Diclofenac

Pharmaceuticals -> NSAIDs

Pharmaceutical

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

log Kow = 4.51

3.9

In water, 2.37 mg/L at 25 °C

4.47e-03 g/L

Breast Feeding; Lactation; Milk, Human; Analgesic Agents; Anti-inflammatory Agents, Nonsteroidal

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

283-285 °C

156-158 °C

283 - 285 °C

Positive

1.78

2.7

Agilent XCT

Electrospray ionization

formic acid (5.3nM)

3.99

3.99

4.2

4.3

4.15

pKa = 4.15

166.4 Ų [M+Na]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID6022923]

157.7 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

157.2 Ų [M+H]+ [CCS Type: TW]

155.98 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

163.79 Ų [M+Na]+

MW 334.24 /Diclofenac potassium salt/

Crystals from water; mp 283-285 °C. UV max (methanol) 283 nm (epsilon 1.01X10+5); (phosphate buffer, pH 7.2) 276 nm (epsilon 1.01X10+5). Solubility at 25 °C (mg/mL): deionized water (pH 5.2) >0; methanol >24; acetone 6; acetonitrile <1; cyclohexane <1; HCl (pH 1.1) <1; phosphate buffer (pH 7.2) 6. pKa 4. Partition coefficient (N-octanol/aqueous buffer): 13.4 /Diclofenac sodium salt/

MW: 411.3; MF: C20H24Cl2N2O3. log Kow = 8 at pH 8.5 /Diclofenac epolamine/

This chemical does not meet GHS hazard criteria for 29.2% (52 of 178) of reports.

Danger

H301 (30.3%): Toxic if swallowed [Danger Acute toxicity, oral]

P203, P260, P264, P270, P273, P280, P301+P316, P301+P317, P318, P319, P321, P330, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 178 reports by companies from 17 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Indications for use in horses: For the control of pain and inflammation associated with osteoarthritis in tarsal, carpal, metacarpophalangeal, metatarsophalangeal, and proximal interphalangeal (hock, knee, fetlock and pastern) joints. ... Limitations: Do not use in horses intended for human consumption. Federal law restricts this drug to use by or on the order of a licensed veterinarian.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including diclofenac sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Diclofenac sodium/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including diclofenac potassium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Diclofenac potassium/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including diclofenac epolamine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Diclofenac epolamine/

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Diclofenac sodium is included on this list. /Diclofenac sodium/

Diclofenac sodium 1% gel and diclofenac epolamine transdermal system should be stored at 25 °C but may be exposed to temperatures ranging from 15-30 °C. Diclofenac gel should not be frozen.

Diclofenac sodium delayed-release (enteric-coated) tablets, diclofenac sodium extended-release tablets, and diclofenac potassium tablets should be protected from moisture and stored in tight containers at a temperature not exceeding 30 °C. Commercially available diclofenac sodium and misoprostol tablets should be stored in a dry area at a temperature not exceeding 25 °C.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Concomitant use of aspirin and a nonsteroidal anti-inflammatory agent (NSAIA) increases the risk for serious GI events. Because of the potential for increased adverse effects, patients receiving diclofenac should be advised not to take aspirin. There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.

Concurrent use /of alcohol or glucocorticoid corticosteroids or chronic therapeutic use of corticotropin or potassium supplements/ with an nonsteroidal anti-inflammatory drug may increase the risk of gastrointestinal side effects, including ulceration or hemorrhage; however, concurrent use with a glucocorticoid or corticotropin in the treatment of arthritis may provide additional therapeutic benefit and permit reduction of glucocorticoid or corticotropin dosage. /Nonsteroidal anti-inflammatory drugs/

Nonsteroidal anti-inflammatory drugs may increase the hypoglycemic effect of these medications /oral antidiabetic agents or insulin/ because prostaglandins are directly involved in regulatory mechanisms of glucose metabolism and possibly because of displacement of the oral antidiabetics from serum proteins; dosage adjustments of the antidiabetic agent may be necessary; ... caution with concurrent use is recommended. /Nonsteroidal anti-inflammatory drugs/

These medications /cefamandole or cefoperazone or cefotetan or plicamycin or valproic acid/ may cause hypoprothrombinemia; in addition, plicamycin or valproic acid may inhibit platelet aggregation; concurrent use with an nonsteroidal anti-inflammatory drug may increase the risk of bleeding because of additive interferences with platelet function and/or the potential occurrence of nonsteroidal anti-inflammatory drug-induced gastrointestinal ulceration or hemorrhage. /Nonsteroidal anti-inflammatory drugs/

For more Interactions (Complete) data for DICLOFENAC (16 total), please visit the HSDB record page.

