftreatmentformostpatientsisimmunosuppression.
Treatmentstopreventtheadverseeffectsof
immunosuppressionshouldbestartedsimultaneouslywiththe
therapy(seeTable1).Thereisnorobustevidencethatlong-term
treatmentactuallycuresthecondition,sosomepatientschoose
toavoidtheadverseeffectsofimmunosuppressivetherapy
andacceptdegreesofweakness.Copingwithouttreatment
isnotalwaysthesafeststrategyaspatientswithsignificant
weakness,particularlyinthebulbarmusculature,areatrisk
ofventilatoryfailureorofneedingintensivecarefollowingan
intercurrentrespiratoryinfection.Immunosuppressivetreatment
isthereforestronglyrecommendedforcontrolofsignificant
bulbarweakness.
Initialtreatmentisusuallywithpyridostigmine,followedby
prednisoneandazathioprineiftheresponseisincomplete.A
combinationofapproachesisoftenusefultocoverdeficiencies
ineachavailabledrug.
Immunosuppressionproducesaveryslowresponse,often
takingmanymonthsto1–2years.1,2Anunrealisticexpectation
ofaspeedyresponseisoftenaproblemforboththepatientand
thedoctor.
Therearefourmainapproachestotreatment,eachwithvery
differentdurationsofeffect,requirements,consequencesand
adverseeffects.
Improve neuromuscular transmission by inhibiting acetylcholinesterase Drugsthatinhibitacetylcholinesteraseincludepyridostigmine,
edrophonium(usedonlyfortesting)andneostigmine(for
intravenoususeinintensivecareunitsonly).Thesedrugs
takeeffectwithinminutesandlastforhours.Althoughthey
arewithoutlong-termadverseeffects,theefficacyofall
Fig. 1
Normal muscular junction
Inthenormalneuromuscularjunction,acetylcholinereleasedfromthenerveterminalfollowinganerveactionpotential,
bindstotheacetylcholinereceptoronthepostsynapticmuscle,triggeringamuscleactionpotentialpropagatedbythe
voltagegatedsodiumchannel.Acetylcholinesterasescavengesandbreaksdownunboundacetylcholine.Inaseparate
pathway,neuralagrinbindsmusclespecifictyrosinekinaseinitiatingclusteringofphosphorylatedrapsynandacetylcholine
receptors,stabilisingthepostsynapticstructureoppositethenerve.
Inmyastheniagraviscausedbyantibodiestotheacetylcholinereceptor,thereisblockadeofthebindingsitefor
acetylcholine,cross-linkingoftheacetylcholinereceptorwithsubsequentinternalisationandreductioninitssurface
expression,andinitiationofcomplementandcellularinflammatorycascadeswithdamagetothepost-andpresynaptic
structures.Themolecularphysiologyofmyastheniagravismediatedbyantibodiestomusclespecifictyrosinekinasehas
notbeenestablished.
acetylcholine
agrin
acetylcholineinapresynapticvesicle
nicotinicacetylcholinereceptor
musclespecifictyrosinekinase
rapsyn
voltagegatedsodiumchannel
acetylcholinebindingsite
acetylcholinesterase
Nerve terminal
Muscle fibre
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158 | VoLuME 30 | NuMbER 6 | DECEMbER 2007
acetylcholinesteraseinhibitorsislimited.Asasoledrugthey
arenotenoughformostpatientswithgeneralised
myastheniagravis.
PyridostigminePyridostigmineisthefirst-linetreatmentformyasthenia
gravis.Itisareversibleinhibitorofacetylcholinesterase
soincreasesacetylcholinestimulationoftheremaining
acetylcholinereceptors.Ifthereareinsufficientacetylcholine
receptorsremainingtotriggeramuscleactionpotential,extra
acetylcholinefromtheactionofthedrugisnotgoingtohelp.
Theunderlyingautoimmunestateisnotaltered.Itisoften
sufficientforptosisalone,butnotfordiplopiaorgeneralised
myastheniagravis.Benefitisoftennotsustained,possiblydue
tocounterproductiveupregulationofacetylcholinesteraseand
downregulationofacetylcholinereceptors.Thedoserequiredis
variable,asisgastrointestinaltolerance.oneapproachistostart
at10mgthreetimesadayandtitrateupto60mg4–6times
daily.A180mg'timespan'preparationisavailablefornocturnal
symptoms.Inpracticeadegreeofpatientcontrolofdosingand
'whenrequired'useisoftenhelpful.
Doseslessthan480mgdailyrarelyproducedepolarisingcrisis.
Increasingweaknessafteranincreaseinthepyridostigmine
dose(whenhighdosesarealreadybeinggiven)suggests
deterioratingdiseaseand/oradepolarisingcrisis.Thismay
requiretreatmentssuchasplasmaexchangeandareductionin
pyridostigminedose.Thepresenceofgastrointestinaladverse
effectsandfasciculations,clinicallyoronelectromyogram,
mightsuggestdepolarisingcrisis.Thepatientmustbe
hospitalisedandthedoseofpyridostigminereducedwhile
theyarecarefullymonitored.Lackofimprovementwith
edrophonium(whichhasaveryshorthalf-life)indicatesthat
furtherpyridostigminewillnotbeuseful.
