Pharmacology of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

1. Introduction/Overview

Non-steroidal anti-inflammatory drugs (NSAIDs) constitute one of the most widely prescribed and utilized classes of therapeutic agents globally. These compounds are defined by their shared ability to inhibit cyclooxygenase (COX) enzymes, thereby reducing the synthesis of prostanoids, which are key mediators of inflammation, pain, and fever. The clinical importance of NSAIDs is underscored by their extensive use across numerous medical disciplines for the management of acute and chronic pain, inflammatory conditions such as rheumatoid arthritis and osteoarthritis, and fever. Their accessibility, both by prescription and as over-the-counter medications, necessitates a thorough understanding of their pharmacology among healthcare professionals to ensure their effective and safe application.

The therapeutic landscape of NSAIDs has evolved significantly since the clinical introduction of aspirin over a century ago. The subsequent discovery of the COX-2 isoform in the early 1990s led to the development of selective COX-2 inhibitors, fundamentally altering the understanding of NSAID mechanisms and their associated adverse effect profiles. This chapter provides a systematic examination of NSAID pharmacology, intended to equip medical and pharmacy students with the foundational knowledge required for rational therapeutic decision-making.

Learning Objectives

• Describe the biochemical mechanism of action of NSAIDs, including the differential inhibition of COX-1 and COX-2 isoforms, and relate this to their therapeutic and adverse effects.
• Classify major NSAIDs based on chemical structure, COX selectivity, and pharmacokinetic properties, and explain the clinical implications of these classifications.
• Outline the pharmacokinetic principles governing NSAID absorption, distribution, metabolism, and excretion, and apply these principles to dosing regimens and special populations.
• Analyze the spectrum of therapeutic applications for NSAIDs, from approved indications to common off-label uses, while weighing their benefits against potential risks.
• Identify major adverse effects, contraindications, and drug interactions associated with NSAID therapy, and formulate monitoring and mitigation strategies for patients.

2. Classification

NSAIDs can be classified according to several overlapping schemas, including chemical structure, pharmacokinetic profile, and selectivity for cyclooxygenase enzyme isoforms. These classifications provide a framework for understanding drug properties and predicting clinical behavior.

Chemical Classification

The chemical backbone of an NSAID is a primary determinant of its pharmacologic properties. Major chemical classes include:

• Salicylates: Characterized by a salicylic acid moiety. Acetylsalicylic acid (aspirin) is the prototypical agent, which uniquely causes irreversible acetylation of COX enzymes. Other examples include diflunisal and salsalate.
• Acetic Acid Derivatives: Also known as arylacetic or indoleacetic acids. This heterogeneous group includes diclofenac, indomethacin, ketorolac, and etodolac. They tend to be potent anti-inflammatory agents.
• Propionic Acid Derivatives: This large class features a chiral carbon, with the S-enantiomer typically responsible for COX inhibition. Examples include ibuprofen, naproxen, ketoprofen, flurbiprofen, and oxaprozin. They are widely used for their favorable analgesic and anti-inflammatory effects.
• Enolic Acid (Oxicam) Derivatives: Characterized by a long elimination half-life, allowing for once-daily dosing. Piroxicam and meloxicam are primary examples, with meloxicam demonstrating some COX-2 selectivity.
• Fenamic Acids (Fenamates): Derivatives of anthranilic acid. Mefenamic acid and meclofenamate are examples, though their use is often limited by a higher incidence of gastrointestinal and other adverse effects.
• Non-Acidic Compounds: Nabumetone is a prodrug that is metabolized to an active acetic acid derivative. Its non-acidic nature may contribute to reduced local gastrointestinal irritation.
• Selective COX-2 Inhibitors (Coxibs): A class defined by high selectivity for the COX-2 isoform. Celecoxib, etoricoxib, and parecoxib (a parenteral prodrug of valdecoxib) are key agents. Rofecoxib and valdecoxib have been withdrawn from many markets due to cardiovascular safety concerns.

