Lecture 1 PDF

Preview

Summary

Lecture 1...

Description

Reviewof ForensicToxicology JS567

Dr.CurtE.Harper ToxicologyDisciplineChief AlabamaDepartmentofForensicSciences

“Everything Everythingisapoison is a poison attherightdose” by Paracelsus “The byParacelsus TheFatherofToxicology Father of Toxicology”

- Dose‐response - Effectvarieswithexposure - Smallamount=noeffect - Largeamount=Fatal Large amount Fatal - BasisforToxicology

Terminology • Pharmacology: Pk &Pd – Pharmacokinetics • Whatthebodydoestothedrug

– Pharmacodynamics • Whatthedrugdoestothebody

• Pharmacy – Healthprofessiontaskedwithensuringsafe andeffectiveuseofpharmaceuticaldrugs

• Toxicology – Pharmacology gonebad!

Pharmacology 101 Dose-Response Effect

EFFECT

Blood l d Conc.

DOSE

Pharmacokinetics Absorption Distribution Metabolism Elimination

Pharmacodynamics Diureticeffect Euphoria

Pharmacokinetics • ADME

Drugatsiteofadministration

1

Absorption

4 • 4processes Druginplasma

• Movementofadrugover timethroughthebody

2 Distribution Drugsintissues

3 Metabolism Metabolite(s)in b li ( ) i tiissues

• Whatthebodydoesto thedrug

4

Elimination

Drugand/ormetabolite(s) Inurine,bile,orfeces

RoutesofAdministration Route

Bioavailability (%)

Characteristics

Intravenous (IV)

100 (by definition)

Most rapid onset

Intramuscular (IM)

75 to  100

Large volumes often feasible; may be painful

Subcutaneous (SQ)

75 to  100

Smaller volumes than IM

O l (PO) Oral

5 tto < 100

Most convenient, may see first pass effects

Rectal (PR)

30 to < 100

Less first pass than oral

Inhalation

5 to < 100

Most rapid onset

80 to  100

Usually slow absorption, prolonged duration of action, action used for lack of first pass effects

Transdermal

First Pass Metabolism 

Definition: Phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation

Aredrugsadministeredintravenouslysubjectto1stpassmetabolism?

DrugReceptorInteractions[Active state]

Property Agonist

Definition • Drugbindstoandactivatesatarget

Analogy Keyfitsthelockandis abletoopenit bl i • Maximalresponsewhenusedathighenough (activateit) concentrations

Partial Agonist

• Dru gproduceslessthanmaximalresponse evenathighenoughconcentrationstocause maximalresponse

Drug‐ReceptorInteractions[Inactive state] Terminology Antagonist

Definition • Inhibittheabilityoftargetstobe activatedbyphysiologicor pharmacologicagonists h l i i

Competitive • Bindtoactivesite;usuallyreversible Antagonist

the effect of the biological • Blocks Blockstheeffectofthebiological agonist

Analogy Keyfitsthelockby can’tgetthelock open Keythatfitsinlock, doesnotopendoor

• Inhibitoryeffectcanbeovercomewhen Ligandconcentrationisraised Non‐ • Bindtoadifferentsitethantheligand; irreversible. competitive A t Antagonist it • Inhibitoryeffectcannotbeovercomeby increasingtheligand concentration

Dead‐boltlock;door willneveropen, even ifkeyisputintolock

GradedDose‐ResponseCurve (Pharmacodynamics) Emax (efficacy) Maximaleffectadrugcan produce

EC50(potency) Measureofhowmuchdrugis requiredtoproduceagiveneffect (affinityforareceptor)

CompetitiveAntagonism

Whyisthecurveshiftedtotheright?

Non‐CompetitiveAntagonism

Whyisthemaxeffectreduced?

Drug‐ReceptorBindingatmolecular level(Anothervisualrepresentation)

Beabletocompare/contrastforexam

Subfields of ForensicToxicology • 1.Forensicdrugtesting • Workplacetesting • PerformanceEnhancementtesting

• 2.Postmortemforensictoxicology • DeathInvestigation

• 3.Humanperformancetoxicology • DUI/DUID

1.ForensicDrugTestingand Monitoring WorkplaceandMilitaryUrineDrugTesting k l d ili i i





SafetyandEconomic(DrugFreeWorkplaceAct1988)



SAMHSA(SubstanceAbuseandMentalHealthServices Administration)regulated



NationalInstituteonDrugAbuse(NIDA‐5)

1.

