Pharmacology of Diclofenac

1. Introduction/Overview

Diclofenac is a non-steroidal 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 extensively prescribed NSAIDs worldwide. Its clinical relevance stems from a potent anti-inflammatory, analgesic, and antipyretic profile, making it a cornerstone in the treatment of various acute and chronic musculoskeletal disorders, including osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. The drug’s importance is further underscored by its availability in multiple formulations—oral, topical, parenteral, and suppository—allowing for tailored therapeutic approaches based on patient-specific factors and clinical scenarios.

Learning Objectives

Upon completion of this chapter, the reader should be able to:

• Describe the chemical classification and pharmacodynamic mechanism of action of diclofenac, with emphasis on cyclooxygenase inhibition and isoform selectivity.
• Outline the pharmacokinetic profile of diclofenac, including absorption characteristics, distribution, metabolic pathways, and elimination, and relate these to dosing considerations.
• Identify the approved therapeutic indications for diclofenac and recognize common off-label clinical applications.
• Analyze the spectrum of adverse effects associated with diclofenac therapy, from common gastrointestinal disturbances to serious cardiovascular, renal, and hepatic risks.
• Evaluate major drug-drug interactions, contraindications, and special population considerations to inform safe and effective clinical prescribing.

2. Classification

Diclofenac is systematically classified within the broader therapeutic and chemical categories of non-steroidal anti-inflammatory drugs.

Therapeutic and Pharmacologic Classification

• Therapeutic Classification: Non-Steroidal Anti-Inflammatory Drug (NSAID), Analgesic, Antipyretic.
• Pharmacologic Classification: Cyclooxygenase (COX) Inhibitor.

Chemical Classification

Chemically, diclofenac is a phenylacetic acid derivative. Its systematic name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid. The molecular structure incorporates two chlorine atoms at the ortho positions of one phenyl ring, which is linked via an amino group to a phenylacetic acid moiety. This specific structure is considered integral to its high potency and its ability to adopt a specific conformation that favors binding to the cyclooxygenase enzyme. It is typically administered as a sodium or potassium salt to enhance water solubility for oral and parenteral formulations, or as a diethylamine salt in certain topical preparations.

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 catalyzes the conversion of arachidonic acid to prostaglandin G₂ (PGG₂) and subsequently to prostaglandin H₂ (PGH₂). PGH₂ serves as the precursor for various prostanoids, including prostaglandins (e.g., PGE₂, PGI₂) and thromboxane A₂ (TXA₂). The pharmacodynamic effects of diclofenac are predominantly a consequence of reduced synthesis of these lipid mediators.

Cyclooxygenase Inhibition and Isoform Selectivity

Diclofenac is a non-selective COX inhibitor, affecting both the COX-1 and COX-2 isoforms. However, it exhibits a degree of selectivity, often quantified as a COX-2/COX-1 inhibitory ratio. In vitro assays suggest diclofenac has a preference for inhibiting COX-2 over COX-1, though this selectivity is considerably less pronounced than that observed with coxibs (selective COX-2 inhibitors). This relative selectivity may contribute to its potent anti-inflammatory effects while partially explaining its gastrointestinal toxicity profile, which, though significant, may differ in pattern from some other non-selective NSAIDs. The inhibition is reversible and competitive with the substrate, arachidonic acid.

Molecular and Cellular Consequences

The inhibition of prostaglandin synthesis mediates the triad of diclofenac’s core effects:

• Anti-inflammatory Action: Prostaglandins, particularly PGE₂, are key mediators of inflammation, causing vasodilation, increasing vascular permeability, and potentiating the action of other mediators like bradykinin and histamine. Their suppression reduces the cardinal signs of inflammation: redness, heat, swelling, and pain.
• Analgesic Action: Prostaglandins, especially PGE₂ and PGI₂, sensitize peripheral nociceptors to mechanical and chemical stimuli (e.g., bradykinin, substance P). By lowering prostaglandin levels at sites of tissue injury, diclofenac raises the threshold for nociceptor activation. A central analgesic mechanism, possibly via inhibition of prostaglandin synthesis within the spinal cord and brain, may also contribute.
• Antipyretic Action: Fever is mediated by PGE₂ synthesis in the preoptic area of the hypothalamus in response to endogenous pyrogens (e.g., interleukin-1). Diclofenac reduces hypothalamic PGE₂ levels, thereby resetting the elevated thermoregulatory set-point to normal.

