DESCRIPTION
Ketoprofen is a drug with anti-inflammatory, antipyretic and analgesic function, derived by arylpropionic acid.
CLASSIFICATION
According to the IUPAC nomenclature is name is RS) -2 - (3-benzoylphenyl) propanoic acid.
It is part of the so-called classical NSAIDs and in particular is attributable to the subgroup of carboxylic acids.
It is used to treat the symptoms of rheumatoid arthritis (Ketoprofen in rheumatoid arthritis: its tolerance and therapeutic effect,Zutshi P,Mason M,1976) , osteoarthritis and of dysmenorrhea. It has therapeutic efficacy in the treatment of ankylosing spondylitis, acute gouty arthritis, bursitis and tendinitis in Reiter's syndrome.
Ketoprofen is also widely used in dentistry.
The efficacy of buffered ketoprofen in postoperative pain after third molar surgery.Seymour RA, Watkinson H, Hawkesford JE, Moore U.2000
Analgesic efficacy and pharmacokinetics of ketoprofen administered into a surgical site.Dionne RA, Gordon SM, Tahara M, Rowan J, Troullos E. 1999
INDICATIONS
Today ketoprofen is the base for many drugs widely used. The best known is certainly Oki but this molecule is also present in other common drugs such as Ketodol, Fastum-Gel, ect. It can be used both by oral and topic administration.
Ketoprofen absorption by muscle and tendon after topical or oral administration in patients undergoing anterior cruciate ligament reconstruction, Sekiya I, Muneta T, 2010
In some cases it can be even injected directly in an intramuscular way. The use of the drug is not advised to women in pregnancy, to people affected by kidney failure (because they can have some problems to eliminate it) or by hepatic damages (in fact in this case the lower metabolism can lead to a build-up of the drug in the liver).
PHARMACOKINETICS
The ketoprofen takeover is very rapid and high. The adsorption take place in particular in the gastrointestinal length. The takeover can be delayed by the contemporary intake of food (because of that the use of drugs containing ketoprofen is usually recommended far off meals). Peaks of drug concentration in plasma are achieved after just one or two hours after administration. The half-life of the drug can be highly variable (from 1 to 35 hours) and it seems due to the fact that ketoprofen is or is not already been taken earlier. The drug reaches the liver, where it is usually metabolized by conjugation with glucuronic acid and by idroxylation. From these reactions the liver is able to produce inactive metabolites. This hepatic metabolism is very fast and so only in pathological situations there can be a build-up of the drug. The metabolites are eliminated by urine. Only the 1% of the drug is eliminated unchanged.
Ketoprofen pharmacokinetics, efficacy, and tolerability in pediatric patients, Kokki H, 2010
MOLECULAR MECHANISM
The main mechanism of action of the drug is due to inhibition of cyclooxygenase., an enzyme that allows the transformation of arachidonic acid to prostaglandin H2, which is the precursor of all prostaglandins. They are chemicals that control many physiological and pathological processes, including inflammation.
Ketoprofen also inhibits the synthesis of leukotrienes, stabilizes lysosomal membranes and acts as antiplatelet agent, it is able to reduce the synthesis of superoxide by polymorphonuclear cells, blocking the NADPH oxidase system by reducing its release at the site of inflammation.
The antipyretic activity of the drug is fulfilled by a central action at hypothalamic level that determines expansion device and the increase of cutaneous blood flow resulting in heat loss.
KETOPROFEN AND ASPIRIN: TWO DIFFERENT MECHANISMS OF ACTION
NSAIDs (nonsteroidal anti-inflammatory drugs) inhibit cyclooxygenase in different ways.
The COX1 and COX2 are long hydrophobic channel, in which enters the arachidonic acid, which then reaches a specific site of the canal that proceeds with its metabolism. The channels of the two COXs have a different shape: in particular, COX2 has a side pocket due to the presence of a hydrophobic amino acid, valine, that is less bulky compared to isoleucine (most massive) which is the aminoacid of COX1.
Classical NSAIDs, as ketoprofen, bind to arginine 120 (Arginine 120 of prostaglandin G/H synthase-1 is required for the inhibition by nonsteroidal anti-inflammatory drugs containing a carboxylic acid moiety. Mancini JA, Riendeau D, Falgueyret JP, Vickers PJ, O'Neill GP. 1995), which is located in both the COX1 and COX2, and with this mechanism they obstruct the entry of arachidonic acid in both channels. Aspirin acts on both channels too, but, unlike other NSAIDs, binds to the serine 530 which is at the top of the long canal, near the binding sites of arachidonic acid. In practice, while the binding of classical NSAIDs block the COX channel and therefore the access of arachidonic acid at the C-terminal site where it is metabolized to produce prostaglandins, the link with aspirin does not prevent the entry of arachidonic acid in the channel, but only its link with the active site.
