Arachidonic acid cascade and the pathogenesis of inflammation
Understanding the mechanism of action of NSAIDs (nonsteroidal anti-inflammatory drugs) is impossible without reviewing the arachidonic acid cascade. Upon cell damage, the enzyme phospholipase A2 cleaves a phospholipid from the cell membrane, forming arachidonic acid. Metabolism then proceeds via two pathways:
- Cyclooxygenase pathway (COX) — produces prostaglandins, thromboxanes, and prostacyclins.
- Lipoxygenase pathway (LOX) — produces leukotrienes A, B, C, D, E (ending in E, frequently with the index 4).
Leukotrienes act as chemoattractants, recruiting neutrophils that produce reactive oxygen species (superoxide, hydrogen peroxide). Hydrogen peroxide damages membranes anew, completing the vicious cycle of chronic inflammation.
Cyclooxygenase isoforms and the mechanism of action of NSAIDs
Fundamentally, a distinction is made between COX-1 and COX-2 (COX-3 also exists, but is neglected in basic models).
- COX-1 is a constitutive enzyme. It maintains the protective gastric mucosal layer, regulates renal blood flow via class E prostaglandins, and ensures the synthesis of thromboxane A2 in platelets for their aggregation.
- COX-2 is an inducible enzyme, activated during inflammation and determining the production of pro-inflammatory prostaglandins.
NSAIDs block COX reversibly or irreversibly. Aspirin (acetylsalicylic acid) inhibits COX irreversibly, which is particularly significant for platelets, producing a sustained antiplatelet effect. COX blockade diverts arachidonic acid into the lipoxygenase pathway, increasing leukotriene levels and the risk of bronchospasm in asthmatics.
Main pharmacological effects
Class E prostaglandins mediate three key processes: they increase pain receptor sensitivity, dilate blood vessels and cause edema, and shift the hypothalamic set point to increase thermogenesis. Therefore, suppressing their synthesis via NSAIDs provides four main effects:
- Analgesic — reduction of pain sensitivity.
- Anti-inflammatory — reduction of edema and hyperemia.
- Antipyretic — fever reduction.
- Antiplatelet — primarily seen with aspirin.
Adverse effects by organ system
- GI tract: ulcerogenic effect, NSAID-induced gastropathy, gastrointestinal bleeding due to blockade of mucosal protective prostaglandins.
- Cardiovascular system: elevated blood pressure (via activation of the RAAS due to decreased renal blood flow), increased risk of myocardial infarction with systemic use.
- Kidneys: decreased GFR, hyperkalemia, nephropathy due to impaired regulation of renal blood flow.
- Blood: thrombocytopenia, autoimmune hemolytic anemia (primarily with aspirin use).
- Liver: hepatotoxicity with elevated transaminases.
- Lungs: bronchospasm due to a compensatory increase in leukotriene levels ("aspirin-induced asthma").
- Nervous system: headache, dizziness.
- Skin: pruritus, rash, desquamation, rarely — allergic reactions up to toxic shock.
Classification and agents
Based on selectivity, NSAIDs are divided into non-selective and selective COX-2 inhibitors.
- Non-selective inhibitors: acetylsalicylic acid (aspirin), diclofenac, ibuprofen, naproxen, indometacin, piroxicam.
- Selective COX-2 inhibitors (coxibs): celecoxib, meloxicam — prolonged suppression of inflammation with relative preservation of the gastric mucosa.
- Non-acetylated salicylates: sodium salicylate — differ from the acetylated form (aspirin) by having less effect on platelets, kidneys, and bronchi.
One should also remember the group of DMARDs (Disease-Modifying Antirheumatic Drugs) — disease-modifying antirheumatic drugs aimed at halting tissue damage in chronic joint diseases.
Clinical selection of the drug
- Aspirin — primarily used as an antiplatelet agent for thrombosis prevention, not the drug of choice for routine analgesia due to toxicity.
- Ibuprofen — the drug of choice for tension headaches due to its optimal balance of efficacy and safety.
- Diclofenac — frequently used topically and for joint pain.
- Indometacin — the drug of choice for gouty arthritis.
- Celecoxib — for rheumatoid arthritis, osteoarthritis, and high risk of gastrointestinal bleeding (peptic ulcer disease).
- Sodium salicylate — for bronchial asthma and renal failure when aspirin and non-selective NSAIDs are contraindicated.
Key points
- NSAIDs block cyclooxygenase, reducing the synthesis of prostaglandins and thromboxanes.
- COX-1 is a constitutive enzyme protecting the stomach and kidneys and mediating platelet aggregation; COX-2 is an inducible enzyme of inflammation.
- Four main effects: analgesic, anti-inflammatory, antipyretic, antiplatelet.
- Rerouting arachidonic acid to the lipoxygenase pathway increases leukotriene levels and the risk of bronchospasm.
- Typical adverse effects: NSAID gastropathy, nephropathy with hyperkalemia, elevated blood pressure, hepatotoxicity, hematological disorders.
- Selective COX-2 inhibitors (celecoxib, meloxicam) are safer for the GI tract during long-term therapy.
- Non-acetylated salicylates are preferred in asthma and renal failure.
- Aspirin irreversibly inhibits COX and is used mainly as an antiplatelet agent.