Additional Mechanisms

Beyond COX inhibition, diclofenac may exert effects through other pathways, though their clinical significance remains less defined. These include possible influences on arachidonic acid release, inhibition of lipoxygenase pathways at high concentrations, and modulation of neutrophil function and free radical scavenging. The contribution of these ancillary mechanisms to its overall clinical profile is not fully established.

4. Pharmacokinetics

The pharmacokinetics of diclofenac are characterized by efficient absorption, high plasma protein binding, extensive hepatic metabolism, and renal excretion of metabolites. Its pharmacokinetic profile can vary depending on the salt form and formulation.

Absorption

Following oral administration, diclofenac is rapidly and almost completely absorbed from the gastrointestinal tract. However, due to a significant first-pass metabolism, its systemic bioavailability is approximately 50-60%. The time to reach peak plasma concentration (t_max) is typically 1-2 hours for immediate-release formulations. Enteric-coated and sustained-release formulations are designed to delay absorption, with t_max ranging from 2-4 hours and up to 6-8 hours, respectively, which can help mitigate peak-related gastrointestinal irritation. Absorption from rectal suppositories is slower and less complete, with bioavailability around 70-80%. Topical formulations are designed for local tissue penetration with minimal systemic absorption; typically, only 5-15% of the applied dose reaches systemic circulation.

Distribution

Diclofenac is extensively bound (>99%) to serum albumin. Its volume of distribution is relatively low (approximately 0.12-0.17 L/kg), indicating confinement largely to the vascular compartment and extracellular fluid. The drug distributes well into synovial fluid, where concentrations can persist longer than in plasma, potentially contributing to a prolonged therapeutic effect in arthritic conditions. It crosses the placenta and is excreted in breast milk in small quantities.

Metabolism

Diclofenac undergoes extensive Phase I and Phase II hepatic metabolism. The primary metabolic pathway involves hydroxylation, primarily via the cytochrome P450 enzyme CYP2C9, and to a lesser extent CYP3A4 and CYP2C8, to form 4′-hydroxydiclofenac, the major metabolite. This is followed by glucuronidation. Another significant pathway is direct glucuronidation of the parent compound, forming acyl glucuronide metabolites. These acyl glucuronides are chemically reactive and have been implicated in the rare but serious hepatotoxic reactions associated with diclofenac. The metabolism is nearly complete, with less than 1% of the dose excreted unchanged in urine.

Excretion

The metabolites of diclofenac are eliminated primarily via the kidneys (60-70% of dose), with the remainder excreted in the bile as glucuronide conjugates, undergoing enterohepatic recirculation. A small fraction is excreted in feces. The elimination half-life (t_1/2) of diclofenac in plasma is short, approximately 1-2 hours. However, due to its persistence in synovial fluid and possibly enterohepatic recirculation, its pharmacodynamic effects often outlast its plasma presence, allowing for twice-daily or even once-daily dosing with modified-release formulations.

Pharmacokinetic Parameters and Dosing Considerations

Key pharmacokinetic parameters include a clearance rate of about 16 L/h and an area under the curve (AUC) that is dose-proportional within the therapeutic range. The short plasma half-life necessitates the use of modified-release formulations for sustained effect in chronic conditions. Dosing must be adjusted in patients with hepatic impairment due to reduced metabolic capacity, while renal impairment primarily affects the elimination of metabolites rather than the parent drug.

5. Therapeutic Uses/Clinical Applications

Diclofenac is approved for a wide range of conditions characterized by pain, inflammation, and fever. Its use should always be at the lowest effective dose for the shortest duration necessary.

