Chapter: Pharmacology of Diclofenac

1. Introduction/Overview

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid derivative class, which has occupied a central position in the therapeutic management of pain and inflammation for several decades. First synthesized in the 1970s and subsequently introduced into clinical practice, it has become one of the most widely prescribed NSAIDs globally. Its clinical relevance stems from a potent anti-inflammatory, analgesic, and antipyretic profile, making it a cornerstone in the treatment of various musculoskeletal, arthritic, and acute painful conditions. The drug’s importance is further underscored by its availability in multiple formulations—including oral, topical, parenteral, and ophthalmic preparations—allowing for tailored therapeutic approaches based on clinical need and patient-specific factors.

The following learning objectives are intended to guide the study of this chapter:

• Describe the chemical classification of diclofenac and its place within the broader NSAID category.
• Explain the detailed molecular mechanism of action, focusing on cyclooxygenase inhibition and other potential pathways.
• Analyze the pharmacokinetic profile of diclofenac, including absorption characteristics, distribution, metabolism, and elimination.
• Identify the approved therapeutic indications, common adverse effects, and significant drug interactions associated with diclofenac therapy.
• Evaluate special considerations for diclofenac use in populations such as the elderly, those with renal or hepatic impairment, and during pregnancy or lactation.

2. Classification

Diclofenac is systematically classified within several hierarchical categories relevant to pharmacology and therapeutics.

2.1. Therapeutic Classification

The primary therapeutic classification is as a nonsteroidal anti-inflammatory drug (NSAID). Within this broad group, it is further categorized as a non-selective cyclooxygenase (COX) inhibitor, meaning it inhibits both COX-1 and COX-2 isoforms, albeit with a degree of selectivity that has been a subject of research. It is employed for its anti-inflammatory, analgesic, and antipyretic properties.

2.2. Chemical Classification

Chemically, diclofenac is a phenylacetic acid derivative. Its full chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid. The presence of two chlorine atoms at the ortho positions of the phenylamine ring and a phenylacetic acid moiety are critical structural features that influence its physicochemical properties, protein binding, and pharmacological activity. This structure differentiates it from other NSAID classes such as propionic acid derivatives (e.g., ibuprofen, naproxen), enolic acids (e.g., piroxicam), and selective COX-2 inhibitors (coxibs).

3. Mechanism of Action

The primary mechanism of action of diclofenac, shared with other traditional NSAIDs, is the inhibition of the enzyme cyclooxygenase (COX), which is pivotal in the arachidonic acid cascade.

3.1. Cyclooxygenase Inhibition

Arachidonic acid, released from membrane phospholipids by phospholipase A₂, is metabolized by cyclooxygenase enzymes to form prostaglandin G₂ (PGG₂) and subsequently prostaglandin H₂ (PGH₂). PGH₂ serves as the precursor for various prostanoids, including prostaglandins (e.g., PGE₂, PGI₂), thromboxane A₂ (TXA₂), and prostacyclin. Diclofenac acts as a competitive, reversible inhibitor of both COX-1 and COX-2. It binds to the active site of the enzyme, blocking the conversion of arachidonic acid. The inhibition constant (K_i) for COX-1 and COX-2 suggests it may have a somewhat greater in vitro inhibitory potency for COX-2, but it is not considered a clinically selective COX-2 inhibitor like celecoxib. The therapeutic effects (anti-inflammatory, analgesic, antipyretic) are primarily mediated through inhibition of COX-2-derived prostaglandins at sites of inflammation. Inhibition of constitutively expressed COX-1 in tissues like the gastric mucosa and platelets is responsible for many of its adverse effects, such as gastrointestinal ulceration and impaired platelet aggregation.

3.2. Additional Molecular and Cellular Mechanisms

Beyond COX inhibition, diclofenac may exert effects through other pathways, though their clinical significance may be secondary. These include:

• Alteration of Arachidonic Acid Release and Uptake: Diclofenac may inhibit phospholipase A₂ activity to a minor degree, reducing the substrate availability for COX.
• Modulation of Other Signaling Pathways: Some evidence suggests diclofenac can affect nuclear factor kappa B (NF-κB) signaling, a key regulator of inflammatory gene expression, and activate the peroxisome proliferator-activated receptor gamma (PPARγ), which has anti-inflammatory effects.
• Effects on Ion Channels: At higher concentrations, diclofenac may inhibit voltage-gated sodium and calcium channels, which could contribute to its local anesthetic-like effects in certain formulations and its cardiac electrophysiological effects.

4. Pharmacokinetics

The pharmacokinetics of diclofenac are complex and influenced by its formulation, which is designed to mitigate its poor solubility and first-pass metabolism.

