recreational (illicit) drugs and cardiovascular diseaseproduction “shake and bake”...
TRANSCRIPT
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Recreational(Illicit)DrugsandCardiovascularDisease
ChristopherBarnettMD,MPH
Director,MedicalCardiovascularIntensiveCareUnitDirector,PulmonaryHypertensionProgram
Medstar HeartandVascularInstituteMedstar WashingtonHospitalCenter
Washington,DC
Case• A24yearoldmalepresentstothehospitalwithabout1monthofworseninglowerextremityswellingandshortnessofbreath
• Heworksasanindependenttechcontractorandhisroommatesaremedicalstudents
• Anechocardiogramisperformedandrevealssevereleftventricularsystolicdysfunction
• Acomprehensiveevaluationrevealsnoreasonforcardiomyopathy
• IVdiureticsandstandardheartfailuretherapyisprovided
• Thedaypriortodischargeheadmitstousingmethamphetaminesohecanstayawaketoworklongerhours
MethamphetamineChemistry• Methamphetaminebelongstoaclassofcompoundscalledphenylethylamines
• Phenylethylamines encompassalargegroupofbiologicallyactivecompounds
• Amphetamine,Dopamine,Epinephrine,MDMA,Bupropion,Ephedrine/Pseudoephredrine
• EphedrineandPseudoephrine arelikelythefirstdiscoveredphenylethylamines
• ExtractedfromEphedra Sinica (mahuang)
• UsedinChinesemedicinefor5,000yrs
• Sympathomimetics usedasstimulant,appetitesuppressant,decongestant,vasopressor,bronchodilator
• Amphetamineandmethamphetamineweredevelopedinthelate1800’sassyntheticalternativestoephedra
ModernUseOfMethamphetamine• AmphetaminesyntheticderivativeofephedrinedevelopedinGermany1887
• InitiallysoldasBenzedrineasdecongestantandbronchodilator
• Stimulanteffectofinhalersledtouseinnarcolepsyandforweight-loss
• Widevarietyofuses:Schizophrenia,alcoholism,migraine,heartblock,dysmenorrhea,persistenthiccups
• Amphetamineat31millionprescriptionsin1967(10billiontabletsmade)
• Methamphetaminesynthesizedincrystallizedformin1920Japan
• UsedbyGermanyinWWIIasPervitin tablets
• Methedrine (methamphetaminetablets)introducedin1940for improvementofmood,energy,weight-loss
• Valo inhalersavailablethatcontained150-200mgmethamphetamine
Vearrier.Diseasea Month2012
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RiseofRecreationalMethamphetamineUse
• Increasedrecreationaluseinthe1960s• Limitationsinprescriptionusesinthe1970s• MotorcyclegangscontinueillicitmanufactureinthePacificNorthwestresultinginthemoniker“crank”becauseitwashiddenincrankcases
• Increaseduseinthe1980sbytruckdriversandbluecollarworkers• Importationofheatedandinhaled“Ice”or“crystal”intoHawaiiinthe1980sfromthePhillipines
• Expansionofmethlabsintheruralwest• Increasedregulationtostopmethproductioninthemid2000s
Gonzales.AnnualReviewofPublicHealth.2010.
StreetNamesforMethamphetamine
• Onehitof“Tina”(1/4gram)isabout$25
Vearrier.Diseasea Month,2012.
Synthesisof(meth)amphetamine MethamphetamineLaboratoryProduction
Red phosphorus
Tablets
Hydrogenchloride
Liquidmeth
Liquid methon bottom
Filtercloth
Causticsoda
Filtercloth
Ice
Acid
STEVE COWDEN, STEVE SUO/THE OREGONIAN
Contrary to popularbelief, most methusers do notoperate meth labs.An estimated 80percent of the U.S.supply comesinstead fromorganized drugcartels, whichmanufacture methfor nationaldistribution in asmall number ofmassive California”superlabs.”Pioneered byMexican drugrunners in the early1990s, these labsrequire enormousvolumes of theessential chemicalsephedrine orpseudoephedrine.Traffickers extractthese inter-changeableingredients fromcough and cold pillssold on the blackmarket.