Elevated serum aminotransferase levels have been reported in up to 15% of patients taking oral diclofenac chronically, but are greater than 3 times the upper limit of normal in only 2% to 4% (Cases 1 and 2). Clinically apparent and symptomatic liver disease with jaundice due to diclofenac is rare (1 to 5 cases per 100,000 prescriptions, occurring in 1 to 5 persons per 10,000 exposed). Nevertheless, more than a hundred instances of clinically apparent liver injury due to diclofenac have been reported in the literature and, in most case series, diclofenac ranks in the top 10 causes of drug induced liver injury. The time to onset of liver injury varies from within a week to over a year after starting. The majority of cases present within 2 to 6 months (Cases 3 and 4), and the more severe cases tend to present earlier. The pattern of injury is almost exclusively hepatocellular, although cases presenting with mixed patterns have been reported. The clinical picture is that of jaundice preceded by anorexia, nausea, vomiting and malaise. Fever and rash occur in 25% of cases and some cases have immunoallergic features, while others resemble chronic hepatitis and have autoimmune features. In most cases, liver histology reveals an acute lobular hepatitis. However, a cases with prolonged latency diclofenac hepatotoxicity can have clinical and histologic features of chronic hepatitis (Case 2). There seems to be greater susceptibility for diclofenac liver injury among women than men. The injury can be severe, and several cases of acute liver failure have been attributed to diclofenac.

TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 245(SRC), from a log Koc of 2.39(2), indicates that diclofenac is expected to have moderate mobility in soil(SRC). The pKa of diclofenac is 4.15(3), indicating that this compound will exist almost entirely in the dissociated form in the environment and anions generally do not adsorb more strongly to organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an anion and anions do not volatilize. Diclofenac is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.1X10-8 mm Hg(SRC), determined from a fragment constant method(5). Little or no biodegradation using a freshwater inoculum(6) suggests that biodegradation is not an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), a Koc value of 245(SRC), from a log Koc of 2.39(2), indicates that diclofenac is expected to adsorb to suspended solids and sediment(SRC). The pKa is 4.15(3), indicating that diclofenac will exist almost entirely in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process. According to a classification scheme(4), an estimated BCF of 3(SRC), from its log Kow of 4.51(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Little or no biodegradation using a freshwater inoculum(7) suggests that biodegradation is not an important environmental fate process in water. Direct photolysis is the predominant removal process in freshwater, exhibiting a half-life of 8 days(8).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), diclofenac, which has an estimated vapor pressure of 6.1X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase diclofenac is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 0.8 hours(SRC), calculated from its rate constant of 1.6X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase Diclofenac may be removed from the air by wet or dry deposition(SRC).

Diclofenac has many similar adverse effects shared with the NSAID family of drugs due to the inhibition of COX enzymes. Because diclofenac appears to act more selectively on COX-2 inhibition, it has an increased associated risk of cardiovascular events and less risk for gastrointestinal events, but this article will also examine the gastrointestinal risk for completeness. The following side effects involve systemic effects that arise from systemic exposure to diclofenac. These are less likely to be involved in the topical application of the medication, as there is less risk of systemic exposure to the drug.

Diclofenac is distributed into breast milk. In one study, long-term use of 150 mg per day produced concentrations of 100 ng/g in the breast milk. An infant of 4 to 5 kg consuming one liter per day would therefore ingest approximately 0.03 mg/kg/day.

Diclofenac’s potential for toxicity is associated with polymorphisms of the cytochrome P450 gene family, which affects the patient’s potential for drug metabolism. OTC NSAID toxicity is not uncommon but is generally limited to mild symptoms with a low risk of serious effects. These effects are usually limited to GI upset, nausea, and dizziness. Severe overdose may lead to more serious symptoms involving seizure, coma, cardiovascular events, and metabolic acidosis.

The antiinflammatory effects of diclofenac are believed to be due to inhibition of both leukocyte migration and the enzyme cylooxygenase (COX-1 and COX-2), leading to the peripheral inhibition of prostaglandin synthesis. As prostaglandins sensitize pain receptors, inhibition of their synthesis is responsible for the analgesic effects of diclofenac. Antipyretic effects may be due to action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat dissipation.

