Mechanism of Action of Paracetamol
Paracetamol (acetaminophen) exerts its analgesic and antipyretic effects primarily through inhibition of prostaglandin synthesis in the central nervous system, with additional contributions from activation of descending serotonergic pathways and the endocannabinoid system. 1
Primary Mechanism: Central Prostaglandin Inhibition
The dominant mechanism involves inhibition of cyclooxygenase (COX) enzymes within the central nervous system and peripheral tissues, though the exact molecular target remains incompletely understood. 2, 1
COX Enzyme Targeting
Paracetamol acts as a reducing cosubstrate at the peroxidase (POX) site of prostaglandin H2 synthetase (PGHS), reducing availability of the ferryl protoporphyrin IX radical cation necessary for COX activity. 3
Recent evidence suggests paracetamol may inhibit a COX-1 variant enzyme rather than classical COX-1 or COX-2, as demonstrated by loss of antipyretic and hypothermic effects in COX-1 knockout mice but retention of these effects in COX-2 knockout mice. 4
The antipyretic effect specifically occurs through complete suppression of LPS-induced prostaglandin E2 elevation in the brain, independent of TRPA1-mediated hypothermia. 5
Why Peripheral Anti-inflammatory Effects Are Absent
- High peroxide tone in peripheral tissues and substrate swamping at the POX site explain paracetamol's lack of peripheral anti-inflammatory effect, platelet inhibition, and gastrointestinal toxicity compared to NSAIDs. 3
Secondary Mechanisms
Endocannabinoid System Activation
- Paracetamol is metabolized to p-aminophenol, which conjugates with arachidonic acid via fatty acid amide hydrolase (FAAH) to form AM404, an active metabolite that activates cannabinoid CB1 receptors and TRPV1 channels. 6, 3, 7
Serotonergic Pathway Modulation
- Paracetamol activates descending serotonergic inhibitory pathways to mediate central analgesic effects, though direct binding to serotonergic molecules has not been demonstrated. 1, 6, 3
Additional Ion Channel Effects
Paracetamol influences transient receptor potential (TRP) channels, voltage-gated Kv7 potassium channels, and inhibits T-type Cav3.2 calcium channels, though clinical relevance remains unclear. 7
It also impacts L-arginine in the nitric oxide (NO) synthesis pathway. 7
Metabolism and Toxicity Mechanism
Paracetamol is metabolized by cytochrome P450 enzymes to N-acetyl-p-benzoquinoneimine (NAPQI) when intracellular glutathione stores become saturated. 2
High doses lead to centrilobular hepatocyte necrosis due to NAPQI accumulation, which is independent of administration route (oral, rectal, or intravenous). 2, 8
Clinical Implications
Comparison with NSAIDs
Unlike NSAIDs, paracetamol shares COX pathway inhibition but lacks significant peripheral prostaglandin blockade, resulting in minimal gastrointestinal, cardiovascular, and renal toxicity at therapeutic doses. 1, 9
Paracetamol is preferred over NSAIDs in cirrhosis because NSAIDs carry unacceptable risks of acute renal failure, hepatorenal syndrome, and gastrointestinal bleeding. 8
Common Pitfalls
Do not assume paracetamol works identically to NSAIDs—the lack of peripheral anti-inflammatory effects means it is ineffective for conditions requiring prostaglandin inhibition at sites of inflammation. 3
Do not exceed 4 grams daily (or 3 grams in chronic use or cirrhosis) to avoid NAPQI-mediated hepatotoxicity. 8
Account for all sources of paracetamol, including combination products, as the hepatotoxic mechanism is route-independent and cumulative. 8