Approved Indications

• Rheumatoid Arthritis: Used to reduce joint pain, swelling, and morning stiffness.
• Osteoarthritis: Effective in managing pain and improving function in degenerative joint disease, particularly of the knee, hip, and hand.
• Ankylosing Spondylitis: Provides symptomatic relief from spinal inflammation and pain.
• Acute Musculoskeletal Disorders: Such as sprains, strains, and tendinitis (e.g., rotator cuff tendinitis).
• Acute Gout: Can be used for the management of acute painful gouty arthritis.
• Post-operative Pain: Used for the management of mild to moderate post-surgical pain, often in combination with other analgesics.
• Primary Dysmenorrhea: Effective in relieving uterine cramping and pain associated with menstruation by inhibiting uterine prostaglandin synthesis.
• Migraine: Certain formulations are approved for the acute treatment of migraine attacks with or without aura.
• Antipyretic: Used to reduce fever.

Off-Label Uses

Several off-label applications are supported by clinical evidence, though they are not formally approved in all jurisdictions.

• Renal Colic: Often used parenterally to relieve pain from ureteral stones, with the added benefit of reducing ureteral spasm and intraluminal pressure.
• Patent Ductus Arteriosus (PDA) Closure: Intravenous diclofenac has been used as an alternative to indomethacin or ibuprofen for pharmacologic closure of PDA in preterm neonates, though this use is highly specialized.
• Topical Use for Actinic Keratosis: A specific 3% gel formulation is used in some regions for the treatment of actinic keratosis, acting through an uncertain mechanism that may involve anti-inflammatory and pro-apoptotic effects.
• Pericarditis: May be used as part of the anti-inflammatory regimen for acute pericarditis.

6. Adverse Effects

The adverse effect profile of diclofenac is consistent with the class effects of non-selective NSAIDs, affecting primarily the gastrointestinal, cardiovascular, renal, and hepatic systems. The risk is dose-dependent and duration-dependent.

Common Side Effects

• Gastrointestinal: Epigastric pain, dyspepsia, nausea, diarrhea, and flatulence are frequent. These are often manageable with food co-administration or the use of enteric-coated formulations.
• Central Nervous System: Headache, dizziness, and vertigo.
• Dermatological: Rash, pruritus.

Serious and Rare Adverse Reactions

• Gastrointestinal Toxicity: Serious complications include gastric or duodenal ulceration, perforation, and gastrointestinal bleeding, which can be fatal. The risk is increased in the elderly, those with a history of ulcer disease, and patients on concomitant corticosteroids or anticoagulants.
• Cardiovascular Risk: Like most NSAIDs (excluding aspirin), diclofenac is associated with an increased risk of serious thrombotic events, including myocardial infarction and stroke. This risk may begin early in treatment and appears to be dose-related. Some meta-analyses have suggested diclofenac may confer a higher relative cardiovascular risk compared to some other traditional NSAIDs like naproxen.
• Hepatotoxicity: Diclofenac can cause hepatocellular injury, ranging from asymptomatic transaminase elevations (occurring in up to 15% of patients) to rare but severe hepatitis, fulminant hepatic necrosis, and liver failure. The mechanism is thought to involve reactive metabolite formation (acyl glucuronides) leading to immune-mediated injury or mitochondrial dysfunction.
• Renal Toxicity: Can cause fluid retention, edema, and hypertension. More seriously, it may induce acute kidney injury via inhibition of renal prostaglandins (PGE₂ and PGI₂) that maintain renal blood flow, particularly in states of volume depletion. Interstitial nephritis and nephrotic syndrome are rare idiosyncratic reactions.
• Hematological: May inhibit platelet aggregation (reversible), prolong bleeding time, and rarely cause agranulocytosis, aplastic anemia, or hemolytic anemia.
• Hypersensitivity: Can precipitate bronchospasm in aspirin-exacerbated respiratory disease (AERD) patients. Severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported.

