Module 9 Unit 1 Flashcards
Mechanisms of Toxicity
The range of toxicity mechanisms
– Immune system related – Receptor-mediated – Enzyme related – Direct physical damage – DNA-related – Reproduction and development
What are Immune system related toxic
- Inflammation
- Hypersensitivity
- Immune suppression
Receptor-mediated
agonist or antagonist (substance which interferes with or inhibits the physiological action of another.)
Enzyme related
• inhibition
Direct physical damage
• eg. to cell membranes
DNA-related
- altered gene expression leading to neoplasia
* altered gene repair leading to neoplasia
Reproduction and development
conception or foetal development
Example of inflammatory reaction
- exposure to lime (CaCO3) on building sites
* Direct skin contact leads to skin damage and local inflammatory reaction
What Strychnine (rodent bait) have an effect of animals
- Strychnine bindsto receptorsinCentralNervous system
- Competitivelyinhibits binding ofglycineto the receptor
- Glycine is an inhibitory neurotransmitter
- inhibition of glycine leads to increase activity in CNS
- Excitment and convulsions, tetanus of skeletal muscles
What does Organophosphates affect
enzyme inhibitors
inhibit an enzyme Acetylcholinesterase (responsible for termination activity of the neurotransmitter Acetyl Choline at nerve terminals )
What does OP insecticides cause
irreversible phosphorylation of AChE active site
• Acetyl Choline’s actions are enhanced/prolonged
• There are ACh receptors in the central nervous system and a range of organs
• phosphate group can migrate in enzyme active site = “ageing”
Signs of OP toxicity
– In the autonomic (involuntary) nervous system • Salivation, Lacrimation, Urination, Defaecation – In skeletal muscles • twitching • tremors • Paralysis – In central nervous system • Seizures and unconsciousness
How to treat OP toxicity
– Limit absorption
• Gastric lavage
• adsorption (activated charcoal)
– Block access of Ach to receptor
• Atropine a receptor blocker at some autonomic receptors – Reactivate phosphorylated AChE
• Pralidoxime
• needs to be given before AChE “ages” and the anticholineterase is irreversibly inactivated
Other mechanisms of OP action
- Chronic low dose exposure leads to receptor desensitisation to Ach -> ? cognitive deficits and behavioural change
- OP induced delayed neuropathy (OPIDN)- permanent damage to peripheral nerves
What toxic is an example of direct physical damage
Paraquet : contact herbicide
Toxicokinetics: Limited absorption; localisation in the lungs, slow absorption from GIT, excreted in urine
What is the mechanism of action of paraquat
transfers an electron to oxygen, free radicals form lipid hydroperoxide ⇒ Membrane damage, cellular degeneration and necrosis
What happens when paraquat is absorbed
– lung is major target organ for toxicity • tachypnoea, progressive dyspnoea • haemorrhage • oedema • damage to alveolar epithelial cells • fibrosis • a delayed response (days to weeks)
Why is paraquat lung selective
– taken up selectively by alveolar epithelial cells
• concentration of paraquat in lungs
– abundance of O2 in lungs
• good environment for production of oxygen free radicals
What initates a free radical (has unpaired electron) casacade
Paraquat
What effect does hydroxyl radical have
• HO•
– highly reactive
– initiates free radical chain reaction in lipid
• lipid peroxidation
• cell membrane damage
• loss of cell function
• cell death
• Death of alveolar lining cells in lung
• Development of scarring in alveoli
• Fibrous scarring impairs gas exchange
• Scarring is irreversible
How to treat paraquat poisoning
– administer adsorbant • remove paraquat from gut • clay, Fuller’s earth, ground-up kitty litter – reduce inspired oxygen levels • reduce free radical production
Why are cats highly susceptible to toxicity (>40mg/kg)
Because cats lack glucuronidation, paracetamol need less to have the same effect. More will be metabolise in phase 1, forming nucleophilic cell macromolecules with paracetamol with N-acetyl-β-benzoquinone imine (highly reactive) which is toxic
What does nucleophilic cell macromolecules with paracetamol cause
Liver and red blood cell damage
Paracetamol toxicity – treatment
– need to replenish/maintain glutathione pool
– cannot administer
• glutathione
• cysteine (cannot be absorbed)
– give N-acetyl cysteine
• will be synthesised into glutathione
• can directly mop up reactive intermediate