4.1. Absorption

Diclofenac is rapidly and almost completely absorbed from the gastrointestinal tract following oral administration. However, it undergoes extensive first-pass hepatic metabolism, resulting in an absolute bioavailability of approximately 50-60%. To address this, several salt forms (sodium, potassium, epolamine) and modified-release formulations (enteric-coated, sustained-release) have been developed. The sodium salt is rapidly absorbed, while the potassium salt may have slightly faster absorption. The time to peak plasma concentration (t_max) varies: 1-2 hours for immediate-release salts, 2-3 hours for enteric-coated tablets, and 5-6 hours for sustained-release formulations. Topical formulations (gels, patches) provide local tissue penetration with minimal systemic absorption; typically, only 6-10% of the applied dose reaches systemic circulation, significantly reducing systemic exposure and adverse effects.

4.2. Distribution

Diclofenac is highly protein-bound (>99%), primarily to serum albumin. Its volume of distribution is relatively low (0.12-0.17 L/kg), indicating limited distribution beyond the plasma compartment. It distributes well into synovial fluid, where concentrations can persist longer than in plasma, potentially contributing to a prolonged therapeutic effect in arthritic joints. It crosses the placenta and is excreted in breast milk in small quantities.

4.3. Metabolism

Diclofenac is metabolized almost exclusively in the liver via cytochrome P450 (CYP) enzymes, with a minor contribution from UDP-glucuronosyltransferases (UGTs). The primary metabolic pathway involves hydroxylation, primarily by CYP2C9, to form 4′-hydroxydiclofenac, the major metabolite. CYP3A4 contributes to the formation of 5-hydroxydiclofenac. These oxidative metabolites are then conjugated with glucuronic acid. A significant and potentially critical pathway is the formation of acyl glucuronide conjugates. These reactive metabolites are implicated in the rare but serious hepatotoxicity associated with diclofenac, as they can bind covalently to hepatic proteins, triggering an idiosyncratic immune response.

4.4. Excretion

Elimination is predominantly renal, with approximately 60-70% of a dose excreted in urine as conjugated metabolites (glucuronides and sulfates). Biliary excretion accounts for most of the remainder, with about 1-2% excreted unchanged in feces. The elimination half-life (t_1/2) of diclofenac in plasma is relatively short, approximately 1-2 hours. However, due to factors such as enterohepatic recirculation and sustained release from synovial fluid, the pharmacodynamic half-life (duration of effect) is longer than the plasma half-life would suggest, allowing for twice-daily or even once-daily dosing with modified-release formulations.

4.5. Dosing Considerations

Standard oral dosing for adults typically ranges from 75 mg to 150 mg daily, divided into two or three doses, or as a single daily dose for sustained-release preparations. The maximum recommended daily dose is 150 mg. Topical gel is commonly applied 4 times daily to the affected area. Dosing must be individualized, using the lowest effective dose for the shortest duration necessary to control symptoms.

5. Therapeutic Uses/Clinical Applications

Diclofenac is approved for a wide spectrum of inflammatory and painful conditions.

5.1. Approved Indications

• Rheumatoid Arthritis and Osteoarthritis: Used to reduce joint pain, swelling, and stiffness, improving functional capacity.
• Ankylosing Spondylitis: Provides symptomatic relief of spinal inflammation and pain.
• Acute Musculoskeletal Disorders: Including sprains, strains, and soft-tissue injuries such as tendinitis (e.g., tennis elbow).
• Acute Gout: Effective in managing the pain and inflammation of acute gouty arthritis.
• Postoperative Pain and Inflammation: Used following dental, orthopedic, and other surgical procedures, often in oral or parenteral formulations.
• Primary Dysmenorrhea: Alleviates uterine cramping and pain by inhibiting prostaglandin synthesis in the endometrium.
• Migraine Attacks: A powder formulation is approved for the acute treatment of migraine with or without aura.
• Ophthalmic Inflammation: Diclofenac sodium ophthalmic solution is used to treat postoperative inflammation following cataract surgery and to inhibit intraoperative miosis.
• Actinic Keratosis: A topical 3% gel is approved for the treatment of this pre-malignant skin condition, with an effect thought to be mediated through anti-inflammatory and possibly pro-apoptotic mechanisms.

5.2. Common Off-Label Uses

• Chronic low back pain.
• Pain management in renal colic (often via parenteral administration).
• As an antipyretic in adults when other agents are contraindicated or ineffective.
• Topical formulations for minor arthritis pain in superficial joints.

6. Adverse Effects

The adverse effect profile of diclofenac is characteristic of non-selective NSAIDs, with gastrointestinal, cardiovascular, and renal effects being of principal concern.