PHARMACOGENOMICS
SIDE EFFECTS
- Intolerance with gastrointestinal manifestations such as dyspepsia, but also more severe consuquences such as gastric ulcers or bleeding. Ketoprofen, in fact, causes damage to the gastric mucosa as a result of inhibition of the synthesis of prostaglandins that inhibit gastric acid secretion, increase blood circulation to the mucosa, exert cytoprotective action.
Influence of Cyclooxygenase Inhibitors on the Function of the Prostaglandin Transporter Organic Anion-Transporting Polypeptide 2A1 Expressed in Human Gastroduodenal Mucosa,Mandery K,Glaeser H,2009
Selective cyclo-oxygenase-2 inhibitors: cardiovascular and gastrointestinal toxicity,Wallace JL,Muscarà MN,2001
Arachidonic acid metabolites and the gastro-intestinal toxicity of anti-inflammatory agents,Whittle BJ,1981
- Reduction of platelet aggregation, bleeding tendency.
- Inhibition of uterine motility.
- Liver disease dose-dependent.
- Inhibition of renal function with decreased flow and glomerular filtration. Inhibition of prostaglandin synthesis in the kidney leads to a reduction in their antagonist function exercised against the action of vasoconstrictor like Angiotensin II and Norepinephrine; in addition there is a reduction of inhibition exerted by prostaglandins on the shedding of chlorine and on the activity of antidiuretic hormone (sodium and water retention). Old patients have greater risk because of renal malfunction caused by age (in fact 50% of over eighty has a 50% reduction in renal function).
- Hypersensitivity reaction, bronchial asthma, endotoxic shock.
Effects of two different inhibitors of the arachidonic acid metabolism on platelet sequestration in endotoxic shock,Sigurdsson GH,Owunnwanne A,1994
- Cardiovascular problems with peripheral edema and heart failure.
- Skin problems, with dermatitis, skin blush, erythema and immuno-allergic syndromes. After the use of ketoprofen (especially during spring and summer) there can be hypersensitive reactions on the skin due to photosensibilization. These skin reactions are the consequence of ketoprofen chemical structure that after the exposition to sunlight is broken into radicals and reactive oxygen species responsible of phototoxic events. In fact because of the sunlight ketoprofen is subjected to decarbossilation from which take origin the radicals with a cytolytic action against the cell membranes.
Photoallergic Contact Dermatitis due to Ketoprofen and Hydrogenated Rosin Glycerol Ester, Rindo T, Kawada A, 2010
Cutaneous adverse effects of ketoprofen for topical use: clinical patterns and costs, Noise B, Haramburu F, 2010
- Systemic problems, with hives and skin blush due to allergic events.
TOXICITY
- Too big doses, which symptoms include sleepiness, abdominal pains, vomit, low blood pressure and broncho-costriction. Usually to overcome the intoxication is used a gastric lavage.
- Gastrointestinal toxicity, which can lead to hemorrhage, ulceration and perforation sometimes deadly. This symptoms can rise at any time ever of the therapy with or without preliminary symptoms. Risk factors for this disease are represented by the age (if the subject is older than sixty) and by concomitant therapies that can influence the blood coagulation.
- Non-Hodgkin lymphoma, as it is assert in many studies which link the use of NSAIDs to a higher risk for the rising of this type of cancer.
- Pregnancy, because the inhibition of prostaglandins synthesis can influence negatively the proceeding of the pregnancy itself and the embryonic development. Some studies suggest and higher risk of miscarriage and of cardiac malformations after the use of ketoprofen during the firsts steps of the pregnancy. Also in the second quarter the drug does not loss its toxicity. In fact its employment can expose the unborn child to cardiac, lung (with the untimely close of the arterial duct and high lung pressure) and kidney damages.
Toxicological evaluation of acyl glucuronides of nonsteroidal anti-inflammatory drugs using human embryonic kidney 293 cells stably expressing human UDP-glucuronosyltransferase and human hepatocytes, Koga T, Yokoi T, 2011
RESISTANCE
There is no evidence suggesting that Ketoprofen gives addiction or resistance.
Giulio Bielli
Maria Giacone