Classification by COX Isoform Selectivity

Based on their relative inhibition of COX-1 versus COX-2, NSAIDs are often categorized as:

• Non-Selective NSAIDs: Inhibit both COX-1 and COX-2 with comparable potency. Most traditional NSAIDs (e.g., ibuprofen, naproxen, diclofenac, indomethacin) fall into this category. Diclofenac and naproxen may show a slight preference for COX-2, but are generally considered non-selective.
• Preferential COX-2 Inhibitors: Inhibit COX-2 with 5- to 50-fold greater potency than COX-1. Meloxicam and etodolac are often placed in this intermediate category.
• Selective COX-2 Inhibitors (Coxibs): Exhibit more than 100-fold selectivity for COX-2 over COX-1 at therapeutic concentrations. Celecoxib and etoricoxib are contemporary examples.

It is critical to recognize that selectivity is a concentration-dependent continuum rather than an absolute dichotomy.

3. Mechanism of Action

The principal mechanism of action for all NSAIDs is the inhibition of the cyclooxygenase (COX) activity of prostaglandin endoperoxide synthase (PGHS). This enzyme catalyzes the committed step in prostanoid biosynthesis: the conversion of arachidonic acid to prostaglandin G₂ (PGG₂) and its subsequent reduction to prostaglandin H₂ (PGH₂). PGH₂ serves as the substrate for specific synthases that produce the downstream effector prostanoids, including prostaglandins (e.g., PGE₂, PGI₂), thromboxane A₂ (TXA₂), and prostacyclin.

Cyclooxygenase Isoforms: COX-1 and COX-2

Two major isoforms of COX exist, encoded by distinct genes and differing in expression patterns and regulation.

• COX-1: Often described as a constitutive or “housekeeping” enzyme. It is expressed in most tissues, including platelets, gastric mucosa, vascular endothelium, and renal collecting ducts. Its products are involved in physiological homeostasis, such as gastric cytoprotection (via PGE₂ and PGI₂), platelet aggregation (TXA₂), and renal blood flow regulation.
• COX-2: Primarily an inducible enzyme, upregulated at sites of inflammation by cytokines (e.g., interleukin-1, tumor necrosis factor), growth factors, and endotoxins. It is responsible for producing the prostanoids that mediate pain, fever, and inflammatory responses. COX-2 is also constitutively expressed in certain tissues, including the brain, kidney, and reproductive tract, where it participates in normal physiological functions.

Molecular Mechanism of Inhibition

NSAIDs inhibit COX by reversibly or irreversibly blocking the access of arachidonic acid to the active site within a long, hydrophobic channel of the enzyme. The specific interaction varies by drug class:

• Irreversible, Time-Dependent Inhibition: Aspirin uniquely acetylates a serine residue (Ser529 in human COX-1, Ser516 in COX-2) near the active site, permanently inactivating the enzyme. In platelets, which are anucleate and cannot synthesize new protein, this results in a functional deficit lasting the lifetime of the platelet (7-10 days). The acetylation of COX-2 also alters its catalytic activity, leading to the production of 15-hydroxyeicosatetraenoic acid (15-HETE) and, in some cells, anti-inflammatory lipoxins.
• Reversible, Competitive Inhibition: Most traditional NSAIDs (e.g., ibuprofen) bind reversibly and competitively with arachidonic acid in the active site. Their duration of action is closely linked to their pharmacokinetic half-life.
• Slow, Tight-Binding Inhibition: Some NSAIDs, such as flurbiprofen, diclofenac, and the coxibs, exhibit a more complex kinetic behavior. They bind reversibly but with very high affinity and a slow off-rate, resulting in a long-lasting inhibition that may persist beyond the drug’s plasma half-life.

Consequences of COX Inhibition

The therapeutic and adverse effects of NSAIDs are direct consequences of reduced prostanoid synthesis.

