Specific Toxins (Sources: revision notes) Flashcards
How is paracetamol metabolised?
Primarily a phase 2 reaction to sulphate and glucuronide metabolites
A small amount is metabolised via the cytochrome P450 system to the toxic metabolite N-acetyl-benzoquinone-imine (NAPQI)
Under normal circumstances NAPQI is detoxified by being bound to glutathione, which is then really excreted
In overdose the phase 2 mechanism is overwhelmed, which results in increased NAPQI production
If NAPQI production exceeds glutathione availability toxicity occurs, which is proportional to the magnitude of overdose
What factors may increase the magnitude of a paracetamol overdose?
- pre-existing glutathione depletion, which occurs in eating disorders, chronic alcoholism, cystic fibrosis and HIV
- pharmacological induction of the P450 system - phenytoin, rifampicin and carbamazepine
What are the symptoms of paracetamol overdose?
Initial symptoms are vague or absent - nausea, vomiting, and sweating
After 24-72 hours increasing hepatic toxicity results in right upper quadrant pain, abnormal LFTs and deterioration in synthetic liver function
AKI can occur - either due to direct toxicity or hepatic-renal syndrome
If heparin injury progressed jaundice, encephalopathy, coagulopathy, hypoglycaemia and multi-organ failure may follow
Why do lactate levels increase in paracetamol overdose?
Very high levels can impair mitochondrial function leasing to anaerobic respiration
Lactate might rise in hepatic failure
How should paracetamol OD be managed?
AC if within 1 hour
Specific antidote is N-acetyl-cysteine (NAC) which is initiated based upon cross-referencing levels with a nome-gram
Levels are only helpful if the whole dose was taken at once, staggered overdoses should be treated with NAC regardless of levels
There is now only 1 nomo-gram in the UK (prior to 2010 there used to be a high-risk and low-risk one)
How does NAC reduce the risk of paracetamol toxicity?
Provides a reservoir of sulfhydryl groups, which bind NAPQI and stimulate the production of glutathione
What are the side-effects of NAC?
Rash
Angio-oedema
Bronchospasm
If they occur give anti-histamine and slow the rate
When is NAC most effective in paracetamol OD?
Within 10 hours but may be effective for several days
When should you refer paracetamol OD patients to a specialist liver centre? (According to the Kings College Hospital Liver Guidelines)
Acidosis (pH < 7.3 after fluid resuscitation)
PT > 100s (INR >6.5)
Grade 3-4 encephalopathy
What are the toxic effects of salicylic acid?
Rapidly converted to salicylic acid
At toxic levels this activates the chemoreceptor trigger zone leading to nausea and vomiting and the respiratory centre which results in respiratory alkalosis
Higher plasma levels lead to uncoupling of cellular respiration and subsequent lactic acidosis
What are the clinical features of salicylate overdose?
fever tinnitus hypoglycaemia vertigo visual disturbance coagulopathy pulmonary oedema
How is salicylate overdose managed?
Mainly supportive
Forced alkaline diuresis - aiming urinary pH 6.0-7.0
Haemodialysis is indicated for those with very high levels (>750 mg/l) to any life-threatening features
Which drug causes the most in hospital deaths from overdose?
TCAs
Which 2 pharmacological mechanisms cause the symptoms in TCA overdose?
- Cholinergic antagonism (the anti-cholinergic toxidrome)
2. Sodium channel blockade
What are the clinical features of TCA overdose?
Cardiovascular - Tachycardia, arrhythmia, hypotension
Neuro - dilated pupils, blurred vision, decreased conscious level, seizures
Resp - Depression
GI - dry mouth, prolonged gastric transit
Other - warm dry skin, urinary retention
What are the 2 key investigations in a TCA overdose?
ECG
ABG
How should a TCA OD be managed?
Activated charcoal - repeated doses may be warranted as TCAs slow gastric transit
I+V
In those with severe toxicity (acidosis, hypotensive, QRS > 100ms, arrhythmia) attempt to increase the pH - reduces the available ionised free drug. This maybe achieved by hyperventilation, or IV sodium bicarb
If unstable arrhythmias occur sodium bicarb, magnesium and lidocaine if required
Bentos should be used for seizures, with barbiturates being second line (don’t use phenytoin)
Which agents are implicated with the serotonin syndrome?
Inhibition of serotonin reuptake - SSRIs, TCAs, tramadol, St Johns Wort, pethidine
Increase in serotonin release - amphetamines, ecstasy
Partial serotonin agonists - LSD, buspirone
What is serotonin syndrome?
Results from hyper-stimulation of serotonin receptors
What are the clinical features of serotonin syndrome?
Altered mentation: - agitation, confusion, rarely seizures
Autonomic dysfunction: - nausea, diaphoresis, tachycardia, tremor, diarrhoea, fever
Neuromuscular hyper-reactivity: - hyper-reflexia, clonus, rhabdo, hyperkalaemia, AKI, DIC
How is serotonin syndrome managed?
Withdraw precipitant
Supportive care incl temp control, rehydration, managing BOP, DIC and rhabdo
Bentos are the first line for agitation, autonomic dysfunction and neuromuscular hyper-reactivity
Limit opioids
The serotonin antagonist cyproheptadine is recommended for severe poisoning
What is neuroleptic malignant syndrome?
An indio-syncratic reaction to anti-psychotics
Blockade of dopaminergic singling in genetically predisposed people results in rigidity, fever and autonomic instability
Most common in anti-psychotics however other drugs that exhibit dopamine antagonism e.g. metalopramide may also be implicated
What are the key features of NMS?
Slow onset over several days to weeks Muscle rigidity with reduced reflexes Elevated WCC and CK common Caused by antagonism of dopaminergic pathways Slow to resolve Mortality up to 10%
