Mefenamic Acid Monograph

Introduction

Mefenamic acid is a non‑steroidal anti‑inflammatory drug (NSAID) belonging to the anthranilic acid derivative class. It functions primarily by inhibiting cyclo‑oxygenase (COX) enzymes, thereby reducing prostaglandin synthesis. The compound was first synthesized in the late 1950s and received regulatory approval in the early 1960s for the treatment of menstrual pain and mild to moderate pain elsewhere. Over subsequent decades, its clinical profile has been clarified, and it remains a useful agent among the broader NSAID family, particularly in gynecologic and postoperative pain settings.

Key learning objectives addressed in this monograph include:

• Identification of the chemical and pharmacological characteristics of mefenamic acid.
• Comprehension of its mechanisms of action at the molecular level.
• Recognition of its pharmacokinetic behavior and factors influencing disposition.
• Application of dosage adjustments in special populations, such as patients with renal impairment.
• Integration of clinical evidence to inform therapeutic decision‑making.

Fundamental Principles

Core Concepts and Definitions

Mefenamic acid is chemically defined as 2-(2-methylphenyl)amino-2-methylbenzoic acid. It is marketed as a crystalline powder, typically formulated in oral tablets or suspensions. The drug exerts its anti‑inflammatory, analgesic, and antipyretic effects through selective inhibition of prostaglandin synthesis, with a modest COX‑1/COX‑2 selectivity profile.

Theoretical Foundations

Prostaglandins are bioactive lipids derived from arachidonic acid via the cyclo‑oxygenase pathway. COX enzymes catalyze the conversion of arachidonic acid to prostaglandin H₂, which is subsequently transformed into various prostaglandins and thromboxanes. By competitively binding to the COX active site, mefenamic acid reduces the production of these mediators, thereby attenuating inflammation, pain, and fever. The drug’s pharmacological effects are proportional to the reduction in prostaglandin concentrations, which can be expressed via the relationship:

C(t) = C₀ × e⁻ᵏᵗ

where C(t) is the plasma concentration at time t, C₀ is the initial concentration, and k represents the elimination rate constant.

Key Terminology

• COX‑1: Constitutive cyclo‑oxygenase involved in gastric mucosal protection and platelet aggregation.
• COX‑2: Inducible cyclo‑oxygenase upregulated during inflammation.
• Half‑life (t_1/2): Time required for the plasma concentration to decrease by 50 %.
• Area Under the Curve (AUC): Integral of the concentration–time curve, representing total drug exposure.
• Clearance (Cl): Volume of plasma from which the drug is completely removed per unit time.

Detailed Explanation

Pharmacodynamics

Mefenamic acid’s principal pharmacodynamic action is the inhibition of COX enzymes. The drug binds to a hydrophobic pocket within the COX active site, forming reversible interactions that obstruct the access of arachidonic acid. This blockade reduces the formation of prostaglandin E₂ (PGE₂), which is a key mediator of pain and fever. The selectivity profile of mefenamic acid is intermediate; it demonstrates greater affinity for COX‑2 at therapeutic concentrations, yet can inhibit COX‑1 at higher doses. Consequently, gastrointestinal side effects may arise due to decreased protective prostaglandins.

Pharmacokinetics

Absorption

Oral absorption is rapid, with peak plasma concentrations (C_max) typically occurring within 1–2 h post‑dose. The absolute bioavailability is approximately 40 – 50 %. Factors such as food intake can delay absorption but do not markedly alter overall exposure.

Distribution

The drug is widely distributed throughout body tissues, exhibiting a volume of distribution (V_d) of roughly 2.5 L/kg. Plasma protein binding is moderate, with an unbound fraction of about 20 %. This binding is primarily to albumin, which may be displaced by other highly protein‑bound drugs, potentially increasing free concentrations.

Metabolism

Mefenamic acid undergoes hepatic phase II conjugation, predominantly via glucuronidation, producing glucuronic acid conjugates that are excreted unchanged. Minor oxidation pathways involve cytochrome P450 enzymes, but these contribute minimally to overall clearance.

Excretion

Renal elimination predominates, with approximately 60 – 70 % of the administered dose excreted unchanged in urine. The renal clearance (Cl_renal) is around 0.5 L/h in healthy adults. Reduced renal function leads to accumulation, necessitating dose adjustment. The drug’s half‑life (t_1/2) is 3–4 h in individuals with normal renal function, extending to 6–8 h in those with mild impairment.

Mathematical Relationships

The relationship between dose, clearance, and AUC is expressed as: AUC = Dose ÷ Clearance. For a single oral dose of 500 mg, with a clearance of 0.5 L/h, the expected AUC would be: AUC = 500 mg ÷ 0.5 L/h = 1000 mg·h/L.

Factors Influencing Pharmacokinetics

• Age: Elderly patients exhibit reduced renal clearance, extending t_1/2.
• Genetic polymorphisms: Variants in UGT1A9 may alter glucuronidation rates.
• Drug–drug interactions: Concomitant use of strong inhibitors of UGT1A9 can increase systemic exposure.
• Renal impairment: Dose reduction of 25 – 50 % is recommended for patients with creatinine clearance <30 mL/min.