• Analgesic Effect: Mediated primarily by inhibition of COX-2 at peripheral sites of injury, reducing the production of PGE₂ and PGI₂. These prostaglandins sensitize peripheral nociceptors to the action of other mediators like bradykinin and histamine, lowering their activation threshold.
• Anti-inflammatory Effect: Results from decreased formation of pro-inflammatory prostaglandins (PGE₂, PGI₂) and thromboxanes at the site of inflammation, leading to reduced vasodilation, edema, and leukocyte infiltration.
• Antipyretic Effect: Exerted within the hypothalamic thermoregulatory center. Pyrogens induce COX-2, leading to increased PGE₂ synthesis, which raises the hypothalamic set-point. NSAIDs lower fever by inhibiting this central PGE₂ production.
• Antiplatelet Effect: Caused by inhibition of platelet COX-1, the primary source of thromboxane A₂ (TXA₂), a potent promoter of platelet aggregation and vasoconstriction. Aspirin’s irreversible effect is unique and forms the basis for its use in cardiovascular prophylaxis.
• Gastrointestinal Toxicity: Largely due to inhibition of constitutively expressed COX-1 in the gastric mucosa, which reduces the synthesis of cytoprotective prostaglandins (PGE₂ and PGI₂) that stimulate mucus and bicarbonate secretion and maintain mucosal blood flow.
• Renal Effects: In the kidney, both COX-1 and COX-2-derived prostanoids (particularly PGI₂ and PGE₂) are involved in maintaining renal blood flow, glomerular filtration rate (GFR), and electrolyte balance, especially in states of decreased effective circulating volume. Their inhibition can lead to fluid retention, hypertension, and acute kidney injury.

4. Pharmacokinetics

The pharmacokinetic profiles of NSAIDs are diverse, influencing their dosing frequency, time to onset of action, and suitability for different patient populations. Most NSAIDs are weak organic acids with pK_a values between 3 and 5.

Absorption

Following oral administration, most NSAIDs are rapidly and extensively absorbed from the gastrointestinal tract, primarily in the stomach and small intestine. Their weak acidic nature promotes absorption in the acidic gastric environment. Food may delay the rate of absorption, particularly for some agents like diclofenac and naproxen, but usually does not significantly reduce the overall extent of absorption (bioavailability). Enteric-coated and sustained-release formulations are available to minimize local gastric irritation or to provide prolonged effect. A few NSAIDs, such as ketorolac and parecoxib, are available for parenteral administration, providing a rapid onset of analgesia useful in postoperative settings.

Distribution

NSAIDs are generally highly plasma protein-bound (>95%), primarily to albumin. This high degree of binding has several implications. It limits their volume of distribution, typically to around 0.1-0.2 L/kg. It also creates a potential for displacement interactions with other highly protein-bound drugs (e.g., warfarin, sulfonylureas), though the clinical significance of such displacement alone is often minor. Due to their lipophilicity, NSAIDs distribute well into synovial fluid, inflamed tissues, and the central nervous system. Concentrations in synovial fluid may be sustained longer than in plasma, which may correlate with prolonged clinical effect.

Metabolism

Hepatic metabolism is the principal route of elimination for the vast majority of NSAIDs. The specific metabolic pathways are varied:

• Phase I Oxidation: Primarily via cytochrome P450 (CYP) enzymes. CYP2C9 is a major isoform involved in the metabolism of many NSAIDs, including ibuprofen, diclofenac, celecoxib, and naproxen. CYP2C19 and CYP3A4 also contribute to the metabolism of some agents.
• Phase II Conjugation: Glucuronidation is a significant pathway for several NSAIDs (e.g., naproxen, ketoprofen). The glucuronide conjugates of some arylacetic acids (like diclofenac) are chemically reactive and have been implicated in rare cases of idiosyncratic hepatotoxicity.
• Prodrugs: Some NSAIDs are administered as inactive prodrugs. Nabumetone is metabolized to its active form, 6-methoxy-2-naphthylacetic acid. Sulindac is a prodrug reduced to its active sulfide metabolite.

Genetic polymorphisms in metabolizing enzymes, particularly CYP2C9, can lead to significant inter-individual variability in drug exposure and response.

Excretion

Elimination occurs predominantly via the kidneys, either as unchanged drug or, more commonly, as inactive metabolites. For most NSAIDs, less than 10% of a dose is excreted unchanged in urine. Renal clearance is influenced by urine pH for some agents; alkaline urine can increase the ionization and excretion of acidic NSAIDs. Biliary excretion and enterolepatic recirculation occur with several NSAIDs (e.g., diclofenac, indomethacin, piroxicam), which can contribute to their long half-lives and potentially to gastrointestinal toxicity.