Cannabinoids(marijuana)

2.

Cocaine

3.

Amphetamines

4.

Opiates(heroin,codeine,morphine)

5 5.

Phencyclidine (PCP) Phencyclidine(PCP)

1.ForensicDrugTestingand Monitoring DopingControl



Competitivesports(human/horses) InternationalOlympicCommittee(IOC) WorldAnti‐dopingAgency(WADA) Drugs





  

Stimulants



Anabolicsteroids



Di ti Diuretics 

Weightloss



Maskothersubstances

2.PostmortemToxicology 2 • CauseofDeath D l d? – Drug–related? • Overdose? • Performanceissue?

• MannerofDeath – Homicide – Suicide – Accident – Natural – Undetermined

3.HumanPerformance 3 • BehavioralToxicology – Identify Identifyandquantifytherelationshipbetweendrugs and quantify the relationship between drugs and and behavioralchanges

• Drugscanenhanceorimpairperformance – Anabolicsteroids,stimulants(lowdoses) – Ethanol,zolpidem(Ambien®)

• Examples – DUI,DFSA,Workplaceinjuries

• Isanindividualimpaired? • Doesthisimpairmentinterferewithsafeoperationofa motorvehicleorotherpotentiallydangerousmachinery?

EthanolMetabolism

Medical‐LegalAspectsofAlcohol.2003.

Case #1– ETOHBack‐extrapolation • 22yearoldmaleconsumedseveral12 martinisatBlueMonkey between10:00PM and3:00AM • Hewenttobedat5:00AM&awokeat8:00 AM • At9:00AMhewasinvolvedinaMVC • At12:00PMabloodsample wascollectedand theBACwas0.060g/100mL • EstimateBACat9:00AM

Case#1– ETOHBack‐extrapolation • Timebetweencrashandbloodsample 9:00 AM – 12:00PM 12:00 PM =3hours 3 hours – 9:00AM

• Eliminationraterange =0.01 0 01– 0.02 0 02g/100mL/hr

• Th TheBACrangeat10:00AMwouldbebetween BAC t 10 00 AM ld b b t xtoyg/100mL. • PerSeLimit=0.08%

GrandRapidsStudy • OriginalStudy – – – – –

Purpose:Evaluationofcrash‐riskofalcohol‐impaireddriving IU,Borkenstein,1962‐63 >13,000drivers(accident/control) d in1964,1966*,1974 Publish edi Ledtoperselaws

• RevisitedStudy – Bloomberg,LongBeach/Ft.Lauderdale,1997‐1999 Bl b L B h/F L d d l 1997 1999 – ~15,000drivers – Reportfinalized:2005

Conclusion:“Theprobabilityofaccidentinvolvement “The probability of accident involvement • Conclusion increasesrapidlyatBACsover0.08%,andexponentially increasesatBACsover0.15%.”

Isthereanincreasedcrashriskassociatedwithusingthisdrug? AlcoholRelativeRiskofBeingInvolvedinaTrafficCrash BAC C(%) 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0 08 0.08 0.09 0.10 0.11 0.12 0.13 0.14 0.15 0.16 0.17 0.18 0.19 0.20 0.21 0 22 0.22 0.23 0.24 >0.25

G rand d R apidsO id O riginal i i l (19 (1974)) 1.00 0.92 0.96 0.80 1.08 1.21 1.41 1.52 1 88 1.88 1.95 5.93 5.93 4.94 4.94 10.44 10.44 21.38 21.38 21.38 21.38 21.38 21.38 21 38 21.38 21.38 21.38 21.38

Grand G d RapidsR id evisited i i d(2009) 1.00 1.03 1.03 1.06 1.18 1.38 1.63 2.09 2 69 2.69 3.54 4.79 6.41 8.90 12.60 16.36 22.10 29.48 39.05 50.99 65.32 81.79 99.78 117 72 117.72 134.26 146.90 153.68

Blomberg“TheLongBeach/FortLauderdalerelativeriskstudy”JournalofSafetyResearch.2009.