/BIRDS and MAMMALS/ The nonsteroidal anti-inflammatory drug diclofenac is extremely toxic to Old World Gyps vultures (median lethal dose ~0.1-0.2 mg/kg), evoking visceral gout, renal necrosis, and mortality within a few days of exposure. Unintentional secondary poisoning of vultures that fed upon carcasses of diclofenac-treated livestock decimated populations in the Indian subcontinent. Because of the widespread use of diclofenac and other cyclooxygenase-2 inhibiting drugs, a toxicological study was undertaken in turkey vultures (Cathartes aura) as an initial step in examining sensitivity of New World scavenging birds. Two trials were conducted entailing oral gavage of diclofenac at doses ranging from 0.08 to 25 mg/kg body weight. Birds were observed for 7 days, blood samples were collected for plasma chemistry (predose and 12, 24, and 48 hr and 7 days postdose), and select individuals were necropsied. Diclofenac failed to evoke overt signs of toxicity, visceral gout, renal necrosis, or elevate plasma uric acid at concentrations greater than 100 times the estimated median lethal dose reported for Gyps vultures. For turkey vultures receiving 8 or 25 mg/kg, the plasma half-life of diclofenac was estimated to be 6 hr, and it was apparently cleared after several days as no residues were detectable in liver or kidney at necropsy. Differential sensitivity among avian species is a hallmark of cyclooxygenase-2 inhibitors, and despite the tolerance of turkey vultures to diclofenac, additional studies in related scavenging species seem warranted.

/AQUATIC SPECIES/ One of the most frequently detected pharmaceuticals in environmental water samples is the anti-rheumatic drug, diclofenac. Despite its increasing environmental significance, investigations concerning the effects of this drug on the early developmental stages of aquatic species are lacking up to now. To determine the developmental toxicity and proteotoxicity of this drug on the growing fish embryos, eggs of zebrafish were exposed to six concentrations of diclofenac (0, 1, 20, 100, 500, 1000, and 2000 microgl(-1)) using DMSO as solvent. Early life stage parameters such as egg and embryo mortality, gastrulation, somite formation, movement and tail detachment, pigmentation, heart beat, and hatching success were noted and described within 48- and 96-h of exposure. After the 96-h exposure, the levels of stress proteins (hsp 70) were determined in both the diclofenac-treated and respective DMSO controls. Results showed no significant inhibition in the normal development until the end of 96 h for all exposure groups. However, there was a delay in the hatching time among embryos exposed to 1000 and 2000 microgl(-1). Late-hatched embryos (108 h) did not differ morphologically from normally hatched embryos. The mortality and average heart rate data did not show significant differences for all embryos in both diclofenac-treated and DMSO control groups. No significant malformations were likewise noted among all developing embryos throughout the exposure period. The levels of heat shock proteins in diclofenac-treated and control embryos did not differ significantly. DMSO control embryos, on the other hand, showed a concentration-dependent increase in hsp 70 levels. We suggest possible modulating effect of diclofenac in DMSO-triggered expression of stress proteins and this might have a possible repercussion on the use of DMSO as solvent in any toxicity assay. Since the present data indicate no significant embryotoxicity and proteotoxicity induced by diclofenac and due to the fact that the concentrations of diclofenac used in the present study is up to 2000-fold higher than the concentrations detected in the environment, it is unlikely that this drug would pose a hazard to early-life stages of zebrafish.

/AQUATIC SPECIES/ In the present study, cytopathology was investigated in the liver, kidney, gills and gut of rainbow trout (Oncorhynchus mykiss) exposed to five different concentrations (1, 5, 20, 100 and 500 ug/L) of the anti-inflammatory drug diclofenac under laboratory conditions. The lowest observed effect concentration (LOEC) for cytological alterations in liver, kidney and gills was 1 ug/L. In the gut, however, no diclofenac-induced cytopathology occurred. As the most prominent reactions induced by diclofenac (1) in the kidney, a severe accumulation of protein in the tubular cells (so called hyaline droplet degeneration), macrophage infiltration and structural alterations (dilation, vesiculation) of the endoplasmic reticulum (ER) in the proximal and distal renal tubules were observed. Furthermore, shortening of podocytes and their retraction from the basal lamina, a thickening of the basal lamina, the formation of desmosomes, and necrosis of endothelial cells in the renal corpuscles occurred; (2) in the liver, the most striking reactions were the collapse of the cellular compartmentation as well as the glycogen depletion of hepatocytes; (3) in the gills, pillar cell necrosis, hypertrophy of chloride cells, and epithelium lifting became evident in the secondary lamellae.