6.1. Common Side Effects

• Gastrointestinal: Epigastric pain, dyspepsia, nausea, diarrhea, and flatulence are frequently reported. These are often dose-related and result from inhibition of COX-1-derived cytoprotective prostaglandins in the gastric mucosa.
• Central Nervous System: Headache, dizziness, and vertigo.
• Dermatological: Rash, pruritus, especially with topical formulations which can cause local skin reactions like dryness, irritation, or contact dermatitis.

6.2. Serious/Rare Adverse Reactions

• Gastrointestinal: Serious complications include gastric or duodenal ulceration, perforation, and gastrointestinal bleeding, which can be life-threatening. Risk factors include advanced age, history of ulcer disease, concomitant use of corticosteroids or anticoagulants, and prolonged high-dose therapy.
• Cardiovascular: Diclofenac, like most NSAIDs (excluding aspirin), is associated with an increased risk of serious thrombotic events, including myocardial infarction and stroke. This risk may begin early in treatment and appears dose-dependent. It is related to the inhibition of vascular COX-2-derived prostacyclin (a vasodilator and inhibitor of platelet aggregation) without concomitant inhibition of platelet COX-1-derived thromboxane A₂ (a pro-thrombotic agent).
• Hepatic: Elevations in liver transaminases (ALT, AST) are common, occurring in up to 15% of patients, and are usually transient and asymptomatic. However, rare cases of severe hepatotoxicity, including fulminant hepatitis, liver necrosis, and jaundice, have been reported. This idiosyncratic reaction is thought to be mediated by reactive acyl glucuronide metabolites.
• Renal: Inhibition of renal COX-derived prostaglandins (which maintain renal blood flow, particularly in states of decreased effective circulating volume) can lead to fluid retention, edema, hypertension, and in susceptible individuals, acute kidney injury (acute interstitial nephritis, papillary necrosis).
• Hypersensitivity: Cross-reactive hypersensitivity reactions can occur in patients with aspirin-exacerbated respiratory disease (AERD). Severe skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, are rare but serious.
• Hematological: Reversible inhibition of platelet aggregation can prolong bleeding time, though to a lesser extent than aspirin. Neutropenia, agranulocytosis, and aplastic anemia are rare.

6.3. Boxed Warnings

In many jurisdictions, diclofenac carries boxed warnings (the strongest FDA-required warning) highlighting:

• Cardiovascular Thrombotic Risk: Increased risk of myocardial infarction, stroke, and cardiovascular death, which can be fatal. This risk may increase with duration of use and is higher in patients with pre-existing cardiovascular disease.
• Gastrointestinal Risk: Risk of GI bleeding, ulceration, and perforation, which can occur at any time during use and without warning symptoms, particularly in the elderly.

7. Drug Interactions

Diclofenac’s high protein binding and metabolic pathways create potential for significant drug interactions.

7.1. Major Drug-Drug Interactions

• Anticoagulants (Warfarin, DOACs) and Antiplatelets: Concomitant use increases the risk of bleeding due to additive effects on hemostasis (impaired platelet function from diclofenac plus anticoagulation) and potential displacement of warfarin from protein binding sites.
• Other NSAIDs and Corticosteroids: Concurrent use with other NSAIDs, including aspirin, or with corticosteroids (e.g., prednisone) significantly increases the risk of GI ulceration and bleeding without providing additional therapeutic benefit.
• Antihypertensives: Diclofenac can reduce the efficacy of diuretics (thiazides, furosemide), ACE inhibitors, and angiotensin II receptor blockers (ARBs) by inhibiting renal prostaglandin synthesis, leading to sodium and water retention and potentially worsening hypertension or heart failure.
• CYP2C9 Inhibitors and Inducers: Drugs that inhibit CYP2C9 (e.g., fluconazole, amiodarone) may increase diclofenac plasma levels, potentially increasing toxicity. Inducers (e.g., rifampin) may decrease its efficacy.
• Lithium and Methotrexate: Diclofenac may reduce renal clearance of lithium and methotrexate, leading to increased plasma levels and risk of toxicity. Close monitoring of serum levels is required.
• Cyclosporine and Tacrolimus: Increased risk of nephrotoxicity due to combined effects on renal blood flow.
• Selective Serotonin Reuptake Inhibitors (SSRIs): May increase the risk of upper gastrointestinal bleeding when combined with NSAIDs.

7.2. Contraindications

• Known hypersensitivity to diclofenac, aspirin, or other NSAIDs (especially in patients with a history of asthma, urticaria, or allergic-type reactions).
• History of asthma, urticaria, or allergic reaction after taking aspirin or other NSAIDs.
• In the setting of coronary artery bypass graft (CABG) surgery.
• Active peptic ulcer disease or recent gastrointestinal bleeding.
• Severe heart failure (NYHA Class IV).
• Severe renal impairment or active kidney disease.
• Third trimester of pregnancy (risk of premature closure of the ductus arteriosus).

