Specific Toxins (Sources: revision notes)

Question 1

How is paracetamol metabolised?

Answer 1

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

Question 2

What factors may increase the magnitude of a paracetamol overdose?

Answer 2

1. pre-existing glutathione depletion, which occurs in eating disorders, chronic alcoholism, cystic fibrosis and HIV
2. pharmacological induction of the P450 system - phenytoin, rifampicin and carbamazepine

Question 3

What are the symptoms of paracetamol overdose?

Answer 3

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

Question 4

Why do lactate levels increase in paracetamol overdose?

Answer 4

Very high levels can impair mitochondrial function leasing to anaerobic respiration
Lactate might rise in hepatic failure

Question 5

How should paracetamol OD be managed?

Answer 5

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)

Question 6

How does NAC reduce the risk of paracetamol toxicity?

Answer 6

Provides a reservoir of sulfhydryl groups, which bind NAPQI and stimulate the production of glutathione

Question 7

What are the side-effects of NAC?

Answer 7

Rash
Angio-oedema
Bronchospasm
If they occur give anti-histamine and slow the rate

Question 8

When is NAC most effective in paracetamol OD?

Answer 8

Within 10 hours but may be effective for several days

Question 9

When should you refer paracetamol OD patients to a specialist liver centre? (According to the Kings College Hospital Liver Guidelines)

Answer 9

Acidosis (pH < 7.3 after fluid resuscitation)
PT > 100s (INR >6.5)
Grade 3-4 encephalopathy

Question 10

What are the toxic effects of salicylic acid?

Answer 10

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

Question 11

What are the clinical features of salicylate overdose?

Answer 11

fever
tinnitus
hypoglycaemia
vertigo
visual disturbance
coagulopathy
pulmonary oedema

Question 12

How is salicylate overdose managed?

Answer 12

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

Question 13

Which drug causes the most in hospital deaths from overdose?

Answer 13

TCAs

Question 14

Which 2 pharmacological mechanisms cause the symptoms in TCA overdose?

Answer 14

1. Cholinergic antagonism (the anti-cholinergic toxidrome)

2. Sodium channel blockade

Question 15

What are the clinical features of TCA overdose?

Answer 15

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

Question 16

What are the 2 key investigations in a TCA overdose?

Answer 16

ECG

ABG

Question 17

How should a TCA OD be managed?

Answer 17

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)

Question 18

Which agents are implicated with the serotonin syndrome?

Answer 18

Inhibition of serotonin reuptake - SSRIs, TCAs, tramadol, St Johns Wort, pethidine
Increase in serotonin release - amphetamines, ecstasy
Partial serotonin agonists - LSD, buspirone

Question 19

What is serotonin syndrome?

Answer 19

Results from hyper-stimulation of serotonin receptors

Question 20

What are the clinical features of serotonin syndrome?

Answer 20

Altered mentation: - agitation, confusion, rarely seizures
Autonomic dysfunction: - nausea, diaphoresis, tachycardia, tremor, diarrhoea, fever
Neuromuscular hyper-reactivity: - hyper-reflexia, clonus, rhabdo, hyperkalaemia, AKI, DIC

Question 21

How is serotonin syndrome managed?

Answer 21

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

Question 22

What is neuroleptic malignant syndrome?

Answer 22

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

Question 23

What are the key features of NMS?

Answer 23

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%

Question 24

What drugs can be used to treat NMS?

Answer 24

Bromocriptine

Dantrolene

Question 25

What are the toxic effects of methanol?

Answer 25

When metabolised it forms formic acid Impedes mitochondrial function resulting in metabolic acidosis Exerts direct toxicity on the optic nerve - causing visual impairment Approx 10ml of pure methanol cause cause permanent blindness

Question 26

What is the fatal dose of methanol?

Answer 26

30mls

Question 27

What is the toxic effect of ethylene glycol?

Answer 27

It's metabolised to glycoaldehyde, glycol ate and oxalate These lead to cerebral oedema Metabolic acidosis Renal failure

Question 28

What are the features of an alcohol OD?

Answer 28

Decreased conscious state, ataxia, dysarthria, vomiting All alcohols are osmotically active Anion gap will be raised

Question 29

How is an alcohol OD managed?

