Pharmacology of paracetamol

This chapter is relevant to no specific section from the 2017 CICM Primary Syllabus, but paracetamol is nonetheless relevant, for many reasons not the least of which is its continued reappearance in the CICM exams (both First Part and Second). These were:

  • Question 1 from the first paper of 2008 (First Part)
  • Question 5 from the first paper of 2014 (First Part)
  • Question 12 from the second paper of 2021 (Second Part)
  • Question 9 from the first paper of 2014 (Second Part)

Both the groups of questions all ask essentially the same thing, i.e. they mainly deal with paracetamol toxicity and its management. The main difference is that the first part questions also ask about its pharmacology, whereas the second part questions usually add some clinical patient history with which to distract the candidate.

Name Paracetamol
Class NSAID?..
Chemistry Para-aminophenol derivative
Routes of administration oral, IV, PR
Absorption Rapidly absorbed; oral bioavailability ~ 80%
Solubility pKa 9.5; moderately soluble (equally badly in water and lipid)
Distribution VOD = 0.9L/kg; 15-20% protein bound
Target receptor Molecular targets are uncertain
Metabolism Hepatic metabolism: major pathway is glucouronidation and sulfation;
minor pathway involves the formation of a toxic metabolite (NAPQI) which needs to be detoxified by conjugation with gluathione
Elimination All products of metabolism are renally excreted
Time course of action Half life of paracetamol is only about 2 hours
Mechanism of action Mechanism of analgesic effect of paracetamol is unclear, and is likely a combination of "effects on prostaglandin production, and on serotonergic, opioid, nitric oxide (NO), and cannabinoid pathways". (Sharma & Mehta, 2014)
Clinical effects Analgesia; co-anagesic effect with other agents; vasodilation when given IV; antipyrexial effect
Single best reference for further information TGA PI document


  • Most paracetamol is metabolised by glucouronidation and sulfation
  • Some (~5%) is metabolised by CYP2E1
  • In the course of this, superoxide and NAPQI are generated
  • In the presence of ample glutathione, NAPQI is rapidly detoxified by conjugation
  • In the presence of massive overdose, glutathione is rapidly depleted
  • As NAPQI levels increase, it binds covalently to numerous proteins, causing toxicity
  • Of particular interest is the uncoupling of oxidative phosphorylation, which results in a failure of ATP synthesis, lactic acidosis, and the release of ionised calcium from mitochondrial stores
  • The consequence of this is hepatocellular apoptosis and necrosis.
  • Supplementation with N-acetylcysteine replenishes glutathione and permits rapid NAPQI detoxification 

Google "pharmacology of paracetamol" and you will get a dozen high-quality resources, all free and vying for your attention. For the CICM trainee, there is little to discriminate between them, other than their length (as they all basically contain the same information, just arranged in different ways and with more or fewer filler words). If one had to recommend a single review, it would be Prescott (1980), which offers a satisfactory brief coverage of the pharmacokinetics and pharmacodynamics.  Graham et al (2013) is also excellent but very long and filled with the sort of digressions and rabbit holes that would infuriate the pragmatic exam candidate, or completely derail the study plan of an easily distracted one. 

Chemical properties and relatives of paracetamol

Paracetamol, or acetaminophen in the US and Canada, is a p-aminophenol derivative  (specifically, it is N-acetyl-para-aminophenol). For whatever reason the US and Canada went with the aminophen part of the chemical name, and the rest of the world went with the para and acetyl. Aminophenols in general are not especially interesting chemicals - they are just a bunch of phenol rings with an amine group in different positions, and paracetamol is a para-aminophenol with an acetyl group hanging off:

paracetamol and the aminophenols

It is of course pointless to discuss these chemicals, as their properties are completely unlike those of paracetamol (for example, p-aminophenol is a rather toxic developer agent used in photography). It is twice as pointless to also show their chemical formulae, as no CICM trainee will ever need to sketch them. Multiplying the pointlessness yet further (is it cubed now?), paracetamol may also be grouped along with COX-inhibiting non-steroidal antiinflammatory agents, except it has no direct anti-inflammatory effects, and is chemically completely dissimilar from the rest of that class. It defies classification, such that even deciding where to put a chapter discussing paracetamol was difficult.  Ultimately, it was felt that the reader should have access to it in the same section as the discussion of the organ it damages most, mainly because normal paracetamol use is much less important for the CICM exam candidate than paracetamol misuse.

Pharmacokinetics of paracetamol

Paracetamol can be administered orally, as it has excellent oral bioavailability, or as an intravenous solution. Suppositories are also available, and are probably safer, as one might expect them to carry a lower risk of overdose. 


