Diclofenac, effect

Figure 15.3. Diclofenac effective permeability pH profile corrected for the unstirred layer effect. The solid line represents the effective membrane permeability, while the dotted line represents the membrane permeabiltiy, corrected by the unstirred layer effect.

Diclofenac is an exceedingly potent COX inhibitor slightly more efficacious against COX-2 than COX-1. Its absorption from the gastrointestinal tract varies according to the type of pharmaceutical formulation used. The oral bioavailability is only 30-80% due to a first-pass effect. Diclofenac is rapidly metabolised (hydroxylation and conjugation) and has a plasma half-life of 1.5 h. The metabolites are excreted renally and via the bile. 

Schwaiger J, Ferling H, Mallow U, Wintermayr H, Negele R (2004) Toxic effects of non-steroideal anti-inflammatory drug diclofenac. Part I. Histopathological alterations and bioaccumulation in rainbow trout. Aquat Toxicol 68 141-150... 

Among pharmacenticals, EE2 has been the snbject of particular recent attention becanse of its ability to canse endocrine disrnption in fish, as has been described in Chapter 15. Low levels of mixtnres of beta blockers, such as propranolol, metoprol, and nadolol have been detected in snrface waters, and there have been investigations of their possible effects on aqnatic invertebrates (Huggett et al. 2002). Veterinary medicines, too, have come nnder scrntiny for example, the dramatic effects of diclofenac on vnltnres, which will be discnssed shortly. Many questions remain to be answered abont the possible ecological effects of complex mixtures of pharmaceuticals and veterinary medicines. 

Conventional WWTPs are, therefore, unable to remove wide ranges of pharmaceuticals and other compounds. For pharmaceuticals, although acute toxicity of aquatic organisms or chronic effects are unlikely with the present concentrations due to dilution effects, a wide range of pharmaceuticals are detected in the Ebro, and the overall toxicity of mixed pharmaceuticals may be high. Further studies are therefore required to assess the interactions of different compounds and the consequential health effects. In a similar manner to other pollutants, pharmaceuticals have a clear sensitivity to climate change through dilution effects, and the projected future decrease in annual precipitation could cause certain compound concentrations (e.g. anti-inflammatory diclofenac and p-blocker pranolol) to reach levels which may cause chronic effects [76]. 

Topical diclofenac in a dimethyl sulfoxide carrier (Pennsaid) is a safe and effective treatment for OA pain. It is thought to act primarily by local inhibition of COX-2 enzymes. The product was under review by the U.S. FDA at the time of this writing. 

Figure 9.3 The effects of varying levels of accessory proteins on CYP2C9 kinetics using diclofenac (a) or (S)-warfarin (b) as substrate probe [219].

It is a well-known fact that a pharmaceutical substance can be prepared by adopting different routes of synthesis based upon the dynamic ongoing research in the field of organic-reaction-mechanisms. Relentless efforts are exerted vigorously by reputed research laboratories across the world to look for shorter routes of synthesis bearing in mind the cost-effectiveness of the final product. For instance diclofenac sodium (an NSAID) can be manufactured by two methods, one using a bromo compound as a starting material while the other is based on a non-bromo compound. Nevertheless, the latter product is more in demand because it is completely devoid of bromine residues in the final product. 

The effect of ionic strength of the release medium on the diclofenac release rates from PDADMAC is shown in Figure 3. It is evident that, in a... 

The effect of drug solubility on the release from PDADMAC is shown in Figure 5. The slightly soluble diclofenac (2.5 wt%) was released over a... 

For highly potent APIs, profound effects can occur at low ng levels, the adverse effect of ethynylestradiol on fish populations is one example [107]. Another example is the development of resistant bacterial strains induced by the release of antibiotics into the environment [112, 113]. Dome et al. [114] concluded that fluoxetine, ibuprofen, diclofenac, propranolol and metoprolol exhibit relatively high acute toxicity to aquatic species. In addition, due to the inherent properties of these chemicals, pharmacodynamic effects were observed in the heart rate of Daphnia magna for the (3-blockers propranolol and metoprolol. 

Celecoxib, a non-steroidal anti-inflammatory drug, is a cyclo-oxygenase-2 selective inhibitor that is as effective as diclofenac and naproxen. It should be used for the shortest period required to control symptoms. Use is associated v/ith an increased risk of thrombotic events and the cyclo-oxygenase-2 selective inhibitors are contraindicated in cerebrovascular disease. Mobic is the proprietary preparation of meloxicam. 

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. 

The first-line agents in the treatment of rheumatoid arthritis are non-steroidal anti-inflammatory drugs such as diclofenac. Diclofenac and indometacin, another NSAID, tend to have similar activity hov/ever, indometacin has a higher incidence of side-effects and therefore diclofenac is more appropriate for initial treatment. Sodium aurothiomalate is classified as a disease-modifying antirheumatic drug and is used as a second-line treatment in rheumatoid arthritis, but has been superseded by methotrexate, administered v/eekly. Paracetamol is often indicated in the management of osteoarthritis. Local intra-articular injections of dexamethasone may be administered for the relief of soft-tissue inflammatory conditions. 

Alternative products to diclofenac include naproxen and mefenamic acid, both of which are non-steroidal anti-inflammatory drugs. Co-codamol is a mixture of the opioid analgesic codeine and paracetamol and it does not possess the anti-inflammatory component. It may be used in pain management either where NSAIDs are contraindicated or in patients who are intolerant to the effects of NSAIDs. 

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