Black Box Warnings

In the United States, diclofenac labeling carries boxed warnings mandated by the Food and Drug Administration for:

• Cardiovascular Thrombotic Events: Highlighting the increased risk of myocardial infarction and stroke, which can be fatal. This risk may increase with duration of use and is present in patients with or without pre-existing cardiovascular disease.
• Gastrointestinal Risk: Emphasizing the risk of ulceration, bleeding, and perforation of the stomach or intestines, which can occur at any time during use and without warning symptoms, particularly in the elderly.

7. Drug Interactions

Diclofenac’s high protein binding, metabolic pathways, and pharmacodynamic effects create potential for numerous clinically significant drug interactions.

Major Drug-Drug Interactions

• Anticoagulants (Warfarin, Heparins, DOACs): Diclofenac increases bleeding risk through synergistic inhibition of platelet function (pharmacodynamic) and potential displacement of warfarin from protein binding sites (pharmacokinetic). Concurrent use requires extreme caution and close monitoring of coagulation parameters.
• Other NSAIDs and Corticosteroids: Concomitant use with other NSAIDs, including aspirin for analgesia, or with corticosteroids (e.g., prednisone) significantly increases the risk of gastrointestinal ulceration and bleeding without providing additional therapeutic benefit.
• Antihypertensives: Diclofenac can reduce the efficacy of diuretics (thiazides, furosemide), ACE inhibitors, angiotensin II receptor blockers (ARBs), and beta-blockers by inhibiting renal prostaglandin synthesis, leading to sodium and water retention and potentially worsening hypertension or heart failure.
• Cyclosporine and Tacrolimus: Concurrent use may increase the nephrotoxic potential of both diclofenac and the calcineurin inhibitor.
• Methotrexate: Diclofenac may decrease renal clearance of methotrexate, potentially leading to increased methotrexate toxicity (myelosuppression, mucositis), particularly with high-dose methotrexate regimens.
• Lithium: Diclofenac can decrease renal clearance of lithium, potentially leading to lithium toxicity. Serum lithium levels require close monitoring if co-administration is necessary.
• Selective Serotonin Reuptake Inhibitors (SSRIs): Concomitant use may increase the risk of upper gastrointestinal bleeding.
• CYP2C9 Inhibitors/Inducers: Drugs like fluconazole (inhibitor) or rifampin (inducer) may alter diclofenac metabolism, affecting its plasma levels and therapeutic or toxic effects.

Contraindications

Diclofenac is contraindicated in the following situations:

• Known hypersensitivity to diclofenac, aspirin, or other NSAIDs, including a history of asthma, urticaria, or allergic-type reactions after taking NSAIDs.
• In the setting of coronary artery bypass graft (CABG) surgery.
• Active gastrointestinal bleeding or peptic ulcer disease.
• Severe heart failure (NYHA Class IV).
• Severe renal impairment or active renal disease.
• Severe hepatic impairment (Child-Pugh Class C) or active liver disease.
• Third trimester of pregnancy due to risk of premature closure of the fetal ductus arteriosus.

8. Special Considerations

Use in Pregnancy and Lactation

Pregnancy: Diclofenac is classified as Pregnancy Category C in the first and second trimesters (US FDA classification; note that the Pregnancy and Lactation Labeling Rule has superseded letter categories, but the concept remains). Use during the first trimester may be associated with a small increased risk of certain congenital malformations (e.g., cardiac defects, gastroschisis). Use in the third trimester is contraindicated (Category D) due to risks of premature closure of the fetal ductus arteriosus, oligohydramnios, and inhibition of labor. It should be avoided in women attempting to conceive, as it may impair fertility.

Lactation: Diclofenac is excreted in breast milk in low concentrations (approximately 0.1-0.3% of the maternal dose). While generally considered compatible with breastfeeding by some authorities due to the low relative infant dose, caution is advised, and the infant should be monitored for potential effects such as diarrhea or rash. Using the lowest effective maternal dose for the shortest duration is recommended.

Pediatric Considerations

Diclofenac is not generally recommended for children under 18 years of age, except in specific circumstances (e.g., juvenile idiopathic arthritis in some countries, or intravenous use for PDA closure in neonates under strict hospital supervision). Dosing, when used, is typically based on body weight (e.g., 1-3 mg/kg/day in divided doses). The risk of Reye’s syndrome, associated with aspirin use in viral illnesses, has not been established with diclofenac, but caution during febrile illnesses is prudent.

