Forensic Toxicology: Fentanyls & Designer Drugs

Origin of Term “Designer Drug”
-From popular science press
-R. Baum “Designer Drugs: Underground Chemists Ply a Deadly Trade”
—Sept 1985
-W. Gallagher, “Beyond Crack: The Growing Peril of Designer Drugs”
—Aug 1986

Definition of Designer Drugs
-Synthesized from common chemicals
-Exempt from DEA control due to unique chemical structure
-Skillfully marketed under attractive or exotic names
-WHO publication 1990
-Chemicals and pharmacological profiles of fentanyls and aminorex
-Does not define the term “Designer Drugs”
-A drug produced by a minor modification in chemical structure of an existing drug resulting in a new substance with similar pharmacologic effects, esp one created to achieve the same effect as a controlled or illegal drug
-Can be charged for miss-labeling
-Synthesized to circumvent legal restrictions
-Novel derivatives of restricted drugs
-No present acknowledged medical use
-May be borrowed from legitimate research
-Most come from china, mexico plays a part

Designer Drugs- Major Chemical Classes
-Arylhexylamines
—PCP analogs
-Arylpiperidines
—N-benzylpiperazine (BZP)
—trifluoromethylphenylpiperazine (TFMPP)
-Lysergimides
—Acetyl- LSD
-Oxazolines
—4-methylaminorex
-Phenylethylamines
—hydroxylated amphetamine derivatives
—methoxy or methylenedioxy- amphetamines
-Synthetic opiates
—meperidine analogs
—fentanyl analogs
-Tryptamines
—alpha-ethyltriptamine (Trip)
—5-methoxy-di-isopropyltryptamine (Foxy)
-Cannabimimetics
—JWH-018
—CP-47=-497
—Hu-210

Drugs that Designer Drugs Mimic: Major Pharmacological Classes
-Cannabimimetics (THC)
-Dissociative anesthetics (PCP, Ketamine)
-Entactogens (MDMA)
-Hallucinogens (LSD)
-Opiates (Fentanyl, meperidine)
-Stimulants (methamphetamine)

Designer Drugs- Challenge to Clinical Toxicology
-unusual or new presentation
-treat only symptoms
-lack of literature support

Designer Drugs- Challenge to the Toxicology Laboratory
-Lack of immunoassays for initial test
-Lack of primary reference material
-Not in commercial Mass Spectra libraries
-No pharmacokinetic data
-No knowledge or data concerning metabolites

Designer Drugs Timeline
-1960s- “Inter Voyage”
—hallucinogens
-1970s- “Speed Kills” “Everything Goes”
—PCP, MPTP
-1980s- “Coke, then Pause that Refreshes”
—fentanyls, oxazolines, methcathinone
-1990s- “Club Drugs- Rave on”
—MDMA, GHB
-2000- “?”
—1-aryl piperazines
—cannabimietics

N-Acetyl-LSD: ALD-52: First Designer Drug Trail
-Possibly “Orange Sunshine” available in Cali through 1968 and 1969
-Source Sonoma County “underground” chemistry lab of Tim Scully
-Scully was arrested and prosecuted
-Defense: ALD-52 not an illicit drug
-was convicted and served time in prison
-Prosecution pointed out defense problems
-ALD-52 is a pro-drug, ingested it readily undergoes hydrolysis to LSD
-Synthesis of ALD-52 required LSD
—based on methods available in the scientific literature at the time
-Scully was convicted and served time in prison

2,5-dimethoxy-4-methylamphetamine:DOM
-Hallucinogen, >3mg
-Mescaline unit (M.I.) 80!
-Street Drug, STP (serenity, traquility, peace)
-Onset 1hr, peak effect 3-5 hr, subdue 7-8 hr
-1968 San Fransisco dose 10 mg, “bad trips” peak effects lasting 16-24 hr
-Many panic reactions

