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Home , Cyproheptadine, Methylene blue, Prochlorperazine

DrugDrug Interactions:Interactions: CombinationsCombinations ThatThat CanCan KillKill YourYour PatientsPatients oror ““warningswarnings ””

Frank LoVecchio, DO, MPH, FACEP, FABMT Medical Director, Banner Drug and Information Center Research Director and Vice Chairman, Maricopa Medical Center, Department of Emergency Medicine Professor, University of AZ College Medicine IntroductionIntroduction

CommonCommon 0.50.5 --2.5%2.5% ofof hospitalizedhospitalized ptspts OnlyOnly 1%1% clinicallyclinically significantsignificant fatal!fatal! MostMost areare predictablepredictable andand preventablepreventable DefinitionDefinition ofof aa DrugDrug InteractionInteraction

TheThe pharmacologicalpharmacological oror clinicalclinical responseresponse toto thethe administrationadministration ofof aa drugdrug combination,combination, differentdifferent fromfrom thatthat anticipatedanticipated fromfrom thethe knownknown effectseffects ofof thethe twotwo agentsagents whenwhen givengiven alone.alone.

Tatro, Drug Interaction Facts 1992

PeoplePeople dondon ’’tt killkill people,people, computerscomputers dodo

 ComputerizedComputerized physicianphysician orderorder entryentry (CPOE)(CPOE) andand decisiondecision supportsupport systemssystems (DSS)(DSS) cancan reducereduce certaincertain typestypes ofof errorerror butbut oftenoften slowslow cliniciansclinicians andand maymay increaseincrease otherother typestypes ofof error.error.

Acad Emerg Med . 2004 Nov;11(11):1135-41 Handler JA, et al cc:cc: LightheadednessLightheadedness

AA 6464 yryr oldold malemale withwith aa historyhistory ofof HTN,HTN, CAD,CAD, andand stablestable anginaangina becamebecame lightheadedlightheaded andand nauseatednauseated shortlyshortly afterafter aa dosedose ofof sildenafilsildenafil (Viagra)(Viagra) Medications:Medications: ASA,ASA, captopril,captopril, isosorbideisosorbide dinitratedinitrate (Isordil)(Isordil)

SildenafilSildenafil andand NitratesNitrates

 ReleasedReleased inin MarchMarch 19981998  OverOver 66 millionmillion RxRx inin firstfirst yearyear  130130 deathsdeaths reportedreported toto FDA,FDA, mostmost cardiaccardiac  ManyMany casescases ofof severesevere hypotensionhypotension inin ptspts takingtaking nitratesnitrates ⇒⇒ 1616 deathsdeaths Lue TF, N Engl J Med 342(24):1802, 2000 SildenafilSildenafil andand NitratesNitrates MechanismMechanism ofof InteractionInteraction

Autonomic Nervous System NO Synthase NITRATES L-Arginine NITRIC OXIDE Ischemia Death Guanylate Smooth muscle relaxation Cyclase (also in vasculature)

GTP ↑ cGMP (Viagra) Phosphodiesterase Type 5 5’GMP PharmacodynamicPharmacodynamic InteractionsInteractions

TheThe useuse ofof twotwo agentsagents whichwhich affectaffect thethe samesame physiologicphysiologic systemsystem CanCan bebe eithereither synergisticsynergistic oror antagonisticantagonistic  calciumcalcium channelchannel blockerblocker ++ betabeta blockerblocker  furosemidefurosemide ++ gentamicingentamicin PharmacokineticPharmacokinetic InteractionsInteractions

AbsorptionAbsorption MetabolismMetabolism DistributionDistribution  cytochromecytochrome p450p450  proteinprotein bindingbinding EliminationElimination diureticsdiuretics && lithiumlithium SurveySurvey Says:Says: HistoryHistory ofof epilepsy,epilepsy, rashrash andand feverfever 55 daysdays afterafter dilantindilantin

 TheThe bestbest agentagent toto switchswitch thethe patientpatient toto is?is? A. ValpraoteValpraote B. CarbamazepineCarbamazepine C. PhenobarbitalPhenobarbital D. LamotrigineLamotrigine AnticonvulsantAnticonvulsant HypersensitivityHypersensitivity SyndromeSyndrome (AHS)(AHS)

