Substance abuse Eran Kozer MD Pediatric Emergency Medicine Assaf Harofeh Medical Center erank@asaf.health.gov.il Outline Case presentation Ethanol Marijuana Opioids Cocaine Amphetamines Designer drugs LSD & other hallucinogens PCP and ketamine Outline Case Presentation Pharmacology (brief) Clinical aspects No discussion of treatments At 4 am a 17 year old boy was found by his parents in his bed with generalized tonic clonic seizures. Taken to the ED (still seizing) P 114 bpm, temp 36.6 0 C RR 20/min, BP 103/70 mm Hg, O 2 sat 97%.
History of complex partial seizures starting at 10 years of age Treated with carbamazepine Seizure free for 5 years Off medications for the last 2 years No recent febrile illness or trauma No petechiea or needle pricks Parents were not aware of substance abuse Lab normal glucose and electrolytes Bicarbonate 13 mmol/l, Anion gap 32 mmol/l, osmolal gap - 26mmol/kg Which tests will you order? DO you think the boy s symptoms were caused by substance abuse? A Yes B No C Can't tell Urine tox screen Ethanol serum level Non of the above
Ethanol Rapid absorption from GI tract (<60 min) One standard drink (15g ethanol bottle of beer, glass of wine, 30 ml liquor) raises ethanol serum level by 36mg/dl Enhancement of GABA activity in GABA receptors Blockade of NMDA (N-methyl-D-aspartate) receptors Ethanol level was 50 mg/dl Clinical manifestations low dose Clinical manifestations high dose Selective CNS depressant at low doses Depress areas of highly integrated functions Loss of restrains & disinhibition Paradoxical stimulation Emotional liability Basic personality features are enhanced General CNS Depressant at high dose Irritability Abusive behavior and aggression Confusion, dysarthria, disorientation, lethargy Loss of protective reflexes Coma (blood ethanol >300 mg/dl) Death
So, is it a mixed overdose? Which of the following drugs may cause seizures? Marijuana Marijuana? Yes No Active ingredient THC Immediate effect when smoked Peak effect 10-30 min Duration 1-4h Binding to specific cannabinoid receptors in the cortex Marijuana Clinical effects Marijuana Physiological effects Alteration of sensation, perception, cognition, psychomotor functions Euphoria, relaxation, sensory alterations Loss of motor skills and judgment Acute psychosis (not common) Seizures - rare Increased heart rate Hypotension/ hypertension Tremor, muscle weakness Bronchodilation Conjunctival injection Increased appetite Urinary retention
Marijuana Chronic heavy users Back to the case Effects on the lungs Tolerance Dependence (psychological and physiologic) Withdrawal symptoms (sleep disturbances, irritability, nausea, decreased appetite) Treated with benzodiazepines and phenytoine. Seizures stopped after 1 hour CT Scan ordered 27-year-old man found at home with decreased level of consciousness, aphasia, and spastic quadraparesis Axial CT scan obtained through brain at level of third ventricle shows symmetric white matter hypoattenuation in optic radiations and posterior limbs of internal capsule, simulating dragon's claws. which substance did he use? Cocaine Marijuana LSD Heroin Keogh, C. F. et al. Am. J. Roentgenol. 2003;180:847-850 Copyright 2007 by the American Roentgen Ray Society
Chasing the Dragon Opioids Inhalation of heated heroin Pharmacokinetic similar to IV Spongiform leukoencephalopathy Initial symptoms may occur after 2 weeks Bradykinesia, ataxia, speech abnormalities Spasticity or hypotonia Death in 25% of the cases Extract of poppy plant Available in various formulations administration by all possible routes (parenteral, oral, transdermal, transmucosal, intranasal, rectal, inhalation) Brief History 1874 Heroin synthesized (marked by Bayer as antitussive agent) Written evidence of opium use from 1500 BC 1804 morphine isolated 1830 s Opium Wars between China and England 1874 Heroin synthesized (marked by Bayer as antitussive agent)
Terminology Opiate alkaloid derived directly from poppy opium (morphine codeine) Opioids agents that are capable of producing opium like effect by binding to opioid receptors Clinical effects CVS peripheral vasodilatation Orthostatic hypotension Flushing GI Reduced motility Reduced gastric acid secretion Increased sphincters tone Back to the case CNS Sedation coma Seizures (pethidine) Antitusive Respiratory Respiratory depression Bronchospasm Pulmonary edema Other Miosis Pruritus The CT scan was normal Slowly recovered Occasional myoclonic jerks Denies substance abuse
? Cocaine Leaves of Erythroxylon Coca Documented use from the 6 th century Local anesthetics solutions "...This Intellectual beverage contains the valuable NERVE STIMULANT and TONIC properties of the coca plant... Pharmacology Mucosal absorption respiratory gastrointestinal Genitourinary (vagina, urethra) Onset of action 1-3 min peak 20-30 min Intravenous / Smoking Onset of action - seconds peak 5 min
CNS Effects CNS Effects CNS stimulation cortex first Restlessness, excitement, increased motor activity Mediated at part by inhibition of dopamine reuptake Lower motor centers Seizures TIA Increased risk of stroke Subarachnoid hemorrhage Dystonic reactions Migraine type headaches Leukoencephalopathy Cerebral vasculitis Psychiatric manifestations Other clinical manifestations (partial list) Amphetamines Hyperthermia Myocardial ischemia Dysrhythmias Cardimyopathy (dilated) DVT Methamphetamine (crack, speed) 3,4 Methylenedioxymethamphetamine (MDMA) - Ecstasy Designer Amphetamines Pulmonary effects (asthma exacerbation pneumothorax, hemorrhage etc.)
