Drug administration diclofenac

Banks AT, Zimmerman HJ, Ishak KG, Harter JG. Diclofenac-associated hepatotoxicity analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology 1995 22(3) 820-7. 

A number of pharmacodynamic studies have investigated whether or not NSAIDs affect the antiplatelet effects of aspirin. Celecoxib 200 mg twice daily, diclofenac 75 mg twice dailyetoricoxib 120 mg daily, lumira-coxib 400 mg daily, meloxicam 15 mg dailynaproxen 500 mg twice daily, parecoxib 40 mg twice dailyand rofecoxib 25 mg daily have all been shown not to alter the antiplatelet effects of aspirin in doses of 75 to 325 mg daily. The effects of ibuprofen ate less elear, and may be related to the order of drug administration. 

Concomitant administration of methotrexate and Voltarol, a proprietary preparation of diclofenac, a non-steroidal anti-inflammatory drug, may result in accumulation of methotrexate as its excretion is reduced. The use of diclofenac and diuretics such as bendroflumethiazide may increase the risk of nephrotoxicity. Concomitant use of alcohol and an angiotensin-converting enzyme inhibitor such as lisinopril (Zestril) may result in an enhanced hypotensive effect. Alcohol and the benzodiazepine diazepam (Valium) may result in enhanced sedation. 

Cevc, G., and G. Blume. 2001. New, highly efficient formulation of diclofenac for the topical, transdermal administration in ultradeformable drug carriers. Transfersomes. Biochim Biophys Acta 1514 191. 

A 0.1% ophthalmic preparation is recommended for prevention of postoperative ophthalmic inflammation and can be used after intraocular lens implantation and strabismus surgery. A topical gel containing 3% diclofenac is effective for solar keratoses. Diclofenac in rectal suppository form can be considered a drug of choice for preemptive analgesia and postoperative nausea. In Europe, diclofenac is also available as an oral mouthwash and for intramuscular administration. 

Highly water soluble drugs, as they are typical for oral administration, can be released from polymer beads with low (< 10%) water- but high ethanolswelling capacity at controlled rates, for up to 8 hours. The release of oxprenolol-HCl (77% water solubility) and diclofenac Na (2.6% water solubility) from drug loaded monoliths is a function of water content and crosslink density. By partial extraction of the drug loaded beads the release can be further slowed down and, in the case of oxprenolol-HCl, delayed for several hours the delay is dependent on water content of the polymer and is the result of the formation of a hydrophobic surface membrane. 

NSAIDs, in particular indomethacin, diclofenac, mepirazole, phenylbutazone, and salicylate, can promote absorption of other drugs, including insulin, ampicillin, cephalothin, cefoxitin, and cefmetazole. Most of these observations were made in the rat and frequently after rectal administration. Several mechanisms by which NSAIDs promote drug absorption have been postulated, but exact mechanisms are not known. As NSAIDs are often irritating to the GI mucosa. 

Aseptic tissue necrosis after intramuscular injection (Nicolau syndrome) has been reported after accidental intra-arterial injection. Antirheumatic drugs are often involved in these reactions and diclofenac has also been implicated (42). Other consequences of intramuscular administration of diclofenac are asymptomatic high serum creatine kinase activity or damage to muscle, nerve, or blood vessels (SEDA-17,109). 

Celecoxib is currently indicated for the relief of signs and symptoms of osteoarthritis and rheumatoid arthritis and to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis as an adjunct to usual care. Celecoxib is at least as effective as naproxen in the symptomatic management of osteoarthritis and at least as effective as naproxen and diclofenac in the symptomatic treatment of rheumatoid arthritis, and it is less likely to cause adverse Gl effects. Celecoxib appears to be effective in the management of pain associated with both of these arthritic conditions, but effectiveness in acute or chronic pain has not been fully demonstrated. Unlike aspirin, celecoxib does not exhibit antiplatelet activity. Concomitant administration of aspirin and celecoxib may increase the incidence of Gl side effects. Another notable potential drug interaction with celecoxib is its ability, like other NSAIDs, to reduce the blood pressure response to angiotensin-converting enzyme inhibitors. A more detailed discussion of the chemical, pharmacological, pharmacokinetic, and clinical aspects of celecoxib is available (81). 

In a single-dose study in 24 healthy subjects, simultaneous administration of ximelagatran 24 mg and enteric-coated diclofenac 50 mg caused no change in the pharmacokinetics of either drug. In this study, there was also no additional effect of the combination on activated partial thromboplastin time or capillary bleeding time, suggesting that no pharmacodynamic interaction occurs. ... 

Apart from the already established formulations, researchers are trying to develop novel oil-based formulations to combat the poor solubility and bioavailablity of NCE. Shevachman et al. developed novel U-type microemulsions to improve the percutaneous permeability of diclofenac. Shah et al.2 2 used microwave heating for the preparation of solid lipid nanoparticles by microemulsion techniques, which resulted in improved particle characteristics. Ki et al. reported sustained-release liquid crystal of injectable leuprolide using sorbitan monooleate. Recently, various novel oil-based drug delivery technologies are reported, which includes tocol emulsions, solid lipid nanopar-ticles, nanosuspensions, Upid microbubbles, sterically stabilized phospholipid micelles, and environmentally responsive drug delivery systems for parenteral administration.25 259... 

A controlled release preparation of diclofenac sodium, a non-steroidal anti-inflammatory agent, was developed for transdennal administration. PVAl and PVAl/polyacrylic acid(PAA) alloy membranes were prepared from a solvent-casting technique using different PVAl/PAA v/v ratios. The release of the drug from the membrane was evaluated under in viti o conditions at pH 7.4. The delivery system provided linear release without time lag, burst effect and boundary layer resistance. The effects of such variables as film thickness and PVAl/PAA ratio on the permeation behaviour of the polymeric membranes are discussed. The optimal PVAl/PAA was found to be 50/ 50. 48 refs. 

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) and is the active ingredient in both the gel and patch formulations described in this chapter. Diclofenac inhibits the enzyme cyclooxygenase (COX), an early component of the arachidonic acid cascade, resulting in reduced formation of prostaglandins, thromboxane, and prostacyclin. It is not completely understood how reduced synthesis of these compounds results in therapeutic efficacy. The chief therapeutic effects of diclofenac are anti-inflammatory activity, anti-nociception and antipyresis. When applied topically (via gel or patch), diclofenac is absorbed into the epidermis. However, the amount of topical diclofenac absorbed and the ultimate systemic exposure is substantially less than that seen after oral administration of the compound. 

Because the newer formulation of injectable diclofenac can be administered as a rapid bolus IV injection, in comparison to the older formulation which must be infused slowly over 30 minutes, measurable plasma levels of diclofenac are observed almost immediately following IV injection of the newer formulation and peak plasma levels are achieved in approximately 3 minutes. The active substance is 99.7% protein-bound, mainly to albumin (99.4%). Parenteral administration of diclofenac avoids the first-pass metabolism observed with orally administered diclofenac, whereby only about 60% of the orally administered drug reaches the systemic circulation in unchanged form [1]. 

Chitosan has also been found to be beneficial in formulation development of delivery systems for local or systemic administration of drug through the rectal route. Chitosan microspheres encapsulating diclofenac sodium incorporated in hydrogels have been designed for efficient rectal administration [126]. Quaternized derivative of chitosan. 

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