Update in Toxicology 2013




K2, Spice, Bath Salts, &
the New Designer Drugs
William Hurley, MD FACEP
Harborview Medical Center
Washington Poison Center
– hurleyw@uw.edu
– hurley@wapc.org
– (800) 222-1222
– (800) 709-0911
Update in Toxicology 2013

Goal
– Increase knowledge in management of
the poisoned patient

Objectives
– Describe manifestations & management
of the stimulant syndrome
– List new designer drugs, their
mechanisms, & their sources
Designer Drugs
Tox Update 2012
Designer Drugs
Designer Drugs
Poisoning Case




A 20 year-old female is found agitated & confused
by family in her dormitory room.
She has no significant past medical history, but the
family suspects she has been “experimenting” with
alcohol & marijuana since starting school.
She is agitated & aggressively ordering care
providers to leave her exam room. Family explains
this is not like her at all.
She is tachycardic, hypertensive, hot, & diaphoretic
– (P 128, BP 180/110)

How would you manage this encounter?
Designer Drugs
20 Year Old Female
Anxious & Agitated

Initial Evaluation ?
Designer Drugs
20 Year Old Female
Anxious & Agitated






Mental Status
A–
B–
C–
D–
E–
Designer Drugs
20 Year Old Female
Anxious & Agitated






Mental Status
A – Open & Protected ?
B – Ventilating & Oxygenating ?
C – Rhythm, Perfusion ?
D - Disability / Seizures
Decontamination, Dextrose ?
E – Exposure, Elimination ?

Poison Center 1-800-222-1222
Designer Drugs
Initial Management



Airway
Breathing
Circulation



WA Poison Center
1-800-222-1222
1-800-709-0911
– 80% of poisonings

Disability/Decontamination
– 90% of poisonings

Exposure/Elimination
– Antidotes
– 100% of poisonings
Designer Drugs
20 Year Old Female
Anxious & Agitated






Agitated, responding to loud verbal
A – Open with intact gag reflex
B - RR 20-24 / minute, clear lungs
C - Tachycardic (Sinus - 130’s)
Hypertensive (180/110)
D - No Seizure, Glucose 108
Decontamination?
E – Elimination?
Designer Drugs
Poisoning Management


ABCDE
Safety Net
– IV, Monitors (ECG & O2)

Focused History
– What, when, why, what has been done?
– What else is available?

Focused Physical Examination
– Toxicologic Syndrome?
Designer Drugs
Toxicologic Syndromes








Asphyxiant
Cholinergic
Anticholinergic
Cyclic
Antidepressant
Opiod
Sedative
Stimulant
Hallucinogenic









Serotonergic
Hepatotoxic
Heavy Metal
Irritant gas
Caustic
Salicylates
Toxic Alcohols
Hydrocarbons
Calcium antagonists
Designer Drugs
Poisoning Management

Physical Examination – Toxicologic Syndrome
Designer Drugs
Poisoning Management

Physical Examination – Toxicologic Syndrome
– Vital Signs
– Mental Status

confused, stimulated, depressed
– Pupils; small or large, reactive or not
– Mucus membranes; color, moisture
– Respiratory

rate & depth, bronchospasm, pulmonary edema
– Gastrointestinal Tract; hyper- or hypoactive
– Skin; color, temperature, moisture
Designer Drugs
Poisoning Case


A 20 year-old female “crazy”
Tachycardic, hypertensive,
warm, & wet
– (P 130, BP 185/110)

Synthetic marijuana?
Designer Drugs
Poisoning Case


A 20 year-old female “crazy”
Tachycardic, hypertensive,
warm, & wet
– (P 130, BP 185/110)


Synthetic marijuana?
Toxicologic Syndrome?
Designer Drugs
Physical Examination
Stimulant Syndrome







Vital Signs
Mental Status
Pupils
Mucus membranes
Respiratory
Gastrointestinal
Skin







T, P, R, BP
Seizures
Dilated & reactive
Moist
Rate, depth
Motility
Pink, warm, moist
Designer Drugs
Spice Case

Roomate produces packets of incense
purchased at a local “head shop.”
Designer Drugs
Designer Drugs
Spice Case


A 20 year-old female “crazy”
Begins screaming & struggling
– Attempting IV
– Has 3 minute seizure

