7 - Chemical Toxicology Flashcards
Lethal dose, 50% (LD 50)
• The amount of a chemical which causes death in 50% of a test population.
- units: mg/kg
• The lower the value, the greater the toxicity.
Legal dose significance
- As an aid in developing emergency procedures in case of a major spill or accident.
- Development of safety guidelines (PPE, documentation)
- Transportation regulations
- Occupational exposure limit
Pharmacodynamics
What the drug does to the body
Pharmacokinetics
What the body does to the drug
Analyte
the material that is being examined
Metabolite
a molecule formed by metabolic processes acting upon a parent molecule
Heroin Pharmacokinetics
Heroin is very quickly metabolized and so detection of metabolites is how we could establish heroin use.
Following the removal of the acetyl groups, morphine is conjugated to glucuronic acid which makes the molecule more hydrophilic and able to be excreted in the urine.
Alcohol metabolises to
reactive aldehydes.
alcohol poisoning
from consumption of methanol, contamination of homemade spirits, metabolised to very reactive and toxic methanal.
Blind drunk
retinal and methanal are similar structures so outcompetes opsin and so no retinal and opsin reaction for vision.
Alcohol detection
metabolised in bloodstream and some is exhaled.
There is a fixed ratio between alcohol in breath and amount in blood - not full proof.
Brethalyzer
The method actually measures alcohol levels by measuring the colour change observed following the reaction of potassium chromate with alcohol.
Infrared
- Modern instruments use infrared light which is absorbed by the alcohol
- the absorbance of the light is proportional to the concentration of alcohol present in the captured breath, which is in turn related to the amount of alcohol in the blood.
Fuel cells
react the alcohol (the fuel) and oxygen into an electrical current.
Aspirin (acetylsalicylic acid)
- Fatal intoxication can occur after the ingestion of 10 to 30g by adults and as little as 3g by children
- Symptoms of aspirin toxicity include nausea, vomiting and elevated temperature along with a wide range of impacts upon central systems supporting balance and often tinnitus.
- Can also result in hyperventilation.
- Severe toxicity can bring about more severe impacts upon central systems and lead to coma and eventually death.
Aspirin Metabolism
aspirin is a “pro-drug” meaning that it needs to undergo metabolism to produce the biologically active compound.
Following the swallowing of aspirin, it is metabolised to salicylate in the acid rich environment of the stomach.
The salicylate is the absorbed into the blood steam.
Aspirin - Determination
- Salicylic acid is rapidly absorbed and peak levels in blood can be seen after only one hour. They may however be delayed in an overdose.
- Measure plasma salicylate concentration 4 hours after suspected consumption and every then every 2 hours until the levels fall.
Aspirin - Management
- Metabolic acidosis – pH of Extra Cellular Fluid (ECF) is too low and so must be increased; hyperventilation is part of the response.
- During metabolic acidosis, which decreases the pH of the ECF, there is an increase in levels of protonated salicylate which can more easily cross membranes and have a more significant impact.
- The hyperventilation seen involves deep gasping breaths and is called Kussmaul respiration. There is also a renal compensation mechanism which is slower but more effective.
Aspirin - Treatment
- Treatment with sodium bicarbonate increases pH to reduce uptake and consequent impact has been used, but is controversial and usually reserved for very serious cases.
- Also IV fluids to stimulate renal clearance – but in overdose clearance routes saturated and the half life increases to 3 – 19 hours!
- Glucose to try to resolve altered mental state.
- In serious cases need to resort to hemodialysis.
Paracetamol - Metabolism
The toxicity of paracetamol lies in the metabolite NAPQI which is normally conjugated to Glutathione (GSH) to form non-toxic compounds which are excreted in the urine.
When GSH levels fall NAPQI levels rise and participate in toxic reactions.
Treatment requires elevation of GSH levels and/or providing a sink for removal of NAPQI.
Paracetamol - Decisions
The risk of toxicity is determined by examining the serum paracetamol concentration and relating that to the suspected time of ingestion.
Paracetamol - Treatment
N-acetylcysteine (NAC – see below) is a substitute for GSH and is actually a metabolic precursor for the synthesis of GSH.