Answer 29

Gastric lavage (no role for AC) The secondary toxic effect of ethylene glycol and methanol can be mitigated by blocking the metabolic pathways that convert the alcohol to toxic products - the ley enzyme is alcohol dehydrogenase - which has a far greater affinity for ethanol than other alcohols Therefore admin of ethanol to its at risk of methanol or ethylene glycol toxicity prevents the production of toxic metabolites The alcohol dehydrogenase inhibitor fomepizole is preferred an an alternative if available

Question 30

What are the effects of cyanide?

Answer 30

It reversibly binds to and inhibits cytochrome oxidase within the mitochondria. The resultant disruption of electron transport chain function blocks aerobic respiration, ATP is only produced by anaerobic means and a cytotoxic hypoxia ensues

Question 31

What are the clinical features of cynaide toxicity?

Answer 31

``` Confusion Seizures Dyspnoea Tachycardia Coma The classical biochemical picture is of unexplained lactic acidosis and high ScvO2 (venous hyperoxia) ```

Question 32

What are the antidotes to cyanide?

Answer 32

``` Gastric lavage is ingested Antidotes include: -Amyl nitrate -Hydroxycobalamin -Sodium thiosulphate -Dicobalt edetate ```

Question 33

How does amly nitrate work?

Answer 33

Converts Hb to methaemoglobin (the iron atom being converted from the ferrous Fe2+ to ferric Fe3+ states) Cyanide had a higher affinity for metHb than for cytochrome oxidase and therefore preferentially binds to the former MetHb, however, has no oxygen binding capacity and high levels may result in failure of oxygen delivery Amly nitrate therapy should be titrated to a metHb of 20-30%

Question 34

How does hydroxycobalamin work in cyanide toxicity?

Answer 34

Vitamin B12a Binds cyanide to form cyanocobalamin, which is excreted in the urine A large dose os required - however there are no apparent side-effects

Question 35

How does sodium thiosulphate work in cyanide toxicity?

Answer 35

Binds cyanide to form thiocyanate, which is excreted in the urine. The reaction is slow and therefore cannot be used in isolation

Question 36

How does dicobalt edetate (EDTA) work in cyanide toxicity?

Answer 36

The cobalt ions bind cyanide in a similar manner to iron It may have a faster onset of action to the other antidotes however the relative cobalt-containing compounds limits the sue of EDTA to severe cases he co-administration of glucose may reduce the risk of EDTA toxicity

Question 37

What is the pharmacology of cyanide toxicity?

Answer 37

CO is produced by the incomplete combustion of carbon, which binds to Hb with an affinity of around 200 times greater than that of oxygen This causes a left-shift in the OHDC and impaired tissue oxygen delivery CO also binds to cytochrome oxidase, in a similar manner to cyanide, resulting in uncoupling of cellular respiration It probably also has a direct neurotoxic effect - particularly in chronic exposure

Question 38

What are the symptoms of carbon monoxide toxicity?

Answer 38

Primarily neurological - ranging from mild confusion to coma The classic cherry red appearance is uncommon COHb is routinely measured by ABG machines The level associated with symptoms varies widely - cigarette smokers frequently have COHb of 10% Levels over 40% are generally accepted to represent a life-threatening exposure Levels over 60% are commonly lethal

Question 39

What is the half-life of CO?

Answer 39

The half-life of CO in plasma is 4 hours whilst breathing room air 1 hour with 100% O2 25 mins when breathing 100% at 3 atm

Question 40

What is the treatment of CO toxicity?

Answer 40

Treatment is aimed at replacing the CO bound to Hb with oxygen

Question 41

What is paraquat?

Answer 41

Chemical contained in pesticide

Question 42

How does paraquat toxicity present?

Answer 42

Lethal dose is 15-20mls of 20% solution Onset of piton is fast Presents with abode pain and vomiting Corrosive effects - mouth, pharynx, oesophagus This is then typically followed by dyspnoea - secondary to cardiac pulmonary oedema, which quickly progresses to irreversible pulmonary fibrosis Cardiac, renal, and hepatic dysfunction also occur

Question 43

How is paraquat OD managed?

Answer 43

AC may reduce absorption Minimise oxygen exposure - high levels are thought to accelerate the fibrotic process Cyclophosphamide and methylprednisolone may reduce the pulmonary inflammatory response palliative care, however, may be the most appropriate approach

Question 44

What effects does iron toxicity have?