Solvent
1. Grindtablets
Tablets ofephedrineor pseudo-ephedrineare groundto a powderin ablender.
Ephedrine orpseudoephed-rine adheres tothe solvent,separating itfrom whitetablet binder.
2. Mix withsolvent
3. Filtering binderThe binder is removedwith a filter. Theremaining solvent iscooked away on lowheat, leaving purepseudoephedrine.
4. Add redphosphorus and acidMixed in on low heat, thepseudoephedrine changesto methamphetamine, butis too acidic.
5. Filterout sludgeRedphosphorussludge isfiltered outusing clothbungeed overa barrel.
6. Addcaustic sodaGives meth abase. Thisprocesscreates intenseheat, so ice isused to coolthe reaction.
7. AddFreon,separateliquidmeth
The methsticks to theFreon andsettles tothe bottom,where it isdrained outusing aspigot.
8. Bubblehydrogenchloride
The gas turnsthe meth intoa salt,lowering itsacidity. Themeth is nowconsumable,but still wet.
9. DryingThe finishedmeth is pouredonto a filtercloth and dried.
10. CuttingThe dry meth isweighed, dilutedwith additives, andpackaged.
At the center of theoperation are fourglobe-shapedflasks on aluminumbases. These 22-liter glass balls withelectric heaters arethe superlab’ssignature feature.Each one sells for$3,000 to $4,000on the street andwill make 110,000doses of meth.Many superlabsstring togethermultiple “22s” foreven biggerproduction.
”BUBBLING 22”
“Bubbling22” Vent
hose
Meth superlab
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SimplifiedMethamphetmaineProduction“ShakeandBake”
MethamphetamineUseIsPervasiveProblem
• U.N.WorldDrugReportcallsmeththemostabusedharddrugonearth
• 26millionmethaddictsworldwideequalsthecombinednumberforcocaineandheroinusers
• MethusecosttheUnitedStates$23.4billionin2005
Gonzales.AnnualReviewofPublicHealth,2010.
MethamphetamineRelatedAdmissionToPubliclyFundedSubstanceAbuseTreatmentPrograms
• Evidenceofgrowingmethamphetamineuseproblemduringtheearly2000
• Restrictionsonsalesofpseudoephedrinemayhavereducedaccesstomethamphetamine
• Evidencesuggestsincreasingglobalmethamphetamineuse
Gonzales.AnnualReviewofPublicHealth.2010.
MethamphetamineLabIncidentsin2004
Linberry.MayoClinicProceedings,2006.
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MethamphetamineUseHasMigratedEastDuringtheLastTwoDecades
Wong.ClinicalCardiol,2013.
MethamphetamineUseHasRemainedConstantintheLastDecade
NationalSurveyonDrugUseandHealth,2014.
MethamphetamineUseIsHigherAmongCertainVulnerablePopulations
• Menwhohavesexwithmen• Associatedwithhighrisksexualbehavior• LinkedtoincreaseinHIVtransmissionandothersexuallytransmittedinfections
• Women• Equallycommonamongmenandwomenincontrasttootherrecreationaldrugs
• Useinitiatedfordepressionandweightloss• Linkedtodomesticviolenceandsexualriskybehavior
• CriminalOffenders• Associatedwithcriminalandviolentbehaviors
Gonzales.AnnualReviewofPublicHealth.2010.
MethamphetamineIsCommonlyUsedInSanFrancisco
SanFranciscoDepartmentofPublicHealth.March,2007.
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PharmacokineticsMethamphetamine
• Route:PO,intranasal,inhaled(smoked),IV,PR• Bioavailability
• Oral67%,inhalation67-90%,nasalinsufflations>79%• Onsetofeffectfastestwithinhalation(5-10seconds)• T1/2=12hr
• “High”canlast8-24hr
• Metabolism• Hepaticmetabolism(CYP2D6)• Ethanolsuppressesmetabolism• Metabolitesincludeamphetamine
Schep.ClinicalToxicology,2010.
