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Acute and Emergency > Paracetamol and Salicylates OD > Flashcards

Paracetamol and Salicylates OD Flashcards

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Royal College: Emergency Medicine flashcards
1
Q

What legislation is in place to number of paracetamol tablets that can be bought at once?

A
  • 1998
  • Limits no. of tablets bought in one purchase
  • 16 tablets atm, up to 32 at pharmacies
  • Paracetamol supplied in blister packs - making obtaining tablets longer
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2
Q

What is paracetamol used for?

A

Most commonly used non-prescription analgesia

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3
Q

What is the therapeutic dose of paracetamol in adults?

A

1g QDS

Max 4g/day

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4
Q

What is the pharmacology of paracetamol?

A
  • After consumption, 95% of paracetamol undergoes glucuronidation (a form of metabolism) –> creates a water-soluble paracetamol conjugate that is eliminated in the urine.
  • Remaining 5% is metabolised using Cytochrome P450 enzymes INTO a toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI)
  • NAPQI binds to glutathione (protein in the body) –> becomes mercapturate derivative, which is a non-toxic metabolic that is excreted in the urine
  • After oral consumption, paracetamol is absorbed from stomach and small intestine
  • Mainly inactivated by liver by conjugation which leads to 2 metabolites; glucuronide or sulphate. This is then really excreted through urine.
  • In OD, liver becomes inundated and paracetamol is metabolise in another pathway. This leads to toxic metabolite this in itself is inactivated by glutathione, so it prevents harm.
  • But when glutathione stores are depletesd to less than 30%, the NAPQI reacts with nucleophilic aspects of the cell leading to necrosis (in liver and kidney tubules)
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5
Q

What is the pharmacology of paracetamol outside therapeutic doses?

A
  • Outside therapeutic doses, the production of NAPQI can significantly exceed the body’s detoxification capacity due to the finite amount of glutathione available (finite amount of glutathione to bind to the NAPQI)
  • Excess NAPQI binds to the hepatocytes causing mitochondrial injury and, in severe cases, may cause acute liver failure or even death.
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6
Q

What are causes of paracetamol OD?

A

Intentional (eg. self-harm)

Unintenional (eg. therapeutic excess error)

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7
Q

What are the types of paracetamol OD?

A

Acute OD
- Excess amounts of paracetamol ingested in < 1 hr
- Usually in the context of self-harm

Staggered OD
- Excess amounts of paracetamol ingested in > 1 hr
- Usually in the context of self-harm

Therapeutic Excess
- Excess paracetamol ingested with the intent to treat pain or fever and without the intent of self-harm

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8
Q

What is the therapeutic excess of paracetamol defined as?

A

Amount ingested is above the licenses daily dose
AND
75mg/kg in 24 hrs or more

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9
Q

What amounts of paracetamol ingested are likely to cause severe liver damage?

A

< 150 mg/kg - unlikely

> 250mg/kg - likely

> 12g total - potentially fatal

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10
Q

Can paracetamol occur from different products?

A

OD can involve excessive doses of the same paracetamol product or the inadvertent use of multiple paracetamol-containing products simultaneously.

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11
Q

Can paracetamol OD result from normal use?

A

Yes, rarely

Due to idiosyncratic differences between individuals’ enzyme activities during the metabolism process

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12
Q

What are RF’s for paracetamol OD and why?

A
  • Hx of self-harm
  • Hx of frequent or repeated use of medication for pain relief
  • Low body weight (< 50 kg) - can cause unintentional OD
  • Cytochrome P450 inducers - increase risk of liver injury after OD
  • Glutathione deficiency
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13
Q

What patients are at increased risk of developing hepatotoxicity following a paracetamol OD?

A

Pts taking liver-enzyme inducing drugs eg:
- Rifampicin
- Phenytoin
- Carbamazepine
- Chronic alcohol excess
- St John’s Wort)

Malnourished patients (eg. Anorexia nervosa) or pts who haven’t eaten for a few days

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14
Q

What may be protective against hepatotoxicity?

A

acute alcohol intake, as opposed to chronic alcohol excess, is not a/w increased risk of developing hepatotoxicity and may actually be protective.

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15
Q

What are Cytochrome p450 inducers?

A

Phenytoin
Phenobarbital
Rifampicin
Primidone

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16
Q

What patients are at risk of glutathione deficiency?

A

eating disorders, alcohol-use disorder, psychiatric disorders, or chronic illnesses reducing nutritional intake

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17
Q

What do clinical features or Paracetamol OD depend on?

