Chemical Pathology IV - Poison and Drug Abuse Flashcards
Toxic dose of paracetamol
Linked with what type of abnormal behavior
> 7.5g
150mg/kg
Deliberate Self-harm or suicidal behavior
Paracetamol metabolism
Paracetamol metabolism: Excreted in urine
1) 5% unchanged
2) UDP- glucuronosyl transferase»_space; Paracetamol glucuronide
3) UDP-sulfate transferase»_space; Paracetamol sulphate
4) CYP»_space; NAPQI** (cellular toxicity)»_space; conjugated with glutathione»_space; Glutathione cysteine mercapturic acid (non-toxic)
Which intermediate metabolite of paracetamol cause cellular toxicity?
What organs affected?
NAPQI
N-acetyl-p=benozequinone imine
Bind to cellular proteins and cause hepatic and renal toxicity
Liver failure + GI symptoms + Kidney injury
Metabolism of paracetamol in overdose?
UDP conjugation and direct excretion is stopped
All paracetamol goes through CYP metabolism to NAPQI
NAPQI not conjugated fast enough into non-toxic Glutathione Cysteine mercapturic acid
Accumulation of NAPQI
Which pathways in paracetamol metabolism can be induced by N-acetylecysteine?
1) NAPQI»_space; conjugation with glutathione»_space; Glutathione Cysteine mercapturic acid
2) Paracetamol»_space; UDP-sulfate transferase»_space; Paracetamol sulphate
Acute presentation of paracetamol overdose?
GI symptoms in 24 hours
Liver failure and kidney injury in 2-3 days
Name of graph used to Dx paracetamol toxicity.
Plasma concentration is measurable after how many hours?
Rumack- matthew normogram
Negatively correlated (non-linear) Decrease in plasma concentration with time
150ug/mL at 4 hours post-ingestion
Half life taken every 4 hours
How to use paracetamol plasma concentration to determine treatment or not?
Refer to the hours post-ingestion
If concentration is above the broken line on reference graph (Rumack-matthew normogram) = Potential for toxicity = treat immediately
Treatment options for paracetamol poisoning
1) N-acetylcysteine: for late presentation, high parenchymal enzyme, massive dose
2) Gastrointestinal decontamination with Activated charcoal
Limitations to Runmack-matthew normogram for Dx of paracetamol toxicity (3)
Problems with
- Extended release pills
- Staggered overdose
- Serum level unpredictable before 4 hours post-ingestion
Pathophysiological mechanism of Carbon monoxide? (3)
- High affinity to Hb, Decrease O2 delivery
- Impair cytochrome oxidase and O2 use in cells
- Lipid peroxidation in CNS: Globus pallidus lesions
What determine elimination half life of Carbon monoxide?
FiO2
FiO2: Percentage of oxygen in the air mixture that is delivered to the patient.
What is Methemoglobin
Continuous production and reduction in vivo
Methemoglobin = a form of hemoglobin that has been oxidized, changing heme iron configuration from the ferrous (Fe2+) to the ferric (Fe3+) state.
methemoglobin does not bind oxygen and cannot deliver oxygen to the tissues.
Causes of high methemoglobin
Congenital
- CYB5A/ C6B5R deficiency (enzymes that convert Fe3+ to Fe2+ for oxygen carrying)
- HbM (conformational change in Hb, cannot carry O2l)
Acquired:
- Medicine
- Chemicals
List some acquired causes of methemoglobin
no need to remember exhaustively
Medication:
- Chloroquine
- Phenazopyridine
- Local anesthetics
Chemicals:
- Antifreeze
- Hydrogen peroxide (disinfectant)
- Nitrates and nitrite
- Napthalene (moth balls)
Treatment of carbon monoxide poisoning?
High FiO2: hyperbaric oxygen therapy
Stop acquired causes of methemoglobin production (e.g. stop exposure to hydrogen peroxide)
Sources of cyanide poisoning
- Fire, burn victim
- Nitroprusside (Malignant hypertension treatment)
- Cyanide, Hydrogen cyanide, Cyanogen, Nitriles, Cyanogenic glycosides
Biochemical markers for cyanide poisoning?