MethamphetaminePharmacology
• Redistributesmonoaminesfromstoragevesiclesintosynapses
• Inhibitsmetabolismofmonoamines
Vearrier etal.Methamphetamine:History,Pathophysiology,AdverseHealthEffects,CurrentTrends,andHazardsAssociatedwiththeClandestineManufactureofMethamphetamine.DiseaseofMonth2012
Cruickshank.Addiction,2009.
Effectsvarydependingondose,route,frequencyofuse
• Lowerdose(5-50mg):euphoria,loweredinhibitions,decreasedfatigue,acuteimprovementofattention,reducedappetite,mild-moderatetachycardia/hypertension
• Higherdose(>50mg):chestpain,tachypnea,tachycardia,HTN,diaphoresis,mydriasis,hyperthemia,hyperreflexia,agitation,delirium,psychosis,vasoconstriction(ischemia,CVA)
• Chronichighdose:cardiomyopathy,HF,PH,cognitiveimpairment,psychosis
• Cardiovasculareffectsstrongcorrelationtodose
Schep.ClinicalToxicology,2010.
MethamphetamineCardiacClinicalPathology
• Acutepathology• Chestpain,tachycardia,HTN• Myocardialinfarction• AorticDissection• SCD
• Chronicpathology• CAD• Cardiomyopathy(DCM)
Kaye.Societyforthestudyofaddiction,2007.
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CardiovascularFindingsOnAutopsyofMethUsersinSanFrancisco
• Significantcardiomegaly(378gvs341g)• Coronaryarterydisease79/413versus6/114controls
• MIonlyidentifiedin1.8%(7/413)• Myocardialfibrosisandcontractionbandnecrosis
• Nocardiomyopathyorpulmonaryhypertension
Karch.JournalofForensicSciences,1999.
AcuteCoronarySyndromesandMethamphetamine• RetrospectivechartreviewfromUCDavis• 33patientswithmethamphetamineandchestpain• 9patientsdiagnosedwithACS• 3patientsfoundtohaveCADoninvasiveevaluation
• Ventricularfibrillationventriculartachycardiaoccurredin2patients
Turnipsee.JOfEmergencyMedicine,2003.
CardiomyopathyAssociatedWithMethamphetamine• Fewcasereportsofdeathassociatedtih LVfailurefrom1940s-1970s
• Firstcaseofalivingpatientwithcardiomyopathyfrommethamphetaminein1989
• 48yearoldwomanwhousedmethamphetamineforweightloss,resolutionwithcessationofmethamphetamine
• 3.4foldhigheroddsofcardiomyopathyamongpatientswhousemeth
Histologicfindings:Concentrichypertrophy,interstitialandperivascularfibrosis,myocytevacuolizationandmedialhypertrophy
Karch.ForensicScienceInternational.2011.
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PossibleMechanismsOfMethamphetamineCardiomyopathy
• Catecholamineexcess• Vasospasmcausingfocalmyocardialdegenerationandnecrosis• Similartomyocardiallesionsinpatientswithpheochromocytoma orTakotsubo
• Increasedreactiveoxygenspeciesandmitochondrialinjury• Directtoxicitythatisindependentofcatecholaminemediatedeffects
• Chronicmethhasleadstodegenerationofultrastructure ofcardiacmyocytes
• Beta-blockadedoesnotpreventdamagesuggestingdirectmyotoxicityinadditiontothetoxicityfromsympatheticoverstimulation.
• Synergisteffectswithalcohol,cocaine
IslamForensicScienceInternational,1995.Kaye,Societyforthestudyofaddiction.2007
CYP2D6PolymorphismsMayPredictMethCardiomyopathy
Sutter.ClinicalToxicology,2013.
MethamphetamineandHeartFailureAtSFGH
• Retrospectivechartreviewof199patientswithmod-severe/severeLVfailure
• 123JudgedNICM,23(18.6%)Methusers• Significantlyyounger(43vs54yrs,P<0.005)• Morehospitaladmissions(3.2vs 0.8,P<0.005)• Homeless(OR6,95%CI1.6-22.5)• Trendtowardin-hospitaldeath(OR4.8,95%CI0.92-25.1)
MethamphetamineHasBeenAssociatedWithPAHandIncreasedMortality
• Of340,iPAH patientsweremorelikelytobeexposed(OR11.6)
• ComparedtoiPAH,reduced5yearsurvival(34%vs.60%)
Chin. Chest, 2006.Zamanian. AJRCCM, 2010.