/AQUATIC SPECIES/ ...The impact of diclofenac on river biofilm communities was investigated at exposures of 10 and 100 ug/L of diclofenac or its molar equivalent in carbon and nutrients. Experiments were carried out with river water during spring and summer using rotating annular reactors as model systems. Diclofenac or nutrients at 10 ug/L were observed to have no significant effect on algal, bacterial, and cyanobacterial biomass in spring, whereas in the summer the nutrient equivalent reduced algal biomass and diclofenac reduced cyanobacterial biomass relative to control biofilms (p<0.05). In contrast, at 100 ug/L diclofenac or nutrients, the result was increased cyanobacterial and bacterial biomass, respectively, relative to control biofilms in spring. In summer, 100 ug/L diclofenac significantly increased bacterial biomass and the nutrient treatment had no significant effect (p<0.05); both treatments resulted in increased biofilm thickness. The glycoconjugate composition of the exopolysaccharide matrix was influenced differentially by the treatments in both seasons. Biolog assessments of carbon use indicated that 100 ug/L diclofenac or nutrients resulted in significant depressions in the use of carbon sources in summer and significant increases in spring. Impacts on protozoan and micrometazoan populations also were assessed. Denaturing gradient gel electrophoresis analyses of community DNA and fluorescent in situ hybridization studies indicated that diclofenac had significant effects on the nature of the bacterial community in comparison with control and nutrient-treated river biofilm communities.

For more Ecotoxicity Excerpts (Complete) data for DICLOFENAC (7 total), please visit the HSDB record page.

Samples of effluent from 18 sewage treatment plants in 14 municipalities in Canada were analyzed for the presence of neutral and acidic drugs over the period from September 1998 to February 1999(1). The median diclofenac influent concentration was 1.3 ug/L; the compound was not detected in any of the effluent samples, detection limit of 0.25 ug/L(1). Diclofenac was detected in effluents of three wastewater treatment plant samples collected in the region of Lake Greifensee, Switzerland between August 16, 1999 and October 22, 1999 at a maximum concentration of 0.99 ug/L(2). The compound was detected in 49 of 49 treatment plant effluents in Germany at a median concentration of 0.81 ug/L, detection limit = 0.05 ug/L(3). The compound was detected in wastewater treatment plant effluents in France, Greece, and Switzerland at a range of 0.25-5.45 ug/L, median of 0.47 ug/L; sampling conducted from February to March 2001(4). Diclofenac removal efficiencies from wastewater treatment plants ranges from 0 to 80% but fall mainly in the range of 21-40%. Average diclofenac concentrations in wastewater treatment plant effluents worldwide were as follows (ng/L): Austria, 1750; Denmark 950; Finland, 1000; France, 750; Germany, 3250; Greece, 750; Italy, 700; Spain, 600; Sweden, 800; Switzerland, 100; UK, not reported; Canada, 1400; USA, 200; Brazil, not reported, Japan, 50, Korea, 400(5). The estimated total discharge in 2002 from riverine, sewage treatment plants, and industrial sources in the Netherlands was 4.075 tons/year(6). Influent and effluent concentrations ranged from 112-438 ng/L (mean 286 ng/L) and 35.3 to 463 ng/L (mean 185 ng/L), respectively, in samples from 2 sewage treatment plants in Beijing, China, sampled monthly from February 2009-January 2010(7).

Using an agricultural soil from Corrstown, County Dublin, Ireland a log Koc of 2.39 was measured(1), corresponding to a Koc of 245(SRC). According to a classification scheme(2), this estimated Koc value suggests that diclofenac is expected to have moderate mobility in soil. The pKa of diclofenac is 4.15(3), indicating that this compound will exist almost entirely in the dissociated form in the environment and anions generally do not adsorb more strongly to organic carbon and clay than their neutral counterparts(4). Adsorption to sediments from Lake Greifensee, Switzerland was found to be negligible(5). When 500 ng/L diclofenac was mixed with one liter of lake water and 1 g sediment/L water, the aqueous phase showed no decrease in concentration following centrifugation and removal of sediment particles(5).

/CASE REPORTS/ No signs or symptoms of toxicity were observed in a few patients who ingested 3.75-4 g of diclofenac. However, vomiting and drowsiness occurred in an adolescent who ingested 2.37 g of the drug.