8. Special Considerations

8.1. Pregnancy and Lactation

Pregnancy: Use during the first and second trimesters should be avoided unless the potential benefit justifies the potential risk to the fetus. NSAID use in the third trimester (after 30 weeks gestation) is contraindicated due to the risk of premature closure of the fetal ductus arteriosus, which can lead to pulmonary hypertension, and the potential for oligohydramnios and prolonged labor. Diclofenac is classified as Pregnancy Category C (first and second trimester) and Category D (third trimester) under the former FDA classification system.

Lactation: Diclofenac is excreted in human milk in low concentrations. While adverse effects on nursing infants are not commonly reported, caution is advised. The use of topical formulations may be preferred in nursing mothers when systemic absorption is minimal.

8.2. Pediatric and Geriatric Considerations

Pediatric: Diclofenac is not generally the first-line NSAID in children. Its use may be considered in specific situations, such as juvenile idiopathic arthritis, under specialist supervision. Dosing is typically weight-based (1-3 mg/kg/day in divided doses). The safety profile in children requires careful monitoring, particularly for hepatic effects.

Geriatric: Patients aged 65 years and older are at increased risk for NSAID-associated adverse events, including GI bleeding, peptic ulceration, acute renal failure, and cardiovascular events. Age-related decreases in renal and hepatic function, comorbid conditions, and polypharmacy contribute to this risk. Therapy should be initiated at the lowest effective dose and for the shortest possible duration. Concomitant use of a gastroprotective agent (e.g., proton pump inhibitor) is often recommended.

8.3. Renal and Hepatic Impairment

Renal Impairment: Diclofenac is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min). In patients with mild to moderate impairment, use requires caution and close monitoring of renal function, as prostaglandins play a compensatory role in maintaining renal perfusion. Fluid status and serum creatinine should be monitored periodically. The drug should be avoided in patients with volume depletion or congestive heart failure.

Hepatic Impairment: Diclofenac is contraindicated in patients with active liver disease or significantly elevated baseline liver enzymes. Metabolism may be impaired in hepatic disease, leading to accumulation. Patients should be monitored for signs and symptoms of liver injury (e.g., nausea, fatigue, jaundice, right upper quadrant pain). Periodic monitoring of liver enzymes is recommended, especially during long-term therapy. Therapy should be discontinued if ALT or AST rise to 3 times the upper limit of normal or if clinical symptoms of hepatotoxicity develop.

9. Summary/Key Points

• Diclofenac is a potent non-selective NSAID, chemically classified as a phenylacetic acid derivative, used for its anti-inflammatory, analgesic, and antipyretic effects.
• Its primary mechanism involves reversible inhibition of both COX-1 and COX-2 enzymes, thereby reducing the synthesis of pro-inflammatory and pain-mediating prostaglandins.
• Pharmacokinetically, it is well-absorbed but undergoes significant first-pass metabolism, is highly protein-bound, metabolized mainly by CYP2C9, and has a short plasma half-life (1-2 hours) but a longer effective duration of action.
• It is indicated for a wide range of conditions including osteoarthritis, rheumatoid arthritis, acute musculoskeletal pain, gout, and dysmenorrhea, and is available in multiple formulations (oral, topical, parenteral).
• Major adverse effects involve the gastrointestinal tract (ulcers, bleeding), cardiovascular system (increased thrombotic risk), kidneys (acute injury, fluid retention), and liver (transaminitis, rare severe hepatotoxicity). Boxed warnings exist for cardiovascular and gastrointestinal risks.
• Significant drug interactions occur with anticoagulants, antihypertensives, other NSAIDs, and drugs metabolized by CYP2C9.
• Special caution is required in the elderly, those with renal or hepatic impairment, and during the third trimester of pregnancy. The lowest effective dose for the shortest duration should always be the guiding principle of therapy.

9.1. Clinical Pearls

• Topical diclofenac gel provides effective relief for osteoarthritis in superficial joints (e.g., knees, hands) with a markedly lower risk of systemic adverse events compared to oral administration.
• Given its cardiovascular risk profile, diclofenac should generally be avoided in patients with established cardiovascular disease or significant risk factors. Naproxen may have a somewhat more favorable cardiovascular risk profile among non-selective NSAIDs.
• Routine monitoring of blood pressure, renal function (especially in at-risk patients), and periodic liver function tests is considered prudent during chronic therapy.
• For patients requiring gastroprotection, concomitant use of a proton pump inhibitor is more effective than misoprostol or H₂ receptor antagonists in preventing NSAID-induced ulcers.
• The presence of epigastric pain is a poor predictor of underlying ulceration; serious GI complications can occur without preceding symptoms.

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