Chemical Toxicology

Question 1

Poisoning

Answer 1

An interaction between a foreign chemical (toxin) and a biological system which results
in damage to a living organism

Question 2

Reasons for poisoning

Answer 2

Accidental
Suicidal
Criminal

Question 3

Where to look where there is suspected poisoning

Answer 3

• plasma [urea], [electrolytes] and [creatinine]
• plasma osmolality and osmolality gap
• blood gases to assess acid-base status
• serum [transaminases] and [bilirubin]
• plasma [glucose]

Question 4

What role does the lab have during poisoning

Answer 4

• monitoring of vital functions • eg measuring blood gases
• demonstration of suspected poison in blood
• monitoring treatment
• eg measuring poison at regular intervals

Question 5

Common Poisons

Answer 5

• paracetamol
• aspirin
• alcohol
• barbiturates
• lithium
• ethyleneglycol
• paraquat
• carbonmonoxide

Question 6

Paracetamol

Answer 6

• analgesic giving relief from fever and pain
• common cause of emergency hospital admission due to its wide availability
• causes 150 deaths approx. each year in UK

Question 7

Paracetamol Toxicity

Answer 7

• paracetamol rapidly absorbed in upper GIT
• metabolised in the liver by conjugation with glucuronide (~40-60%) by UDP-glucuronyl transferase, sulphate (~20-30%) by arylsulphotransferase to form non-toxic metabolites
• a small amount (~5-10%) is metabolised by cytochrome P450 to produce N-acetyl-p-benzoquinoneimine (NAPQI)
• NAPQI is normally conjugated with glutathione in liver cells to produce non-toxic mercapturic acid and cysteine conjugates
• in overdose liver enzymes are saturated and large amounts of NAPQI exhaust glutathione stores
• free NAPQI can bind to cells causing hepato- and nephrotoxicity

Question 8

Toxic dose of paracetamol

Answer 8

• dose of 15g (adults) and 4g (children) can cause hepatotoxicity
• such doses deplete liver glutathione by 70%
• in some patients doses of 50g+ are not toxic
due to variation in metabolism
• [paracetamol] > 300 mg/L 4 hours after ingestion cause serious liver damage but not <120 mg/L

Question 9

Clinical features of stage 1 paracetamol poisoning

Answer 9

0.5-24h Within hours of ingestion, patients may experience anorexia (loss of appetite), nausea (sickness) and vomiting. Patients may suffer from malaise (feeling unwell) but often appear normal.

Question 10

Stage 2 clinical features of paracetamol poisoning

Answer 10

24 – 48 hours
Symptoms of stage II are less severe with perceived recovery. Right upper quadrant pain due to liver damage may occur. Blood biochemistry shows increases in liver enzymes and bilirubin. Renal function deteriorates but [urea] remains low because of decreased hepatic urea formation. Prothrombin time prolonged

Question 11

Clinical features of Stage 3 paracetamol poisoning

Answer 11

72 – 96 hours
Symptoms of liver necrosis occur. Coagulation defects, jaundice and renal failure may occur. Liver encephalopathy has been reported. Liver biopsy reveals necrosis. Nausea and vomiting may reappear. Patients may present with coma and anuria (failure to produce urine) which often precedes death due to liver failure.

Question 12

Clinical features of stage 4 paracetamol poisoning

Answer 12

4 – 14 days
If stage III damage is not irreversible then liver function returns to normal.

Question 13

Paracetamol Poisoning: Investigation

Answer 13

• plasma [paracetamol]
• blood samples taken at least 4 hours post dose
• probability of developing hepatotoxicity
• based as a guide for patient management
• plasma [aminotransferases] / [bilirubin] • plasma [creatinine]

Question 14

Paracetamol Measurement: Analytical

Answer 14

• chromatographic • HPLC / GLC
• chemical
• paracetamol reacted with sulphanilic acid / sodium nitrite in alkaline solution to produce a yellow diazo complex whose absorbance is measured.
• enzymatic
• paracetamol converted to acetate and p-aminophenol by enzyme aryl acylamidase. The p-aminophenol reacts with alkaline o-cresol in presence of copper / ammonium ions to produce a coloured complex whose absorbance is measured.

