Forensic Toxicology: Fentanyls & Designer Drugs

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

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

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

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

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

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

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

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

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

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

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

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)

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

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.

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

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

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 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

Abuse of Transdermal Patches

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

Sufentanyl

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

Potency Illicit Fentanyl Analogs v Morphine

-Fentanyl -> 200 -Alpha-methylfentanyl -> 400 -Trans-3-methylfentanyl -> 400 -Cis-3-methylfentanyl -> 7000

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 Metabolism

-Fentanyl to Norfentanyl and Despropropionylfentanyl which are both inactive

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

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

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

Poency of Therapeutic Fentanyl Analogs v Morphine

-Heroin -> 5 -Alfentanyl -> 30 -Fentanyl -> 100 -Sufentanyl -> 2000 -Carfentanyl -> 3200 -Lofentanyl -> 6000

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

Fentanyl Abuse- Routes of Administration

-IV -Transdermal -Transmucisal/Oral -Smoking ---transdermal patches

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

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)

Rules of IV Fentanyl

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

Medical Fentanyl Analogs

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

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

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

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

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

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

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

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

Clinical Toxicology of Fentantyl

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

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

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

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

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

Designer Drugs- Challenge to Clinical Toxicology

-unusual or new presentation -treat only symptoms -lack of literature support