SpecialTopics: Terminology • Impairment • • • •

Deteriorationofjudgment, D t i ti fj d t att ttention,lossoffinemotorskills ti l f fi t kill Increasedreactiontime Diminishedofsensoryperception Grossphysicalsignsmaybeabsent!!

• Intoxication • Advancedstateofimpairment • Grossphysicalsigns h l • “Impairment"becomes"intoxication"isuniquetothesubjectand dependsontolerance.

• Invisiblevs.visiblesigns • Subjectcanbeimpairedwithoutanyvisiblesigns.

SpecialTopics:Tolerance • Reductionofeffectivenessofadrugafteraperiodof continuous or large‐dose administration • Apersontakingdrugschronicallyasprescribedmayhave minimal side effects due to tolerance minimalsideeffectsduetotolerance • Maymask impairmentbutdoesnoteliminateit • Effectspecific** • Ultimatelytolerancewillbeevidentbasedontheindividual’s behaviorandperformanceonSFSTs

DREMatrix&12StepProcess HANDOUT • DSHDNIC – Dumbsh**haddrugsnowincustody

• • • • •

DIDDrugs DID Drugs DIDC CASH ANTs BIPED‐VD‐MISOT

Manners ofDeath 1. 2. 3. 4 4. 5.

Homicide Suicide Accident Natural Undetermined

• Toxicologyassistswith: – EstablishingManner andCause ofdeath

• Example:SuicidebyMethadoneOverdose Example: Suicide by Methadone Overdose • Example:Natural(polypharmacycontributory) • Positive andnegative findingsareimportant!

Postmortem Redistribution (PMR) PostmortemRedistribution(PMR) • Movementofdrugsfromoneareatoanother bydiffusionafterdeath • Simplediffusion – Movementfromareaofhigh concentrationtoareaoflowconcentration • Example:Fromstomachorlivertocentral(heart)blood

Arethedrugconcentrationsinbloodcollected the drug concentrations in blood collected • Are atautopsyrepresentativeoftheconcentrations at the time of death? atthetimeofdeath? – Example:TricyclicAntidepressants

FactorsthatInfluence PostmortemBloodTests l d • *Sitesampling* – Centralblood – Peripheralblood

• Decomposition • Mannerofdeath – Trauma

• Handlingof dl f body b d – CPR

• Conditionsofdeath – Aspiration,seawater,IV

• Methodofbloodsampling – Blindthoracicstick Blind thoracic stick

• Timesincedeath • Samplestorage – Temp.,Preservatives

• Typeofblood – Serum,plasma – Whole Blood

• Volumeofdistribution • Lipophilicity • pKaofdrug

SiteSampling • Central(heartblood) Central (heart blood) – Contributionsfromheart,liver,lungtissue

Peripheral blood preferred • Peripheralbloodpreferred – Femoral – “Vesselshouldbeligatedproximally,suchthat backflowfrominferiorvenacavaormorecentral compartments does not occur” compartmentsdoesnotoccur

• Usecleanornew hypodermicsyringe

MJ:AUnique DrugClass • PsychologicalEffects CNS D t Sti l t (L d ) – CNSDepressant+Stimulant(Lowdoses) – CNSDepressant(Highdoses) – Sedation,Euphoria,Hallucinations,Confusion,Dizziness

• Physiological – Redeye,increasedheartrate,drymouth,increased appetite vasodilation eyelid tremors appetite,vasodilation,eyelidtremors

• *Durationofeffects* – – – –

Peak=10‐30minutes Averageduration(euphoria)=2‐3hours Baselinereturn(behavior,physiological)=3‐5hours Residualeffects=24hours

Acute Use(1Joint) • LOQ=0.5ng/mL LOQ = 0 5 ng/mL – Detectiontimesdependenthighlyoncut‐off

Detection Times (plasma) • DetectionTimes(plasma) – THC=3to27hours – THC‐COOH=2to7days

• THC...