A

Ingestion method and time from overdose to presentation

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18
Q

What are the different ingestion methods?

A

Acute
Staggered
Acute on chronic

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19
Q

What is paracetamol often combined with and how may this affect presentation?

A

Paracetamol is often combined with opioids (e.g. codeine and dihydrocodeine); so a concomitant opioid toxidrome may be present.

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20
Q

What are typical early features of paracetamol OD?

A

< 12 hours

Potentially asymptomatic
N+V
Mild/moderate abdominal pain/tenderness

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21
Q

What are typical late features of a paracetamol OD?

A

12-36 hrs

Moderate/severe abdominal pain
Metabolic acidosis
Jaundice
AKI
Hepatic encephalopathy
Coma

Bruising or systemic haemorrhage may indicate coagulopathy secondary to impaired hepatic clotting factor production

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22
Q

What areas should be covered in a history?

A

Preparation ingested: combination, strength

Length of time the paracetamol products were ingested over

Time since ingestion

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23
Q

What investigations may be done?

A
  • Not all pts need investigation

Can do:
- Paracetamol concentration
- LFTs
- INR
- U & E’s
- Creatinine
ABG
- Plasma bicarbonate
- Plasma glucose
- FBC
- Clotting screen - PT indicates severity of liver failure

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24
Q

What must be said about the paracetamol concentration?

A

Some labs may underestimate paracetamol concentration by as much as 40% if the blood test is taken during treatment with acetylcysteine.

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25
Q

When is the paracetamol level taken?

A

4 hours post-ingestion
OR
as soon as patient arrives if:
- Time of overdose > 4hrs
- Staggered overdose

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26
Q

How often should the INR be checked?

A

12 hourly

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27
Q

When do paracetamol OD pts need to be referred?

A

Hospital assessment required if:
- The presence of sx (e.g. jaundice)
- Deliberate paracetamol OD for self-harm (regardless of dose)
- Ingested dose >75 mg/kg over 1 hour or less
- All staggered paracetamol overdoses

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28
Q

What does the management of a paracetamol OD depend on?

A

Type of OD (acute vs staggered)
Time since ingestion
Patient characteristics

Depends on severity and category of the overdose

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29
Q

What can be used to rationalise treatment?

A

As long as the time interval since ingestion is MORE THAN 4 hrs

Can use a paracetamol treatment graph

30
Q

What is the general treatment regimen for paracetamol OD?

A

Resuscitation - Maintain ABCDs

  • Activated charcoal if ingested < 1 hour ago
  • ?Gastric emptying
  • N-acetylcysteine (NAC)
  • Liver transplantation
31
Q

What patients may benefit from activated charcoal?

A

Those who present within 1 hour may benefit from activated charcoal to reduce absorption of the drug

32
Q

When should acetylcysteine be given?

A
  • Plasma paracetamol concentration is on or above a single treatment line joining points of 100 mg/L at 4 hours and 15 mg/L at 15 hours, regardless of risk factors of hepatotoxicity
  • There is a staggered overdose* or there is doubt over the time of paracetamol ingestion, regardless of the plasma paracetamol concentration

OR

  • Patients who present 8-24 hours after ingestion of an acute overdose of more than 150 mg/kg of paracetamol even if the plasma-paracetamol concentration is not yet available
  • Patients who present > 24 hours if they are clearly jaundiced or have hepatic tenderness, their ALT is above the upper limit of normal

Acetylcysteine should be continued if the paracetamol concentration or ALT remains elevated whilst seeking specialist advice

33
Q

What is considered to be a staggered OD?

A

if all the tablets were not taken within 1 hour

34
Q

How is acetylcysteine given?

A

Infused over 1 hour
(rather than the previous 15 minutes) to reduce the number of adverse effects

35
Q

What can an adverse effect of acetylcysteine be and how is this managed?

A
  • Commonly causes an anaphylactoid reaction (non-IgE mediated mast cell release).
  • Anaphylactoid reactions to IV acetylcysteine are generally treated by stopping the infusion, then restarting at a slower rate.
36
Q

when is acetylcysteine most effective?

A

Within 8 hrs of ingestion

37
Q

How does N-acetylcysteine work?

A

A precursor for glutathione, promoting normal conjugation of any remaining paracetamol

Also supplies thiols that function as antioxidants.

After 8 hours, efficacy decreases sharply

38
Q

How should paracetamol OD be calculated and managed during pregnancy?