RareRare adverseadverse eventevent (1/1,000(1/1,000 toto 1/10,000)1/10,000) characterizedcharacterized byby ,fever, rash,rash, andand internalinternal organorgan involvementinvolvement (,(liver, kidney,kidney, CNS,CNS, lungs),lungs), usuallyusually withwith lymphadenopathy,lymphadenopathy, 11--88 weeksweeks afterafter drugdrug initiationinitiation ItIt isis notnot dosedose --relatedrelated andand cancan recurrecur ifif thethe drugdrug isis rere --startedstarted Crit Care Clin. 1997 Oct;13(4):727-39. Hypersensitivity Syndrome. Morkunas AR, Miller MB. AHS:AHS: ClinicalClinical FindingsFindings

 FeverFever  Rash,Rash, exfoliativeexfoliative suggestssuggests StevensStevens --JohnsonJohnson SyndromeSyndrome oror ToxicToxic EpidermalEpidermal NecrolysisNecrolysis  LymphadenopathyLymphadenopathy isis seenseen inin 2/32/3 ofof patients,patients, hashas beenbeen associatedassociated withwith ““pseudolymphomapseudolymphoma ””  LiverLiver involvement:involvement: mildmild transaminitistransaminitis toto fulminantfulminant hepatichepatic necrosisnecrosis  OtherOther findingsfindings inin AHSAHS includeinclude eosinophilia,eosinophilia, hematologichematologic abnormalities,abnormalities, andand nephritisnephritis  LessLess commoncommon findingsfindings includeinclude myalgias,myalgias, arthralgias,arthralgias, rhabdomyolysis,rhabdomyolysis, pneumonitis,pneumonitis, andand thyroiditis,thyroiditis, whichwhich resultsresults inin hypothyroidismhypothyroidism approximatelyapproximately 22 monthsmonths afterafter presentation.presentation. TreatmentTreatment ofof AHSAHS

 DiscontinueDiscontinue offendingoffending drugdrug andand supportivesupportive carecare  TheThe useuse ofof systemicsystemic corticosteroids,corticosteroids, IVIV immunoglobulins,immunoglobulins, andand antihistaminesantihistamines isis controversialcontroversial  DueDue toto thethe highhigh degreedegree ofof crosscross --reactivityreactivity amongamong thethe aromaticaromatic ,anticonvulsants, patientspatients shouldshould notnot bebe switchedswitched toto anotheranother medicationmedication inin thisthis class!!class!!  FamilyFamily membersmembers ofof patientspatients withwith AHSAHS shouldshould bebe warned,warned, andand maymay wantwant toto undergoundergo testingtesting priorprior toto startingstarting anyany ofof thethe drugsdrugs inin thisthis classclass ?Survey?Survey SaysSays

 3030 yearyear oldold onon VenlafaxineVenlafaxine A.A. IbuprofenIbuprofen (Effexor)(Effexor) complainscomplains ofof B.B. MeperidineMeperidine severesevere ankleankle painpain afterafter aa trauma.trauma. ObviousObvious fracturefracture isis C.C. MorphineMorphine notednoted withwith goodgood pulses.pulses. D.D. FentanylFentanyl SheShe requestsrequests analgesics.analgesics. WhichWhich isis potentiallypotentially mostmost harmful?harmful? SerotoninSerotonin SyndromeSyndrome

AcuteAcute increaseincrease inin serotoninserotonin atat thethe

5HT5HT 1A receptorreceptor  PProducedroduced byby 22 serotonergicserotonergic drugsdrugs simultaneouslysimultaneously initiatinginitiating serotonergicserotonergic drugdrug increasedincreased dosingdosing overdoseoverdose SerotoninSerotonin SyndromeSyndrome MedicationsMedications InvolvedInvolved

 MAOIMAOI ’’s,s, TCATCA ’’s,s, SSRISSRI ’’ss  ,Venlafaxine, ,trazodone, nefazodonenefazodone  Meperidine,Meperidine, dextromethorphandextromethorphan  SumatriptanSumatriptan  ““EcstasyEcstasy ””  LithiumLithium ChangingChanging AntidepressantsAntidepressants