History of MPTP
-1976 23 yr graduate student develops parkinsonian symptoms after injecting homemade MPPP
-1982 Six IV drug addicts develop severe parkinsonism from “new heroin” MPTP identified in illicit samples
-1983 MPTP treated monkeys develop biochemical and pathological alterations similar to patients with parkinsonism
-1983 first of 3 former pharmaceutical workers identified with MPTP toxicity; exposure in 1964
-1984 Parkinsonism in drug abusers “snorting” MPTP

Parkinson’s Disease
-Due to dopamine deficiency in extrapyramidal brain nuclei
-Disease of aging, usual onset after 50 yr
-No cure, only treat symptoms
-Symptoms
—Muscle rigidity
—loss of power of voluntary motion
—tremor
—dementia

Fentanyl
-Potent analgesic for acute pain
-Primary analgesic in surgical procedures
-Indicated as a pre-anesthetic, primary anesthetic and post-surgical anethetic
-Synthetic very potent analgesic with short duration
-Injections of 50-100 ug produces analgesia and rapid unconsciousness
-Incidence of incomplete amnesia, hypotension or hypertension less than morphine
-Duration of respiratory depression shorter than morphine

History of Fentanyl
-First synthesized in Belgium in the 1950s
-Accepted clinical usage in 1963 as surgical anesthesia
-Administered IV and/or IM
-Through the 1970s abuse rare
—stolen from hospitals

Medical Fentanyl Analogs
-In surgical procedures administered only by physicians
-Patient is on respirator or respirator is immediately available
-Naloxone antidote is immediately available

Alfentanyl
-25% analgesic and 10% respiratory depression potency as fentanyl
-Beta t1/2= 1.5 hr
-Vd= 40-70L
-Ultra-short duration of action, 15 min
-8 ug/kg = 5-16 min anesthesia, recovery within 2-20 min
-Surgical anesthesia, plasma= 200-300 ng/ml

Remifentanyl
-Short-acting, inducing agent and adjunct to general anesthesia
-Anesthetic dose in adults 1 ug/kg IV bolus; followed by 0.25-1.0 ug/kg/min infusion
-Vd= 0.2-0.4 L/kg
-Plasma half-life= 6-16 min
-Plasma values 26-34 min after infusion
—2 ug/kg, 3.0 ng/mL
—5 ug/kg, 6.7 ng/ml
—15 ug/kg, 21 ng/ml

Sufentanyl
-Extremely potent analgesic
-Beta t1/2 = 2.5 hr
-Vd= ~150L
-10-30 ug/kg doses for cardiac surgery

Poency of Therapeutic Fentanyl Analogs v Morphine
-Heroin -> 5
-Alfentanyl -> 30
-Fentanyl -> 100
-Sufentanyl -> 2000
-Carfentanyl -> 3200
-Lofentanyl -> 6000

Clinical Toxicology of Fentantyl
-Respiratory depression
-Bradycardia
-Hypothension
-Chest wall rigidity
-Nausea, vomiting
-Hypothermia
-Convulsions
-die of an opiate OD

Rules of IV Fentanyl
-In surgical procedures administered only by physicians
-Patient is on respirator of is immediately available
-Naloxone antidote is immediately available

Therapeutic Fentanyl- Routes of Administration
-IV up to 60 ug/kg
—2-20 ml ampules of 50 ug/ml
—in combination with 2.5 mg droperidol
-IM
*Transdermal patch
-Oral transmucosal (lollipop)

Fentanyl Pharmacokinetics
-Alpha-t1/2 = 13-28 min
-Beta-t1/2 = 1.5-6 hr
-Bioavailability
—transmucosul ~50%
—oral ~30%
-Vd = 300L (4-5 l/kg)
-Blood.plasma= 1.0
-Extensive metabolism
—P450 3A4
-Only ~8% of dose excreted in urine as parent drug