A

Toxic dose should be calculated using the patient’s pre-pregnancy weight

Acetylcysteine dose should be calculated using the patient’s actual pregnant weight.

39
Q

When can treatment be stopped?

A

Patients should have repeat blood tests (including paracetamol concentration, INR, and LFTs) taken before the end of treatment with acetylcysteine.

Decisions around stopping treatment are complex and depend on the clinical situation.

Take advice from guidelines

40
Q

is a previous anaphylactic run to acetylcysteine a contraindication?

How can this be managed?

A

No

Prophylactic treatment with antihistamines should be considered in patients with a history of previous sensitivities to acetylcysteine.

41
Q

When is acetylcysteine more likely to cause adverse effects?

A

If paracetamol concentrations are low or absent

42
Q

What patients are adverse effects to acetylcysteine more common in?

A

Females
Asthmatics
Pts with FHx of allergy

43
Q

How should patients who have taken a deliberate overdose be managed?

A

Undergo a psychosocial assessment of their needs and risks by a specialist mental health professional.

Subsequent management dependent on this

44
Q

What are complications of paracetamol OD?

A

Common:
- N + V
- Abdominal pain

Severe:
- Acute liver failure
- Renal impairment
- Death

45
Q

What is the King’s College Hospital criteria for liver transplantation (paracetamol liver failure)

A

Arterial pH < 7.3, 24 hours after ingestion

or ALL of the following:
- prothrombin time > 100 seconds
- creatinine > 300 µmol/l
- grade III or IV encephalopathy

46
Q

What are salicylates?

A

Group of meds of which aspirin is most common

Other examples:
- NSAIDS
- Oil of wintergreen
- Certain antacids and antidiarrhoeal meds

47
Q

What is an intentional OD?

A

Means of causing self-harm or a suicide attempt

48
Q

How can salicylate OD happen unintentionally?

A

Many non-prescription aspirin-containing products are available, and many cold and flu remedies also contain aspirin, increasing the risk of patients unknowingly exceeding the safe dose

49
Q

What is the main thing salicylate OD leads to?

A

A mixed respiratory alkalosis and metabolic acidosis

Early stimulation of the respiratory centre leads to a respiratory alkalosis, whilst later the direct acid effects of salicylates (combined with acute renal failure) may lead to an acidosis.

In children - metabolic acidosis tends to predominate.

50
Q

What is the pathophysiology of mild salicylate toxicity?

A
  • Salicylates directly irritate the gastric lining.
  • Can also cause ototoxicity through a multifactorial process, involving reduced cochlear blood flow secondary to vasoconstriction and changes to cochlear cells.
51
Q

What is the pathophysiology of higher doses of salicylates?

A

In higher doses, the pharmacodynamics of salicylate poisoning leads to a mixed respiratory alkalosis and metabolic acidosis.

In moderate/severe toxicity, salicylates stimulate the cerebral medulla, leading to hyperventilation and respiratory alkalosis.

52
Q

How does salicylate OD lead to anaerobic metabolism and metabolic acidosis?

A

Metabolisation of salicylates causes uncoupling of oxidative phosphorylation, resulting in anaerobic metabolism.

This causes heat production and pyrexia and increased lactic acid production –> metabolic acidosis.

The acidic effects of salicylates also contribute to the associated acidosis.

Hyperventilation then worsens in response to the acidosis until the body can no longer compensate.

53
Q

What are features of a salicylate OD?

A

hyperventilation (centrally stimulates respiration)
tinnitus
lethargy
sweating, pyrexia*
nausea/vomiting
hyperglycaemia and hypoglycaemia
seizures
coma

54
Q

How do salicylates lead to pyrexia?

A

They cause the uncoupling of oxidative phosphorylation leading to decreased adenosine triphosphate production, increased oxygen consumption and increased carbon dioxide and heat production

55
Q

Salicylate OD sx - mild toxicity

A

N+V
Epigastric pain
Tinnitus
Dizziness
Lethargy

56
Q

Salicylate OD sx - moderate toxicity

A

Sweating
Fever
Dyspnoea
Hyperventialion
Confusion

57
Q

Salicylate OD sx - severe toxicity

A

Confusion
Convulsions
Coma
Hallucinations
Cerebral oedema
Pulmonary oedema

58
Q

What is the acid-based staging for salicylate OD?

A
59
Q

What are important areas to cover in a salicylate OD hx?

