Table of Contents · 6 sections
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drug classes in the world. Every physician, regardless of specialty, works with NSAIDs daily. On pharmacology exams, questions about the COX mechanism, selectivity, and side effects appear with a 100% probability. This article provides a comprehensive overview with tables, a selection algorithm, and clinical nuances.
Mechanism of action: COX-1 and COX-2
All NSAIDs inhibit the enzyme cyclooxygenase (COX), which converts arachidonic acid into prostaglandins:
- COX-1 is a constitutive enzyme. It operates continuously, performing 'housekeeping' functions: protection of the gastric mucosa (prostaglandin E₂), platelet aggregation (thromboxane A₂), and renal blood flow.
- COX-2 is an inducible enzyme. It is activated during inflammation and produces pro-inflammatory prostaglandins (PGE₂, PGI₂) that cause pain, swelling, and fever.
The ideal NSAID selectively blocks COX-2 (anti-inflammatory effect) and spares COX-1 (no side effects). In practice, absolute selectivity is unattainable.
Classification of NSAIDs by selectivity
| Type | Drugs | COX-1/COX-2 ratio | Features |
|---|---|---|---|
| Non-selective | Ibuprofen, diclofenac, ketorolac, indometacin, piroxicam | ~1:1 | Maximum GI side effects |
| Moderately COX-2 selective | Meloxicam, nimesulide | ~1:5-10 | Lower gastrotoxicity, a compromise |
| Highly COX-2 selective (coxibs) | Celecoxib, etoricoxib | >1:100 | Minimum GI effects, but ↑ cardiogenic risk |
| COX-1 selective | Aspirin (low doses) | 170:1 | Irreversible inhibition of platelet COX-1 → antiplatelet effect |
Main drugs: comparative table
| Drug | Analgesic potency | Anti-inflammatory | Gastrotoxicity | Features |
|---|---|---|---|---|
| Ibuprofen | ++ | ++ | + | Baseline NSAID, OTC, least toxic among non-selective |
| Diclofenac | +++ | +++ | ++ | Potent, but increases cardiovascular risk |
| Ketorolac | ++++ | ++ | +++ | Strongest analgesic among NSAIDs. Maximum 5 days! |
| Indometacin | +++ | ++++ | +++ | Strongest anti-inflammatory. Numerous side effects. |
| Meloxicam | ++ | +++ | + | Moderately selective. Taken once daily |
| Celecoxib | ++ | +++ | ± | Coxib. Minimal GI effects, but cardiovascular risk |
| Aspirin (325+ mg) | ++ | ++ | ++ | NSAID at high doses, antiplatelet at low doses (75-100 mg) |
Side effects of NSAIDs
Gastrointestinal tract (gastrotoxicity)
The most frequent side effect. COX-1 inhibition reduces the production of protective prostaglandin E₂ in the gastric mucosa. Result: erosions, ulcers, bleeding. Risk factors: age >65, history of peptic ulcer disease, concurrent use of anticoagulants, glucocorticoids.
Prevention: prescribing PPIs (omeprazole) in the presence of risk factors, using selective NSAIDs. Read more about peptic ulcer disease: diagnosis and treatment.
Kidneys (nephrotoxicity)
Prostaglandins maintain renal blood flow during hypovolemia. NSAIDs reduce glomerular filtration rate → AKI, sodium and water retention, hyperkalemia. Especially dangerous in the elderly, patients with CKD, or those taking ACE inhibitors/diuretics.
Cardiovascular system
All NSAIDs (except aspirin and naproxen) increase the risk of myocardial infarction and stroke. Coxibs do so to a greater extent. Rofecoxib (Vioxx) was withdrawn from the market in 2004 precisely due to cardiotoxicity.
Aspirin triad (Widal's syndrome)
Asthma + nasal polyposis + aspirin intolerance. Mechanism: COX blockade → excess leukotrienes → bronchospasm. All non-selective NSAIDs are contraindicated in such patients.
NSAID selection algorithm
- Determine the goal: analgesia, anti-inflammatory effect, or antiplatelet therapy
- Assess risk factors: GI (peptic ulcer?), kidneys (GFR?), heart (CHD, hypertension?)
- Low GI risk, low cardiovascular risk → ibuprofen or naproxen
- High GI risk, low cardiovascular risk → celecoxib or meloxicam + PPI
- High cardiovascular risk → naproxen (lowest cardiovascular risk) + PPI
- Severe pain (short-term) → IM ketorolac, maximum 5 days
Frequently asked questions
Can NSAIDs be taken during pregnancy?
NSAIDs are contraindicated in the third trimester as they cause premature closure of the fetal ductus arteriosus. In the first and second trimesters, use is restricted to strict indications. Exception: low-dose aspirin for preeclampsia prophylaxis (as prescribed by a physician).
How does aspirin differ from other NSAIDs?
Aspirin irreversibly acetylates platelet COX-1 (for the entire lifespan of the platelet, 7–10 days). Therefore, in low doses (75–100 mg), it is used as an antiplatelet agent rather than an NSAID.
Which NSAID is the safest?
There are no absolutely safe NSAIDs. For the GI tract: celecoxib. For the heart: naproxen. A compromise for most patients is ibuprofen at the minimum effective dose for a short course.
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