Drug Induced Coma & Abusive Drugs

1. Drug Induced Coma&Abusive Drugs Dr. ML Tse

2. 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

3. Molecular Basics • Receptors • Ligand linked ionophore • G-protein coupled  Cyclase activation  ion channels • Steroid hormone receptors  DNA • Tyrosine kinase receptor (Insulin, growth factors)

4. Cellular Basics of Neurotransmission • Neurotransmission +/--  Ionophores Na,Ca, K, Cl

5. Cellular Basics of Neurotransmission • Neuromodulation • Receptor mediated • Non-receptor mediated NO, CO

7. Basic Neuropharmacology • Amino Acid Transmitters major CNS transmitters • Excitatory • Glutamate (Glu) • Aspartate • Cystate • Homocystate • Inhibitory • -aminobutyric acid (GABA) • Glycine • Taurine • -alanine • Purinoreceptors • Inhibitory • Adenosine

8. Glutamate Receptors • AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionate) • NMDA (N-methyl-D-aspartate) • Kainate • mGlu: Metabotrophic receptor

9. N-methyl-D-aspartate Receptor

10. GABAA Receptor

11. Convulsant Glutamic Acid Glutamate Glutamic acid decarboxylase Pyridoxal Phosphate Hydrazines Isoniazid GABA

12. Adenosine Receptor • Diffuse CNS Inhibition “Blake” effect • Sleep induction • Endogenous anti-convulsant • xanthines antagonist

13. Serotonergic Pathways • 5 HT • 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 Raphe pons

14. NE pathways • Locus Ceruleus in caudal pons • 5 major tracts • ,12, 1 •  Morphine, endorphins, • 2 agonist (clonidine)Firing • Amphetamines, TCA, Opioid withdrawal Firing • Global orientation to external stimuli Locus Ceruleus

15. Dopaminergic Pathways Putamen caudate • 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  Prefrontal cortex ventral tagamental limbic Substantia nigra

16. Cholinergic Pathways • Poorly understood • Acetycholine • Diffuse innervation • Cognition, consciouness • Anti-cholinergics, organophosphates • Alzheimer’s ?cholinergic dysfunction

17. Consciousness Background Arousal Prefrontal cortex Limbic system Hyppocampus Basal Ganglions Efferent Sensory Afferent

18. 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

19. Management • Decontamination: ?cyanide • ABC, prevent secondary insult • H’stix • History • Toxidrome: • Focal signsCT 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

20. Abusive Substances

21. 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

22. 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

23. 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

24. 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?

25. Party Pills

26. Opioid • Opium, extract of poppy (Papaver somniferum) contains ≥10% morphine • Heroin (diamorphine) since 1874, marketed by Bayer 1898, preferred : euphoric, rush

27. 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

28. 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 glottisnegative intrathoric pressure • Withdrawal • Bodypacker

29. 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

30. Party Drugs • Amphetamines • LSD • Ketamine • Cocaine • Nematazepam

31. Clinical Presentation • Acute • Bad trips • Injury • Specific problems related to the substance • Chronic • Poor immune, poor health • Psychiatric: brain damage?

32. Party Pills • Ecstacy • May or may not contains MDMA • ketamine, MA, barbituate, benzo, panado • Different strength • Unpredictable effect

33. Trip

34. Good Trip

35. Bad Trip

37. Amphetamines • Speed sulph, uppers, whizz: powder form • Ice: crystalized form of metamphetamine epinephrine amphetamine Methamphetamine

38. Amphetamines • 179 entries of designer amphetamines Phenylethylamines I Have Known And Loved

39. Amphetamine • Presynaptic Dopamine and Catecholamine release • Peripheral  and  Sympathomimetic • Central: • NE  Alertness • DA Glu behavioral and psycho • 5-HT (high dose) thermoregulation, psychosis

40. MDMA( 3,4-methylenedioxymethamphetamine) MDMA serotonin

41. MDMA • Ecstasy, XTC, Adam • Stimulant(amphetamine) + mild hallucinogenic (weak LSD)

42. Clinical Presentation • Tweaking

43. Clinical Presentation • Heat stroke • Intracerebral haemorrhage • Dysrrhythmias • Cerebral infarct • Myocardial ischaemia • Pneumothorax, pneumomediastinum • Hyponatraemia • Rhabdomyolysis • Injury • Fine-5HT neuron damage in braincognitive, psychiatric, behavioral problem

44. Rx • Benzodiazepine: usually at toxicological dose • Haloperidol • Minimize physical restrain • Cooling

45. 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

46. Cocaine powder Crack cocaine

47. Cocaine • Fast Na channel blockage • Catecholamine reuptake inhibition • CNS stimulation: cortexbrain stem • DA reuptake inhibition •  excitatory amino acids • Activemetabolites: benzoylecgonine, norcocaine • More dangerous with alcohol

48. Clinical Presentation • Hyperthermia • Myocardial ischaemia, dysrhythmia, aortic dissection • ICH, Cerebral infarction, seizures • PneumoT / M, Pulmonary edema • Rhabdomyolysis • Gut ischaemia • Cardiomyopathies

49. 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

50. Hallucinogens • Lysergamids • LSD: D-lysergic acid diethylamide • Indolealkylamines • Ibogaie • Psilocybin • Phenylethylamines • Mescaline, MDMA • Tetrahydrocannibinoids • Marijunana • Hashish • Anticholinergics • Jimsonweed(Datura stramonium)