Khat (gat) Amphetamines Clinical manifestations Cathinone Stimulation of adrenergic receptors in the CNS and peripheral nervous system Similar to cocaine but tend to be longer Amphetamines setting Amphetamines CNS effects Rave parties Speed runs (days up to weeks) Agitation Seizures (less common than cocaine) Intracerebral hemorrhage Headache Euphoria Anorexia Bruxism
Amphetamines CNS effects Amphetamines CNS effects Choreoatheotid movements Compulsive behavior Hyperreflexia Hyperthermia (central) Paranoid psychosis Dopaminergic activity Tend to reoccur May lead to suicide and homicides Amphetamines Other effects Amphetamines Other effects CVS Hypertension, tachycardia, dysrhythmias, MI, aortic dissection, vasospasm Diaphoresis, tachypnea, mydriasis, tremor, nausea. Rhabdomyolysis, muscle rigidity Acute lung injury Ischemic colitis
Amphetamines lab abnormalities Designer drugs Leukocytosis Hyperglycemia Hyponatremia Elevated CK Elevated liver enzymes Myoglobinuria Legal highs Designed by pharmacists to bypass legislation Not included in the Dangerous Drug Ordinance Sold over the internet Street shops Other phenethylamines (2C drugs) Synthetic cannabinoids Synthetic cathinones (bath salts) Piperazines
Phenethylamines (2C drugs) A clinical picture of both stimulatory and hallucinogenic effects Tachycardia, hypertension, euphoria, agitation, psychosis, and hallucinations Other effects seen with serotonergic and sympathomimetic toxicity No data on long term effects Paramethoxymethamphetamine (PMMA), a hallucinogenic synthetic substituted amphetamine Was marketed in Israel because it was not included in the Israeli Controlled Substances Act (CSA).
Clinical effects PMMA and paramethoxyamphetamine (PMA) belong to a group of methoxylated phenethylamine derivatives PMA enhances the release of serotonin, inhibits its reuptake and metabolism Little effect on the dopaminergic system PMA has monoamine oxidase (MAO)-A inhibitory properties. Tachycardia Hypertension Hyperthermia Nystagmus Muscle spasm Bruxism Visual hallucinations Cardiac arrhythmias Respiratory failure Renal failure Seizures Death In fatal cases hyperthermia with a core temperature ranging between 39 and 42.8 C Synthetic cannabinoids Synthetic cathinones (bath salts)
Piperazines Piperazines Initially developed as antihelminthic drugs but later studied as antidepressants Piperazines are some of the most common active substances found in drugs purchased on the Internet. Typical users are young males Most symptoms with piperazine use resemble a sympathomimetic toxidrome Insomnia, anxiety, headaches, nausea, tremors, shakiness, diaphoresis, dizziness, palpitations, shortness of breath, confusion, hallucinations, and paranoia. Since all of the above may cause seizures what is the next step? Toxicology screen: blood Toxicology screen: blood? Toxicology screen: Urine? Volatile alcohols Acetaminophen Salycilates Others
Urine toxic screen Immunoassays: most common but non specific Cannabis metabolites, Cocaine metabolites, Opiate metabolites, Metahdone Amphetamines, Metamphatamines PCP GHB Benzodiazepines, barbiturates TCA Urine toxic screen Drugs that may be missed by toxicology screen HPLC (High Pressure Liquid Chromatography) - more than 700 toxins can be identified GCM LSD Fentanyl Lorazepam Ketamine GHB...
LSD & other Hallucinogens Other hallucinogenic agents Acts on serotonin receptors in the CNS Lysergic acid & derivates Phenylethylamines Anticholinergics belladonna alkaloids MDMA Mushrooms LSD & other Hallucinogens LSD & other Hallucinogens Physiologic effects Mydriasis, tachicardia, hypertension, tachypnea hyperthermia, diaphoresis, (mild) Nausea and vomiting Precede hallucinogenic effects CNS effects Dizziness Hyperactivity Muscle weakness Ataxia Altered mental status Coma Hippus (spasmodic rhythmical pupillary dilation and constriction)
Psychological effects Psychological effects Usually fully awake Emotional liability Loss of body image Alteration in visual perception Excessive attention to details Usual thoughts may look novel and profound Intensification of sensory perceptions (colures are brighter, sound magnification) Synthesis (hearing colures ) Acute psychiatric effects LSD - Long term effects Acute panic reaction (most common) Psychosis Major depression Prolonged psychosis Severe depression Exacerbation of preexisting psychiatric disease
Hallucinogen Persisting Perception Disorder (HPPD) Dissociative agents Flashbacks (usually of former hallucinogenic experience) May be triggered by stress or illness Few month to 5 years No established treatment Initially developed as anesthetic agents PCP (phencyclidine) Ketamine Dissociative agents - pathophysiology Available forms NMDA receptors in the cortex and limbic structures Antagonize (not competitive) glutamate action Monoaminic reuptake inhibition σ (sigma) receptors Ach receptors PCP - powder, liquid, tablets, leaf mixture (for smoking), rock crystals Ketamine powder, tablets, liquid; rarely used IV
Clinical Manifestations Clinical Manifestations - CNS Sympathomimetic effects Hypertension Cerebral hemorrhage (rare) Vomiting (marijuana) Both cholinergic and anticholinergic effects (miosis or mydriasis, bronchospasm, hypersalivation) Nystagmus Ataxia & altered gait Diplopia Dystonic reactions Myoclonic movements Tremor Seizures (rare) Clinical Manifestations CNS Few words on treatment Diminution of sensory modalities Depersonalization, hostility Alteration of body image Dissociation calm; agitated; stupor; delirium; apathy; coma Don t forget the ABC s Check bedside glucose if the patient is obtunded Thiamine? for ethanol intoxication not routinely used in teenagers Naloxon Other antidotes rarely used
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