Management?
Designer Drugs
Stimulant Agents - ?
Designer Drugs
Stimulant Agents


Cocaine
Amphetamines
– Methamphetamine, Ecstasy,
methylphenidate, phentermine

Decongestants
– Ephedrine, Pseudo-ephedrine

Beta Stimulators
– Albuterol, caffeine, theophylline

Withdrawal States
– EtOH, benzodizepine, GHB
Designer Drugs
Designer Drugs
Cannabinoids
Cannabinoids




Spice products - Europe in 2004
“Herbal smoking blend”
“Not for Human Consumption”
Synthetic agents, created to simulate
effects of cannabis


CNS cannabinoid receptors
Derived from cathinones (“Khat”)
Designer Drugs
Cannabinoids


Sold in small
packets
Variety of names
– K2, Spice Gold,
Spice Diamond,
Spice Silver,
Spice of Life

Retail U. S. $25-$40
Designer Drugs
Plant & Herbal Blends



Marketed as incense
Desire for ‘legal high’
Ability to avoid
detection on drugsof-abuse testing
(THC)
Designer Drugs
What’s up with the Eye?
Designer Drugs
What’s up with the Eye?





Wide-open-eye
imprint
Allusion to ‘‘Dune’’
Fictional drug
‘‘Melange’’
Called ‘‘the spice”
Excessive use
caused blue sclera
Designer Drugs
Cannabinoids

Heterogeneous structured compounds
– Agonize endogenous cannabinoid
receptors
– Include phytocannabinoids derived from
Cannabis sativa (delta 9-THC)
– Endogenous cannabinoids
– Synthetics
Designer Drugs
Synthetic Cannabinoids

Synthesized 1960s at
Hebrew University (HU)
– HU-210


Pfizer 1970s;
Cyclohexylphenol series
J W Huffman (JWH) 80s
– JWH-018, JWH-073,
JWH-200
Designer Drugs
Cannabinoids
Signs & Symptoms






Tachycardia
Hypertension
Hyperthermia
Anxiety
Seizures
Paranoia &
hallucinations
Designer Drugs
European
Experience



Within weeks of
regulatory control
Non-prohibited
cannabinoids
found in products
Structures
heterogeneous
– No THC rxn
Designer Drugs
Synthetic Cannabinoids
2010
JWH – 250
13%
JWH – 73
11%
U.S. DEA, Office of Diversion Control
U.S. DEA Activity


March, 2011
Temporary Schedule I
– unsafe, highly abused, no medical usage

Five synthetic cannabinoids
– JWH-018, JWH-073, JWH-200
– CP-47,497 & Cannabicyclohexanol
– HU-210 all ready Schedule I
Designer Drugs
Synthetic Cannabinoids
2011
JWH – 250
12%
AM-2201
29%
JWH – 210
9%
JWH-122
12%
JWH-18
14%
U.S. DEA, Office of Diversion Control
Synthetic Drug Abuse
Prevention Act of 2012


Signed into law July 9, 2012
Adds certain classes of synthetic
cannabinoids & two substituted
cathinones—mephedrone and MDPV—
to the federal controlled substances
act.
Designer Drugs
Designer Drugs
Stimulant Agents






Cocaine
Amphetamines
Decongestants
Beta Stimulators
Withdrawal States
Cannabinoids
– JWH-018, JWH-073, JWH-200
– CP-47,497, Cannabicyclohexanol
– HU-210
Designer Drugs
Stimulant Agents
Mechanisms of Action - ?
Designer Drugs
Stimulant Agents
Mechanisms of Action
Stimulant Agents
Mechanisms of Action

Central inhibition of catecholamine
reuptake
– Epinephrine, norepinephrine


Peripheral stimulation of alpha & beta
receptors
Additional effects (nuances)
– Na channel / local anesthetic (cocaine)
– Serotonin reuptake inhibition (MDMA)
Designer Drugs
Designer Drugs
Stimulant Toxicity
Clinical Management - ?
Designer Drugs
Stimulant Toxicity
Clinical Management

