Drug Induced Coma&

Abusive DrugsDr. 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

Repolarization

Rest-70mV

Depolarization

Cellular Basics of Neurotransmission

• Neuromodulation– Receptor mediated– Non-receptor mediated NO,

CO

Basic Neuropharmacology

• Amino Acid Transmitters major CNS transmitters– Excitatory

• Glutamate (Glu)• Aspartate• Cystate• Homocystate

– Inhibitory -aminobutyric acid

(GABA)• Glycine• Taurine -alanine

• Purinoreceptors• Inhibitory

• Adenosine

Glutamate Receptors

• AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionate)

• NMDA (N-methyl-D-aspartate)

• Kainate

• mGlu: Metabotrophic receptor

N-methyl-D-aspartate Receptor

GABAA Receptor

Convulsant

HydrazinesIsoniazid

Glutamate Glutamic Acid

Glutamic acid decarboxylasePyridoxal Phosphate

GABA

Adenosine Receptor

• Diffuse CNS Inhibition “Blake” effect

• Sleep induction• Endogenous anti-

convulsant • xanthines

antagonist

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

NE pathways

• 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

Locus Ceruleus

Dopaminergic Pathways

• 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

ventral tagamental

Substantia nigra

Prefrontal cortex

limbic

Putamencaudate

Cholinergic Pathways

• Poorly understood• Acetycholine• Diffuse innervation• Cognition,

consciouness• Anti-cholinergics,

organophosphates• Alzheimer’s ?

cholinergic dysfunction

Consciousness

Prefrontal cortex

Limbic system

Hyppocampus

Basal Ganglions

Sensory Afferent

Background A

rousal

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?

• Ecstacy– May or may not

contains MDMA – ketamine, MA,

barbituate, benzo, panado

– Different strength

• Unpredictable effect

Party Pills

Trip

Good Trip

Bad Trip

Amphetamines

• Speed sulph, uppers, whizz: powder form

• Ice: crystalized form of metamphetamine

epinephrine

amphetamineMethamphetamine

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( 3,4-

methylenedioxymethamphetamine)

serotoninMDMA

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.