Molecular and systemic mechanisms
The effects of most non-steroidal anti-inflammatory drugs (NSAIDs) are based on the inhibition of the cyclooxygenase (COX) enzyme. It catalyzes the conversion of arachidonic acid into thromboxanes and prostaglandins (Pg).
Two main isoforms of the enzyme are distinguished:
- COX-2 (inducible). Activated in response to an inflammatory process. Its inhibition provides the clinical effects we need: antipyretic, analgesic, and anti-inflammatory.
- COX-1 (constitutive). Present in the body constantly and performs protective physiological functions: maintains blood flow in the kidneys, protects the gastric mucosa, and regulates platelet aggregation. Inhibition of COX-1 underlies typical adverse reactions (nephrotoxicity and gastrotoxicity).
At the systemic level, drugs work in several directions simultaneously:
- Antipyretic effect: the synthesis of prostaglandin E2 (PGE2) directly in the hypothalamus decreases. Because of this, the "set point" of the thermoregulatory center returns to normal values, and body temperature drops.
- Analgesic effect: the production of prostaglandins that increase the sensitivity of peripheral pain receptors to inflammatory mediators (histamine, bradykinin) is reduced. In addition, drugs are able to cross the blood-brain barrier (BBB), providing a central analgesic effect.
- Anti-inflammatory effect: the production of mediators directly at the site of inflammation is inhibited in a dose-dependent manner.
Dose-dependence and pharmacokinetics (using aspirin as an example)
The clinical effect of acetylsalicylic acid strictly depends on the prescribed dose.
| Dose range | Predominant effect |
|---|---|
| Low (80–325 mg/day) | Antiplatelet |
| Moderate (500–1500 mg/day) | Antipyretic and short-term analgesic |
| High (>3000 mg/day) | Anti-inflammatory |
The drug is rapidly absorbed in the stomach and small intestine, reaching peak concentration in 1–2 hours, and easily crosses the BBB. An important pharmacokinetic feature: at therapeutic doses, the kinetics remain linear (half-life is about 3 hours). However, when high doses are prescribed, metabolic enzymes become oversaturated, kinetics change, and the half-life increases significantly—up to 15 hours.
Paracetamol metabolism and overdose risks
Paracetamol itself is a pharmacologically active metabolite of phenacetin (an obsolete and banned antipyretic agent due to high toxicity).
Unlike its predecessor, the paracetamol molecule initially contains a hydroxyl group (–OH). This allows the substance to bypass the dangerous stage of oxidative dealkylation (cleavage of the ethyl group), which produces toxic intermediates, and proceed directly to phase II detoxification in the liver—conjugation reactions. The resulting sulfates and glucuronides are highly water-soluble and rapidly excreted by the kidneys.
In paracetamol overdose, hepatic glutathione reserves are depleted. As a result, the toxic intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQI), formed with the participation of cytochrome CYP2E1, accumulates, leading to hepatocyte necrosis. Also, an overdose (or prolonged intake of phenacetin) can provoke the formation of methemoglobin. Acetylcysteine acts as a specific antidote, replenishing glutathione stores in the liver.
Rules for choosing antipyretics in pediatrics
The key criterion when prescribing symptomatic therapy for fever in children is minimizing the risk of severe adverse effects. Paracetamol is recognized as the safest and most reliable antipyretic.
- Dosage regimen: orally 10–15 mg/kg is prescribed, in rectal suppositories — 15–20 mg/kg. The maximum daily dose should not exceed 60 mg/kg.
- Release forms: liquid forms (syrups, soluble powders) are preferable to solid tablets, as they provide faster and more complete absorption.
- Limitations: the course of treatment should not exceed 3 days to prevent dose-dependent hepatotoxic effects.
A number of drugs in pediatrics are excluded from routine practice or strictly restricted due to specific life-threatening reactions:
- Acetylsalicylic acid (aspirin): since 1999, absolutely contraindicated in patients under 15 years of age against the background of acute viral infections (influenza, ARVI, chickenpox). The reason is the risk of developing hemorrhagic syndrome and severe Reye's syndrome (hepatocerebral insufficiency with a mortality rate of up to 50%).
- Metamizole sodium (analgin): capable of causing unpredictable and fatal bone marrow suppression (agranulocytosis). In many countries it has been withdrawn from circulation, and in the Russian Federation its use in children has been strictly controlled since 2000.
- Phenacetin, antipyrine, aminophenazone: highly toxic and not used as independent agents. However, they may be part of some older combination products (e.g., Cefekon suppositories), which requires special attention when taking a pharmacological history.
The "Three P" rule for safe temperature reduction in children: Paracetamol — Preferred drug, Pill for no more than 3 days.
Class and exam questions
Why do classical NSAIDs cause stomach ulcers and renal failure?
Most of them inhibit COX-1 — the enzyme that normally ensures the synthesis of protective prostaglandins (PGE2, PGI2). Without them, the gastrointestinal mucosa loses gastroprotection, and adequate blood flow in the kidneys is impaired.
What is the main danger of using analgin in children?
Metamizole sodium (analgin) has pronounced hematotoxicity. It can provoke unpredictable and potentially fatal bone marrow suppression — agranulocytosis. For this reason, its use in pediatrics is sharply limited.
How does the antidote work in paracetamol poisoning?
In paracetamol overdose, glutathione stores in the liver are depleted, leading to the accumulation of a toxic metabolite and hepatocyte necrosis. Administration of acetylcysteine restores glutathione levels and prevents liver destruction.
How does the half-life of aspirin change with increasing dose?
At therapeutic doses, the drug's kinetics are linear, and the half-life is about 3 hours. But at high doses, metabolic enzymes become saturated, which causes the half-life to increase to 15 hours.
What else to study on this topic
- Extended mechanism of action of NSAIDs using indomethacin as an example (effect on phospholipases A and C, inhibition of neutrophil proliferation).
- Pathogenesis of ulcerogenic action and nephrotoxicity development during COX-1 blockade.
- Mechanism of methemoglobin formation with prolonged phenacetin intake.
- The role of cytochrome CYP2E1 in the formation of the toxic metabolite NAPQI.
- Features of taking a pharmacological history when suspected use of outdated combination drugs.
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