Paracetamol is well-absorbed from the intestinal tract. It is highly dependent on stomach emptying rate, as none of it absorbs in the stomach, and together with readily available laboratory monitoring, this has made paracetamol an excellent marker substance with which to measure gastric emptying rate. Oral bioavailability is generally reported as 70-90%


Forrest et al (1982) reported that paracetamol is distributed fairly evenly throughout the body, with a volume of distribution of about 0.9L/kg. With a pKa of 9.5, most paracetamol is not ionised in the body fluids. Only about 15-20% of it is protein-bound, mainly to red cells, and the rest is reluctantly dissolved in water.


From the exam perspective, this is the value-loaded mark scoring part. There are two main pathways for the metabolism of paracetamol. If you want to do things the easy way, you add a glucouronide sugar moiety or a sulfate group to the original molecule, forming a relatively benign water-soluble metabolite. Glucouronidation accounts for 50% of the total disposal and sulfation for 35%, but oxidation reduction and hydrolysis can also occur as a part of Phase I metabolism (Zhao et al, 2011). These reactions are all functionally the same: they produce some inoffensive molecule which is of minimal interest to the exam candidate.

The more interesting metabolite is generated when there is an excess of paracetamol. In that scenario, a minority CYP450-dependent metabolic pathway becomes prominent, which typically accounts for less than 5% of the total paracetamol clearance. This pathway generates superoxide anions and  N-acetyl-p-benzo-quinone imine, or NAPQI. Unless there is enough glutathione around to conjugate with NAPQI, the accumulation of this metabolite leads to all manner of cellular damage, mainly stemming from covalent bonds which appear to form between NAPQI and various essential cellular proteins (for example, enzymes responsible for oxidative phosphorylation). The liver is not the only organ to take a critical hit from this - renal tubules can also become targets.

paracetamol toxicity flowchart with medium detail


Even though the first pass metabolism of paracetamol is relatively unimpressive, it is cleared quite rapidly from the blood, perhaps because it is not very protein-bound. The plasma half-life is 2-4 hours, according to Prescott (1980). Only about 5% of the drug can escape unchanged in the urine, and the rest is metabolised rapidly in the liver, exiting through the kidneys as glucouronide and sulfate metabolites.

Pharmacodynamics of paracetamol

Paracetamol is grouped along with NSAIDs even though its own antiinflammatory activity is rather minimal. The main reason for this is that the analgesic effect of paracetamol is thought to be exerted by COX inhibition, even though the downstream effect is not locally anti-inflammatory in the same way as, for example, diclofenac or indomethacin might be. Paracetamol will not reduce the swelling in your arthritic joints, nor will it give you gastric ulcers. The mechanism of action is not very well understood, and to recognise this seems to be a major part of answering an exam question on paracetamol.  CICM examiners appear to be suggesting that some of the candidates might have scored extra marks because they acknowledged that there is no clear answer ("the uncertain nature ... of the mechanism of action of paracetamol was alluded to in better responses")

Analgesic effects

A recent review article by Przybyła et al (2021) points at some known molecular behaviours of paracetamol which could be used to explain its analgesic effect:

  • COX-2 dependent peripheral mechanism: though paracetamol does not cause clinically relevant suppression of COX activity (to the point where it would interfere with gastric mucosa or platelet function), there is some evidence that it has COX-inhibitory peripheral effects. Yes, reader, it looks like it might have even reduced the inflammation from something, eg. from oral surgery. Without going into extensive detail, it appears paracetamol would be a pretty good nonselective COX inhibitor if it were not for the abundance of hydrogen peroxide (H2O2) in the extracranial sites of inflammation, which maintains COX activity (as it is essential for the ongoing availability of oxygen molecules). With abundant peroxide, the peripheral tissue concentration of paracetamol (not much above 100 μmol/L after a 1g dose) is about ten times lower than what would be necessary to have anti-inflammatory activity.
  • COX-3 dependent central mechanism: Paracetamol appears to selectively inhibit COX-3, an isoform of the cyclooxygenase enzyme which is mainly expressed in the brain. This may have some impact on the central processing of pain.
  • Endocannabinoid mechanism: Paracetamol may act on this neuromodulation system by some roundabout way. Mice lacking endocannabinoid receptors did not benefit from the analgesic effects of paracetamol, for example. 
  • Transient receptor potential (TRP) channels in peripheral nociceptors are the mechanotransducers and chemotransducers responsible for some of the sensation of pain, inflammation and heat. They are, for example, responsible for some of the sensory effects of menthol, wasabi and chilli. Paracetamol might interfere with their function in some subtle way.
  • Effect on Cav3.2 calcium channels which are T-type calcium channels and which seem to be involved in the modulation of cellular excitability. Again, knockout mouse modelling seems to be the main reason to believe that paracetamol has some influence on this system
  • Nitric oxide synthesis is supposedly inhibited in the presence of paracetamol, suggesting it has some influence over NO-mediated neurotransmission.
  • NAPQI enhances the activity of Kv7 potassium channels, which might hyperpolarise dorsal horn neurons.
  • Serotonergic effect: it appears that the effects of paracetamol are inhibited by 5-HT antagonists