StopStop MAOIMAOI startstart SSRISSRI inin 22 weeksweeks StopStop SSRISSRI startstart MAOIMAOI inin 22 weeksweeks ifif fluoxetinefluoxetine thenthen 44 weeksweeks SpectrumSpectrum ofof ClinicalClinical FindingsFindings

Boyer et al. N Engl J Med 352;11:1112 -20, 2005 SerotoninSerotonin SyndromeSyndrome ClinicalClinical PresentationPresentation  CognitiveCognitive andand behavioralbehavioral  dizziness, restlessness, agitation, delerium, seizures, coma  AutonomicAutonomic nervousnervous systemsystem  diaphoresis, ↑ HR, ↑ BP, ↑ T  NeuromuscularNeuromuscular  hyperreflexia, muscle stiffness, rigidity  lower extremities

Mills, Critical Care Clinics 13(4):763-83, 1997 SerotoninSerotonin SyndromeSyndrome TreatmentTreatment

StopStop allall serotonergicserotonergic agentsagents CyproheptadineCyproheptadine (Periactin)(Periactin) 44--88 mgmg POPO BenzodiazepinesBenzodiazepines -- titratetitrate toto effecteffect AggressiveAggressive sedation/paralysis/coolingsedation/paralysis/cooling forfor criticallycritically illill butbut isis rarelyrarely neededneeded A Few Other Causes of Drug -Induced Heat Illnesses

∆MS Hot Miscellaneous MH a a Post-anesthesia NMS -blockers a a SS SSRI’s “plus” a a ACS Dry skin, etc a a ST Moist skin a a

a

SurveySurvey Says:Says: WhichWhich ofof thethe followingfollowing isis thethe mostmost commoncommon sideside --effecteffect ofof NeurolepticsNeuroleptics // ?Antipsychotics? a.a. AkathisiaAkathisia b.b. DystoniaDystonia c.c. MalignantMalignant HyperthermiaHyperthermia d.d. NeurolepticNeuroleptic MalignantMalignant SyndromeSyndrome AntiemeticsAntiemetics inin thethe ED:ED: aa randomizedrandomized controlledcontrolled trialtrial comparingcomparing 33 commoncommon agentsagents

 This randomized, -controlled, double -blind trial compares 1.25 mg , 10 mg , 10 mg , and placebo.  Droperidol ( -54.5 mm) was significantly better than metoclopramide ( -40.2 mm) or prochlorperazine ( -40.5 mm) at reducing at 30 minutes (P = .04).  There were no significant differences in rescue medication or patient satisfaction; however, droperidol had significantly higher (71.4% vs 23.5%) at 24 -hour follow -up. Braude D, Soliz T, Crandall C, Hendey G, Andrews J, Weichenthal L. Am J Emerg Med. 2006 Mar;24(2):177-82. ?Survey?Survey SaysSays

 2424 yearyear oldold onon seldaneseldane forfor A.A. AzithromycinAzithromycin URIURI symptoms.symptoms. YouYou B.B. ErythromycinErythromycin diagnosisdiagnosis sinusitis.sinusitis. YouYou agreeagree toto prescribeprescribe andand C.C. OfloxacinOfloxacin antibiotic.antibiotic. WhichWhich isis thethe D.D. FlagylFlagyl bestbest choice?choice? cc: Palpitations

 2424 yryr oldold femalefemale returnsreturns nownow andand complainscomplains ofof palpitationspalpitations andand dizziness.dizziness. RecentlyRecently diagnoseddiagnosed withwith bronchitisbronchitis andand treatedtreated withwith .erythromycin.  PtPt alsoalso selfself --treatingtreating withwith OTCOTC ’’ss acetaminophenacetaminophen andand PropulusidPropulusid ()(Cisapride) cc:cc: PalpitationsPalpitations

 Vitals,Vitals, physicalphysical examinationexamination unremarkableunremarkable  HxHx ofof palpitationspalpitations >>>> monitormonitor FDAFDA Withdrawals/RestrictionsWithdrawals/Restrictions DueDue toto ProlongationProlongation ofof thethe QTQT IntervalInterval

