J Laes Medical Toxicology

1. JoAn Laes, MD
Medical Toxicology Fellow
HealthPartners Institute for Graduate Medical Education
September 2013
Current Drugs of Abuse

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

3. › 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 Fellowship
HealthPartners Institute for Graduate Medical
Education

4. › 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

5. › 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

10. › Dopamine and Norepinephrine: Sympathomimetic effects
› Serotonin: Hallucinogenic effects
› There is overlap between the neurotransmitter effects and
many drugs affect several neurotransmitters
Neurotransmission

12. Sympathomimetic Effects

13. Hallucinogenic Effects

15. Synthetic Cannabinoid

16. › 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

17. › Functionally (NOT structurally) similar to tetrahydrocannabinol (THC)
Synthetic Cannabinoid

18. › Other effects
– Tachycardia
– Postural
hypotension
Clinical Effects: Cannabinoids

19. › Faster onset, quicker elimination
› Additional mechanism of action
– Serotoninergic effects
› Nausea/vomiting
› Hypertension
› Tachycardia
› Seizures
Synthetic Cannabinoids Effects

20. › Hennepin Regional
Poison Center
– 9/1/2012 – 9/1/2013
› Received calls about 90
exposures to THC
homologues
Minnesota Trends

21. › 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?

22. › 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
Legal
i. 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

24. Phenethylamines

25. › Backbone molecular structure
Phenethylamines

26. › Amphetamine, methamphetamine, 3,4-methylenedioxy-
methamphetamine (MDMA), mescaline
“Original” Phenethylamines

27. › Substitutions on backbone structure
– Structural variation alters spectrum of activity, potency and effects
› “Hallucinogenic” versus “Stimulant” properties
“New” Phenethylamines
2C-I
25I-NBOMe

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

29. – 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

30. › 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

31. 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

33. › 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

34. › “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

35. Ecstasydata.org

36. › 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

38. › “Failed” pharmaceuticals
– Potential antidepressant
› Similar effect as amphetamines and MDMA
– Dopamine, norepinephrine, serotonin
– Frequently sold as ecstasy
Piperazines

40. › 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)

41. › Methoxetamine
– First reported 2011
– Very similar effects as ketamine
Ketamine Derivatives
0
2
10
2011 2012 2013
Hennepin regional Poison Center
Methoxetamine Exposures
Methoxetamine

42. › 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

44. Ketamine and PCP Effects
› Affects Several neurotransmitters
– NMDA, Opioid, Norepinephrine, Serotonin
› Clinical Effects
– Dissociative
– Alteration of pain perception
– Potential stimulation of the cardiovascular system

46. Tryptamines

47. Synthetic Tryptamines

48. › Euphoria
› Time distortion
› Hallucination, Religious experience
› Gi: nausea and vomiting
› Neuro: Seizures
– Risk of serotonin syndrome
Tryptamine Clinical Effects

49. › 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, hallucin
ations
› Emergency Department
– Hr 95, BP 120/70, T 98.6
– Mental status: mildly altered

50. › Management of a patient you suspect has had a toxic
ingestion
Now…

51. › 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

52. › 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

53. › 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

54. › 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

55. Cardiovascular Toxicology Principles

56. › QTc>500 ms is associated with a 2- to 3-fold higher risk for TdP
Prolonged QT interval

57. Torsades des Pointes

58. › 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

59. › Increased Adrenergic tone
– Sympathomimetics
› Myocardial Sensitization
– Halogenated hydrocarbons
› Dust-off
› Altered repolarization/conduction abnormalities
– Sodium channel blockade
› Tricyclic antidepressants
› Cocaine
› Diphenhydramine
› Antidysrhythmics
Ventricular Tachyarrhythmias

61. › 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

62. › 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

63. › 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

64. › 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

65. › 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

66. › and Questions?
Thank You