Mechanism of action
From a chemical perspective, acetaminophen is a weak acid (pKa 9.5) capable of donating a proton. It is an active metabolite of phenacetin.
The main mechanism of action is inhibition of cyclooxygenase (COX). Unlike classical nonsteroidal anti-inflammatory drugs, the drug blocks the enzyme predominantly in the central nervous system. In addition, it is hypothesized that the drug's effect on the serotonergic and cannabinoid systems of the brain contributes to its analgesic effect.
Pharmacological effects and indications
The drug produces two pronounced pharmacological effects:
- Analgesic (pain relief).
- Antipyretic (fever-reducing).
Critically important: acetaminophen completely lacks anti-inflammatory activity. In terms of clinical efficacy in reducing fever and relieving pain, it is comparable to acetylsalicylic acid (Acidum acetylsalicylicum).
Indications for prescription:
- Reduction of fever in febrile conditions.
- Relief of pain syndrome: headache, myalgia, neuralgia, joint pain.
Metabolism and biotransformation
The metabolism of Paracetamolum is a complex process occurring in the liver and involving several biotransformation pathways:
- Microsomal oxidation (N-oxidation): Carried out by endoplasmic reticulum enzymes (cytochrome P-450 system). Isoenzymes CYP1A2 and CYP2E1 are involved in the metabolism.
- CYP1A2 is diet- and environment-dependent: induced by tobacco smoke components, fried foods, cruciferous vegetables, as well as drugs (omeprazole, rifampicin, phenobarbital). Inhibited by antibiotics (ciprofloxacin, macrolides) and cimetidine.
- CYP2E1 is closely linked to alcohol metabolism. Induced by chronic ethanol intake (Spiritus aethylicus) and isoniazid. Inhibited by disulfiram and ritonavir.
- Biosynthetic reactions (Conjugation): The drug undergoes glucuronidation (forming glucuronic acid esters or amides) and sulfation (forming sulfates).
Toxicology and side effects
At therapeutic doses, the drug is safe and side effects are rare. However, acetaminophen has a narrow therapeutic window: the toxic dose exceeds the therapeutic dose by only 3 times.
Pathogenesis of poisoning (toxification): During microsomal oxidation (mainly via CYP2E1), a reactive and highly toxic intermediate metabolite is formed — N-acetyl-p-benzoquinone imine. Under normal conditions, it is rapidly detoxified in the cytosol by the enzyme glutathione-S-transferase through conjugation with glutathione.
In case of overdose or induction of the CYP2E1 enzyme (e.g., in chronic alcoholism or isoniazid intake), the formation of the toxic metabolite increases sharply. This leads to the depletion of glutathione stores. The free metabolite causes severe toxic damage — hepatocyte necrosis (hepatotoxic effect) and kidney damage.
Antidote therapy: In case of poisoning, emergency administration of sulfhydryl group donors (acetylcysteine, methionine) is necessary. The drugs are effective only within the first 12 hours after poisoning, as they replenish glutathione stores to inactivate the metabolite.
Formulations and prescription guidelines
According to the prescription reference book, the drug is administered orally.
- Dosage form: 0.2 g tablets.
- Dosing regimen: Orally, 1-2 tablets 4 times a day.
- Maximum Single Dose (MSD): 0.5 g.
- Maximum Daily Dose (MDD): 1.5 g.
Briefly: answers to topical questions
What are the absolute contraindications for prescribing paracetamol?
Absolute contraindications for prescribing paracetamol (Paracetamolum) are liver disorders and chronic alcoholism. Chronic alcohol consumption induces the CYP2E1 isoenzyme, which increases the risk of liver damage when taking paracetamol.
In what pharmaceutical dosage forms is paracetamol available for children?
For children, paracetamol is available in the following dosage forms:
- infusion solution — contraindicated in the neonatal period, up to 1 month;
- rectal suppositories — used from 3 months;
- oral suspension — used from 3 months.
PARAcetamol: Liver (hepatotoxicity), Analgesic, Disrupts COX in the CNS, Antipyretic (without anti-inflammatory effect).
Class and exam questions
Why doesn't acetaminophen relieve inflammation?
The drug inhibits cyclooxygenase predominantly in the central nervous system. It has virtually no effect on prostaglandin synthesis in peripheral tissues, which is why it lacks anti-inflammatory activity.
What is the danger of combining paracetamol and alcohol?
Chronic ethanol intake acts as an inducer of the CYP2E1 isoenzyme. This leads to the accelerated formation of the toxic metabolite (N-acetyl-p-benzoquinone imine), rapid glutathione depletion, and a high risk of liver necrosis even at therapeutic doses.
How does the antidote work in case of overdose?
Acetylcysteine and methionine are sulfhydryl group donors. They replenish depleted stores of endogenous glutathione, which is required for binding and inactivating the toxic metabolite.
What else to study on this topic
- Microsomal oxidation and the cytochrome P-450 system (CYP1A2, CYP2E1)
- Conjugation reactions: glucuronidation and sulfation
- The role of glutathione and glutathione-S-transferase in xenobiotic detoxification
- The phenomenon of toxification during drug metabolism
- Differences between non-narcotic analgesics and classical NSAIDs
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