A

The amount and preparation of the salicylate taken

Intentional or accidental overdose

Isolated or mixed overdose

60
Q

Is considering a mixed OD important?

A

Yes, consider mixed OD in any pt presenting w acute drug toxicity

Pts may be unaware they have consumed toxic quantities of diff drugs

Management of toxidrome varies

61
Q

What are clinical findings in a mod-severe salicylate toxicity?

A

Warm peripheries and bounding pulse
Tachypnoea and hyperventilation
Cardiac arrhythmia
Acute pulmonary oedema

62
Q

What investigations may be done in salicylate OD? What should they monitor and what may they show?

A
  1. Obs - Tachypnoea and tachycardia common
  2. ECG - for arrhythmias. Monitor QRS duration and QT interval for prolongation
  3. Blood glucose - exlcude hypo or ketoacidosis. Hypo and hyper both may be seen in salicylate OD
  4. ABG - nitially, hyperventilation causes respiratory alkalosis, but this will then progress to metabolic acidosis with a partial respiratory compensation, with a normal or high pH.
  5. Plasma salicylate concentration
  6. Plasma paracetamol concentration - do in all pts to check for mixed OD
  7. FBC - to exclude infection
  8. U&E’s - electrolyte disturbances. Hyperkalaemia common. Urea and creatinine may be high (AKI)
  9. LFTs - for hepatic dysfunction
  10. Coagulation - INR and PT increased in hepatic dysfunction
63
Q

When is Plasma salicylate concentration measured?

A

At least 2 hrs after ingestion
Repeated every 2 hrs until the salicylate concentration peaks

64
Q

What imaging may be done in a salicylate OD and why?

A

CT head if pt has altered mental state and an intracranial pathology suspected

65
Q

How is salicylate OD classified?

A

According to clinical sx and peak salicylate levels:
Mild toxicity: <300 mg/L
Moderate toxicity: 300 - 700 mg/L
Severe toxicity: >700 mg/L

66
Q

How are salicylate OD’s managed?

A
  • ABCDE (if severe OD, can lose airway control)
  • No antidote!! SO mainly supportive care
  • Fluid resus
  • Potassium replacement with IV infusion, if hypokalaemia
  • Cooling measures to address hyperthermia
  • IV benzo’s to manage convulsions
  • CPAP if lung injury or pulmonary oedema
  • Psych support
  1. Activated charcoal (presenting within 1hr, ingested >125mg/kg)
    Can do second dose if plasma salicylate level continues to rise or who have taken enteric-coated preparations (absorption may be slower).

OR

Gastric lavage (presenting within 1he, ingested > 500mg/kg)

  1. Urinary alkalinization with IC sodium bicarbonate - enhances elimination of aspirin in the urine. Optimum uric pH is 7.5-8.5
  2. Haemodialysis - tx of choice in severe poisoning
67
Q

How does sodium bicarbonate work in salicylate OD?

A

Reduces the transfer of salicylates into the CNS and enhances the urinary excretion of salicylates (otherwise known as urinary alkalinisation).

Urine pH should be monitored with the optimal pH 7.5-8.5.

68
Q

What should be done before starting sodium bicarbonate?

A

Correct plasma potassium!

69
Q

What are indications for haemodialysis in salicylate OD?

A

serum concentration > 700mg/L
metabolic acidosis resistant to treatment
acute renal failure
pulmonary oedema
seizures
coma

70
Q

What patients should you be careful of haemodialysis in?

A
  • Plasma concentrations > 700 mg/L
  • AKI
  • Congestive cardiac failure
  • Non-cardiogenic pulmonary oedema
  • Coma
  • Convulsions
71
Q

What is the difference between haemodialysis and haemofiltration?

A

Haemodialysis
- Diffusion of solutes from high to low concentration across a semipermeable membrane.

Haemofiltration
- Uses convection and high pressure to force solutes from the blood to the dialysis fluid for disposal.
- Much slower

Haemodiafiltration combines the two processes.

Haemodiafiltration or haemodialysis alone should be used to remove salicylates from the plasma and correct the metabolic acidosis.

72
Q

What are complications of a salicylate OD?

A

ARDS
- bilateral pulmonary oedema with hypoxia, not explained by HF
- Mx: intubation and ventilation

Seizures
- Higher incidence with higher OD
- Benzo’s used for prolonged seizures

Drug-indued hepatitis

Cardiac arrest
- Prolonged QT interval regularly seen. Can –> Polymorphic VTach and/or VFib

Acute and Emergency (17 decks)

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