JoAn Laes, MDMedical Toxicology FellowHealthPartners Institute for Graduate Medical EducationSeptember 2013

Current Drugs of Abuse

› Diagnosis, management and prevention of poisoning and other adverse health effects due to medications, occupational and environmental toxins, and biological agents

Medical Toxicology

› Division of Emergency Medicine at Regions Hospital

› The Regions Toxicology Service is actively engaged in patient consultations throughout the Twin Cities as well as education and research– Bedside consultation at Regions Hospital– Medical direction at Hennepin Regional Poison Center

Medical Toxicology FellowshipHealthPartners Institute for Graduate Medical Education

› Current Drugs of Abuse and Epidemiology– Focus on emerging synthetic drugs

› Pharmacology and clinical effects

› Pre-Hospital Management of Drug Overdose– Synthetic drug abuse diagnosis and management– EKG in toxicology– Naloxone administration

Outline

› Recent dramatic increase in unregulated synthetic psychoactive substances– Wide availability due to

› Loopholes in legality› Easy to obtain from headshops or internet› Promoted by discussion boards/self study on internet

› Many can cause life threating health effects– Unknown ingredients– No consistency in manufacturing

Synthetic Drugs

› Dopamine and Norepinephrine: Sympathomimetic effects

› Serotonin: Hallucinogenic effects

› There is overlap between the neurotransmitter effects and many drugs affect several neurotransmitters

Neurotransmission

Sympathomimetic Effects

Dopamine

Norepinephrine

Hallucinogenic Effects

Serotonin

5-HT2a

Synthetic Cannabinoid

› Synthetic Cannabinoids– synthesized chemicals placed on dried plant material and smoked– HU210 first synthesized in 1988

› potency more than 100x THC– ‘CP’ compounds

› Developed as potential analgesic in 1980 by a pharmaceutical company– ‘JWH’ compounds

› Developed for research› JWH-018

Synthetic Cannabinoids

› Functionally (NOT structurally) similar to tetrahydrocannabinol (THC)

Synthetic Cannabinoid

› Other effects– Tachycardia– Postural

hypotension

Clinical Effects: Cannabinoids#1 reported effect: relaxation

› Faster onset, quicker elimination

› Additional mechanism of action– Serotoninergic effects

› Nausea/vomiting› Hypertension› Tachycardia› Seizures

Synthetic Cannabinoids Effects

› Hennepin Regional Poison Center– 9/1/2012 – 9/1/2013

› Received calls about 90 exposures to THC homologues

Minnesota Trends

› Consumers becoming more experienced with use

› Clinicians becoming more experienced with effects of synthetic drugs

› Legislation has decreased availability and use

Why the decline in calls?

› Federal DEA Scheduled– AKB48 (APINACA) and 5F-

AKB48 (5F-APINACA)– CP 47,497 and

homologues– HU-210– JWH-018– JWH-073– UR-144 and XLR11

Legali. Naphthoylindoles, 1-Pentyl-3-(1-naphthoyl)indole (JWH-018 and AM-678); 1-Butul-3-(1-naphthoyl)indole (JWH-073);1-Pentyl-3-(4-methoxy-1-naphthoyl)indole (JWH-081); 1-[2-(4-morpholinyl)ethyl]-3-(1-naphthoyl)indole (JWH-200)(ii) Napthylmethylindoles, 1-Pentyl-1H-indol-3-yl-(1-naphthyl)methane (JWH-175);1-Pentyl-1H-indol-3-yl-(4-methyl-1-naphthyl)methan (JWH-184).(iii) Naphthoylpyrroles, (5-(2-fluorophenyl)-1-pentylpyrrol-3-yl)-naphthalen-1-ylmethanone (JWH-307).(iv) Naphthylmethylindenes, E-1-[1-(1-naphthalenylmethylene)-1H-inden-3-yl]pentane (JWH-176).(v) Phenylacetylindoles, :1-(2-cyclohexylethyl)-3-(2-methoxyphenylacetyl)indole (RCS-8); 1-pentyl-3-(2-methoxyphenylacetyl)indole (JWH-250);1-pentyl-3-(2-methylphenylacetyl)indole (JWH-251); 1-pentyl-3-(2-chlorophenylacetyl)indole (JWH-203).(vi) Cyclohexylphenols, 5-(1,1-dimethylheptyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol (CP 47,497); 5-(1,1-dimethyloctyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol (Cannabicyclohexanol or CP 47,497 C8 homologue)(vii) Benzoylindoles,. 1-Pentyl-3-(4-methoxybenzoyl)indole (RCS-4); 1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole (AM-694); (4-methoxyphenyl-[2-methyl-1-(2-(4-morpholinyl)ethyl)indol-3-yl]methanone (WIN 48,098 or Pravadoline).(viii) Others specifically named: (6aR,10aR)-9-(hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl) -6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol (HU-210);(6aS,10aS)-9-(hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl) -6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol (Dexanabinol or HU-211); 2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de] -1,4-benzoxazin-6-yl-1-naphthalenylmethanone (WIN 55,212-2).