Half-life and Dosing Considerations

The elimination half-life (t_1/2) of NSAIDs ranges from approximately 1-2 hours (ibuprofen, diclofenac) to over 50 hours (piroxicam). This parameter is the primary determinant of dosing frequency.

• Short Half-life (t_1/2 < 6 hours): Ibuprofen (2 h), diclofenac (1-2 h), ketoprofen (2 h). These agents typically require dosing 3 to 4 times daily for sustained anti-inflammatory effect, though their analgesic effect may be shorter.
• Intermediate Half-life (t_1/2 6-12 hours): Naproxen (12-15 h), etodolac (7 h). Usually administered twice daily.
• Long Half-life (t_1/2 > 12 hours): Piroxicam (50 h), meloxicam (20 h), celecoxib (11 h), nabumetone (24 h). Suitable for once-daily dosing, which may improve adherence.

It is noteworthy that the pharmacodynamic duration of action, particularly for drugs exhibiting tight-binding inhibition, may exceed the pharmacokinetic half-life.

5. Therapeutic Uses/Clinical Applications

NSAIDs are employed across a broad spectrum of medical conditions, primarily for symptom relief. They are not disease-modifying agents but are highly effective for managing pain, inflammation, and fever.

Approved Indications

• Analgesia: NSAIDs are first-line agents for mild to moderate acute pain (e.g., postoperative pain, dental pain, musculoskeletal injuries, dysmenorrhea) and chronic pain conditions like osteoarthritis and chronic low back pain. Ketorolac is notable for its potent analgesic efficacy, comparable to some opioids, and is used for short-term management of moderately severe acute pain.
• Anti-inflammatory Therapy: A cornerstone in the management of inflammatory arthropathies, including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and acute gouty arthritis. They reduce joint swelling, tenderness, and morning stiffness.
• Antipyresis: Effective for reducing fever in adults and children, though aspirin is avoided in children and adolescents with viral illnesses due to the risk of Reye’s syndrome.
• Antiplatelet Therapy: Low-dose aspirin (75-325 mg daily) is indicated for the secondary prevention of cardiovascular and cerebrovascular events (myocardial infarction, stroke) and for primary prevention in selected high-risk individuals. Its irreversible platelet inhibition is unique among NSAIDs.
• Closure of Patent Ductus Arteriosus (PDA): Intravenous ibuprofen or indomethacin is used in preterm neonates to promote closure of a hemodynamically significant PDA by inhibiting locally produced prostaglandins that maintain ductal patency.

Common Off-Label Uses

• Pericarditis: Aspirin or other NSAIDs (e.g., ibuprofen) are used as first-line therapy to relieve pain and inflammation in acute pericarditis, often in combination with colchicine.
• Migraine Headache: Certain NSAIDs, such as ibuprofen, naproxen, and diclofenac potassium, are effective for the acute treatment of migraine attacks.
• Cancer Prevention: Long-term use of aspirin has been associated with a reduced risk of colorectal cancer and possibly other gastrointestinal cancers, leading to its consideration for chemoprevention in specific high-risk populations.
• Prevention of Heterotopic Ossification: Indomethacin or other NSAIDs are used prophylactically following total hip arthroplasty or other major orthopedic procedures to reduce the formation of ectopic bone.

The choice of a specific NSAID is often based on the balance between desired therapeutic effect (e.g., analgesia vs. anti-inflammation), dosing convenience, individual patient risk factors (especially GI and CV risk), cost, and prior response.

6. Adverse Effects

The inhibition of physiologically important prostaglandins underlies the major adverse effect profile of NSAIDs, which can affect multiple organ systems. The risk is influenced by drug-specific factors (e.g., COX selectivity, half-life), dose, duration of therapy, and patient-specific risk factors.

Gastrointestinal Adverse Effects

Gastrointestinal toxicity is the most common adverse effect of non-selective NSAIDs, ranging from dyspepsia to life-threatening complications.

