Methamphetamines Methamphetamines and other stimulants and other stimulants Risk factors for pulmonary arterial Risk factors for pulmonary arterial hypertension? hypertension? Kelly Chin, MD Kelly Chin, MD UT Southwestern Medical Center UT Southwestern Medical Center Dallas, TX Dallas, TX
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Methamphetamines Methamphetamines and other stimulantsand other stimulants
Risk factors for pulmonary arterial Risk factors for pulmonary arterial hypertension?hypertension?
Kelly Chin, MDKelly Chin, MDUT Southwestern Medical CenterUT Southwestern Medical Center
Dallas, TXDallas, TX
IntroductionIntroduction
Methamphetamines probably cause PAHMethamphetamines probably cause PAHMechanism: like Mechanism: like fenfluraminefenfluramine, probably , probably acts on the serotonin transporteracts on the serotonin transporterRates of methamphetamine use Rates of methamphetamine use
Vary by geographical areaVary by geographical areaIncreased during the 1990sIncreased during the 1990s
Drugs and toxins associated with PAHDrugs and toxins associated with PAHEvian meeting 1998, as Evian meeting 1998, as referencedreferenced by by SimonneauSimonneau et al. (et al. (JACCJACC 2004;43:5S2004;43:5S--12S)12S)
Very likelyVery likelyAmphetaminesAmphetaminesLL--tryptophantryptophan
Cocaine: Collazos J. Respir Med. 1996;90:171, Yakel DL Jr Am Heart J. 1995;130:398. Methamphetamine: Schaiberger PH Chest. 1993;104:614.
MethamphetamineNH
CH3
CH3
NH2
CH3
NH
CH3
CH3F3CFenfluramine
Amphetamine
Substrate type releasers: Increase release of NE, DA, 5HT through substrate mediated exchangeDisrupt intracytoplasmic storage vesicles
Amphetamine and methamphetamine: more potent releasers of dopamine and norepinephrineFenfluramine: more potent releaser of serotonin
Background: Background: FenfluramineFenfluramine and and DexfenfluramineDexfenfluramine
IPPHS: PPH (N=95) IPPHS: PPH (N=95) vsvs Normal ControlNormal ControlFenfluramineFenfluramine >3 >3 mosmos: 23.1 (6.9: 23.1 (6.9--77.7)77.7)FenfluramineFenfluramine <3 <3 mosmos: 1.8 (0.5: 1.8 (0.5--5.7)5.7)AmphetamineAmphetamine--like appetite suppressant: 8.4% like appetite suppressant: 8.4% vsvs 2.3%, but 2.3%, but only 2 cases and 3 controls did not also have only 2 cases and 3 controls did not also have fenfluraminefenfluramineexposureexposure
32 year old male referred for dyspneaLaid off from a maintenance job 6 months ago –unable to perform physical activity, loses insurance Develops syncope, echo suggests elevated RVSPInitial SHx: cocaine very remotely, occ MJ and prior amphetamines. “The amphetamine use was very rare”.
