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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