Mechanism of action and pharmacodynamic triad
The therapeutic effect of NSAIDs is based on the inhibition of the cyclooxygenase (COX) enzyme, which disrupts the synthesis of prostaglandins (PGs). This provides three baseline clinical effects:
- Anti-inflammatory. Suppression of COX-2 activity reduces the local production of key inflammatory mediators—prostaglandins $D_2$, $E_2$, and prostacyclin ($I_2$).
- Analgesic (pain-relieving). Decreasing the concentration of $PGE_2$ protects pain receptors from sensitization (hypersensitization). As a result, receptors stop reacting acutely to chemical irritants such as histamine and bradykinin, which are abundantly released in the focus of inflammation. These drugs are most effective specifically for inflammatory pain.
- Antipyretic. The target is the thermoregulatory center in the anterior hypothalamus. Lowering $PGE_2$ levels triggers heat dissipation mechanisms: peripheral blood vessels dilate, and sweating increases. Important nuance: NSAIDs only reduce febrile (elevated) temperature and have no effect on normal body temperature.
Classification by selectivity
All drugs in this group are classified based on which specific COX isoforms they block, as well as the reversibility of their binding to the enzyme:
- Nonselective inhibitors (block COX-1 and COX-2):
- Irreversible action: salicylates (acetylsalicylic acid).
- Reversible action: propionic acid derivatives (ibuprofen, ketoprofen, naproxen), acetic acid derivatives (diclofenac, indomethacin, ketorolac), oxicams (piroxicam, meloxicam), pyrazolidines (phenylbutazone), and fenamates (mefenamic acid).
- Preferential COX-2 inhibitors: sulfonanilides (nimesulide).
- Selective COX-2 inhibitors: coxibs (celecoxib, rofecoxib).
Unique properties of aspirin
Acetylsalicylic acid is the historical standard and prototype of the entire NSAID group. Its precursors (natural salicylates) were extracted from willow bark (Salix) and meadowsweet (Spiraea, Filipendula ulmaria). The synthetic drug was developed by Felix Hoffmann in 1899.
The primary pharmacological difference of aspirin is its ability to inhibit COX irreversibly via acetylation. In low doses (80–325 mg/day), the drug exhibits a pronounced antiplatelet effect.
The mechanism is based on cellular differences:
- In platelets: aspirin irreversibly shuts down COX-1. Because platelets lack a nucleus, they cannot synthesize a new enzyme. The production of the pro-aggregant thromboxane $A_2$ ceases for the entire lifespan of the cell (3–7 days).
- In endothelial cells: vascular cells have a nucleus. They rapidly synthesize COX de novo and restore the production of prostacyclin ($PGI_2$), which inhibits aggregation.
As a result, the balance of clotting factors shifts toward protecting blood vessels from thrombosis.
Alternative metabolic pathway: lipoxygenase
In addition to the classical cyclooxygenase pathway, arachidonic acid can act as a substrate for another enzyme: 5-lipoxygenase. This cascade synthesizes a separate group of eicosanoids known as leukotrienes.
Leukotrienes are potent inflammatory mediators. They are actively involved in the pathogenesis of allergic reactions and play a significant role in the development of respiratory and cardiovascular diseases.
Therapy management strategy
The fundamental principle of pharmacology states: inflammation is viewed as a protective, evolutionarily developed response of the organism. Therefore, the pharmacological suppression of this process requires strict justifications.
Indications for prescribing NSAIDs include:
- High symptom severity (presence of severe, debilitating pain or dangerous hyperthermia).
- Prolonged course (transition of the inflammatory process into a chronic form).
- Specific pathogenesis (autoimmune nature of inflammation, where the immune system mistakenly attacks its own tissues).
Briefly: answers to topical questions
What side effects do nonselective COX inhibitors cause in the gastrointestinal tract?
Nonselective COX inhibitors cause NSAID-gastropathy. The main adverse effect is ulcerogenic action, manifesting as damage to the epithelium of the stomach and duodenum.
- Ulceration of the mucous membrane.
- Gastrointestinal bleeding—a risk of complication exacerbated by decreased platelet aggregation.
The pathogenesis of these disorders is associated with COX-1 inhibition, decreased synthesis of protective prostaglandins, reduced secretion of mucus and bicarbonates, and increased hydrochloric acid secretion.
What is the difference between the physiological functions of the COX-1 and COX-2 isoforms?
Cyclooxygenase isoforms perform fundamentally different roles in the body, determined by their expression patterns and synthesized products.
| Isoform | Expression type | Main physiological functions |
|---|---|---|
| COX-1 | Constitutive (constant) | Regulation of renal blood flow, gastroprotection, regulation of platelet aggregation, microcirculation, and uterine tone |
| COX-2 | Inducible | Expressed by inflammatory cells and triggered directly at the site of inflammation |
COX-1 blockade disrupts protective homeostasis, whereas COX-2 inhibition implements the anti-inflammatory effect of the drugs.
What is the mechanism of "aspirin-induced asthma" development when taking NSAIDs?
The mechanism of "aspirin-induced asthma" involves the blockade of the cyclooxygenase pathway of arachidonic acid metabolism by aspirin and NSAIDs. The accumulating arachidonic acid is redirected to the alternative lipoxygenase pathway. This results in the excessive synthesis of leukotrienes, which trigger bronchospasm in predisposed individuals.
Class and exam questions
Why do NSAIDs lower temperature only in fever?
The drugs act on the thermoregulatory center in the hypothalamus, which is stimulated by prostaglandins exclusively during an inflammatory process. At normal body temperature, this pathological mechanism is not engaged, so NSAIDs do not affect it.
What is the difference between the effect of aspirin on platelets and the endothelium?
Platelets lack a nucleus and cannot resynthesize the COX-1 enzyme after its irreversible blockade by aspirin. Vascular endothelial cells contain a nucleus, allowing them to rapidly resume enzyme synthesis and continue producing the antiplatelet agent prostacyclin.
How exactly do NSAIDs exert their analgesic effect?
They reduce the production of prostaglandin $E_2$. This prevents the sensitization (hypersensitization) of pain receptors to chemical irritants such as histamine and bradykinin, which are released in the focus of inflammation.
What else to study on this topic
- Chemical structure and structural heterogeneity of molecules of various NSAID groups.
- Detailed analysis of the arachidonic acid cascade and the role of phospholipase A2.
- Side effects of NSAIDs: gastropathy, nephrotoxicity, and cardiovascular risks.
- Historical stages of salicylate use from phytotherapy to synthetic pharmacology.
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