• Dyspepsia and Gastric Erosions: Common, occurring in up to 20% of users, but poorly correlated with the presence of serious mucosal injury.
• Peptic Ulcer Disease and Complications: NSAID use increases the risk of gastroduodenal ulcers, bleeding, perforation, and obstruction by 3- to 5-fold. Risk factors include advanced age (>65 years), history of ulcer or GI bleeding, concomitant use of corticosteroids, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs), high-dose or multiple NSAID therapy, and serious systemic disease.
• Mechanisms: The topical irritant effect of acidic drugs contributes minimally; the primary mechanism is systemic inhibition of COX-1-derived mucosal prostaglandins, compromising mucosal defense. COX-2 selective inhibitors (coxibs) demonstrate a significantly lower incidence of endoscopic ulcers and symptomatic GI events compared to non-selective NSAIDs.

Renal Adverse Effects

Renal prostaglandins are crucial for maintaining renal blood flow in states of compromised intravascular volume (e.g., heart failure, cirrhosis, dehydration, chronic kidney disease).

• Fluid and Electrolyte Disturbances: Sodium and water retention, edema, hypertension, and hyperkalemia (due to suppressed renin release).
• Acute Kidney Injury (AKI): Typically a hemodynamically mediated, reversible pre-renal azotemia. Risk is heightened in patients with existing renal impairment, volume depletion, or concomitant use of other nephrotoxic agents.
• Interstitial Nephritis and Papillary Necrosis: Less common, idiosyncratic reactions, often associated with prolonged, high-dose use. Phenacetin, now rarely used, was classically associated with analgesic nephropathy.

COX-2 selective inhibitors appear to confer similar risks of renal impairment as non-selective NSAIDs, as COX-2 is constitutively expressed in the kidney.

Cardiovascular Adverse Effects

All NSAIDs, with the possible exception of naproxen, have been associated with an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke.

• Mechanism: Inhibition of vascular endothelial COX-2 reduces the synthesis of prostacyclin (PGI₂), a potent vasodilator and inhibitor of platelet aggregation, without concomitantly inhibiting platelet COX-1-derived thromboxane A₂ (TXA₂). This creates a pro-thrombotic, pro-hypertensive imbalance. This risk is inherent to the pharmacologic class.
• Risk Magnitude: The risk appears to be dose- and duration-dependent, and is highest in patients with established cardiovascular disease or multiple risk factors. The cardiovascular risk associated with coxibs prompted the withdrawal of rofecoxib and valdecoxib.
• Hypertension and Heart Failure: NSAIDs can elevate blood pressure and antagonize the effects of antihypertensive drugs (e.g., ACE inhibitors, diuretics, beta-blockers). They can also precipitate or exacerbate heart failure due to fluid retention.

Hepatic Adverse Effects

Elevations in serum transaminases (up to three times the upper limit of normal) occur in approximately 15% of patients taking NSAIDs and are usually asymptomatic and reversible. Idiosyncratic, clinically significant hepatotoxicity is rare but can be severe. Diclofenac is associated with a slightly higher risk of hepatotoxicity, potentially related to the formation of reactive acyl glucuronide metabolites.

Other Adverse Effects

• Central Nervous System: Headache, dizziness, tinnitus (especially with high-dose aspirin), aseptic meningitis (particularly with ibuprofen in patients with systemic lupus erythematosus), and cognitive dysfunction in the elderly.
• Hematologic: All NSAIDs (except aspirin) reversibly inhibit platelet aggregation, prolonging bleeding time. Aplastic anemia and agranulocytosis are rare idiosyncratic reactions.
• Hypersensitivity Reactions: NSAIDs can precipitate bronchospasm, urticaria, or angioedema, particularly in patients with asthma, chronic urticaria, or nasal polyps (a triad known as aspirin-exacerbated respiratory disease – AERD). This reaction is not IgE-mediated but is due to shunting of arachidonic acid metabolism towards leukotriene production when the COX pathway is blocked.
• Skin Reactions: Photosensitivity (especially with piroxicam and ketoprofen), Stevens-Johnson syndrome, and toxic epidermal necrolysis (rare).

Black Box Warnings

In many regulatory jurisdictions, NSAIDs carry a class-wide black box warning highlighting the following risks:

• Increased risk of serious gastrointestinal bleeding, ulceration, and perforation, which can be fatal. These events can occur at any time during use and without warning symptoms.
• Increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may increase with duration of use and in patients with cardiovascular disease or risk factors.
• Risk of serious renal events, including acute kidney injury, which may progress to renal failure.