/CASE REPORTS/ Acute diclofenac overdosage produces manifestations that are mainly extension of adverse effects of the drug. Loss of consciousness, increased intracranial pressure, and aspiration pneumonitis were reported in a 17 year old male who died 2 days after ingestion 5 g of diclofenac.

/CASE REPORTS/ A case of hypoxic brain damage that occurred after intramuscular injection of diclofenac due to a severe anaphylactic reaction /is presented/. A 38-year-old nurse treated herself for acute lower back pain with 100 mg diclofenac intramuscularly. Five minutes later, she collapsed and developed coma and respiratory arrest. After cardiopulmonary resuscitation she was transferred to hospital. On admission she was comatose and received controlled ventilation of the lungs. Magnetic resonance imaging and computerized tomography showed signs of hypoxic brain injury and the patient died from central cardiopulmonary failure 7 days later. Intramuscular treatment with non-steroidal anti-inflammatory drugs such as diclofenac has rare but potentially severe side-effects.

/CASE REPORTS/ Upper gastrointestinal tract complications due to non-steroidal anti-inflammatory drugs are well recognised. However, adverse effects on large intestinal mucosa are less common and less well recognised, even though they carry a significant morbidity and mortality. Here we report a case of colonic perforation in a healthy woman without any underlying colonic pathology associated with ingestion of slow release diclofenac sodium. /Diclofenac sodium/

For more Human Toxicity Excerpts (Complete) data for DICLOFENAC (13 total), please visit the HSDB record page.

Indications for use in horses: For the control of pain and inflammation associated with osteoarthritis in tarsal, carpal, metacarpophalangeal, metatarsophalangeal, and proximal interphalangeal (hock, knee, fetlock and pastern) joints. ... Limitations: Do not use in horses intended for human consumption. Federal law restricts this drug to use by or on the order of a licensed veterinarian.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including diclofenac sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Diclofenac sodium/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including diclofenac potassium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Diclofenac potassium/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including diclofenac epolamine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Diclofenac epolamine/

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Diclofenac sodium is included on this list. /Diclofenac sodium/

M01AB05

M01AB05

D - Dermatologicals

M - Musculo-skeletal system

S - Sensory organs

M - Musculo-skeletal system

Diclofenac inhibits cyclooxygenase-1 and -2, the enzymes responsible for production of prostaglandin (PG) G₂ which is the precursor to other PGs. These molecules have broad activity in pain and inflammation and the inhibition of their production is the common mechanism linking each effect of diclofenac. PGE₂ is the primary PG involved in modulation of nociception. It mediates peripheral sensitization through a variety of effects. PGE₂ activates the G_q-coupled EP₁ receptor leading to increased activity of the inositol trisphosphate/phospholipase C pathway. Activation of this pathway releases intracellular stores of calcium which directly reduces action potential threshold and activates protein kinase C (PKC) which contributes to several indirect mechanisms. PGE₂ also activates the EP₄ receptor, coupled to G_s, which activates the adenylyl cyclase/protein kinase A (AC/PKA) signaling pathway. PKA and PKC both contribute to the potentiation of transient receptor potential cation channel subfamily V member 1 (TRPV1) potentiation, which increases sensitivity to heat stimuli. They also activate tetrodotoxin-resistant sodium channels and inhibit inward potassium currents. PKA further contributes to the activation of the P2X3 purine receptor and sensitization of T-type calcium channels. The activation and sensitization of depolarizing ion channels and inhibition of inward potassium currents serve to reduce the intensity of stimulus necessary to generate action potentials in nociceptive sensory afferents. PGE₂ act via EP₃ to increase sensitivity to bradykinin and via EP₂ to further increase heat sensitivity. Central sensitization occurs in the dorsal horn of the spinal cord and is mediated by the EP₂ receptor which couples to G_s. Pre-synaptically, this receptor increases the release of pro-nociceptive neurotransmitters glutamate, CGRP, and substance P. Post-synaptically it increases the activity of AMPA and NMDA receptors and produces inhibition of inhibitory glycinergic neurons. Together these lead to a reduced threshold of activating, allowing low intensity stimuli to generate pain signals. PGI₂ is known to play a role via its G_s-coupled IP receptor although the magnitude of its contribution varies. It has been proposed to be of greater importance in painful inflammatory conditions such as arthritis. By limiting sensitization, both peripheral and central, via these pathways NSAIDs can effectively reduce inflammatory pain. PGI₂ and PGE₂ contribute to acute inflammation via their IP and EP₂ receptors. Similarly to β adrenergic receptors these are G_s-coupled and mediate vasodilation through the AC/PKA pathway. PGE₂ also contributes by increasing leukocyte adhesion to the endothelium and attracts the cells to the site of injury. PGD₂ plays a role in the activation of endothelial cell release of cytokines through its DP₁ receptor. PGI₂ and PGE₂ modulate T-helper cell activation and differentiation through IP, EP₂, and EP₄ receptors which is believed to be an important activity in the pathology of arthritic conditions. By limiting the production of these PGs at the site of injury, NSAIDs can reduce inflammation. PGE₂ can cross the blood-brain barrier and act on excitatory G_q EP₃ receptors on thermoregulatory neurons in the hypothalamus. This activation triggers an increase in heat-generation and a reduction in heat-loss to produce a fever. NSAIDs prevent the generation of PGE₂ thereby reducing the activity of these neurons.