Central inhibition of catecholamine reuptake
– Benzodiazepines (GABA receptor agonists)
 0.1-0.2 mg/kg Diazepam IV (5-10 mg)
 0.05 mg/kg Lorazepam or Midazolam IV or IM
(2-5 mg)
 Repeat every 5-10 minutes for seizures, every
10 minutes until calm
– Neuroleptics (monitor the QT interval)
 2-5 mg IM or slow IV Haloperidol or Droperidol
Designer Drugs
Stimulant Toxicity
Management

Peripheral stimulation of
alpha & beta receptors
– Benzodiazepines
(cardiac receptors)
– Vasodilators;
phentolamine,
nitroprusside
– Cardiac monitoring

Additional effects
– Benzodiazepines
– Hydration, Cooling,
Neuromuscular paralysis
Designer Drugs
Spice Case


A 20 year-old female “crazy”
Tachycardic, hypertensive,
warm, & wet
– (P 140, BP 185/110)


Diazepam 5 mg IV X 2
Temp 104.4o
– Urine reddish brown
– IV ½ NS with 2 amps NaHCO3
Designer Drugs
Spice Case



CT head negative
Urine Tox negative
Admitted ICU
– Continuous EEG
monitoring

Awakens next morning
–
–
–
–
Admits binge of “Spice”
Peak CPK 14,000
No renal failure
Discharged home intact
day #3
Designer Drugs
Smoking ‘Bath Salts’

26 y.o. male –
agitated & confused

3 day binge
– Smoking ‘Bolivian
Bath Salts’

Roomate found
him face-down on
floor
Designer Drugs
26 Year Old Male
Agitated & Confused

Management?
Designer Drugs
Initial Management



Airway
Breathing
Circulation



WA Poison Center
1-800-222-1222
1-800-709-0911
– 80% of poisonings

Disability/Decontamination
– 90% of poisonings

Exposure/Elimination
– Antidotes
– 100% of poisonings
Designer Drugs
26 Year Old Male
Agitated & Confused






Agitated, responding to loud verbal
A – Open with intact gag reflex
B - RR 28 / minute, clear lungs
C - Tachycardic (Sinus - 130’s)
Hypertensive (160/100)
D - No Seizure, Glucose 120
Decontamination?
E – Elimination?
Designer Drugs
‘Bath Salts’ Case





Agitated, responds to loud verbal stimuli
No trauma
Pupils 6 mm
P 130 BP 160/100
Diaphoretic & Hot
Designer Drugs
Physical Examination
Stimulant Syndrome







Vital Signs
Mental Status
Pupils
Mucus membranes
Respiratory
Gastrointestinal
Skin







T, P, R, BP
Seizures
Dilated & reactive
Moist
Rate, depth
Motility
Pink, warm, moist
Designer Drugs
“Bath Salts”


“White Ice, Ocean Snow,
Lunar Wave, Purple Wave,
Ivory Wave, Ivory Soft,
Vanilla Sky, Bliss”
$20 packets from
convenience stores, truck
stops & via Internet
Designer Drugs
“Bath Salts” - Compounds


Very similar to amphetamines
Side effects largely the same we see
with amphetamines in large dose
– Jeffrey Baldwin, University of Nebraska
Medical Center


Typically snorted, smoked, injected
Can be mixed with water as a beverage
Designer Drugs
Snorting &
Smoking Bath Salts
Designer Drugs
“Bath Salts” - Contents


Mephedrone
MDPV (3,4-methylenedioxypyrovalerone)
Designer Drugs
Mephedrone - Europe




Cathinone derivative
Marketed as ‘plant feeder’
‘not for human consumption’
Potentially addictive &
Increasingly popular legal
substitute for cocaine &
ecstasy
Designer Drugs
MDPV – 3,4 methylendioxypyrovalerone

Epinephrine
& Norepinephrine
re-uptake
inhibitor
Designer Drugs
MDPV – 3,4 methylendioxypyrovalerone



Epinephrine & Norepinephrine re-uptake
inhibitor
Beta ketone ‘research chemical’
Intake (Dose 5-15 mg);
– Oral (capsule, ‘bombing,’ beverage)
– Rectal, Insufflation, Smoking, IV
– Onset 1 hr, Peak 1.5 hr, Duration 3-12 hrs
Designer Drugs
MDPV Toxicity -?
Designer Drugs
“Bath Salts” Toxicity





