current drugs of abuse
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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
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