Ketoprofen: Synthesis, Side effects, and Drug interactions

Description

Ketoprofen, chemistry 3-benzoyl by name-Alpha-Methyl toluylic acid, is a non-steroidal anti-inflammatory analgesics, has anti-inflammatory, analgesic, analgesic effects. Analgesic activity is better than similar drugs, and the length of holding time and toxic side effects are little, secure and better tolerance. At first in, France's listing formally entered China in 1973, the eighties, developed now multiple formulations such as an oral tablet, paster, diaphragm, and at home and abroad, obtained very widely.

Synthesis

Ketoprofen is synthesized from 3-methylbenzophenone, which undergoes bromination and forms 3-bromo-methylbenzophenone. The reduction of the resulting product by sodium cyanide gives 3-cyanomethylbenzophenone, which is reacted with the diethyl ester of carbonic acid in the presence of sodium ethoxide. The resulting cyanoacetic ester derivative is alkylated by methyl iodide, and the resulting product undergoes acidic hydrolysis, forming ketoprofen. The synthesis method figure is shown below.

Uses

Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) belonging to the family of propionics derived from arylcarboxylic acid with analgesic and antipyretic effects. It works by inhibiting cyclooxygenase 1 and 2 (COX 1 and COX 2) enzymes reversibly, which decreases the production of pro-inflammatory prostaglandin precursors. Ketoprofen has been widely used in managing inflammatory and musculoskeletal conditions, pain, and fever in children and adults. It crosses the blood-brain barrier, and therefore, it has the potential to cause central analgesic effects. The pediatric use of ketoprofen has been investigated for the treatment of pain and fever, peri- and post-operative pain, and inflammatory pain conditions.

Side effects

The known adverse events of ketoprofen include cardiovascular reactions (peripheral edema), central (headache, drowsiness, etc.), dermatological (skin sensitization and photosensitization after topical use), blood (edema, platelet dysfunction, etc.), liver (increased liver enzymes), gastrointestinal (vomiting, diarrhea, ulcers, and bleeding in the stomach, etc.), ophthalmic, renal, respiratory (asthma), systemic (sweating, hives, etc.)[1].

Drug interactions

Despite being 99% protein, ketoprofen does not appear to alter the pharmacokinetics of other highly protein-bound drugs, such as oral antidiabetic agents or anticoagulants. Single-dose bioavailability was unchanged when ketoprofen was given with food or with antacid. In addition, no clinically significant interactions were detected between ketoprofen and digoxin or hydrochlorothiazide (pharmacodynamic assessments after 4 days of dosing in both studies). Concurrent administration of aspirin reduced the protein binding of ketoprofen, but this was offset by accelerated plasma clearance. Although these offsetting effects resulted in no net change in the plasma concentration of free ketoprofen, the complex nature of the kinetic interaction might lead to unpredictable individual variations. Therefore, coadministration with aspirin is not recommended. Concurrent administration of ketoprofen did not affect salicylate pharmacokinetics; however, probenecid reduced both protein binding and clearance of ketoprofen. The latter appeared to be secondary to inhibiting glucuronidation of ketoprofen and probenecid, which are transformed by the same biochemical pathway[2].

Consequently, combined treatment with these agents should be avoided. Thyss et al described several cases of impaired clearance of methotrexate and serious toxic, even fatal, consequences after coadministration with ketoprofen or diclofenac. Reduced clearance of methotrexate at high doses has been known in association with aspirin or indomethacin. It is a class phenomenon related to the inhibitory effects of NSAIDs on renal prostaglandins. With the growing use of methotrexate as a remitting agent in rheumatoid arthritis, the risk of this potentially life-threatening interaction should receive wide recognition.

References

[1] Claudia Carbone. “The safety of ketoprofen in different ages.” Journal of Pharmacology Pharmacotherapeutics 4 Suppl 1 (2013): S99–S103.

[2] Kantor, T G. “Ketoprofen: a review of its pharmacologic and clinical properties.” Pharmacotherapy 6 3 (1986): 93–103.

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