35 patients, Michigan ED’s
Agitation - 23 patients (66%)
Tachycardia - 22 (63%)
Delusions/hallucinations - 14 (40%)
17 patients hospitalized, 1 DOA
– MDPV Identified

MMWR / May 20, 2011 / Vol. 60 / No. 19
Designer Drugs
‘Bath Salts’ Case





Agitated for 18 hours
at hospital
Tachycardia resolves
with IV benzos & fluids
Temp 104.1
Urine (+) benzos only
CK Peak 6500
Designer Drugs
Cannabinoids &
Bath Salts 2010 - 2011
Olives TD, et al. Bath salts: the ivory wave of trouble.
West J Emerg Med. 2012 Feb;13(1):58-62.
Designer Drugs
“Bath Salts” - Banned

DEA Temporary Schedule I (Oct 2011)
– Up to 12 months for permanent

Louisiana, Florida, North Dakota, WA
– New York, Kentucky, Mississippi - Pending

PC calls fell with Louisiana ban
– Now ordering by Internet
– Shipping to Mississippi

Executive Health February 04, 2011
Designer Drugs
Stimulant Agents







Cocaine
Amphetamines
Decongestants
Beta Stimulators
Withdrawal States
Cannabinoids
‘Bath Salts’
– Mephedrone
– MDPV
Designer Drugs
New “Rave” (2 C agents)

Minneapolis, MN 17 March 2011
– Eleven hospitalized (16-21 y.o.)
– 2 critical, 1 dead

Konawa, OK 7 May 2011
– Seven hospitalized (19-20 y.o.)
– 2 critical, 1 dead

2,5-dimethoxy-4-ethyl-phenethylamine
Designer Drugs
2, 5, I-NBOMe Deaths
Erowid.org (Extracts)

March 2012 – Adult male South
Australia
– 2C-I-NBOMe & 2C-B-NBOMe (MVC)

June 2012 – 17 & 18 yo males MN
– Mixed 25i with chocolate candy

July 2012 - 25 yo female, NC
– 25i pills, died >12 hours after ingestion
Designer Drugs 2011
2 Ci Blotter Paper
Designer Drugs
Designer Drugs
2 C-I
Designer Drugs
Phenethylamines
Chemical Name
Street Name
3,4,5-trimethoxyMescaline
phenethylamine
2C-E 2,5-dimethoxy-4-ethylEuropa
phenethylamine
2C-B 2,5-dimethoxy-4-bromo- Bees, Bromo, Bromo mescaline,
phenethylamine
Nexus, Spectrum, Toonies, Venus
2C-I 2,5-dimethoxy-4-iodoN-Bomb
phenethylamine
2C-T7 2,5-dimethoxy-4Blue Mystic, Vanilla Aroma
propylthio-phenethylamine
Designer Drugs
Phenethylamines

Agonist/antagonist 5-HT receptor
– Hallucinations
– Over-stimulation & agitation
(amphetamines)

Multiple forms
– Tablets, capsules, powder for insufflation

Kinetics
– Onset 20 min, peak 2 hrs, duration 6-12 hrs
Designer Drugs
Designer Drugs
Phenethylamines
Clinical Effects
– Hallucinations, agitation, seizures
– Hyperthermia, tachycardia, hypertension,
tachypnea
– Extreme/rapid cycling emotions
– Mydriasis, flushing, diaphoresis
– Nausea, vomiting,
– Facial dystonia (teeth grinding, grimacing)
– Rhabdomyolysis
Designer Drugs
Phenethylamines (cont)
– Insufflation - immediate pain nasal mucosa
– Law enforcement officers
Phenethylamine laboratories
 Mucous membrane & respiratory symptoms

Designer Drugs
Phenethylamines

Legal control
– 2C-B & 2C-T7 – Schedule I
– 2C-E & 2C-I - not scheduled


controlled substance analogs
“Bad trips” ?alleviated by SSRIs?
– Not studied nor recommended
Designer Drugs
Stimulant Agents








Cocaine
Amphetamines
Decongestants
Beta Stimulators
Withdrawal States
Cannabinoids
‘Bath Salts’
Phenethylamines
– 2 CE & 2 CI
Designer Drugs
Stimulant Agents
Mechanisms of Action

Central inhibition of catecholamine
reuptake
– Epinephrine, norepinephrine


Peripheral stimulation of alpha & beta
receptors
Additional effects (nuances)
– Na channel / local anesthetic (cocaine)
– Serotonin reuptake inhibition (MDMA)
Designer Drugs
Poisoning Management


ABCDE – Poison Center (1-800-222-1222)
Safety Net
– IV, Monitors (ECG & O2)

Focused History
– What, when, why, what has been done?
– What else is available?