ImmunosuppressionTheprincipaldrugsusedtosuppresstheimmunesystem
inmyastheniagravisareprednisone(aglucocorticoid)and
azathioprine.Theresponsetothesetreatmentscantakeweeksto
manymonths,withthemaximaleffecttakingmonthstoyears.1,2
PrednisonePrednisoneoranothercorticosteroidistheprimary
immunosuppressantusedinmyastheniagravis.Sustained
improvementorremissioncanbeachievedwhilepatients
remainontreatment.Atypicalcourseforgeneralised
myastheniagraviswoulduse1mg/kgprednisonedaily
(0.5mg/kgforocularmyastheniagravis)untilclinicalcontrol
isachievedandthenweaningeitherdirectlyorbyinitial
conversiontoalternatedailydosage,withthedeterminationof
amaintenancedosebytrialanderrorduringaslowwithdrawal
ofmedicationovermanymonths.Deteriorationinmyasthenia
graviscanoccurinthefirstfewweeksoftreatmentsothedose
isoftenincreasedslowly.Themeantimetomaximaleffectof
prednisoneinmyastheniagravisissixmonths–muchlonger
thanmostexpect.
AzathioprineAzathioprineisusedasasteroidsparingdrugandadditional
immunosuppressantwithprednisone.Inarandomisedtrial,
afterthreeyearsoftreatment,63%ofpatientswithmyasthenia
gravistakingazathioprinewereoffallprednisone,versus
20%takingplacebo,butnoeffectwasseeninthefirstyear.2
Comparedtothemetabolicconsequencesofcontinued
corticosteroids,theproblemsofazathioprineseemsignificantly
less.However,thelong-termconsequencesdoincludean
increasedriskofskincancersandasmallpossibleincrease
intheriskofhaematologicalmalignancies.Aboutone-fifth
Table 1
Prophylaxis of the complications of immunosuppression
osteoporosisprevention Measurebonedensitybeforetreatmentandyearlywhileontreatment.StartcalciumandvitaminDsupplements.Bisphosphonatesmayreducebonelossassociatedwiththechronicuseofglucocorticoids.
Cardiovascularrisk Riskfactormodificationshouldbestandardandincludesadvicetostopsmoking,startanexerciseprogramandmanagehypertension.
Pepticulcerprevention HelicobacterscreeningandprophylactictreatmentwithprotonpumpinhibitorsorH2antagonistsseemsappropriateforthosewithapasthistoryofpreviousulcerationorconcordantuseofnon-steroidalanti-inflammatorydrugs.
Infectionprophylaxis Useofinactivatedvaccinessuchasinfluenzaisrecommended.Livevaccinesarecontraindicated.AchestX-rayshouldbeperformedpriortotreatment.MorespecifictestingfortuberculosismaybeindicateddependingonhistoryandchestX-rayresults.
Malignancyprevention Skincancerratesareincreasedinpatientsusingazathioprine.Afullyearlydermatologicalsurveyisrecommended.Exhortsunprotectionandcancersurveillance.Regularcervicalsmearsarerecommended.Eyeprotectionmayalsolimitcataractdevelopment.
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| VoLuME 30 | NuMbER 6 | DECEMbER 2007 159
ofpatientscannottakeazathioprineduetorash,hepatitis,
myelosuppression,nauseaorvomiting,butthisisusually
evidentwithintwoweekstotwomonths.Somedoctors
routinelyuseazathioprineforpatientswithgeneralised
myastheniagravisstillrequiringmorethan10mgprednisone
perdayatsixmonths,orifseverediseaseisobviousearlier.
Other drugsIfnotusingazathioprine,othersteroid-sparingdrugsused
includemycophenolatemofetil,cyclosporin,methotrexateand
cyclophosphamide.Experiencewiththesedrugsisgenerally
derivedfromretrospectiveseries.noneofthesehaveproven
efficacyinrandomisedtrialsexceptforcyclophosphamide,and
choiceofdrugdependsonageandcompetencyofthepatient
pluslocalexperienceofthephysician.Inpracticetheyare
frequentlyusedwithapparentsuccess,butlikeazathioprinethe
responseisoftenslow.
Mycophenolatemofetilisapharmacologicallysimilar
alternativetoazathioprinebuttworecentrandomisedcontrolled
trialsfailedtodemonstratebenefitinmyastheniagravis.*The
durationofbothtrialswaslessthanayear.Asitworksinthe
samepathwayasazathioprinethismayhavebeeninadequate
anditremainswidelyused.
Rituximab,amonoclonalantibodyspecifictoCD20(onBcells),
orbonemarrowablationwithautologoustransplantare
treatmentsoflastresort.
Remove or block autoantibodies Plasmaexchangeremovesautoantibodiesandintravenous
immunoglobulinisthoughttoblockautoantibodies.These
treatmentstakeeffectwithindays,butonlylastweeksbefore
treatmentneedstoberepeated.Theyhaveakeyrolein
stabilisingseveremyastheniagravisandinpreparationfor
surgery,orinpregnancy.
Plasmaexchangeisexpensiveandonlyavailableinmajor
hospitals.Itrequiresgoodintravenousoralternativelycentral
catheteraccess,butacentrallineincreasestheriskofinfection.
Intravenousimmunoglobulin,apurifiedbloodproduct,isalso
veryexpensiveandisinlimitedsupply.Itsmodeofaction
remainsunclear.
ThymectomyThymectomyhasapossibleimmunomodulatoryroleinthe
absenceofthymoma.Resultsofaglobalrandomisedtrial
areawaited.†Theeffectofathymectomyappearstotake
years.non-randomisedretrospectivedatasuggestthereisan
increasedcompleteremissionratefromthymecto