Acid/ base balance?
pO2?
3 markers:
- Thiocyanate (long half-life)
- Cyanide
- ATCA (Stable minor metabolite)
High anion gap metabolic acidosis due to lactate (Lactate >8mmol/L)
Decreased A-V pO2 gradient
Antidotes to Cyanide? (2)
Sodium nitrite
Hydroxocobalamin
Pathophysiological mechanism of cyanide poisoning?
Inhibits cytochrome oxidase
> > Stop electron transport chain»_space; Cannot crate hydrogen ion gradient»_space; Cannot make ATP
Testing for cyanide poisoning?
Spot tests and definitive tests:
- Colorimetric dipstick reaction (Koenig reaction, turn purple)
- Test metabolites: Thiocyanate, ATCA, Cyanide
2 sources of methanol poisoning?
Pathophysiological mechanism?
Fake wine, Industrial solvent
Cytochrome oxidase inhibitor, similar to cyanide poisoning»_space; Lactic acidosis from tissue hypoxia
Test for methanol poisoning?
Potassium permanganate + Sodium bisulfite + chromotropic acid»_space; Purple colored compound
How to use anion gap and osmolar gap to tell the time of methanol poisoning?
Methanol»_space; formaldehyde»_space; formate»_space; metabolic acidosis
Initial:
High Osmolar gap due to methanol (presence of osmotically active solutes)
Late:
High Anion gap as most methanol is turned into Formate
2 treatment for methanol poisoning
Ethanol
Fomepizole - Alcohol dehydrogenase inhibitor
Acid/base balance after salicylate poisoning?
Define level for salicylate poisoning?
What to test for salicylate poisoning?
Metabolic acidosis (lactate) + respiratory alkalosis Toxic: >= 2.2mmol/L
Test blood salicylate levels - check conversion of methylsalycylate to salicylate by liver
Testing for Salicylate poisoning?
Take blood:
- Liquid chromatography + Time of flight mass spectrometry
2 reasons why urine toxicology not useful in overdose management? (check)
- Always a retrospective test: Not real-time diagnosis
- Incidental findings are not helpful in real-time management
Use of urine toxicology screening?
Point of care tests (at A&E)
Test for drug abuse?
Immunoassays: general unknown screening (find class of drug) + target analysis of drug abuse (find exact drug)
- Opiates: methadone, fentanyl…
- Methamphetamine/ Amphetamine
- Benzodiazepine
- Cocaine
- Cannabis
5 functional classes of abused drugs?
- Stimulants
- Depressants
- Dissociative
- Psychedelics/ Hallucinogen
- Cannabinoids
MoA of CNS stimulants
5 Examples of stimulants
Increase dopaminergic or serotoninergic activity
- Arousal, hyperactivity…etc
Cocaine Amphetamine MDMA Ritalin Caffeine
MoA of CNS depressants
Overdose effect?
3 examples?
Depress CNS activity: anxiety suppression, sedation, pain relief
Overdose = coma
Examples:
- Opioids, benzodiazepines
- Z-drugs (Zopiclone, Zolpidem)
- GABAnergic drugs
MoA of CNS dissociatives
Overdose effect?
3 examples?
Distort sensory perception, detachment from environment and self
Overdose: General anesthesia, respiratory suppression, seizures, K-hole
Ketamine, Phencyclidine (PCP_
MoA of CNS pyschedelics
3 examples?
Change mood and perception, increase serotoninergic activity, Hallucination
LSD
Tryptamines
Psilocybin mushrooms
MoA of cannabinoids
Types
Activate CB1 and CB2 receptors
THC - tetrahydrocannabinol
CBD - Cannabidiol
4 examples of TCM poisoning
Toxic plant alkaloids: Aconitum, Solanaceous…
Cardiac glycosides
Gelsemium alkaloids
Heavy metals
What to do if plasma paracetamol concentration persists and does not go below dotted line on Runmack-matthew normogram?
Suspect sustained release formula
Give N-acetylcysteine
Lactate caused metabolic acidosis + High initial osmotic gap + Late high anion gap?
Methanol poisoning