Focused Physical Examination
– Toxicologic Syndrome?

Laboratory Studies?
Designer Drugs

Bath Salts and Stimulants Designer Drugs Expanded, Urine Test (8756U)
– Methamphetamine, Amphetamine, O-Desmethyltramadol
– MDMA, MDEA, MDA, DOM
– Mephedrone, MDPV, Pyrovalerone,, Ethylone, Flephedrone, Buphedrone,
Methedrone, Methylone, Cathinone, Methcathinone
– 2C-B 2C-C 2C-E 2C-H 2C-I 2C-N 2C-P 2C-T-2 2C-T-7

Synthetic Cannabinoid Metabolites Screen Expanded, Urine (Forensic) Test (9562U)
– AM-2201, JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH-210,
JWH-250, & RCS-4 metabolites
Tox Update 2012
Stimulant Toxicity - Key Points

Central & Peripheral catecholamine surge
– Characteristic clinical toxicological syndrome

Specific agents
– Cocaine, amphetamines, decongestants,
cannabinoids, Mephedrone, MDPV, phenethylamines
– Often unavailable for decontamination & detection
– Treat the patient, not the agent

Importance - reduce severity of poisoning
(avoid complications)
– Benzodiazepines & Hyperthermia prevention
Designer Drugs
“Spice” References
– Gunderson EW, et al. "Spice" and "K2" herbal highs: a
case series and systematic review of the clinical effects
and biopsychosocial implications of synthetic cannabinoid
use in humans. Am J Addict. 2012 Jul-Aug;21(4):320-6.
– Simmons JR, et al. Intoxication from smoking "spice”.
Ann Emerg Med. 2011 Feb;57(2):187-8.
– Vardakou I, et al. Spice drugs as a new trend: mode of
action, identification & legislation. Toxicol Lett 2010 Sep
1;197(3):157-62.
– Schneir AB, et al. "Spice" Girls: Synthetic Cannabinoid
Intoxication. J Emerg Med 2010 Dec 15.
Designer Drugs
“Bath Salts” - References
o Borek HA, et al. Hyperthermia and multiorgan failure after abuse of
"bath salts" containing 3,4-methylenedioxypyrovalerone. Ann
Emerg Med. 2012 Jul;60(1):103-5.
o Prosser JM, Nelson LS. The toxicology of bath salts: a review of
synthetic cathinones. J Med Toxicol. 2012 Mar;8(1):33-42.
o Murray BL, et al. Death following recreational use of designer drug
"bath salts" containing 3,4-Methylenedioxypyrovalerone (MDPV). J
Med Toxicol. 2012 Mar;8(1):69-75.
o Kasick DP, et al. "Bath salt" ingestion leading to severe intoxication
delirium: two cases and a brief review of the emergence of
mephedrone use. Am J Drug Alc Abuse. 2012 Mar;38(2):176-80.
o Emergency department visits after use of a drug sold as "bath
salts"--Michigan, November 13, 2010-March 31, 2011. MMWR 2011
May 20;60(19):624-7.
o Psychonaut WebMapping Research Group, Mephedrone Report,
Institute of Psychiatry, King's College London, London, UK (2009).
Designer Drugs
Update in Toxicology 2013

Goal
– Increase knowledge in management of
the poisoned patient

Objectives
– Describe manifestations & management
of the stimulant syndrome
– List new designer drugs, their
mechanisms, & their sources
Designer Drugs
Update in Toxicology 2013




K2, Spice, Bath Salts, &
the New Designer Drugs
William Hurley, MD FACEP
Harborview Medical Center
Washington Poison Center
– hurleyw@uw.edu
– hurley@wapc.org
– (800) 222-1222
– (800) 709-0911