7. Drug Interactions

NSAIDs participate in numerous pharmacokinetic and pharmacodynamic drug interactions, many of which are clinically significant.

Major Pharmacodynamic Interactions

• Anticoagulants (Warfarin, DOACs) and Antiplatelet Agents: NSAIDs increase the risk of bleeding through multiple mechanisms: additive antiplatelet effects (reversible inhibition), potentiation of warfarin effect via pharmacokinetic interactions, and induction of gastric erosions. The concurrent use of NSAIDs with warfarin or other anticoagulants requires extreme caution and close monitoring.
• Antihypertensive Agents: NSAIDs can attenuate the blood pressure-lowering effects of ACE inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, and diuretics by inhibiting renal prostaglandin-mediated vasodilation and promoting sodium retention. This interaction is particularly problematic with thiazide and loop diuretics, whose efficacy is reduced.
• Corticosteroids (e.g., Prednisone): Concomitant use significantly multiplies the risk of peptic ulcer disease and gastrointestinal bleeding.
• Selective Serotonin Reuptake Inhibitors (SSRIs): SSRIs impair platelet function and increase the risk of upper gastrointestinal bleeding when combined with NSAIDs.
• Other NSAIDs, including Low-Dose Aspirin: Concurrent use of two or more NSAIDs (including over-the-counter products) increases toxicity without enhancing efficacy. The concomitant use of ibuprofen (and possibly naproxen) may interfere with the antiplatelet cardioprotective effect of low-dose aspirin by competitively blocking access to platelet COX-1.

Major Pharmacokinetic Interactions

• Lithium: NSAIDs can reduce renal clearance of lithium by up to 60%, potentially leading to lithium toxicity. This effect is due to inhibition of renal prostaglandins, which normally promote lithium excretion. Close monitoring of serum lithium levels is mandatory.
• Methotrexate: NSAIDs may reduce the renal tubular secretion of methotrexate, potentially increasing its plasma concentration and toxicity, particularly with high-dose methotrexate regimens used in oncology. The risk with low-dose weekly methotrexate for rheumatoid arthritis is lower but still warrants caution.
• Cyclosporine and Tacrolimus: The combination with NSAIDs synergistically increases the risk of nephrotoxicity.
• Drugs Metabolized by CYP2C9: NSAIDs that are substrates (e.g., celecoxib) or inhibitors (e.g., fluconazole co-administered with an NSAID) of CYP2C9 can interact with other drugs metabolized by this enzyme, such as phenytoin, warfarin, and some sulfonylureas.

Contraindications

Absolute contraindications to NSAID therapy include:

• Active peptic ulcer disease or recent gastrointestinal bleeding.
• History of hypersensitivity (asthma, urticaria, angioedema) to aspirin or any other NSAID.
• Severe renal impairment or active kidney disease.
• Third trimester of pregnancy (risk of premature closure of the fetal ductus arteriosus and delayed labor).
• Coronary artery bypass graft (CABG) surgery (peri-operative period for oral NSAIDs).

8. Special Considerations

Use in Pregnancy and Lactation

• Pregnancy (First and Second Trimester): NSAIDs are generally not recommended as first-line analgesics. If use is necessary, it should be at the lowest effective dose for the shortest duration. NSAIDs are classified as FDA Pregnancy Category C (first and second trimester) and Category D (third trimester).
• Pregnancy (Third Trimester): Contraindicated. NSAID use after 30 weeks of gestation is associated with a risk of premature closure of the fetal ductus arteriosus, leading to pulmonary hypertension. They may also inhibit uterine contractions, leading to delayed parturition and an increased risk of postpartum hemorrhage.
• Lactation: Most NSAIDs are considered compatible with breastfeeding, as they are excreted in breast milk in very low concentrations. Ibuprofen is often the preferred agent due to its extensive safety data. Aspirin is generally avoided due to theoretical risks of Reye’s syndrome and potential effects on platelet function in the infant.