Minnesota Statute

Phenethylamines

Molly

25-N-BOMe

Bromo-Dragon-Fly

2C-E and 2C-I

Bath SaltsMephedrone

MDPVMethylone

25-I

MDMA

› Backbone molecular structure Phenethylamines

› Amphetamine, methamphetamine, 3,4-methylenedioxy-methamphetamine (MDMA), mescaline

“Original” Phenethylamines

› Substitutions on backbone structure– Structural variation alters spectrum of activity, potency and effects

› “Hallucinogenic” versus “Stimulant” properties

“New” Phenethylamines

2C-I

25I-NBOMe

› Neurotransmitters– 5-HT (Serotonin) receptor agonists – Norepinephrine and dopamine

Phenethylamines

Mixed Sympathomimetic and Serotenergic Effects

– Cardiovascular› tachycardia, hypertension,

palpitations, chest pain– Autonomic

› Diaphoresis, hyperthermia, hyper-reflexia, clonus

– Psychiatric› aggression , agitation, anxiety,

Phenethylamines Clinical Presentation

– Neurological › psychosis, hallucinations ,

seizures– Muscular

› tremors, muscle hyperactivity, hyperthermia, Gastrointestinal

– Gastrointestinal› Abdominal pain, nausea and

vomiting, diarrhea

› Review of 17 calls regarding exposures to “Hallucinogenic Amphetamines”– Tachycardia : 80%

› ~110-130bpm– Hallucinations: 50%– Seizure: 25%– Elevated CK: 25%

› 300-900– Benzodiazepines given : 60%

› Lorazepam 2mg– Mydriasis: 25%– Hyperthermia: 10%

› 101-103F

Hennepin Regional Poison Center

Hennepin Regional Poison center

20 teenagers from a Minnesota suburb were on a “Party Bus” and were partying with 25-I• One teenager seemed to have taken more than his party-mates• Had two seizures and EMS was called• Intubated and sedated and admitted to intensive care unit

• 5/1/13-9/19/13• 5 calls about exposure to

25-I

› Male patient being seen in southern Minnesota, reportedly ingested LSD 2 hours prior to call to poison center– The hit was on a piece of Paper he dissolved

under his tongue

› Symptoms– agitation, dilated pupils, hr 110

› Treatment– agitation improved with 2mg lorazepam

› Follow up– Patient reports the drug was 25-NBOMe

25I-NBOMe

› “purer” form of MDMA– May contain other synthetic stimulants

› 2013:Hennepin Regional Poison Center 11 calls about Molly– Poison Center also is seeing a resurgence in Ecstasy

› 2013 more than double the calls than in 2012

Ecstasydata.org

› Two teenagers partying on the beach– Reported drinking liquid “Molly” – Family member called EMS after noting one

of the teenagers to be hallucinating, shaking, and flushed

– EMS › Shaking, rigidity, pupils 8mm and sluggish› Muttering nonsensically and agitated

– Hospital› 16 mg lorazepam

– Became more altered but still tremulous and rigid› Intubated

– Temp increased to 106.4, HR 200› Benzodiazepine drip and external cooling

initiated› Extubated hospital day 2

– No permanent sequelae

Tales from St.Paul

› “Failed” pharmaceuticals– Potential antidepressant

› Similar effect as amphetamines and MDMA– Dopamine, norepinephrine, serotonin– Frequently sold as ecstasy

PiperazinesClinically similar to phenethylamines

› Phencyclidine derivatives– 3-methoxyeticyclidine (3-MeO-PCE)– 4-MeO-PCP

› Europe 2011– Minnesota Regional Poison Center

› PCP– 9/2011-9/2013

› 62 exposures

Phencyclidine (PCP) and ketamine derivatives(Arylcyclohexylamines)

› Methoxetamine– First reported 2011– Very similar effects as ketamine

Ketamine Derivatives

2011 2012 20130

2

10

Hennepin regional Poison CenterMethoxetamine Exposures

Methoxetamine

› 1,3-Dimethylamine (DMAA)– Also called: methylhexanamine or geranium extract)– Uses

› Recreational party drug› Dietary supplements

– Jack3d› FDA received 86 adverse event reports thought to be related to DMAA

– Adverse events: depression, anxiety, vomiting, loss of consciousness, chest pain, death

Ketamine and Derivatives

Ketamine and PCP Effects› Affects Several neurotransmitters– NMDA, Opioid, Norepinephrine, Serotonin

› Clinical Effects– Dissociative– Alteration of pain perception– Potential stimulation of the cardiovascular system

Tryptamines

Synthetic Tryptamines

› Euphoria

› Time distortion

› Hallucination, Religious experience

› Gi: nausea and vomiting

› Neuro: Seizures– Risk of serotonin syndrome

Tryptamine Clinical Effects

› 9/2012-9/2013– 4 exposures

› Foxy methoxy› DMT› 4-ACO-DMT

Hennepin Regional Poison Center› Life in Suburbia– 2 teenagers bought 4-ACO-

DMT off internet› Snorted 10 lines› Paranoia, tremulous,

hallucinations› Emergency Department

– Hr 95, BP 120/70, T 98.6– Mental status: mildly altered

› Management of a patient you suspect has had a toxic ingestion

Now…

› Sympathetic/Autonomic – Agitation, increased motor activity, tachycardia, hypertension