Initial Work-up
RA 10 PA 80/46 (48) PCWP 8 CO 2.7 PVR 22 RA 10 PA 80/46 (48) PCWP 8 CO 2.7 PVR 22 wuwuNo vasodilator responseNo vasodilator responseMRI: MRI:
LVEDV 73 ml LVEF 61%LVEDV 73 ml LVEF 61%RVEDV 179 ml RVEF 32%RVEDV 179 ml RVEF 32%
1 month later admitted with volume overload1 month later admitted with volume overload+ + toxtox screen: amphetamines, MJscreen: amphetamines, MJAdmits to MJ; denies amphetamines Admits to MJ; denies amphetamines –– reports reports pseudoephedrinepseudoephedrine
4 months later: severe volume overload, admitted4 months later: severe volume overload, admittedUtoxUtox: amphetamines: amphetaminesNot taking his medicationsNot taking his medicationsFamily reports Family reports ““irrational behaviorirrational behavior””
Denies drug use: confirmatory sendDenies drug use: confirmatory send--out out toxtox screen screen positive for methamphetamine and amphetaminepositive for methamphetamine and amphetamineClinic followClinic follow--up at 5 months: doing better, volume well up at 5 months: doing better, volume well controlled, continues to deny drug usecontrolled, continues to deny drug use
Motivation for the studyMotivation for the study
Women Men1. Fenfluramine 1. Stimulants2. CTD 2. HIV (almost all used stimulants)3. Congenital Heart 3. Familial / CTD
0
10
20
30
40
50
60
IPAH Fenfluramine CTD Amphetamine /Cocaine Alone
Congenital HeartDisease
HIV Portal HTN Familial Amphetamine /Cocaine Total
Men
Women
Total
Study: stimulant use in idiopathic PAH compared with other forms of PH
UCSD (La Jolla)Only amphetamine, methamphetamine, cocaine Categorized as:
Idiopathic PAHPAH with known risk factors (familial PAH, CVD, CHD, anorexigen)CTEPH (chronic thromboembolic PH)
Excluded: PAH due to HIV, liver disease
Screened: 614 Other PHLung diseaseLeft heart diseaseHIV with PAH / CTEPHPortal hypertension with PAHOther PA obstruction*Acute / recent PE
Mean Age 47.2 49.1 53.0Mean PAP (mm Hg) 50.2 42.2 46.5Gender (% female) 72% 89% 56%Race
White 74% 76% 82%Black 5% 4% 13%Hispanic 11% 7% 2%Asian / Pacific Island 3% 9% 2%Other or Unknown 6% 5% 0.7%
Results: Stimulant UseResults: Stimulant Use
0
.05
.1
.15
.2
.25
.3
.35
.4
Pro
por
tion
Rep
orti
ng
Stim
ula
nt
Use
Idiopathic Pulmonary Arterial Hypertension
Pulmonary Arterial Hypertension with Known Risk Factors
Chronic ThromboembolicPulmonary Hypertension
28.9%
3.7% 4.4%
Specific StimulantsSpecific Stimulants
Idiopathic PAH
(N=97)
PAH known risk factors
(N=106)
CTEPH (N=137)