Diclofenac has pharmacologic actions similar to those of other prototypical NSAIAs. The drug exhibits anti-inflammatory, analgesic, and antipyretic activity. The exact mechanisms have not been clearly established, but many of the actions appear to be associated principally with the inhibition of prostaglandin synthesis. Diclofenac inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase; at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as prostaglandin G/H synthase-1 (PGHS-10 and -2 (PGHS-2), respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway. Diclofenac, like other prototypical NSAIAs, inhibits both COS-1 and COS-2. Although the exact mechanisms have not been clearly established, NSAIAs appear to exert anti-inflammatory, analgesic, and antipyretic activity principally through inhibition of the COS-2 isoenzyme; COX-1 inhibition presumably is responsible for the drugs' unwanted effects on GI mucosa and platelet aggregation.

As for all non-steroidal anti-inflammatory drugs the pharmacodynamic effects of diclofenac sodium are of anti-inflammatory, analgesic and antipyretic character due to the decrease of the prostaglandin synthesis from arachidonic acid by inhibition of the cyclo-oxygenase activity. It also induces deleterious effects on gastric and intestinal mucosa and an inhibition of platelet aggregation. /Diclofenac sodium/

The terminal half-life of diclofenac is approximately 2 h, however the apparent half-life including all metabolites is 25.8-33 h.

Following application of diclofenac epolamine transdermal system, the elimination half-life of diclofenac is approximately 12 hours. /Diclofenac epolamine/

Following IV administration of diclofenac sodium in healthy adults, the half-life of diclofenac reportedly averages about 3 minutes in the initial distribution phase, about 16 minutes in the intermediate (redistribution) phase, and about 1-2 hours in the terminal (elimination) phase. /Diclofenac sodium/

Elimination: Up to 6 hours

Diclofenac undergoes oxidative metabolism to hydroxy metabolites as well as conjugation to glucuronic acid, sulfate, and taurine. The primary metabolite is 4'-hydroxy diclofenac which is generated by CYP2C9. This metabolite is very weakly active with one thirtieth the activity of diclofenac. Other metabolites include 3'-hydroxy diclofenac, 3'-hydroxy-4'methoxy diclofenac, 4',5-dihydroxy diclofenac, an acylglucuronide conjugate, and other conjugate metabolites.

The extent of metabolism of diclofenac sodium in excised viable human skin was investigated using combination HPLC and radioactivity assay. In an earlier diffusion experiment using an in vitro flow-through diffusion system, radiolabelled diclofenac sodium in either lotion (Pennsaid) or aqueous solution was applied to viable human skin, either as single dose or multiple dose (8 times over 2 days). In this study, the receptor fluid samples from the diffusion experiment were subjected to extraction and the aliquot was analysed using HPLC to separate diclofenac and authentic metabolites. Based on the radioactivity of each HPLC fraction, the collection time of the fractions was compared with the retention time of diclofenac and metabolites in standard solutions. The samples from a single or multiple dose application of lotion showed radioactivity in mainly one fraction, whose retention time corresponded with diclofenac. Other HPLC fractions showed none or only small amounts of radioactivity within the error range of the assay. The same results were obtained with the pooled samples from the application of the lotion or of aqueous solution. The results suggest that diclofenac sodium does not undergo metabolism in viable human epidermis during percutaneous absorption in vitro. Hence, with topical application to human skin in vivo, diclofenac will be delivered with minimal, if any, metabolism. /Diclofenac sodium/