Geriatric Considerations

Patients aged 65 years and older are at increased risk for NSAID-related adverse events, particularly gastrointestinal bleeding, peptic ulceration, acute renal failure, and cardiovascular events. Age-related declines in renal and hepatic function may also alter pharmacokinetics. Therapy should be initiated at the low end of the dosing range, and patients should be monitored closely. The use of topical diclofenac may be preferred for localized conditions (e.g., osteoarthritis of the knee) to minimize systemic exposure.

Renal Impairment

In patients with mild to moderate renal impairment (creatinine clearance ≥30 mL/min), caution is required. Diclofenac should be avoided in patients with severe renal impairment (creatinine clearance <30 mL/min) or those on dialysis, as it is not significantly removed by dialysis and the risks of fluid retention and further renal deterioration are high. Renal function should be assessed before initiating chronic therapy.

Hepatic Impairment

Diclofenac is contraindicated in patients with severe hepatic impairment or active liver disease due to its extensive hepatic metabolism and potential for hepatotoxicity. In patients with mild to moderate hepatic impairment (Child-Pugh Class A or B), a dose reduction may be necessary, and liver function tests should be monitored regularly. Patients should be advised to report symptoms such as fatigue, nausea, jaundice, right upper quadrant pain, or “flu-like” symptoms.

9. Summary/Key Points

Bullet Point Summary

• Diclofenac is a potent non-selective NSAID, chemically a phenylacetic acid derivative, with anti-inflammatory, analgesic, and antipyretic properties mediated primarily through reversible inhibition of cyclooxygenase (COX-1 and COX-2) enzymes.
• It exhibits complex pharmacokinetics: good oral absorption with significant first-pass effect, high plasma protein binding, extensive hepatic metabolism via CYP2C9 to active and inactive metabolites, and a short plasma half-life (1-2 hours) that belies a longer duration of clinical effect.
• It is indicated for a wide range of inflammatory and painful conditions, including rheumatoid arthritis, osteoarthritis, acute musculoskeletal pain, gout, and dysmenorrhea. Topical formulations offer a favorable risk-benefit profile for localized conditions.
• The adverse effect profile is class-typical, with serious risks including gastrointestinal ulceration/bleeding, increased cardiovascular thrombotic events, dose-related hepatotoxicity, renal impairment, and hypersensitivity reactions. These risks necessitate using the lowest effective dose for the shortest possible duration.
• It has numerous significant drug interactions, most notably with anticoagulants, antihypertensives, diuretics, lithium, methotrexate, and other NSAIDs.
• Special caution is required in the elderly, patients with pre-existing cardiovascular, renal, or hepatic disease, and during late pregnancy. It is generally avoided in pediatric populations.

Clinical Pearls

• The choice between diclofenac and other NSAIDs should be individualized, weighing its potent efficacy against its specific risk profile, particularly concerning cardiovascular and hepatic safety.
• For chronic management of osteoarthritis, initiating therapy with a topical formulation before considering oral administration may mitigate systemic toxicity.
• Patients prescribed oral diclofenac should be counseled to take it with food or milk to reduce gastrointestinal upset, but this does not eliminate the risk of serious GI events.
• Baseline assessment of cardiovascular risk, renal function (serum creatinine), and hepatic function (transaminases) is recommended before starting chronic therapy, with periodic monitoring thereafter.
• Clinicians should maintain a high index of suspicion for hepatotoxicity, as elevated transaminases can occur without symptoms; routine monitoring of liver enzymes may be considered within the first several months of therapy.
• In patients requiring low-dose aspirin for cardioprotection, concomitant use of diclofenac may interfere with aspirin’s antiplatelet effect due to competitive binding at the COX-1 active site. Staggered dosing (administering aspirin at least 30-60 minutes before diclofenac) may be considered, though the clinical significance of this interaction is complex.

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