Fentanyl Plasma Concentration
-IV 60 ug/kg
—100 ng/ml declining at 1 hr to 10 ng/ml
-IV 2 ug/kg
—11 ng/ml declining at 1 hr to 1 ng/ml
-Transdermal patch 100 ng/ml
—1.9-3.8 ng/ml
-Lollipop
—0.2-1.6 ug/ml

Fentanyl Metabolism
-Fentanyl to Norfentanyl and Despropropionylfentanyl which are both inactive

Fentanyl Abuse- Routes of Administration
-IV
-Transdermal
-Transmucisal/Oral
-Smoking
—transdermal patches

Transdermal Fentanyl Patches
-Prescribed for severe chronic pain, cancer
-Deaths due to ill informed patients applying multiple patches
—drug abuse
—accidential death
—suicides
-dont use morphine patches because of tolerance –>dose would get out of hand

Design of Fentanyl Patch
-4 layers
—adhesive layer, rate-controlling membrane, drug reservoir, backing layer
-Fentanyl free base in alcohol in ethylhydroxy-cellulose drug reservior
-Vinyl acetate rate-controlling membrane
-Adhesive contains fentanyl
-Even after the patch is removed, the skin also act as a reservoir and will still release the drug

Duragesic
-Transdermal patches for treatment of chronic pain
-Duragesic is continuous release transdermal patch designed to release fentanyl, 25 ug/h per 10 cm3 of surface area
-The patches are available in 10, 20, 30 and 40 cm3 sizes releasing 25, 50, 75, and 100 ug/hr fentanyl , respectively.
Patches released 2-10 mg over 72 hr
-Desired therapeutic blood concentrations are obtained 8 to 12 hours after patch application
-In controlled studies of non-opiate tolerant patients, Duragesic 100 ug/h provided pain relief equivalent to 60 mg/day of morphine

Fentanyl patch Extended Toxicity
-After a patch is removed, fentanyl is concentrated in the cutaneous layers beneath the site of the removed patch
-Drug absorption continues into the systemic circulation from this site
-thus, simple patch removal does not, in itself, cease exposure to the drug

Tegaderm
-Consists of a thin polyurethane membrane coated with a layer of an acrylic adhesive
-Permeable to both water vapor and oxygen
-Impermeable to mirco-organisms
-Effective barrier to external contamination, whilst producing a moist enviornment at the surface of the wound by reducing water vapor loss
-For shallow wounds, scab formation is prevented and epidermal regeneration occurs at faster rate.

Incidence of other drugs detected in Duragesic Chronic Pain Pains
-546 urine specimens
—opiates, 48%
—benzodiaepines, 43%
—barbiturates, 3%
—methadone, 4%
—marijuana metabolite, 3%
—cocaine metabolite, 1%
—no drugs detected, 25% of the specimens

Abuse of Transdermal Patches
-External fentanyl from patch and inject
-Chew patches
-Heat patches and inhale vapors
-Street value 25-50$

Actio- Oral Transmucosal Fentanyl Citrate
-Transmucosal Lozenge
—cherry flavor
—similar to a lollipop
—medication enters body through the lining of the mouth
-Lollipop- berry flavor
-Various doses,micrograms
—200
—400
—600
—800
—1200
—1600

Aerosol Fentanyl
-October 2002, 41 Chechen Islamic terrorist took 700 people hostage, mostly women and children in a Moscow theater
-19 terrorist were women wired with explosives
-After 2 days, Russian security forces released fentanyl aerosol in theater, entered theater
-All 41 terrorist killed by troops or aerosol
-129 hostages died from fentanyl insufficient antidote available

Diluents Present in Illicit Heroin
-Cutting agents
—sugars: mannitol, lactose
-Products of Incomplete Synthesis
—6 monoacetylmorphine
—6 acetylcodeine
-Other drugs
—historically- quinine
—today- generic drugs
—today- fentanyl

Janssen Synthesis
-5 step procedure
-Long synthetic time
-Requires advanced chemistry skills
-Chemical precursors difficult to obtain
-Complex equipment and glassware required
-heating, refluxing and distillation required