Pediatric Considerations

Ibuprofen and naproxen are commonly used in children for fever and pain. Dosing is based on body weight. Aspirin is contraindicated in children and adolescents (<19 years) with febrile viral illnesses (especially influenza and chickenpox) due to the strong association with Reye's syndrome, a rare but severe condition characterized by acute encephalopathy and fatty liver degeneration. NSAIDs should be used cautiously in children with dehydration or compromised renal function.

Geriatric Considerations

Older adults are particularly susceptible to NSAID-related adverse effects due to age-related pharmacokinetic changes (reduced renal clearance, altered protein binding), increased prevalence of comorbidities (hypertension, heart failure, renal impairment, peptic ulcer disease), and polypharmacy. The principles of geriatric pharmacotherapy—”start low, go slow,” use the lowest effective dose for the shortest duration, and avoid if possible—are paramount. COX-2 selective inhibitors or non-selective NSAIDs with concomitant gastroprotection (proton pump inhibitor or misoprostol) may be considered in high GI-risk patients, but CV risk must be concurrently evaluated.

Renal Impairment

NSAIDs should be avoided in patients with moderate to severe renal impairment (eGFR < 30 mL/min/1.73m²). In patients with mild impairment or those at risk (e.g., elderly, heart failure), if use is unavoidable, agents with a short half-life and no active metabolites are preferred (e.g., ibuprofen over piroxicam). Dosing intervals may need to be extended. Renal function and fluid status should be monitored closely.

Hepatic Impairment

NSAIDs should be used with caution in patients with significant hepatic impairment (Child-Pugh Class B or C). Reduced albumin levels can increase the free fraction of highly protein-bound drugs, and impaired metabolism can lead to drug accumulation. Agents with significant hepatic metabolism (e.g., diclofenac, celecoxib, naproxen) may require dose reduction or avoidance. Monitoring of liver function tests is advisable.

9. Summary/Key Points

• NSAIDs exert their therapeutic effects (analgesic, anti-inflammatory, antipyretic) and many adverse effects through the inhibition of cyclooxygenase (COX) enzymes, thereby reducing prostanoid synthesis.
• Two main COX isoforms exist: constitutively expressed COX-1 (involved in homeostasis) and inducible COX-2 (primarily involved in inflammation). Drug selectivity for these isoforms influences the safety profile, particularly regarding gastrointestinal and cardiovascular risks.
• Pharmacokinetic properties, especially elimination half-life, vary widely among NSAIDs and dictate dosing frequency. Most are highly protein-bound, extensively metabolized in the liver, and renally excreted.
• Major therapeutic applications include management of pain (acute and chronic), inflammatory conditions, fever, and, for aspirin specifically, cardiovascular prophylaxis.
• The most significant adverse effects involve the gastrointestinal tract (ulcers, bleeding), cardiovascular system (increased thrombotic risk, hypertension), and kidneys (acute injury, fluid retention). These risks are class-wide but modulated by drug selectivity and patient factors.
• Numerous and potentially serious drug interactions exist, primarily pharmacodynamic with anticoagulants, antihypertensives, and corticosteroids, and pharmacokinetic with lithium and methotrexate.
• Special caution is required in vulnerable populations: NSAIDs are contraindicated in the third trimester of pregnancy, should be used judiciously in the elderly and those with renal/hepatic impairment, and aspirin is avoided in children with febrile illnesses.

Clinical Pearls

• No NSAID is completely free of cardiovascular risk. The choice of agent should involve an individualized assessment of gastrointestinal and cardiovascular risk factors.
• For patients at high gastrointestinal risk but low cardiovascular risk requiring chronic NSAID therapy, a COX-2 selective inhibitor or a non-selective NSAID combined with a proton pump inhibitor represents a rational strategy.
• Use the lowest effective dose for the shortest duration necessary to control symptoms. Regularly re-evaluate the need for continued therapy.
• Patient education is crucial: advise patients about over-the-counter NSAID use, the importance of not exceeding recommended doses, and the recognition of warning signs such as black stools, abdominal pain, swelling, or chest pain.
• When prescribing NSAIDs, consider drug interactions comprehensively, including over-the-counter medications and herbal supplements the patient may be taking.

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