Ibuprofen

Classification:
» Analgesics
» Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Musculoskeletal Agents
» Antiinflammatory Agents
» Nonsteroidal antiinflammatory drugs (NSAIDs)

Description: Ibuprofen is an oral, nonsteroidal anti-inflammatory drug (NSAID) of the propionic acid chemical class. Ibuprofen is a racemic mixture of 2 isomers; however, only the l-isomer of ibuprofen has been shown to have clinical activity. Although d-isomer is considered inactive, it is slowly and incompletely converted to the l-isomer in adults and probably children and may serve as a circulating reservoir for the active drug. All NSAIDs carry an increased risk of serious gastrointestinal adverse effects including bleeding, ulceration, and perforation of the stomach or intestines and may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke. The lowest effective ibuprofen dose for the shortest possible duration is recommended, as the risk for adverse effects may increase with duration of use. A retrospective review by FDA Advisory Committees of short-term efficacy trials of a related non-prescription strength NSAID indicated that an increase in CV events was not apparent during the studies. Therefore, a cardiovascular boxed warning in non-prescription product labeling (e.g., Advil®) is not required at this time. However, it is important to note that CV risk was not the focus of the studies, and further information is needed to determine if a cause and effect relationship exists between non-prescription strength NSAID use and adverse cardiovascular outcomes. Ibuprofen is indicated for the treatment of rheumatoid arthritis, osteoarthritis, and dysmenorrhea. It also is used for its antipyretic effects and for the alleviation of mild to moderate pain. In addition, clinical studies have demonstrated its effectiveness in the treatment of ankylosing spondylitis, gout, and psoriatic arthritis. Ibuprofen lysine (NeoProfen®), an intravenous formulation indicated to close a clinically significant patent ductus arteriosus in infants weighing 500 - 1500 grams who are no more than 32 weeks gestational age when usual medical management is ineffective, was approved by the FDA in April 2006; commercial availability in the U.S. is expected in July 2006. Ibuprofen was approved by the FDA in 1974. A topical formulation for treating minor muscle pain is under investigation.

Mechanism of Action: Ibuprofen competitively inhibits both cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, by blocking arachidonate binding resulting in analgesic, antipyretic, and anti-inflammatory pharmacologic effects. The enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step of the synthesis prostaglandins and thromboxanes that are involved in rapid physiological responses. COX isoenzymes are also responsible for a peroxidase reaction, which is not affected by NSAIDs. In addition, NSAIDs do not suppress leukotriene synthesis by lipoxygenase pathways. COX-1 is constitutively expressed in almost all tissues, while COX-2 appears to only be constitutively expressed in the brain, kidney, bones, reproductive organs, and some neoplasms (e.g., colon and prostate cancers). COX-1 is responsible for prostaglandin synthesis in response to stimulation by circulating hormones, as well as maintenance of normal renal function, gastric mucosal integrity, and hemostasis. However, COX-2 is inducible in many cells in response to certain mediators of inflammation (e.g., interleukin-1, tumor necrosis factor, lipopolysaccharide, mitogens, and reactive oxygen intermediates).
Advil Childrens Oral Suspension (Susp 100 mg/5ml )

Anti-inflammatory Activity: The anti-inflammatory mechanism of ibuprofen is due to decreased prostaglandin synthesis via inhibition of COX-1 and COX-2. It appears that the anti-inflammatory effects may be primarily due to inhibition of the COX-2 isoenzyme. However, COX-1 is expressed at some sites of inflammation. COX-1 is expressed in the joints of rheumatoid arthritis or osteoarthritis patients, especially the synovial lining, and it is the primary enzyme of prostaglandin synthesis in human bursitis. Ibuprofen is slightly more selective for COX-1 than COX-2.
Analgesic Activity: Ibuprofen is effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, ibuprofen has an indirect analgesic effect by inhibiting the production of further prostaglandins and does not directly affect hyperalgesia or the pain threshold.
Antipyretic Activity: Ibuprofen promotes a return to a normal body temperature set point in the hypothalamus by suppressing the synthesis of prostaglandins, specifically PGE2, in circumventricular organs in and near the hypothalamus. Ibuprofen may mask fever in some patients, especially with high or chronic dosing.
GI Effects: Gastrointestinal side effects of ibuprofen are primarily contributed to COX-1 inhibition; however, potential role of COX-2 inhibition in the GI tract has not been fully elucidated.
Platelet Effects: The inhibition of platelet aggregation seen with ibuprofen is due to dose-dependent inhibition of COX-1 in platelets leading to decreased levels of platelet thromboxane A2 and an increase in bleeding time (see Adverse Reactions). The inhibition of platelet aggregation is reversible within 24 hours of discontinuation of ibuprofen. This differs from aspirin, which irreversibly binds to COX-1 in platelets inhibiting this enzyme for the life of the cell.
Renal Effects: In the kidney, prostaglandins, produced by both COX-1 and COX-2, are important regulators of sodium and water reabsorption through PGE2 and of renal function and hemodynamics via PGI2 in response to vasoconstrictive factors (e.g., endothelin-1, a factor that increases peripheral vascular resistance) and through effects on the renin-angiotensin system. In conditions where renal blood flow is dependent upon prostaglandin synthesis, administration of NSAIDs can result in significant decreases in renal blood flow leading to acute renal failure. In addition, alterations in sodium and water reabsorption may worsen in increased blood pressure, which can be significant in selected individuals.

Pharmacokinetics: Ibuprofen is administered orally and is approximately 80% absorbed from the gut. Although the peak concentration is lower and time to peak concentration is slower if the drug is taken with food, the extent of ibuprofen absorption is not affected. The oral bioavailability of ibuprofen is similar between the different dosage forms, but the time to reach peak concentrations is roughly 120, 62, and 47 minutes following administration of tablets, chewable tablets, or suspension, respectively. A linear dose-response is noted for single ibuprofen doses up to 800 mg. With single doses up to 10 mg/kg, a dose response relationship exists in febrile children. There is also a correlation between the reduction of fever and drug concentration over time. In children, the antipyretic effect begins within 1 hour and peaks within 2 - 4 hours. In treatment for inflammation, a few days to 2 weeks is generally required before a therapeutic response occurs. Ibuprofen is highly protein-bound (about 90 - 99%). Ibuprofen is metabolized via hepatic oxidation by cytochrome P450 2C9 to two inactive metabolites. Plasma half-life is between 2 and 4 hours. Ibuprofen is excreted in the urine, 50 - 60% as metabolites and approximately 10% as unchanged drug. Some biliary excretion may occur. Excretion is usually complete within 24 hours of oral administration.

Special Populations: The elimination half-life of ibuprofen is significantly prolonged in patients with moderate to severe cirrhosis. Prospective studies of ibuprofen in patients with renal failure have not been conducted; however, dosage reduction is recommended in patients with chronic renal failure.

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[ Revised 5/24/2006 3:43:00 PM ]

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