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Download Drug induced coma & Party drugs by Dr ML Tse
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Drug Induced Coma & Abusive Drugs Dr. ML Tse Basic Concept • Brain activity = Interplay of neuron depolarization • Ion channel activities • Voltage-gated IC & Ligand-linked IC • Opening / Closing Production / Destruction control by receptor activites Molecular Basics • Receptors – Ligand linked ionophore – G-protein coupled Cyclase activation ion channels – Steroid hormone receptors DNA – Tyrosine kinase receptor (Insulin, growth factors) Cellular Basics of Neurotransmission • Neurotransmission +/-- Ionophores Na,Ca, K, Cl Depolarization Repolarization Rest -70mV Cellular Basics of Neurotransmission • Neuromodulation – Receptor mediated – Non-receptor mediated NO, CO Basic Neuropharmacology • Amino Acid Transmitters major CNS transmitters – Excitatory • • • • • Purinoreceptors • Inhibitory Glutamate (Glu) Aspartate Cystate Homocystate – Inhibitory • • • • -aminobutyric acid (GABA) Glycine Taurine -alanine • Adenosine Glutamate Receptors • AMPA (-amino-3hydroxy-5-methyl-4isoxazole propionate) • NMDA (N-methyl-Daspartate) • Kainate • mGlu: Metabotrophic receptor N-methyl-D-aspartate Receptor GABAA Receptor Convulsant Glutamate Glutamic Acid Glutamic acid decarboxylase Pyridoxal Phosphate Hydrazines Isoniazid GABA Adenosine Receptor • Diffuse CNS Inhibition “Blake” effect • Sleep induction • Endogenous anticonvulsant • xanthines antagonist Serotonergic Pathways • 5 HT Raphe pons – Midline of pons – locus ceruleus, interpeduncular nucleus – Pacemaker like 1—5 spikes / sec – Inhibitory modulation – 2 systems: fine axons and beaded large axons – Fine 5HT axons damage by MDMA – Pineal gland NE pathways Locus Ceruleus • Locus Ceruleus in caudal pons • 5 major tracts • ,12, 1 • Morphine, endorphins, • 2 agonist (clonidine)Firing • Amphetamines, TCA, Opioid withdrawal Firing • Global orientation to external stimuli Dopaminergic Pathways Putamen caudate Prefrontal cortex ventral tagamental limbic Substantia nigra • Complex : utra short ; intermediate length; long systems-midbrain to neostriatum and limbic system • D1 – 5 R • Learning behaviour, memory, motor • ?Final common pathway for addiction • Amphetamine, cocaine antipsychotics Cholinergic Pathways • • • • Poorly understood Acetycholine Diffuse innervation Cognition, consciouness • Anti-cholinergics, organophosphates • Alzheimer’s ?choliner gic dysfunction Consciousness Background Arousal Prefrontal cortex Limbic system Sensory Afferent Hyppocampus Basal Ganglions Efferent Drug Induced Coma • Direct effect on neurons – Receptor mediated – Non-receptor mediated • Secondary Insult due metabolic disturbance – Seizure, coma, death as the final common pathway of intoxication Management • • • • • Decontamination: ?cyanide ABC, prevent secondary insult H’stix History Toxidrome: – – – – – – Focal signsCT brain Opioid, DUMBBELL, Serotonergic, Anti-cholinrgic,etc, convulsants…. Trial of naloxone Stable unconscious Vs Unstable Unconscious ECG: rate, QRS, QTc Therapeutic use of other antidote • ABG: ?MUDPILE; Osmolar gap, – Lactic acidosis with normal PaCO2 ?cellular asphysants • Panadol level-co-ingestion?1 in 500 • CXR, AXR • ??Urine screening • Supportive Abusive Substances Sedative-Hypnotics • Benzodiazepines (since 1955) – GABAA R agonist Cl channel sedative,anxiolytic, muscle relaxing, amnesic – Peripheral benzodiazepine receptors (whole body): mitochondrial outer membrane – adrenal, pituitary, reproductive, heart ; RBC • GHB -hydroxybutyrate (since 1960s) – Bodybuilding, Mood-enhancer, Date-rape – Receptor in basal ganglion – GH, enkephalin dopamine Benzos OD • Sleep like toxidrome • Children: ataxia • Paradoxical CNS effects: delirium, psychosis, nightmares with age • Death due to combined overdose • Dx co-ingestion & supportive Mx • Routines screening not helpful: – False –ve: • active metabolites, • triazolam & aprazolam: low active serum concentration • Flunitrazepine, clonazepine –ve immunoessay – +ve result: • Co-ingestion common • Co-morbidity BenzosOD • Routine flumazenil not recommended • Contraindications: – – – – – Seizure Hx Co-ingestion Long term user ECG evidence of TCA Abnormal vitals • Withdrawal – Anxiety, panic attacks, headache, tremors, paresthesia, seizure GHB • Toxidrome: cyclical coma:deep coma/agitated episodes, resp depression, rigidity, myoclonus face limbs, bradycardia • Typically pull out the ET tube and fully awake in 6 hrs • Flumazenil not consistent • Withdrawal? Party Pills Opioid • Opium, extract of poppy (Papaver somniferum) contains ≥10% morphine • Heroin (diamorphine) since 1874, marketed by Bayer 1898, preferred : euphoric, rush Opioid Receptors • : euphoria, analgesia, respiration • • • • • • : miosis, spinal analgesia : ?analgesia, dopamine nigrostriatal : not considered as opioid R, ,: ?? G-protein linked Euphoria, addiction : Dopamine release & -R stimulation in mesolimbic system Clinical Presentation • M & M more due to IV use, cutting agent, contaminant, poor health • Overdose: – Typical toxidrome • Fentanyl: muscle rigidity, urine screen -ve • Dextromethorphan: anti-cholinergic • Methadone: choreoathetosis – pulmonary edema • Direct effect • Neurogenic: acute withdrawal on naloxone, high PaCO2 • Forceful inspiration against closed glottisnegative intrathoric pressure • Withdrawal • Bodypacker Pitfalls in Mx • Urine immunoessay – +ve codeine, poppy seed – --ve synthetic opioid • Naloxone – Bag-valve mask ventilation – Small incremental dose 0.1mg – Adequate respiration as end-point – Infusion: 2/3 effective bolus / hour Party Drugs • • • • • Amphetamines LSD Ketamine Cocaine Nematazepam Clinical Presentation • Acute – Bad trips – Injury – Specific problems related to the substance • Chronic – Poor immune, poor health – Psychiatric: brain damage? Party Pills • Ecstacy – May or may not contains MDMA – ketamine, MA, barbituate, benzo, panado – Different strength • Unpredictable effect Trip Good Trip Bad Trip Amphetamines • Speed sulph, uppers, whizz: powder form • Ice: crystalized form of metamphetamine epinephrine Methamphetamine amphetamine Amphetamines • 179 entries of designer amphetamines Phenylethylamines I Have Known And Loved Amphetamine • Presynaptic Dopamine and Catecholamine release • Peripheral and Sympathomimetic • Central: – NE Alertness – DA Glu behavioral and psycho – 5-HT (high dose) thermoregulation, psychosis MDMA ( 3,4methylenedioxymethamphetamine) MDMA serotonin MDMA • Ecstasy, XTC, Adam • Stimulant(amphetamine) + mild hallucinogenic (weak LSD) Clinical Presentation • Tweaking Clinical Presentation • • • • • • • • • • Heat stroke Intracerebral haemorrhage Dysrrhythmias Cerebral infarct Myocardial ischaemia Pneumothorax, pneumomediastinum Hyponatraemia Rhabdomyolysis Injury Fine-5HT neuron damage in braincognitive, psychiatric, behavioral problem Rx • Benzodiazepine: usually at toxicological dose • Haloperidol • Minimize physical restrain • Cooling Cocaine • Leaves of coca plant in S. America • Use in religious rituals since 6th century • Identified in 1857 • Add in Coca-cola • >6 Million >12y.o. Americans had tried Cocaine powder Crack cocaine Cocaine • Fast Na channel blockage • Catecholamine reuptake inhibition • CNS stimulation: cortexbrain stem – DA reuptake inhibition – excitatory amino acids • Activemetabolites: benzoylecgonine, norcocaine • More dangerous with alcohol Clinical Presentation • Hyperthermia • Myocardial ischaemia, dysrhythmia, aortic dissection • ICH, Cerebral infarction, seizures • PneumoT / M, Pulmonary edema • Rhabdomyolysis • Gut ischaemia • Cardiomyopathies Cocaine • Benzo for agitation, HT • IV Nitrate, phentolamine, morphine,verapamil for ACS • Diltiazem, Verapamil for atrial arrhythmia • NaHCO3, lignocaine, amiodarone for ventricular arrhythmia • Torsade (K channel blocking): MgSO4 Hallucinogens • Lysergamids – LSD: D-lysergic acid diethylamide • Indolealkylamines – Ibogaie – Psilocybin • Phenylethylamines – Mescaline, MDMA • Tetrahydrocannibinoids – Marijunana – Hashish • Anticholinergics – Jimsonweed(Datura stramonium) LSD • 1938 by Albert Hoffmann, popularized in 60s • 5-HT2 antagonist – diminish filtering of sensory input hallucination • Glutamate ,D1, D2 • Indirect sympathetic stimulation in locus ceruleus • Psychological effect varies on dose, emotionexpectations, environment. LSD • In the form of blotting paper • “Fing-Ba” Clinical Presentation • Bad trip: panic reactions, frightening illusions, sense of loss of self-control • Hyperthermia • Mydriasis, HT, tachycardia, diaphoresis– usually less severe • Mx: – Benzodiazepine +/-- haloperidol – Minimize physical restrain – Rx hyperthermia and rarely rhabdomyolysis Ketamine • • • • • • Related to Phencyclidine (Angel dust) Dissociative anaesthetic Microwaving Ketelar Out-of body feel NMDA blockage Biogenic amine reuptake blockage: – NE – DA • Ketamine inhalation device • Ketamine powder Clinical Presentation • • • • • • • • Psychomotor disturbance Delirious to comatose Nystamus Vomiting Injury Sympathetic / muscarinic symptoms Mx: Benzo +/-- Haloperidol , quiet environment Brain damage– Olney’s lesion: NMDA antagonist neurotoxicity.