The pharmacology of NSAIDs is broad and diverse, yet the function of NSAIDs can be summarised quite neatly. NSAIDs have three principal effects: pain-killing (analgesic), fever-reducing (antipyretic), and anti-inflammatory effects (when administered at high doses). These three effects are highly advantageous in the clinical setting as so many patients are afflicted by one or more of these symptoms. For this reason, NSAIDs find use in conditions such as headache and migraine, to inflammatory arthritic conditions (ankylosing spondylitis, psoriatic arthritis), to postoperative pain, back pain, and gout – among many others.

Here, we’re going to take you through the pharmacology of NSAIDs, first looking at the various classes (and respective mechanisms), before going on to assess their contraindications, adverse effects, and pharmacokinetics.

Pharmacology of NSAIDs

There are many, diverse classes of NSAID – most of which can be found in the graphic below. NSAIDs – or nonsteroidal anti-inflammatory drugs – share a common mode of action, which involves inhibiting cyclooxygenase enzymes (COX enzymes, hereafter). Different NSAIDs inhibit COX isoenzymes – COX-1 and COX-2 – to different extents, and this differential mode of action among NSAIDs is what explains their differing adverse effect profiles (and, indeed, their therapeutic profiles). COX inhibition is vital, as it’s COX enzymes which are responsible for the generation of prostanoids – substances which consist of three main components:

  • Prostaglandins – responsible for inflammatory/anaphylactic reactions
  • Prostacyclins – active in resolution phase of inflammation
  • Thromboxanes – mediators of vasoconstriction

The therapeutic effect of NSAIDs not only depends on the NSAID chosen, but also the dose at which the NSAID is administered. At high doses, NSAIDs agonise peroxisome proliferator-activated receptor gamma (PPAR-γ) – PPARs being substances which modulate gene expression for the production of pro-inflammatory mediators such as TNFα, IL-1, and inducible nitric oxide synthase. Again, it’s worth emphasising that the different therapeutic response of NSAIDs depends wholly upon their selectivity for the various COX isoenzymes. The table below lists NSAIDs in accordance with their ability to selectively inhibit these isoenzymes:

NSAID Selectivity for COX Isoenzymes

The table above should only be considered an approximation of NSAID selectivity. NSAID pharmacology – given its diversity – mitigates against rash generalisations, but this is a sufficiently accurate representation of NSAID selectivity in the inhibition of COX isoenzymes. Most NSAIDs competitively inhibit (reversibly) both isoenzymes to some degree, though aspirin – as an exception – irreversibly inhibits its target. Before shuttling on toward the adverse effects of NSAIDs, we must first understand the differences between COX-1 and COX-2 isoenzymes – so what are they?

  • COX-1 is involved in many physiological processes – hence why it is referred to as a constitutively expressed. It plays a role, for instance, in protecting the stomach lining. COX-1 prevents the stomach mucosa from being eroded by gastric acid.
  • COX-2 is, in contrast to COX-1, only facultatively expressed – and is typically expressed during inflammatory states. It is by targeting this isoenzyme that NSAIDs demonstrate their anti-inflammatory effect.

Nonselective COX-1/COX-2 inhibitors – such as aspirin, ibuprofen, and naproxen – target COX-1 and, as a result, stomach prostaglandin levels are reduced. For this reason, gastrointestinal side-effects (see below) are considerably more common with these NSAIDs. NSAIDs also exert an antipyretic effect by inhibiting prostaglandin E2 synthesis from the hypothalamus – a prostanoid directly responsible for the onset of fever. Different NSAIDs have different capabilities at reducing prostaglandin E2 production: ibuprofen has been shown to have a greater antipyretic effect than paracetamol, for example.

(Paracetamol – or acetaminophen – is technically not considered an NSAID, as it has negligible anti-inflammatory powers. It does inhibit COX-2, but only in the central nervous system – hence why it is an effective analgesic.)