 WithdrawnWithdrawn  (Seldane) - 1998  (Hismanal) - 1999  Grepafloxin (Raxar) – 1999  ““BlackBlack boxbox ””  Cisapride (Propulsid) - 2000  Levomethadyl (Orlaam) - 2001  Droperidol (Inapsine) - 2002 TheThe QTQT IntervalInterval

male < 450 msec female < 460 msec

Goldfranks Toxicologic Emergencies 7 th ed EarlyEarly AfterAfter --depolarizationdepolarization TriggeringTriggering aa DysrhythmogenicDysrhythmogenic BeatBeat

triggered beat

Early after -depolarization (EAD) interrupting phase 3 repolarization. Under some conditions, a triggered beat can arise from an EAD (black arrow, right)

Goodman & Gilman 9 th ed PharmacokineticPharmacokinetic InteractionInteraction

terfenadine astemizole - potassium channels erythromycin cisapride - CYP3A4

QT prolongation terfenadine carboxylate (active) torsades desmethylastemizole (inactive) ? (inactive)

Woosley, JAMA 269;1532 -6, 1993 AvailableAvailable DrugsDrugs AssociatedAssociated w/w/ QTQT prolongationprolongation

 Disopyramiide,Disopyramiide, ,procainamide, ,quinidine, ,sotalol, ,bepridil, amiodaroneamiodarone  Erythromycin,Erythromycin, ,clarithromycin, sparfloxacinsparfloxacin  Droperidol,Droperidol, ,haloperidol, ,mesoridazine, ,thioridazine, ,chlorpromazine, quetiapinequetiapine  MethadoneMethadone Drugs associated with prolonged QTC and Torsades

  Phosphorus  Arsenic   Astemizole  Scorpion venom  Bepridil  Terfenadine     antidepressants    Cisapride  Procainamide  Citalopram  Quinidine  Emetine   Fluoride (secondary to  hypocalcemia)  Lorcainide   Moricizine  Ketoconazole   Erythromycin   Mercury (organic)    N-Acetylprocainamide   Sotalol  (particularly thioridazine, mesoridazine) XXXX QTC.COM

AtypicalAtypical AntipsychoticAntipsychotic DrugsDrugs andand thethe RiskRisk ofof SuddenSudden CardiacCardiac DeathDeath

PotentPotent InhibitorsInhibitors ofof CYP3ACYP3A

 Erythromycin,Erythromycin, clarithromycin,clarithromycin, ciprofloxacinciprofloxacin  AzoleAzole antifungalsantifungals (ketoconazole, fluconazole)  ,Diltiazem, verapamilverapamil  SSRISSRI ’’ss (footnote),(footnote), nefazodonenefazodone  ProteaseProtease inhibitorsinhibitors (ritonovir, indinavir)  CimetidineCimetidine (not as potent but very common) TimeTime PlasmaPlasma ConcentrationConcentration CurveCurve

Bailey et al. Br J Clin Pharmacol 46:101 -110, 1998 CommonCommon DrugsDrugs MetabolizedMetabolized Significantly/ExclusivelySignificantly/Exclusively byby CYP3CYP3

 AntidepressantsAntidepressants  , venlafaxine  CalciumCalcium channelchannel blockersblockers  ProteaseProtease inhibitorsinhibitors  Cyclosporine,Cyclosporine, tacrolimustacrolimus  MidazolamMidazolam

Wilkerson, N Engl J Med 352;21:2211 -21 ?? SurveySurvey sayssays

 YourYour nextnext patientpatient A. Adenosine 6 mg presentspresents onon DipyridamoleDipyridamole B. Adenosine 12 mg (Persantine(Persantine ®®)) andand hashas C. Adenosine 3 mg SVTSVT .. TheThe bestbest drugdrug atat thisthis timetime is?is? AdenosineAdenosine drugdrug InteractionsInteractions

 CarbamazepineCarbamazepine maymay increaseincrease heartheart block.block.

 DipyridamoleDipyridamole potentiatespotentiates effectseffects ofof adenosine;adenosine; reducereduce dosedose ofof adenosine.adenosine.