Methamphetamine alone 16 4 2
Amphetamine alone 3 0 0
Cocaine alone 1 0 2
Methamphetamine + cocaine 7 0 1
Amphetamine + cocaine 1 0 1
Total 28 4 6
Most patients reported heavy useMost patients reported heavy use
49 M 1998 Cocaine, methamphetamine, heroin IV for 25 years.
53 F 1998 Methamphetamine and cocaine use for 20 years.
47 F 2000 Methamphetamine use for 15 years, last use 1998.
40 M 1999 Amphetamines for 20 years.
38 F 1999 Inhaled methamphetamine use for 17 years, last ~1994.
43 M 2004 Crystal methamphetamine and cocaine for 15 years
46 F 2003 Cocaine and methamphetamine for 13 years
41 M 2001 Methamphetamine use for approximately seven years.
Uncertain DurationUncertain Duration
30 F 2003 Methamphetamine use continuing up until diagnosis, none IV34 F 2000 Methamphetamine use40 M 1999 Inhaled crystal methamphetamine use41 F 2004 Methamphetamine, cocaine use last use one year prior to dx42 F 2002 Methamphetamine use45 F 1999 Amphetamine history, none in many years51 F 2004 Methamphetamine use (snorted) up until <1 mo prior to dx54 M 1999 Methamphetamine use, “none for four years”57 M 2004 Crystal methamphetamine use67 F 2003 Amphetamine containing diet pills in her twenties
Odds RatioOdds Ratio
Idiopathic PAH vs. PAH with known risk factors
Idiopathic PAH vs. CTEPH
Any Stimulant UseUnadjusted
10.4 (3.5-31) p<0.001 8.9 (3.5-22) p<0.001
Full model (includes Age, gender, race)
10.1 (3.3-30) p<0.001 8.1 (3.1-21) p<0.001
Final model 10.1 (3.4-30) p<0.001 7.6 (3-20) p<0.001
Methamphetamine, final model
7.7 (2.6-24) p<0.001 11.6 (3.3-40) p<0.001
ProblemsProblems
RetrospectiveRetrospectiveMissing data: more data missing in the IPAHMissing data: more data missing in the IPAH
?Less likely to ask someone with CTEPH / risk ?Less likely to ask someone with CTEPH / risk factor for PAHfactor for PAHOr some stimulant histories reported as Or some stimulant histories reported as ““noncontributorynoncontributory”” were likely negativewere likely negative
Geography and control group issuesGeography and control group issues
Past year use of methamphetamine by persons 12 years or older by region and gender: 2002-2005
Lifetime rates: ~5%
Source: The NSDUH Report January 26, 2007Source: The NSDUH Report January 26, 2007
Percentages of Persons Aged 12 or Older Reporting Past Year Methamphetamine Use, by State: 2002, 2003, 2004, and 2005
Source: national Clandestine Laboratory Database (http://www.dea.gov/concern/map_lab_seizures.html)
More on potential mechanisms
MonamineMonamine transporters: clear the synaptic cleft transporters: clear the synaptic cleft of NE, DA, 5HTof NE, DA, 5HTSerotonin transporter is present in other tissues:Serotonin transporter is present in other tissues:
Lungs: endothelium and Lungs: endothelium and smooth musclesmooth musclePlacentaPlacentaPlatelets Platelets Other vesselsOther vesselsGI tractGI tract
Smooth muscle growth: serotonin Smooth muscle growth: serotonin receptor vs. serotonin transporterreceptor vs. serotonin transporter
Serotonin leads to greater smooth muscle Serotonin leads to greater smooth muscle proliferation in PPH than controlproliferation in PPH than control
• Blocked by fluoxetine (Prozac: SSRI)
• Not blocked by ketanserin, 5HT receptor antagonist
Eddahibi J Clin Invest 108:1141
More on the 5HT Transporter in PHMore on the 5HT Transporter in PH
Levels of the serotonin transporter protein are Levels of the serotonin transporter protein are increased in idiopathic PAH increased in idiopathic PAH
LL LL polymorphism accounts polymorphism accounts for some of the increasefor some of the increase
Marcos Circ Res. 2004;94:1263
OverexpressionOverexpression of the 5HT transporterof the 5HT transporter
BMPR2 +/BMPR2 +/-- mice increase RVSP with mice increase RVSP with serotoninserotoninaa
OverexpressionOverexpression alone is sufficient to cause alone is sufficient to cause elevated pulmonary pressures in elevated pulmonary pressures in animalsanimalsbb
More susceptible to chronic hypoxic and More susceptible to chronic hypoxic and monocrotalinemonocrotaline induced induced PHPHcc
Less susceptible to acute hypoxic Less susceptible to acute hypoxic vasoconstrictionvasoconstriction
a. Long Circ Res. 2006;98:818b. MacLean MR Circulation 2004;109:2150c. Guignabert Circ Res. 26 2006;98:1323
Does Methamphetamine lead to Does Methamphetamine lead to serotonin release?serotonin release?
•• In vitro IC50 values for In vitro IC50 values for release release ((nanomolarnanomolar): ): •• Higher values = less potent Higher values = less potent •• Methamphetamine: nine times less potent then Methamphetamine: nine times less potent then fenfuraminefenfuramine•• Amphetamine: twentyAmphetamine: twenty--two times less potent than two times less potent than fenfluraminefenfluramine
Negus SS J Pharmacol Exp Ther. 2007;320:627-36
Drug levels among arrestees in Bakersfield, CaliforniaDrug levels among arrestees in Bakersfield, CaliforniaTypical dosesTypical doses
Amphetamine for ADHD: 5Amphetamine for ADHD: 5--40 mg40 mgAbuse: 50 to several 1000 mg reported with illicit useAbuse: 50 to several 1000 mg reported with illicit use
How much methamphetamine is How much methamphetamine is enough to cause PAH?enough to cause PAH?