IPAHOtherPAHCTEPH
PercentM
ethExpo
sure
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MethamphetamineUseinPatientswithIdiopathicPAHAtUCSF
• 56%(72/128)hadhistoryofmethuse• Nodifferenceinhemodynamics (mPAP,CO),6MW,O2use,age,oruseofPDE-5,ERAs,inhaledprostacyclins orcombinationtherapy
• SignificantdifferenceinsurvivalforidiopathicPAHmeth(+)versusidiopathicPAHmeth(-)
CocaineIsDerivedFromthePlantErythroxylum coca• LeaveschewedbySouthAmericanIndians
• Cocaineisolatedinthe1850s
• Usedin“tonics”andoriginalCocaCola
• Varietyofmedicalusesincludingananestheticandtreatmentofmorphineaddiction
PhysiologicActionsofCocaine
• Inhibitscatecholaminereuptakeatsympatheticnerveterminals
• Increasessensitivityoradrenergicreceptorstonorepinepherine
• BlocksNa+andK+channels(classIantiarrhythmic)• Stimulatesendothelinrelease• Inhibitsnitricoxideproduction• Activatesplateletsandplateletaggregation
Schwartz.Circulation,2010.
About1.5MillionPeopleAreCurrentCocaineUsers
NationalDrugAbuseSurvey,2014.
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CharacteristicsofCocaineUsers
Qureshi.Circulation,2001.
PhysiologicConsequencesofCocaineUse
Schwartz.Circulation,2010.
MechanismsofActionofCocaine
Schwartz.Circulation,2010.
CocaineChestPainIsMoreCommonThanMIFromCocaine• Presentingwithcardiovascularcomplaints56%• Presentingwithchestpain40%• Presentingwithmyocardialinfarction6%• Mortality1%
Schwartz.Circulation,2010.
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Approximately1In4MIinYoungerPersonsIsAttributabletoCocaine
Qureshi.Circulation,2001.
CharacteristicsofCocaineChestPainandMI
• Chestpainonsetassoonas60minutesoraslongas18hoursafteruse
• RiskofMIdeclinesquicklyafterthefirst4hours• Complicationsarerare>12hoursafterarrival,usuallypresentonarrival
• InpatientswithMI,non-obstructivediseasewiththrombusisacommonfinding
• Recurrentchestpainiscommoninpersistentcocaineusers
Schwartz.Circulation,2010.
CharacteristicsCocaineUsersWithStroke:ICHFromAneurysmCommonInCurrentCocaineUsers
• Oddsofinhospitalmortalityandpooroutcome2.4
Toossi.JofStokeandCerebrovacsular Disease,2010.Martin-Schild.Stroke,2010.
CocaineCardiomyopathy
• Dogandrabbitmodelsdevelopcardiomyopathyaftercocaineexposure
• LeftventriculardysfunctioniscommoncocaineusersundergoingangiographywithEF<30%in18%ofpatients
• 5.3%ofpatientswithacuteheartfailureintheADHERE-EMregistryreportedcocaineuse
Om. AmJCard,1992.Hale.AmHeartJ,1989.
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AorticDissectionFromCocaine
• Incidencevariesbycenter0.5%-37%ofaorticdissections
• Youngerandmorelikelytobesmokers• Nodifferenceinpresentation• Thirtydaymortality10%higherincocaineusers
Eagle.Circulation,2002.Hsue.Circulation,2002.Daniel.JVasc Surg,2007.
SuggestedAlgorithmforTreatmentofCocaineChestPain
Schwartz.Circulation,2010.
TreatmentofMethandCocaineCardiomyopathy• Abstinence• Standardguidelinedirectedheartfailuretherapy• UnclearroleofAICDgivenriskofventriculararrhythmias