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Current drugs of abuse
 

Current drugs of abuse

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J Laes

J Laes
Medical Toxicology

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  • Officially recognized as a medical subspecialty by the American Board of Medical Specialties
  • Unknown ingredients: buyer beware, mislabeling (intentional and unintentional), incorrect synthesisNo consistency in manufacturing: home chem labs, potencies and purity not regulated
  • Monitoring the future: Included bath salts only in 2012. The annual prevalence rates were 0.8%, 0.6%, and 1.3% for grades 8, 10, and 12, respectively
  • -EU Early warning system receives reports of one new substance a week in 2013. -Recent years dominated by synthetic cannabinoid receptor agonists (CRAs), phenethylamines and cathinones (though cathinone less in 2012)-Poison center data:Search for hallucinogenic amphetamines 5/1/13-9/19/1333 cases: 12 Molly, 8 ecstasy, 5 25-IAges 15-30: 29casesHallucinogenic tryptamines 9/12-9/20134 exposures. Foxy methoxy, dmt, 4-aco-dmt x2,
  • -recent development is increasing proportion of substances reported that are from less known and more obscure chemical groups. (more variations on phenethylamines or synthetic cannabinoids, by just changing a functional group on the structure)
  • -Many products contain a mixtures of substances.
  • Most synthetic drugs have their effect through these 3 neurotransmitters. Dopamine: reward, pleasure, addictionNorepinephrine: attention, memory, Both sympathomimetic: alpha and beta receptors (hypertension through vasoconstriction and alpha receptors, tachycardia through beta receptors, increased metabolism through beta receptors
  • Serotonin: obsession/compulsion, hallucination,Effects: blood vessels, autonomic systems (hyperthermia, tachycardia, cardiovascular, ) , smooth muscles (especially in gi tract), cns, and plateletsThe triad of serotenergic excess is autonomic dysfunction, neuromuscular dysfunction (clonus, hyperreflexia, ocular clonus), and altered mental status
  • www.unodc.org/drugs
  • Sold as herbal incense, potpourri
  • CannabinoidsClass of structurally related chemical compounds in the marijuana plantTetrahydrocannabinol-synthetic cannabinoids: sold in retail stores, on the internet, in head shops called “herbal incense” or “potpourri”--unregulated, batch to batch variance-History: HU210: Regarded as “classic cannabinoid”-non classical cannabinoids: cyclohexylphenols /3 arylcyclohexophenols , “JWH”. JWH-018 best known. Includes aminoakylindoles, naphtoindoles, phenylacetylindoles
  • Most reported symptom: RELAXATIONEffect the cannabinoid receptors CB1 and CB2-cannabinoid receptors: regulate movement, coordination, learning and memory, and higher cognitive functions such as judgement and pleasurecb2 receptors regulate immune function
  • Minnesota HPRC: increase in July and August (likely due to the pilot study with Duluth)
  • The data from the American Association of Poison Control Centers may not reflect actual epidemiology of useIncreased measures to prevent distribution
  • www.unodc.org/drugs
  • Phenyl ring joins to an amine group using an ethyl chain
  • It occurs naturally in the peyote cactus (Lophophorawilliamsii),[1] the San Pedro cactus (Echinopsispachanoi) and in the Peruvian torch (Echinopsisperuviana), and as well in a number of other members of the Cactaceae plant family.
  • -substitution of iodine or bromine at position 4 results in increased hallucinogenic effects, as does changing the carbon branch chain attached to the amine group-Bromo dragon fly: Steric rings increase potency and inhibit Metabolism-Report from the US 35 patients to ed during 3 month period after ingesting bath salts thought to contain MDPV or mephedrone
  • Routes: pills, FLY compounds powder, oral doses for the “D” substances. Ingestion most common route.“d “ series: longer lasting and more potent, more liable for vasoconstriction. Adverse effects of d series: agitation, tachycardia, mydriasis, hallucination, limb ischemia, seizures, liver and renal failure.PMMA thought to have very high toxicity
  • -Difficult to tell the syndromes apart-agitation most commonly reported, but also cardiac, psychiatric and neurologic
  • One outlier that had a seizure, had documented tachycardia of 200? Another ranged up to 150Hypertension not really commented on in the exposures
  • He was afebrileDeveloped renal failure without rhabdomyolysis, which resolved
  • 25I-NBOMe and 25C-NBOMe: Class: N-benzyl phenethylamines – hallucinogenic phenethylaminesPotent 5-HT2A receptor agonist. Related to the 2c series (which is scheduled, but Nbom isn’t)Blotter paper, dropper bottlesPossibly mistaken for lsdLinked to recent deaths (N-MOMB, smiles)Nicknames: 25I, INB-MeO, Solaris, Smiles, N-Bomb, Cimbi-5Fun history:First Synthesized in early 1990’s Developed as a 5-HT2A tag for PET scans in brain research
  • crystalline powder that is snorted.
  • Difficult to identify exactly what they are taking, have to go off general clinical syndromes
  • I’m trippin balls!
  • www.unodc.org/drugs