Answer 44

Effects at a sub cellular level | Free radical production impacts upon mitochondrial function and impairs the Kreb's cycle

Question 45

What are the clinical features of iron toxicity?

Answer 45

Direct musical injury leads to abode pain, vomiting, diarrhoea and haematemesis Early GI symptoms are commonly followed by a tent phase of around 24 hours In patients with severe toxicity this is followed by multi-organ failure - hypovolaemia, myocardial dysfunction, vasodilatation, iron-induced mitochondrial dysfunction may impair oxygen utilisation, iron inhibition of PT induces coagulopathy, heptatoxicty is common due to high iron levels in the portal circulation and the high metabolic activity of the liver - may progress to hepatic necrosis

Question 46

How is iron toxicity managed?

Answer 46

Supportive GI decontamination - whole bowel irrigation Deferoxamine is the antidote of choice - cheating agent that binds ferric iron to form ferrioxamine, a water-soluble compound excreted from the kidneys, it needs to be given early as it only binds within the plasma, associated with hypotension and the risk of ARDS

Question 47

How do beta blocker and calcium channel antagonist overdoses present?

Answer 47

hypotension bradycardia cardiac failure - may include decreased conscious level, syncope, kidney injury beta blockers may also cause hypoglycaemia calcium channel blockers may cause hyperglycaemia

Question 48

How are beta-blocker and calcium-channel antagonists overdoses managed?

Answer 48

Standard means of increasing cardiac output can be attempted but may have limited success e.g fluids, atropine for bradycardia, catecholamines, pacing, calcium chloride infusion Improvement in cardiac performance may be better achieved by manipulation of metabolic pathways 1. Glucagon - large doses increase intracellular cAMP concentrations via an adrenergic independent mechanism 2. Increasingly high dose insulin therapy is being used e.g. 0.5-1 unit/kg/hr titrated to cardiac effect with concurrent glucose administration

Question 49

How does digoxin exert its effects?

Answer 49

It's a cardiac glycoside It exerts its effects by: 1. anti-muscarinic activity leading to a slow AV conduction 2. Blockade of the sodium-potassium ATP-ase pump in the cardiac membrane - the resultant increase in the intracellular sodium leads to increased influx of calcium via the sodium-calcium pump - the increase in intracellular calcium has a positive inotropic effect

Question 50

Which common drugs may interact with digoxin and raise its plasma level?

Answer 50

Amoxicillin Clarythromycin Amiodarone Quinine

Question 51

How is digoxin excrete?

Answer 51

Renal | Therefore AKI may impair clearance

Question 52

Which electrolyte abnormalities potentiate the effects of digoxin?

Answer 52

Hypomagnesaemia Hypokalaemia Hypernatraemia Hypercalcaemia

Question 53

What are the symptoms of acute digoxin toxicity?

Answer 53

hypotension and bradycardia

Question 54

What ECG changes are associated with digoxin toxicity?

Answer 54

AV block Paroxysmal tachycardia with AV block Sinus bradycardia Ventricular tachycardia

Question 55

How is digoxin toxicity managed?

Answer 55

AC if within 2 hours of ingestion Atropine for bradycardia Digoxin specific antibody fragments bind free digoxin in the plasma, creating a concentration gradient down which tissue digoxin will move

Question 56

What are the indications for digoxin-specific antibody fragments (digoxin-Fab)?

Answer 56

Ingestion of > 10mg Chronic ingestion with a serum steady state level >6ng.ml Any arrhythmia, not responding to conservative measures Serum K >5.5 secondary to acute digoxin overdose Each vial binds 0.5 mg digoxin RRT is ineffective due to high volume of distribution and high protein binding

Question 57

Describe the pharmacology of lithium

Answer 57

Mood stabilising agent used in bipolar disorder Mechanism of action is unclear It's a monovalent cation that is rapidly absorbed and widely distributed to all body compartments, it's not protein bound. Excreted unchanged by the kidney Toxicity can be acute, acute on chronic or chronic

Question 58

What are the clinical features of lithium toxicity?

Answer 58

Ataxia, dysarthria, tremor, seizures, decreased LOC, N+V, diarrhoea, polyuria, AKI, nephrogenic diabetes insipidus (a common side-effect, even within therapeutic range)

Question 59

How is lithium OD managed?

Answer 59

Haemodyalisus clears lithium | Hyponatraemia impairs renal clearance of lithium and should therefore e avoided