Adverse Effects and Drug Interactions

The pharmacology of NSAIDs is such that is leads to an assorted range of potential adverse effects.  These adverse effects range from the mild and moderate to the severe and downright dangerous. NSAIDs should be used with caution, for example, in patients with a history of gastrointestinal problems, and in patients who suffer from irritable bowel syndrome. This is because NSAIDs are associated with an increased risk of gastrointestinal bleeding and ulcer formation. Approximately 15 percent of patients’ experience dyspepsia on administration of NSAIDs, too.

There are other adverse effects worth considering:

  • Aspirin is associated with cardioprotective effects and is frequently prescribed for patients who have experienced a myocardial infarction. Taking aspirin with other NSAIDs decreases this cardioprotective effect over time.
  • NSAIDs themselves, particularly of the COX-2 selective variety, substantially increase the risk of myocardial infarction, stroke, and heart failure. Research suggests that naproxen may be the least damaging in this regard.
  • Some NSAIDs – such as indomethacin, piroxicam, and ketoprofen – are more likely to induce adverse gastrointestinal effects than other NSAIDs.
  • NSAIDs cause vasoconstriction of afferent renal arterioles of the glomeruli. This is because prostaglandins ordinarily cause vasodilation in these same arterioles. For this reason, NSAIDs may cause, or worsen, renal impairment and elimination of other drugs.
  • NSAIDs are not recommended during pregnancy as they may close the fetal ductus arteriosus. Some NSAIDs are used during pregnancy though such as aspirin and indomethacin (the latter of which may be used to treat polyhydramnios).

This is by no means an exhaustive list of NSAID adverse reactions, but it shines a clinical light on some of the most relevant. NSAIDs are also associated with their own range of potential drug interactions, some of which can be found below. We’ll only take a look at a select few as it links back to the pharmacology of NSAIDs discussed earlier:

  • NSAIDs interact with anticoagulant drugs – such as warfarin, as NSAIDs have a hypocoagulability effect.
  • NSAIDs interact with diuretics, not least because NSAIDs reduce renal blood flow.
  • NSAIDs inhibit elimination of drugs such as lithium and methotrexate.
  • NSAIDs reduce the therapeutic effect of antidepressants, such as SSRIs.
  • NSAIDs interact with ACE inhibitors, to the extent that the former may worsen high blood pressure.


Moving from the pharmacology of NSAIDs, to their adverse effects, and finally onto their pharmacokinetics. From a pharmacokinetic perspective most NSAIDs are defined as weak acids which, due to gastric pH partitioning, means some amount is absorbed from the stomach. The vast majority of the drug is, however, absorbed from the surface of the small intestine. Enteric-coated formulations of NSAIDs have been designed in order to limit exposure to the gastric mucosa – meaning gastrointestinal adverse effects are also limited.

Other drugs – such as diclofenac – have short half-lives, prompting formulators to design modified-release formulations. This prolongs diclofenac’s duration of action and, at the same time, reduces dosage frequency – thereby increasing patient compliance. Some NSAIDs are administered via parenteral routes – such as IV/IM – for rapid analgesia, not least ketorolac. Other NSAIDs – such as diclofenac – are also available rectally which helps bypass direct gastric irritation.

The vast majority of NSAIDs undergo hepatic metabolism to produce inactive metabolites. Their half-lives, though, differ considerably – with diclofenac having a short half-life of just 1-2 hours, compared to meloxicam which has a half-life of around 20 hours. As a result, those NSAIDs with short half-lives necessitate more frequent dosing when compared to NSAIDs with long half-lives. Piroxicam undergoes enterohepatic recycling, meaning its half-life is particularly long – up to 50 hours long. Aspirin is converted into an active metabolite – salicylic acid – and inactivated by conjugation with glycine and glucuronic acid. Aspirin has a half-life of 2-3 hours at low doses.

Test your knowledge of the pharmacology of NSAIDs with our latest quiz – ten questions based on all the material covered in this article.

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