  • Similar effects as amphetamines1-benzylpiperazine (1-BZP):like amphetamine)MCPP (like mdma), TFMPP, MZBP, PFPP (-tmfpp used in conjunction with 1-bzp)Widespread use in Europe through 2004. controls implemented in 2008. -mcpp may be widespread used in manufacturing of trazodone and nefazodone-generic names: pep pills, social tonics, . Street names: jax, a2, legal x, -pills, capsules, loose powders, mainly consumed by ingestion
  • www.unodc.org/drugs
  • Meo derivatives appeared in Europe 2010 as “research chemicals”
  • Ketamine: Street names: special k, , kit kat, vitamin k. NMDA antagonist. Some binding to opiate receptors.-pharmaceutical preps usually liquid and the powder is evaporated off and insufflated, powder and capsules also available-Adverse effects: stimulates the cardiovascular systemMethoxetamine: ketamine derivative, similar to pcp effects lasy 7 hoursDMAA:Cathinone replacement (other name 1,3-dimethylamlamine)
  • 4/2013:Annemerg medicine: reports 3 cases of cerebral hemorrhage after use of DMAADec 2012 military medicine: collapse from cardiac arrest and death
  • FDA 2012DMAA illegalissued warning letters to companies to take off the market or reformulateMost companies warned are no longer distributing products with DMAA.
  • http://www.youtube.com/watch?v=txqiwrbYGrs&noredirect=1
  • www.unodc.org/drugs
  • Pharmacology:Selective agonist of 5-HT2A-potentiation of tryptophan NeuromodulationAmine alkaloidNeurotansmitters found in plants, fungi and animalsNatural: serotonin, melatonin, bufotenin, 5-MeO-DMT, Dimethyltrypatmine (DMT)PsilocybinUse limited but has been increasing over past 5 years
  • Names: foxy methoxyCapsule , tablet, powder, or liquid form. Swallowed, sniffed, smoked or injectedEffect: restless, agitation, gi distress, muscle tension
  • Related to serotoninExpand on tryptamine clinical effects
  • 2x: 4ACODMT
  • Mixed Sympathomimetic and serotonin effectsOtherhyponatremia
  • Sympathetic activation: includes hypertension, tachycardia, agitationExcited delirium covered previouslyAfter benzodiazepines: barbiturate, propofolData on antipsychotics: review, also qtc prolongation though phenethylamines not known for this
  • Other reason for no neuroleptics:Some excited delirium deaths havebeen thought to be due to ventricular dysythmias and sudden cardiac death related to QT prolongation. However,most excited delirium deaths that occur while on a monitor have shown asystolic or ventricular escape rhythmsand have not been secondary to prolonged QT syndromedegenerating to ventricular tachycardia or ventricular fibrillation
  • Cardiomyopathy, myocardial infarction
  • Administer when qtc interval >500msecOverdrive pacingIsoprotenerol mechanism
  • Torsade riskTorsade is a rare condition! prevalenceProlonged qt interval-no threshold of QTc prolongation at which TdP is certain to occur-QTc>500 ms is associated with a 2- to 3-fold higher risk for TdP-drug-induced LQTS, the QT interval may be prolonged during normal sinus rhythm without adverse effect, but after a pause (eg, after an ectopic beat or during transient atrioventricular block)-Not all QT-prolonging drugs are associated with risk for TdP. Therefore, it appears that QT prolongation alone is insufficient and that heterogeneity of repolarization may also be necessary to produce an arrhythmogenic response. Electrolyte :Hypokalemia, hypomagnesemia, hypocalcemiaAge and abnormal heart
  • Isoprotenerol mechanismSecond line prolonged qtcmanagement:Second LineIsoprotenerolOverdrive pacing
  • Drug induced vt and vf should be cardiovertedDrug induced shock: ivf, norepinephrineVentriculartachydysrhythmias: excessive circulating catecholaminesDust off: fluorinated hydrocarbons. Toluene (glue, spray paint)
  • Widening into sine waveOrDevelopment of reentrant circuit from slowness and ventricular tachycardia develop
  • Note normal qrs is 120msec. Continue to watch rhythm strip to see if QRS narrowsGenerally effect in 5 minutesIf widens again continue to administer amps of bicarbonate
  • Recent evidence suggests that a dose of 13 µg/kg naloxone (approximately 1 mg in an 80 kg person) produces 50% receptor occupancy, however, this is also influenced by the dose of opioid ingested or injected. -unclear if naloxone causes pulmonary edema-.4mg in opiate dependent patient likely to produce withdrawalHowever
  • Mycyk and route:Nebulized naloxone is a safe and effective needleless alternative for prehospital treatment of suspected opioid overdose in patients with spontaneous respirations.

Current drugs of abuse Current drugs of abuse Presentation Transcript

  • JoAn Laes, MD Medical Toxicology Fellow HealthPartners Institute for Graduate Medical Education September 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 Fellowship HealthPartners 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
  • Hallucinogenic Effects
  • 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
  • › 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 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
  • Phenethylamines
  • › 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
  • – 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 Piperazines
  • › 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 0 2 10 2011 2012 2013 Hennepin regional Poison Center Methoxetamine 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, hallucin ations › 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
  • › 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