 TheophyllineTheophylline andand caffeinecaffeine (methylxanthines)(methylxanthines) antagonizeantagonize adenosine'sadenosine's effects;effects; maymay requirerequire increasedincreased dosedose ofof adenosine.adenosine. Ray, et al. N Engl J Med 351;11:1089-96, 2004 Ray, et al. N Engl J Med 351;11:1089-96, 2004 InducersInducers ofof CYP450CYP450 u IncreaseIncrease thethe metabolismmetabolism ofof drugsdrugs v subtherapeutic dosing u LipidLipid solublesoluble u GradualGradual onsetonset -- daysdays toto weeksweeks u IfIf stopped,stopped, thethe effecteffect willwill disappeardisappear InducersInducers ofof CYP450CYP450

Rifampin,Rifampin, isoniazidisoniazid ,Phenobarbital, ,phenytoin, carbamazepinecarbamazepine CigaretteCigarette smokesmoke (PAH(PAH ’’s)s) ChronicChronic ethanolethanol LowerLower DosesDoses ofof AmbienAmbien ?? SurveySurvey Says?Says?

 YourYour nextnext patientpatient hashas peakedpeaked tt waveswaves andand aa potassiumpotassium ofof 66 meq/L.meq/L. YouYou administeradminister calciumcalcium andand theythey diedie shortlyshortly afterafter  WhichWhich drugdrug werewere theythey on?on?  A. Digitalis  B. Verapamil  C. Potassium supplements

DigoxinDigoxin ToxicityToxicity Drug Interactions:  Quinidine  Verapamil  Diltiazem  Amiodarone   Macrolides and tetracyclines (reversal of inactivation of digoxin by enteric bacterium Eubacterium lentum )

cc: Bruising

6767 yryr oldold femalefemale w/w/ multiplemultiple medicalmedical problemsproblems sentsent inin byby herher neurologistneurologist complainingcomplaining ofof lightheadednesslightheadedness andand aa bruisebruise onon herher thigh.thigh. Medications:Medications: gyburide,gyburide, ,nifedipine, enalapril,enalapril, ,aspirin, ,timolol, warfarin,warfarin, ,cimetidine, colace.colace. cc:cc: BruisingBruising

Gen:Gen: pale,pale, slightlyslightly diaphoreticdiaphoretic femalefemale Vitals:Vitals: HRHR 105105 irregular,irregular, BPBP 120/75120/75 Skin:Skin: severalseveral ecchymosisecchymosis onon legslegs w/w/ largestlargest 77 xx 1010 xx 44 cmcm onon LL thighthigh Abd:Abd: nontender,nontender, melanicmelanic stoolstool cc:cc: BruisingBruising

 LaboratoryLaboratory  hemoglobinhemoglobin == 88 g/dLg/dL (baseline(baseline 1313 g/dL)g/dL)  plateletsplatelets == 280,000280,000  PTPT >> 5050 secsec WarfarinWarfarin

 FrequentlyFrequently involvedinvolved inin drugdrug interactionsinteractions  LowLow therapeutictherapeutic indexindex  BleedingBleeding isis aa significantsignificant complicationcomplication

Holbrook et al. Arch Int Med 165:1095 -1106, 2005 WarfarinWarfarin MechanismMechanism ofof InteractionInteraction

 AlteredAltered CYPCYP metabolismmetabolism (1A2, 2E1, 3A4)  inhibited, induced  DrugDrug synergismsynergism  , NSAIDS, ticlodipine  DrugDrug antagonismantagonism  high vit K foods, enteral nutrition Vitamin K rich foods

- warfarin - cc:cc: BruisingBruising

 BecauseBecause thethe patientpatient waswas startedstarted onon warfarinwarfarin aa fewfew weeksweeks priorprior byby herher cardiologistcardiologist forfor atrialatrial fibrillation,fibrillation, herher familyfamily physicianphysician beganbegan cimetidinecimetidine toto preventprevent GIGI bleeding.bleeding.

CaseCase ofof BigBig GirlGirl BlueBlue

 AA patientpatient presentspresents withwith aa lacerationlaceration toto herher scalp.scalp. NoNo LOC.LOC. YouYou administeradminister LidocaineLidocaine withwith epinephrineepinephrine andand areare calledcalled toto thethe room.room.  SheShe isis complainingcomplaining ofof dizziness,dizziness, ,headache, andand dyspnea.dyspnea. TheThe triagetriage RNRN callscalls aa medicalmedical alertalert becausebecause thethe patientpatient isis obviouslyobviously cyanotic.cyanotic.  InIn thethe resuscitationresuscitation room,room, youyou findfind anan alertalert patientpatient with:with: BPBP 120/50120/50 PP 120120 R24R24 T99T99 pulsepulse oxox 85%85% (on(on 70%70% FIOFIO 2 byby mask)mask) andand thisthis appearanceappearance BlueBlue LadyLady