› Hyperthermia, rhabdomyolysis, acidosis

› Cardiovascular– Arrhythmia

› Usually sinus tachycardia– Acute coronary syndrome, aortic dissection, intracranial hemorrhage

› Neurological and Psychiatric– Seizures– Psychosis, hallucinations

Medical Complications of Synthetic Drugs

› Benzodiazepines, benzodiazepines, benzodiazepines– Decrease catecholamine excess

› Could consider vasodilators› Phentolamine (alpha-antagonist)› Nitroglycerin

› Avoid artificial modulation of heart rate – Beta blockers– Calcium channel blockers– Anti-arrhythmics

› Lidocaine is potential option however

Treatment: Sympathetic Activation and Cardiovascular

› Benzodiazepines, benzodiazepines, benzodiazepines

› Other agents– Neuroleptics

› Example: holperidol (Haldol), Droperidol, Olanzapine (Zyprexa)– may paradoxically worsen symptoms– No randomized placebo studies comparing benzodiazepines to neuroleptics in

phenethylamine intoxication– Avoid if patient has qt prolongation

– Ketamine› Benefit: rapid onset, lack of respiratory depression› Risks: laryngospasm, stimulatory cardiovascular effects resulting in increased

tachycardia and hypertension

Treatment: Neurologic and Psychiatric Symptoms

› Fluid Resuscitation

› Reduction of Hyperthermia– External cooling- ice packs– Reduction of muscle activity with sedation– Severe: intubate, paralyze, internal cooling– Do not recommend

› Antipyretics – lower the hypothalamic set point– don’t decrease catecholamine excess

Treatment: Hyper-metabolic state

Cardiovascular Toxicology Principles

Common

Take Note

More Concerning

› QTc>500 ms is associated with a 2- to 3-fold higher risk for TdP

Prolonged QT interval

Torsades des Pointes

› If QTc>500ms– Administer 2 grams magnesium sulfate

› stabilizes cardiac membranes› Corrects hypomagnesemia

› If torsades de pointes occurs– Address correctable factors

› Give more magnesium, consider potassium– Do not administer qt prolonging antiarrhythmics

› Example: Amiodarone

Prolonged QTc Management

› Increased Adrenergic tone– Sympathomimetics

› Myocardial Sensitization– Halogenated hydrocarbons

› Dust-off

› Altered repolarization/conduction abnormalities– Sodium channel blockade

› Tricyclic antidepressants› Cocaine› Diphenhydramine› Antidysrhythmics

Ventricular Tachyarrhythmias

› If QRS>100msec– Sodium Bicarbonate 1-2 meq/kg

› ~2-3 amps for average male– Use caution with anti-arrhythmics

› Especially class 1a (procainamide) and 1c (flecainide), beta blockers, amiodarone– Sodium channel blockers: prolong the qrs

› Class 1b may be acceptable– Lidocaine

Management of Prolonged QRS

› Wide variation in recommended dosing– Poisin-dex: .4-2mg– Goldfrank Toxicology: .04mg-> .4mg->2mg->10mg

› Reasons for variability– Amount needed depends on amount of receptors occupied by opioid

› 1mg naloxone occupy 50% receptors› low dose may prolong time to improvement of ventilation

– Precipitation of acute withdrawal in chronic users› .4mg

– Half life of naloxone 60-90 minutes› Re-narcotized if discharged early

› Route– Studies conclude that intramuscular, subcutaneous, intranasal and

nebulized naloxone viable alternatives if no intravenous access but note potential erratic absorption› May affect time to onset and total dose received› Viable alternatives if no intravenous access

Naloxone

› National Survey of Drug Use and Health, 2012 report

› American Association of Poison Control Centers

› United Nations Office on Drugs and Crime

› Emerging Drugs of Abuse Presentation, Katie Adams, MSE (2013)

› New and Emerging Drugs of Abuse, Greg Janis, Med Tox (2012)

Select References

› Dean, Be Vang, et al. "2C or not 2C: phenethylamine designer drug review."Journal of Medical Toxicology (2013): 1-7.

› Seely, Kathryn A., et al. "Spice drugs are more than harmless herbal blends: A review of the pharmacology and toxicology of synthetic cannabinoids." Progress in Neuro-Psychopharmacology and Biological Psychiatry 39.2 (2012): 234-243.

› Stellpflug, Samuel J., et al. "2-(4-Iodo-2, 5-dimethoxyphenyl)-N-[(2-methoxyphenyl) methyl] ethanamine (25I-NBOMe): Clinical Case with Unique Confirmatory Testing." Journal of Medical Toxicology (2013): 1-6.

Selected References

› and Questions?

Thank You