In humans, metabolism of the commonly used nonsteroidal antiinflammatory drug diclofenac /compound/ 1 yields principally the 4'-hydroxy /compound/ 2, 5-hydroxy /compound/ 3, and acyl glucuronide /compound/ 4 metabolites. All three metabolites have been implicated in rare idiosyncratic adverse reactions associated with this widely used drug. Therefore, for mechanistic toxicological studies of /compound/ 1, substantial quantities of 2-4 are required and their syntheses and characterization are described here. Key steps were a convenient two-step preparation of aniline /compound/ 5 from phenol, efficient and selective 6-iodination of amide /compound/ 18, and high-yielding Ullmann couplings to generate diarylamines /compound/ 11 and /compound/ 21. The acyl glucuronide /compound/ 4 was obtained by Mitsunobu reaction of /compound/ 1 (free acid) with allyl glucuronate /compound/ 23 followed by Pd(0) deprotection, using a modification of a published procedure. /Investigators/ report full characterization of /compound/ 4 ... /Investigators/ report also the metabolic fates of the synthetic metabolites: /compound/ 2 and /compound/ 3 were glucuronidated in rats, but only /compound/ 3 formed glutathione adducts in vivo and by enzymatic synthesis via a quinoneimine intermediate. A previously undescribed glutathione adduct of /compound/ 3 was obtained by enzymatic synthesis. Compound /compound/ 4 formed an imine-linked protein conjugate as evinced by sodium cyanoborohydride trapping.

Diclofenac is eliminated predominantly (approximately 50%) as its 4'-hydroxylated metabolite in humans, whereas the acyl glucuronide (AG) pathway appears more important in rats (approximately 50%) and dogs (>80-90%). However, previous studies of diclofenac oxidative metabolism in human liver microsomes (HLMs) have yielded pronounced underprediction of human in vivo clearance. We determined the relative quantitative importance of 4'-hydroxy and AG pathways of diclofenac metabolism in rat, dog, and human liver microsomes. Microsomal intrinsic clearance values (CL(int) = V(max)/K(m)) were determined and used to extrapolate the in vivo blood clearance of diclofenac in these species. Clearance of diclofenac was accurately predicted from microsomal data only when both the AG and the 4'-hydroxy pathways were considered. However, the fact that the AG pathway in HLMs accounted for ~75% of the estimated hepatic CL(int) of diclofenac is apparently inconsistent with the 4'-hydroxy diclofenac excretion data in humans. Interestingly, upon incubation with HLMs, significant oxidative metabolism of diclofenac AG, directly to 4'-hydroxy diclofenac AG, was observed. The estimated hepatic CL(int) of this pathway suggested that a significant fraction of the intrahepatically formed diclofenac AG may be converted to its 4'-hydroxy derivative in vivo. Further experiments indicated that this novel oxidative reaction was catalyzed by CYP2C8, as opposed to CYP2C9-catalyzed 4'-hydroxylation of diclofenac. These findings may have general implications in the use of total (free + conjugated) oxidative metabolite excretion for determining primary routes of drug clearance and may question the utility of diclofenac as a probe for phenotyping human CYP2C9 activity in vivo via measurement of its pharmacokinetics and total 4'-hydroxy diclofenac urinary excretion.

The metabolism of (14)C-diclofenac in mice was investigated following a single oral dose of 10 mg/kg. The majority of the drug-related material was excreted in the urine within 24 hr of administration (49.7%). Liquid chromatographic analysis of urine and fecal extracts revealed extensive metabolism to at least 37 components, with little unchanged diclofenac excreted. Metabolites were identified using a hybrid linear ion-trap mass spectrometer via exact mass determinations of molecular ions and subsequent multi-stage fragmentation. The major routes of metabolism identified included: 1) conjugation with taurine; and 2) hydroxylation (probably at the 4'-and 5-arene positions) followed by conjugation to taurine, glucuronic acid or glucose. Ether, rather than acyl glucuronidation, predominated. There was no evidence for p-benzoquinone-imine formation (i.e. no glutathione or mercapturic acid conjugates were detected). A myriad of novel minor drug-related metabolites were also detected, including ribose, glucose, sulfate and glucuronide ether-linked conjugates of hydroxylated diclofenac derivatives. Combinations of these hydroxylated derivatives with acyl conjugates (glucose, glucuronide and taurine) or N-linked sulfation or glucosidation were also observed. Acyl- or amide-linked-conjugates of benzoic acid metabolites and several indolinone derivatives with further hydroxylated and conjugated moieties were also evident. The mechanisms involved in the generation of benzoic acid and indolinone products indicate the formation reactive intermediates in vivo that may possibly contribute to hepatotoxicity.

