Paracetamol
Reviewed and revised 11 November 2016
CLASS
- simple analgesic and antipyretic – not an NSAID as it lacks significant anti-inflammatory effects
- acetaminophen
MECHANISM OF ACTION
- Tissue- specific inhibitory effect on COX via a reduction reaction on the COX enzyme in the presence of a low peroxide environment
- CNS effects of paracetamol
- selective inhibition of cyclo-oxygenase (COX) and decreased prostaglandin production
- pro-drug of N-arachidonoylphenolamine (AM404)
- acts directly on vanilloid subtype 1 receptors
- acts indirectly on cannabinoid type 1 (CB1) receptors via decreased N-arachidonoylethanolamide uptake
- affects thermoregulatory and nociceptive pathways
- paracetamol may interact with opioid pathways
- synergistic analgesic effect at spinal and supraspinal levels (mu, delta and kappa receptors)
- Peripheral effects
- weak COX 1 & 2 inhibitor in peripheral tissues
- blocks impulse generation within the bradykinin-sensitive chemoreceptors to decrease afferent nociceptive impulses
- poor anti-inflammatory and antiplatelet properties and better side-effect profile than NSAIDs due to peroxide sensitivity
PHARMACEUTICS
- IV, PO, PR
- modified release formulation is available (e.g. panadol osteo)
DOSE
- 20mg/kg load -then 15mg/kg Q4-6hrly
- maximum = 90mg/kg/day or 4g daily
INDICATIONS
- analgesia
- anti-pyretic
ADVERSE EFFECTS
- transient LFT changes
- hepatotoxicity
- acute overdose
- repeated supratherapeutic ingestion
- can occasionally occur with conventional paracetamol dosing (e.g. malnourished state, chronic excessive alcohol consumption)
- IV paracetamol associated with hypotension in the critically ill (affects up to 1/4 ICU patients) (Kelly et al, 2016)
- pyroglutamic acidosis (rare), usually in patients with sepsis and renal impairment treated with flucloxacillin
- allergy (rare)
- hemolytic anaemia and methaemoglobinaemia are very rare
- interstitial nephritis and papillary necrosis do not occur (as they did with the paracetamol precursor phenacetin)
PHARMACOKINETICS
- Absorption
- rapid and complete from GI tract (gastric and small intestine) with peak blood concentrations at 30-60 min
- slower and incomplete if given rectally
- Distribution
- Vd 1L/kg (likely increased in critical illness)
- poorly protein bound
- non-ionised so penetrates BBB
- Metabolism
- hepatic via saturatable glucuronidation and sulphation pathways
- toxic metabolite NAPQI accumulates in overdose
- Elimination
- t ½ = 2 h
- relatively unaffected by renal function
EVIDENCE
- reduces temperature in fever by about 0.25C
References and Links
CCC Pharmacology Series
Respiratory: Bosentan, Delivery of B2 Agonists in Intubated Patients, Nitric Oxide, Oxygen, Prostacyclin, Sildenafil
Cardiovascular: Adenosine, Adrenaline (Epinephrine), Amiodarone, Classification of Vasoactive drugs, Clevidipine, Digoxin, Dobutamine, Dopamine, Levosimendan, Levosimendan vs Dobutamine, Milrinone, Noradrenaline, Phenylephrine, Sodium Nitroprusside (SNiP), Sotalol, Vasopressin
Neurological: Dexmedetomidine, Ketamine, Levetiracetam, Lignocaine, Lithium, Midazolam, Physostigmine, Propofol, Sodium Valproate, Sugammadex, Thiopentone
Endocrine: Desmopressin, Glucagon Therapy, Medications and Thyroid Function
Gastrointestinal: Octreotide, Omeprazole, Ranitidine, Sucralfate, Terlipressin
Genitourinary: Furosemide, Mannitol, Spironolactone
Haematological: Activated Protein C, Alteplase, Aprotinin, Aspirin, Clopidogrel, Dipyridamole, DOACs, Factor VIIa, Heparin, LMW Heparin, Protamine, Prothrombinex, Tenecteplase, Tirofiban, Tranexamic Acid (TXA), Warfarin
Antimicrobial: Antimicrobial Dosing and Kill Characteristics, Benzylpenicillin, Ceftriaxone, Ciprofloxacin, Co-trimoxazole / Bactrim, Fluconazole, Gentamicin, Imipenem, Linezolid, Meropenem, Piperacillin-Tazobactam, Rifampicin, Vancomycin
Analgesic: Alfentanil, Celecoxib, COX II Inhibitors, Ketamine, Lignocaine, Morphine, NSAIDs, Opioids, Paracetamol (Acetaminophen), Paracetamol in Critical Illness, Tramadol
Miscellaneous: Activated Charcoal, Adverse Drug Reactions, Alkali Therapies, Drug Absorption in Critical Illness, Drug Infusion Doses, Epidural Complications, Epidural vs Opioids in Rib Fractures, Magnesium, Methylene Blue, Pharmacology and Critical Illness, PK and Obesity, PK and ECMO, Sodium Bicarbonate Use, Statins in Critical Illness, Therapeutic Drug Monitoring, Weights in Pharmacology
Toxicology: Digibind, Flumazenil, Glucagon Therapy, Intralipid, N-Acetylcysteine, Naloxone, Propofol Infusion Syndrome
Journal articles
- Jefferies S, Saxena M, Young P. Paracetamol in critical illness: a review. Critical care and Resuscitation. 14(1):74-80. 2012. [pubmed]
- Kelly SJ, Moran JL, Williams PJ, et al. Haemodynamic effects of parenteral vs. enteral paracetamol in critically ill patients: a randomised controlled trial. Anaesthesia. 71(10):1153-62. 2016. [pubmed]
- Young P, Saxena M, Bellomo R. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. The New England journal of medicine. 373(23):2215-24. 2015. [pubmed] (aka HEAT trial)
Critical Care
Compendium
Chris is an Intensivist and ECMO specialist at The Alfred ICU, where he is Deputy Director (Education). He is a Clinical Adjunct Associate Professor at Monash University, the Lead for the Clinician Educator Incubator programme, and a CICM First Part Examiner.
He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives. He was one of the founders of the FOAM movement (Free Open-Access Medical education) has been recognised for his contributions to education with awards from ANZICS, ANZAHPE, and ACEM.
His one great achievement is being the father of three amazing children.
On Bluesky, he is @precordialthump.bsky.social and on the site that Elon has screwed up, he is @precordialthump.
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