Siegfriend Synthesis
-2 step procedure
-Short synthesis time
-Minimal chemistry skills needed
-Chemical precursors easy to obtain
-Complex equitment not required
-No heating, refulxing and distillation required

Clandestine manufacture of Fentanyl
-“White China”
—February 1993 Fentanyl lab in Goddard. KS
—reported to be responsible for the death of at least 300 people due to overdoses
—distributed throughout Eastern U.S. including MD, PA, and NY

Toxicology of Illicit Fentanyl Deaths
-Cocaine (BE) and morphine concentrations lower when fentanyl present
—consistent with substitution
—may not be simultaneous use
-Heart blood values greater than peripheral
—postmortem redistribution (B1/B2 = 2.8)
—incomplete redistribution
-Users report profound respiratory depression
—takes your breath away; die before you get high
-Many deaths with syringe present/ in body

Scene Investigation of Illicit Fentanyl Deaths
-Death rapid, usually “works at scene”
—if death in presence of other addicts, they may remove the perceived “good dope” from scene
-Multiple deaths at one scene have occurred
-Some young, inexperienced users (rare for heroin)
-most are experienced heroin users who are not aware of fentanyl potency
-Deaths in time clusters as the fentanyl available

History of Designer Fentanyls
-1979 Orange County, CA- two apparent heroin deaths, no drugs detected
-1980 15 additional deaths from “China White”
—no drugs detected
-1981 DEA reports alpha-methylfentanyl in “China White”
-1981 DEA places alpha-methylfentanyl in Schedule 1 of controlled substance act
1984 acetylfentanyl and 3-methylfentanyl appear on illicit drug market in Cali
-1986 15 3-methylfentanyl deaths in Pittsburgh
-1987 12 difference fentanyl derivatives identified in 110 deaths in Cali in the 1980s

Potency Illicit Fentanyl Analogs v Morphine
-Fentanyl -> 200
-Alpha-methylfentanyl -> 400
-Trans-3-methylfentanyl -> 400
-Cis-3-methylfentanyl -> 7000

Illicit Fentanyl Analogs
-Not studied in man, other than abuse
-Pharmacological activity as with legal fentanyl analogs
-Isomers composition of 3-methylfentanyl (cis,trans) depends on synthetic method
-Duration of action
—alpha-methylfentanyl -> 30 min
—3-methylfentanyl -> 4 hr

Minimum Lethal Dose of Fentanyl Illicit Analogs
-Fentanyl -> 250 ug/kg (18 mg)
-Alpha-methylfentanyl -> 125 ug/kg (9 mg)
-P-fluorofentanyl -> 250 ug/kg (18 mg)
-3-methylfentanyl -> 3 ug.kg (0.2 mg)

Fentanyl- Physical Constants
-Molecular Weight
—free base 336.5
—soluble citrate salt 528.6
-pKas of tertiary nitrogens= 7.3 and 8.4
-Octanol/water partition coefficient
—pH 7.4= 816/1

Fentanyl Analysis
-ELISA
-Extraction
—liquid/liquid
—solid phase
-GC/MS
—fentanyl EI 245, 246, 189, 146 m.z
—sufentanyl EI 289, 290, 140 m/z
-Derivatize norfentanyl
—acetylation
-Quantification- GC/MS-SIM
* really have to look for it because of low concentrations

Fentanyl and Norfentanyl in Urine by GC-MS
-IDed and quanted by GC/MS in SIM mode
-M/Z ions monitored were
—F, 245, 146, 246
—D5-F, 250, 251
—NF-acetyl derivative, 231, 158, 132
—D3-NF-acetyl derivative 236
-Quantification by compating ions
—fentanyl 250/245
—norfentanyl 236/231
-The LODs and LOQs for both fentanyl and norfentanyl were 3 ng/ml
-The upper limit of linearity
—fentanyl -> 250 ng/ml
—norfentanyl -> 400 ng.ml

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