The reader should be cautioned that none of these have been measured directly, and most are inferences and speculations from unrelated animal research. When there's seven different competing theories as to how something works, you can be fairly sure that the topic remains poorly understood.

Antipyretic effects

Paracetamol is often prescribed as an antipyretic, i.e. it is though to lower the body temperature of a febrile patient. Leaving aside discussions of clinical efficacy (it does however appear to be effective), the mechanism of action here seems to be a COX-related inhibition of prostaglandin synthesis, specifically PGE2, in the hypothalamus (Mirrasekhian et al, 2018). A more elaborate explanation, which is entirely unnecessary for exam purposes, can be reviewed at the chapter on the pharmacological control of temperature and shivering.

Haemodynamic effects

Paracetamol acts as an arteriodilator, particularly when given IV. Kelly et al (2016) and Chiam et al (2016) produced some data to support the idea that this is an effect entirely independent of the supposed mannitol diuresis (as most paracetamol IV formulations come with mannitol as an excipient). SVRI clearly decreased in the patients infused with paracetamol. The mechanism appears to be related to the activity of paracetamol metabolites on the abovementioned K7v potassium channels (van der Horst et al, 2020)


Graham, Garry G., et al. "The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings." Inflammopharmacology 21.3 (2013): 201-232.

Jefferies, Sarah, Manoj Saxena, and Paul Young. "Paracetamol in critical illness: a review." Critical Care and Resuscitation 14.1 (2012): 74-80.

Prescott, L. F. "Kinetics and metabolism of paracetamol and phenacetin." British journal of clinical pharmacology 10.S2 (1980): 291S-298S.

Willems, Marleen, A. Otto Quartero, and Mattijs E. Numans. "How useful is paracetamol absorption as a marker of gastric emptying? A systematic literature study." Digestive diseases and sciences 46.10 (2001): 2256-2262.

Kelly, S. J., et al. "Haemodynamic effects of parenteral vs. enteral paracetamol in critically ill patients: a randomised controlled trial." Anaesthesia 71.10 (2016): 1153-1162.

Forrest, John AH, J. A. Clements, and L. F. Prescott. "Clinical pharmacokinetics of paracetamol." Clinical pharmacokinetics 7.2 (1982): 93-107.

Zhao, Lizi, and Gisèle Pickering. "Paracetamol metabolism and related genetic differences." Drug metabolism reviews 43.1 (2011): 41-52.

Przybyła, Grzegorz W., Konrad A. Szychowski, and Jan Gmiński. "Paracetamol–An old drug with new mechanisms of action." Clinical and Experimental Pharmacology and Physiology 48.1 (2021): 3-19.

Mallet, Christophe, et al. "Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia." Pain 139.1 (2008): 190-200.

Tsaganos, Thomas, et al. "Randomized, controlled, multicentre clinical trial of the antipyretic effect of intravenous paracetamol in patients admitted to hospital with infection." British Journal of Clinical Pharmacology 83.4 (2017): 742-750.

Mirrasekhian, Elahe, et al. "The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1‐mediated hypothermia and is associated with prostaglandin inhibition in the brain." The FASEB Journal 32.10 (2018): 5751-5759.

Chiam, Elizabeth, et al. "The haemodynamic effects of intravenous paracetamol (acetaminophen) in healthy volunteers: a double‐blind, randomized, triple crossover trial." British journal of clinical pharmacology 81.4 (2016): 605-612.

van der Horst, Jennifer, et al. "Acetaminophen (paracetamol) metabolites induce vasodilation and hypotension by activating Kv7 potassium channels directly and indirectly." Arteriosclerosis, thrombosis, and vascular biology 40.5 (2020): 1207-1219.

Ouellet, Marc, and M. David Percival. "Mechanism of acetaminophen inhibition of cyclooxygenase isoforms." Archives of biochemistry and biophysics 387.2 (2001): 273-280.