For more Metabolism/Metabolites (Complete) data for DICLOFENAC (7 total), please visit the HSDB record page.

144O8QL0L1

DICLOFENAC

Mechanisms of Action [MoA] - Cyclooxygenase Inhibitors

Physiologic Effects [PE] - Decreased Prostaglandin Production

Chemical Structure [CS] - Anti-Inflammatory Agents, Non-Steroidal

Established Pharmacologic Class [EPC] - Nonsteroidal Anti-inflammatory Drug

Anti-inflammatory agents that are non-steroidal in nature. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions. They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects.

Compounds or agents that combine with cyclooxygenase (PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES) and thereby prevent its substrate-enzyme combination with arachidonic acid and the formation of eicosanoids, prostaglandins, and thromboxanes.

Diclofenac is completely absorbed from the GI tract but likely undergoes significant first pass metabolism with only 60% of the drug reaching systemic circulation unchanged. Many topical formulations are absorbed percutaneous and produce clinically significant plasma concentrations. Absorption is dose proportional over the range of 25-150 mg. Tmax varies between formulations with the oral solution reaching peak plasma concentrations in 10-40min, the enteric coated tablet in 1.5-2h, and the sustained- and extended-release formulations prolonging Tmax even further. Administration with food has no significant effects on AUC but does delay Tmax to 2.5-12h.

Diclofenac is mainly eliminated via metabolism. Of the total dose, 60-70% is eliminated in the urine and 30% is eliminated in the feces. No significant enterohepatic recycling occurs.

Diclofenac has a total volume of distribution of 5-10 L or 0.1-0.2 L/kg. The volume of the central compartment is 0.04 L/kg. Diclofenac distributes to the synovial fluid reaching peak concentration 2-4h after administration. There is limited crossing of the blood brain barrier and cerebrospinal fluid concentrations only reach 8.22% of plasma concentrations. Doses of 50 mg delivered via intramuscular injection produced no detectable diclofenac concentrations in breast milk, however metabolite concentrations were not investigated. Diclofenac has been shown to cross the placenta in mice and rats but human data is unavailable.

Diclofenac has a plasma clearance 16 L/h.

Onset of absorption is delayed when diclofenac sodium is administered orally as delayed-release (enteric-coated) tablets, but the extent of absorption does not appear to be affected. /Diclofenac sodium/

Measurable plasma concentrations of diclofenac have been observed in some fasting individuals within 10 minutes of receiving diclofenac potassium conventional tablets. /Diclofenac potassium/

MEDICATION

Use (kg) in Switzerland (2009): >5000

For the acute and chronic treatment of signs and symptoms of osteoarthritis and rheumatoid arthritis.

Oxalyl chloride and 2,6-dichlorodiphenylamine are condensed to form the N,N-diphenyloxanilyl chloride that cyclizes under Friedel-Crafts conditions to yield 1-(2,6-diphenyl)isatin. Wolff-Kishner reduction of the 3-oxo group gives the lactam, which on hydrolysis affords the free acid. Neutralization with NaOH produces the salt. /Diclofenac sodium/

Preparation: NL 6604752; A. Sallmann, R. Pfister, US 3558690 (1966, 1971 both to Geigy)

Table: Diclofenac Sodium Combination Preparations [Table#6838]

Table: Diclofenac Potassium Preparations [Table#6839]

Table: Diclofenac Epolamine Preparations [Table#6840]

Table: Diclofenac Sodium Preparations [Table#6841]

Table: Diclofenac Preparations [Table#6842]

Pharmaceuticals -> Musculo-skeletal system -> Antiinflammatory and antirheumatic products -> Antiinflammatory and antirheumatic products, non-steroids -> Acetic acid derivatives and related substances

Pharmaceuticals

Synthesis: acylation of N-phenyl-2,6-dichloroaniline with chloroacetyl chloride gives the corresponding chloroacetanilide, which is fused with aluminum chloride to give 1-(2,6-dichlorophenyl)-2-indolinone. Hydrolysis of the indolinone with dilute aqueous-alcoholic sodium hydroxide affords the desired sodium salt directly. /Diclofenac Sodium/

Preparation: NL 6604752; A Sallmann, R Pfister, US 3558690 (1966, 1971 both to Geigy)