Question 15

Management of paracetamol poisoning

Answer 15

activated charcoal
• administered within 1-2 hours after ingestion
• prevents absorption of paracetamol from gut
N-acetyl cysteine
• administered intravenously for patients who present late, vomiting or are in a coma
• increases hepatic glutathione synthesis improving detoxification of NAPQI by liver
• may act as glutathione substitute enhancing sulphate conjugation

methionine
• administered orally (2.5g/4 hours for 12 hours) in early, uncomplicated cases
• increases hepatic glutathione synthesis improving detoxification of NAPQI by liver

Question 16

Aspirin

Answer 16

• has analgesic, antipyretic and anti- inflammatory properties
• exists in its active salicylate form in blood
• poisoning common because of its wide availability

Question 17

Metabolism of Aspirin

Answer 17

salicylate is eliminated from body by:
• conjugation with glycine to form salicyluric acid
• conjugation with glucuronide to form phenol and acyl
glucuronides
• hydroxylated to gentisic acid
pathways become saturated in overdose

Question 18

Aspirin toxicity

Answer 18

• following absorption aspirin metabolised to salicylate stimulates respiratory centre (hyperventilation) causing dehydration due to water loss
• hyperventilation causes a reduction in PCO2 producing a respiratory alkalosis
• renal compensation occurs by excreting more HCO3 and K+ ions whilst retaining H+ ions
• purpose of renal compensation is to correct respiratory alkalosis but instead contributes towards latent metabolic acidosis ie mixed acid-base disorder
• salicylate uncouples oxidative phosphorylation reducing ATP production

• decline in ATP stimulates glycolysis and accumulation of pyruvate and lactate (both acids)
• uncoupling of oxidative phosphorylation causes increased heat production and therefore sweating and fever (further fluid loss and dehydration)
• increased breakdown of glycogen occurs to provide glucose for glycolysis thus [glucose] increases but hypoglycaemia may occur when glucose stores are used up
• lipids are broken down producing ketone bodies that exacerbate the metabolic acidosis
• salicylate inhibits enzymes of TCA cycle causing accumulation of ketoglutarate and oxaloacetate (acids)
• salicylate induces nausea / vomiting causing further fluid / electrolyte loss

Question 19

Aspirin: Toxic Dose

Answer 19

• potentiallylethaldose~24to30ginadults
• inchildrenunder18-months,deathcanoccur
with as little as 300mg
• therapeutic[salicylate]is50mg/Lbutashigh as 250 mg/L in rheumatoid arthritis patients
• toxicity occurs when [salicylate] is > 300 mg/L
• severe cases have [salicylate] ~ 1000 mg/L

Question 20

Aspirin Poisoning: Clinical

Answer 20

• nausea
• vomiting
• sweating
• hyperventilation
• tinnitus
• confusion / unconsciousness • severevolumedepletion

Question 21

Aspirin Poisoning: Investigation

Answer 21

• plasma [salicylate]
• measured on presentation and every 4-6 hours till below
toxic range
• salicylates precipitate out and deposit in the stomach because of its acid environment
• acid-base status

Question 22

Aspirin Measurement: Analytical

Answer 22

• chemical
• salicylate reacts with ferric nitrate under acidic conditions (Trinder’s reagent) forming purple coloured complex whose absorbance is measured

Question 23

Aspirin Poisoning: Management

Answer 23

gastric lavage
• washing out of stomach for up to 24 hours after ingestion as salicylate remains unabsorbed in gut
activated charcoal
• administered 50g initially followed by 25g every 4 hours
• binds to salicylate preventing its absorption from gut
bicarbonate infusion
• increases urinary excretion of salicylate
fluid / electrolyte / acid-base correction
• replace fluid, electrolytes and rectify acid-base balance

haemodialysis
• used in severe aspirin poisoning where plasma [salicylate] > 800 mg/L
• relies on principle of dialysis
• blood from patients artery circulated through dialyser on one side of a semi-permeable membrane whilst solution of normal electrolytic composition circulates on the other side
• waste products, poisons and small molecules cross the membrane and purified patient blood returned to body via vein