Methamphetamine/Amphetamine treatment admissionsMethamphetamine/Amphetamine treatment admissionsRoute of administration: 1993Route of administration: 1993--20032003
Source: 2003 SAMHSA Treatment Episode Data Set (TEDS).
What about ADHD?What about ADHD?
Amphetamine (prior study) 22 times less potent Amphetamine (prior study) 22 times less potent than than fenfluraminefenfluramineMethylphenidate: minimal 5HT activityMethylphenidate: minimal 5HT activity
Longer hours of workLonger hours of workWeight lossWeight lossBetter sexBetter sex
HIV in MSMHIV in MSM““RecreationalRecreational”” methmeth: 26%: 26%Outpatient, drug free: 62%Outpatient, drug free: 62%Residential treatment: 90%Residential treatment: 90% Molitor et al., 1998; Shoptaw et al.,
2002; VNRH, unpublished data
California: 2002California: 2002--20032003
35,947 individuals were admitted to treatment in 35,947 individuals were admitted to treatment in California under the Substance Abuse and Crime California under the Substance Abuse and Crime Prevention Act funding.Prevention Act funding.Of this group, 53% reported MA as their primary Of this group, 53% reported MA as their primary drug problemdrug problemTreatment: equally successful to that of other Treatment: equally successful to that of other drugs: 40drugs: 40--60% relapse rate60% relapse rate
SSRI AntidepressantsSSRI Antidepressants
Do increase local levels of serotoninDo increase local levels of serotoninAntidepressants in general (SNAPH) not associated with Antidepressants in general (SNAPH) not associated with PAHPAHaa
SSRIsSSRIs block rather than promote serotonin induced smooth block rather than promote serotonin induced smooth muscle cell growth muscle cell growth in in vitrovitrobb
Use of Use of SSRIsSSRIs is not associated with increased mortality in is not associated with increased mortality in patients with established patients with established PAHPAHcc. . BUT maternal use of BUT maternal use of SSRIsSSRIs has been linked to persistent has been linked to persistent pulmonary hypertension of the newborn; the cause for this pulmonary hypertension of the newborn; the cause for this discrepancy remains discrepancy remains unclearuncleardd. .
a. Rich S Chest 2000;117:870b. b. EddahibiEddahibi S. S. Circulation. Circulation. Apr 18 2006;113(15):1857Apr 18 2006;113(15):1857--1864.; Marcos E 1864.; Marcos E Circ ResCirc Res. 2004;94:1263. 2004;94:1263--1270.1270.c. c. KawutKawut SM SM PulmPulm PharmacolPharmacol TherTher. . 2006;19(5):3702006;19(5):370--374.374.d. Chambers CD d. Chambers CD N N EnglEngl J Med. J Med. Feb 9 2006;354(6):579Feb 9 2006;354(6):579--587.587.
Use increased significantly through the 1990Use increased significantly through the 1990’’s, now s, now primarily inhaled or smoked.primarily inhaled or smoked.Long halfLong half--life life
Acutely: Acutely: catecholaminescatecholamines may lead to hypertension, may lead to hypertension, dehydration, renal failure, MIdehydration, renal failure, MICan have paranoia for daysCan have paranoia for days
10 times higher rates of use among IPAH: suggests 10 times higher rates of use among IPAH: suggests associationassociationRisk, minimum dose / duration of use unknown but Risk, minimum dose / duration of use unknown but usually years of abuseusually years of abuseMethamphetamine epidemic began on the West CoastMethamphetamine epidemic began on the West Coast