 WhatWhat ’’ss goinggoing on?on? A. pulmonary embolism B. aortic dissection C. poisoning D. E. pneumothorax MethemoglobinemiaMethemoglobinemia  Cyanosis in the setting of adequate delivery and a pulse oximeter ~ mid -80% range is suggestive of methemoglobinemia (oxidized )  Commonly occurring from excessive exposure to oxidizing agents, such as , dapsone, nitrobenzene;  G6PD deficiency – and more frequently associated with significant .  Rx is administration of oxygen and  Methylene blue will not be effective and will induce hemolysis in those with G6PD deficiency HighHigh RiskRisk DrugsDrugs

 WarfarinWarfarin  FrequentlyFrequently prescribedprescribed  TheophyllineTheophylline  SignificantSignificant toxicitytoxicity  CyclosporineCyclosporine  LowLow therapeutictherapeutic  MAOIMAOI ’’ss windowwindow  LithiumLithium  OneOne majormajor routeroute ofof eliminationelimination  DigoxinDigoxin

HighHigh RiskRisk PatientsPatients

 ElderlyElderly  altered , multiple medications  ComplexComplex medicalmedical hx/multiplehx/multiple MDMD ’’ss  SpecificSpecific medicalmedical conditionsconditions  HIV/AIDS  transplant HIVHIV ++ PatientPatient

 55--20%20% incidenceincidence  multiple meds  meds w/ high interaction potential  meds w/ significant toxicity (risk/benefit)  MD ’s unfamiliar w/ meds PharmacodynamicPharmacodynamic

 BoneBone marrowmarrow suppressionsuppression  ganciclovir, TMP -SMZ, zidovudine  PeripheralPeripheral neuropathyneuropathy  , didanosine (ddI), stavudine, zalcitabine  PancreatitisPancreatitis  didanosine (ddI), pentamidine PharmacokineticPharmacokinetic

 ProteaseProtease inhibitorsinhibitors (inhibitors)  AntifungalsAntifungals (inhibitors)  AntituberculousAntituberculous (inducers)  AnticonvulsantsAnticonvulsants (inducers)

StSt JohnsJohns WortWort

 DepressionDepression

 CYPCYP inhibitorinhibitor  MAOMAO inhibitorinhibitor  SerotoninSerotonin syndromesyndrome GinkoGinko BilobaBiloba

 Dementia

 Hemorrhage  warfarin, aspirin, rofecoxib RecognizingRecognizing Drug/DrugDrug/Drug InteractionsInteractions

 ObtainObtain completecomplete medicationmedication historyhistory  IdentifyIdentify highhigh riskrisk patientspatients  IdentifyIdentify highhigh riskrisk drugsdrugs  QT prolongers  IdentifyIdentify inhibitors/inducersinhibitors/inducers ofof CYPCYP MyMy RulesRules

1. Limit the total number of drugs, dose and duration (The more problems, the more problems) 2. Extremes of age deserve caution 3. If you are giving IV contrast, check medications and hydrate, consider bicarbonate 4. Never use Meperidine 5. Consider (now low dose) 6. Love P450 7. Know high risk drugs 8. If in doubt avoid, succinylcholine 9. If in doubt, use benzo ’s 10. Consider help prn RecentRecent ReferencesReferences

 Roden, Drug -induced prolongation of the QT interval. N Engl J Med 350;10:1013 -1022, 2004  Ray et al, Oral erythromycin and the risk of sudden death from cardiac causes. N Eng J Med 351;11:1089 -1096, 2004  Wilkinson, and variability among patients in drug response. N Engl J Med 352;21:2211 -21, 2005  Liu, Drugs and the QT interval – Caveat Doctor. N Engl J Med 351;11:1053 -56, 2004  Holbrook et al. Systematic overview of warfarin and its drug and food interactions. Arch Int Med 165:1095 -1106, 2005  Boyer et al. The syndrome. N Engl J Med 352:1112 - 20, 2005  Barrett, B.J. and P.S. Parfrey, Preventing Nephropathy Induced by Contrast Medium. N Engl J Med, 2006. 354(4): p. 379 -386