Formulation and Dosage Forms

Mefenamic acid is available in immediate‑release tablets (125 mg, 250 mg) and suspension formulations for pediatric use. Extended‑release preparations have been investigated but are not widely adopted due to variable release profiles. The recommended adult dosage for dysmenorrhea is 500 mg orally, 3–4 times daily, not exceeding 1500 mg per 24 h. For postoperative pain, a similar regimen is employed, with careful monitoring of cumulative dose.

Drug Interactions

Concurrent administration with other NSAIDs can produce additive gastrointestinal toxicity. Anticoagulants such as warfarin may have enhanced anticoagulant effects when combined with mefenamic acid due to reduced platelet aggregation. Drugs that compete for UGT1A9-mediated metabolism (e.g., duloxetine) may increase mefenamic acid exposure. Additionally, cimetidine may slightly inhibit hepatic glucuronidation, leading to higher plasma concentrations.

Adverse Effects and Contraindications

Common adverse effects include gastrointestinal discomfort, dyspepsia, and mild dizziness. Severe events such as gastric ulceration, bleeding, or perforation have been reported, particularly with prolonged use or high doses. Renal toxicity, manifested as interstitial nephritis or oliguria, is rare but noteworthy. Hepatic dysfunction is uncommon but must be monitored in patients with pre‑existing liver disease. Contraindications encompass active peptic ulcer disease, severe hepatic impairment, and hypersensitivity to NSAIDs.

Clinical Significance

Therapeutic Use

Mefenamic acid is primarily indicated for the management of primary dysmenorrhea and mild to moderate pain, including postoperative discomfort. Its relatively short half‑life allows for flexible dosing schedules. The drug’s efficacy is comparable to that of other NSAIDs, such as ibuprofen, but it may have a distinct side‑effect profile due to its COX selectivity.

Clinical Trials and Evidence

Randomized controlled trials have demonstrated that mefenamic acid reduces menstrual pain intensity by approximately 30 – 40 % relative to placebo. In postoperative pain models, it has shown equivalent analgesic potency to diclofenac when administered at similar dose levels. Meta‑analyses indicate that the risk of upper gastrointestinal bleeding is increased by 1.5–2 fold compared with placebo, underscoring the need for cautious use in at-risk populations.

Guidelines and Recommendations

Clinical guidelines recommend mefenamic acid as a second‑line agent for dysmenorrhea when paracetamol or ibuprofen are ineffective or contraindicated. In patients with a history of peptic ulcer disease, concomitant proton pump inhibitors are advised. For patients with renal impairment, dose reduction or discontinuation is recommended based on the level of creatinine clearance. Pregnancy safety classification indicates potential fetal risk; thus, use is discouraged after the first trimester.

Clinical Applications/Examples

Case Study 1: Primary Dysmenorrhea

A 28‑year‑old woman presents with moderate menstrual pain lasting 3–4 days each cycle. She has no significant medical history. A trial of mefenamic acid 500 mg orally 3 times daily is initiated. Pain scores decrease from 7/10 to 3/10 within 48 h. No adverse effects occur during the course. This case illustrates the typical therapeutic response and tolerability in a healthy adult.

Case Study 2: Postoperative Pain Management

A 45‑year‑old male undergoes laparoscopic cholecystectomy. Postoperatively, he reports a pain score of 6/10. Mefenamic acid 500 mg orally every 8 h is administered, achieving a reduction to 2/10 after 12 h. The patient tolerates the regimen well, with no gastrointestinal complications over a 48‑hour period. This scenario demonstrates the drug’s utility in acute pain settings.

Case Study 3: Combination with Other NSAIDs or Anticoagulants

A 65‑year‑old woman with atrial fibrillation is on warfarin therapy. She requires analgesia for a fractured wrist. Mefenamic acid is avoided due to potential interaction with warfarin, as it may potentiate anticoagulant effects. Instead, acetaminophen is prescribed. This example highlights the importance of evaluating drug interactions in polypharmacy patients.

Problem‑Solving Approach to Dose Adjustment in Renal Failure

Consider a 70‑year‑old patient with chronic kidney disease stage 3 (creatinine clearance 45 mL/min). The standard 500 mg dose may lead to drug accumulation. A dose reduction to 250 mg once daily is recommended. Monitoring of renal function and drug levels is advised if available. This approach mitigates the risk of nephrotoxicity while maintaining analgesic efficacy.

Summary/Key Points

• Mefenamic acid is an anthranilic acid NSAID that inhibits COX enzymes, reducing prostaglandin synthesis.
• Oral absorption is rapid; peak plasma concentrations occur within 1–2 h.
• The drug is primarily excreted unchanged by the kidneys; renal impairment necessitates dose adjustment.
• Common adverse effects include gastrointestinal discomfort and, rarely, bleeding.
• Clinical indications encompass primary dysmenorrhea and mild to moderate postoperative pain.
• Drug interactions with other NSAIDs, anticoagulants, and UGT1A9 inhibitors must be considered.
• Key pharmacokinetic equations: AUC = Dose ÷ Clearance; C(t) = C₀ × e⁻ᵏᵗ.
• Clinical pearls: In patients with gastrointestinal risk factors, co‑prescription of proton pump inhibitors is advisable; in renal impairment, a 50 % dose reduction is often sufficient.

References

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