What is the mechanism of action of mefenamic acid (Nonsteroidal Anti-Inflammatory Drug (NSAID)) in a patient with asthma and Chronic Obstructive Pulmonary Disease (COPD)?

Mechanism of Action of Mefenamic Acid

Mefenamic acid inhibits both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, thereby blocking prostaglandin synthesis, which mediates its analgesic, anti-inflammatory, and antipyretic effects. 1

Core Pharmacological Mechanism

• Mefenamic acid is a potent, non-selective inhibitor of prostaglandin synthesis by blocking both COX-1 and COX-2 isoforms, preventing the conversion of arachidonic acid to prostaglandins. 1, 2

• Prostaglandins sensitize afferent nerves and potentiate bradykinin-induced pain in animal models, so their inhibition reduces pain perception. 1

• The anti-inflammatory action results from decreased prostaglandin production in peripheral tissues, as prostaglandins are key mediators of inflammation. 1

• Mefenamic acid achieves therapeutic plasma concentrations (10-20 mcg/mL after a 1-gram dose) that produce measurable in vivo effects consistent with its in vitro potency. 1

Critical Safety Considerations in Asthma and COPD

Use mefenamic acid with extreme caution in patients with asthma, particularly those with nasal polyps or recurrent sinusitis, as it can trigger severe bronchospasm through COX-1 inhibition. 3, 4

Respiratory Risk Stratification

• Aspirin-exacerbated respiratory disease (AERD) affects 7-21% of adults with asthma, representing a pseudoallergic reaction mediated by COX-1 inhibition that shunts arachidonic acid metabolism toward the leukotriene pathway. 3, 4, 5

• The prevalence of NSAID-induced bronchospasm is 0.07% in the general population but increases dramatically to 21% in adults with asthma, especially those with nasal polyps or chronic rhinosinusitis. 3

• High cross-reactivity exists among all COX-1 inhibiting NSAIDs, meaning patients who react to aspirin will likely react to mefenamic acid and other non-selective NSAIDs. 4, 5

Cardiovascular and Respiratory Complications

• NSAIDs, including mefenamic acid, increase the risk of atrial fibrillation, particularly in new users and patients with respiratory disease (asthma/COPD), with a relative risk of 3.67 (95% CI: 1.96-6.88). 3

• NSAIDs may increase AF risk through renal and cardiovascular actions that elevate blood pressure and plasma volume while reducing the antiarrhythmic effects of prostacyclin via COX-2 inhibition. 3

• Mean blood pressure increases by approximately 5 mm Hg with NSAID use, which can worsen hypertension and congestive heart failure. 3

Safe Alternatives for High-Risk Patients

For patients with asthma or COPD requiring analgesia, acetaminophen ≤1000 mg is the first-line choice, followed by selective COX-2 inhibitors as second-line options. 4, 5

• Selective COX-2 inhibitors (such as celecoxib) demonstrate only 8-11% cross-reactivity rates in patients with NSAID hypersensitivity, making them significantly safer than non-selective NSAIDs like mefenamic acid. 5

• Acetaminophen at doses ≤1000 mg is the safest analgesic alternative for high-risk asthmatics, as it has minimal COX-1 inhibitory activity. 4

When Mefenamic Acid Must Be Used

• Formal aspirin provocation testing should be performed before NSAID therapy in asthmatics with high-risk features (nasal polyps, chronic rhinosinusitis, prior documented NSAID reaction). 4

• Aspirin desensitization followed by daily maintenance therapy can be considered for selected cases requiring NSAIDs for medical necessity, but this is a specialized procedure requiring 1-3 day protocols under direct medical supervision. 4, 5

• Avoid mefenamic acid entirely in patients with severe, poorly controlled asthma without formal desensitization, as the risk of life-threatening bronchospasm outweighs potential benefits. 4

Pharmacokinetic Considerations

• Mefenamic acid is rapidly absorbed with peak plasma levels at 2-4 hours and an elimination half-life of approximately 2 hours, allowing for relatively quick onset of action. 1

• The drug is >90% protein-bound to albumin and undergoes extensive hepatic metabolism via CYP2C9 to active metabolites that may accumulate in renal or hepatic dysfunction. 1

• Approximately 52% is excreted renally (primarily as glucuronides) and 20% fecally, necessitating dose adjustments in patients with renal or hepatic impairment. 1