indication

For symptomatic treatment of rheumatoid arthritis, juvenile rheumatoid arthritis and osteoarthritis. May be used to treat mild to moderate pain and for the management of dysmenorrhea. May be used to reduce fever. Has been used with some success for treating ankylosing spondylitis, gout and psoriatic arthritis. May reduce pain, fever and inflammation of pericarditis. May be used IV with opiates to relieve moderate to severe pain. Ibuprofen lysine may be used IV to treat patent ductus arteriosus (PDA) in premature neonates.

pharmacology

Ibuprofen is a nonsteroidal anti-inflammatory agent (NSAIA) or nonsteroidal anti-inflammatory drug (NSAID), with analgesic and antipyretic properties. Ibuprofen has pharmacologic actions similar to those of other prototypical NSAIAs, which are thought to act through inhibition of prostaglandin synthesis.

mechanism of action

The exact mechanism of action of ibuprofen is unknown. Ibuprofen is a non-selective inhibitor of cyclooxygenase, an enzyme invovled in prostaglandin synthesis via the arachidonic acid pathway. Its pharmacological effects are believed to be due to inhibition cylooxygenase-2 (COX-2) which decreases the synthesis of prostaglandins involved in mediating inflammation, pain, fever and swelling. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Inhibition of COX-1 is thought to cause some of the side effects of ibuprofen including GI ulceration. Ibuprofen is administered as a racemic mixture. The R-enantiomer undergoes extensive interconversion to the S-enantiomer in vivo. The S-enantiomer is believed to be the more pharmacologically active enantiomer.

toxicity

Side effects: May cause peripheral edema and fluid retention. Use caution in patients with congestive heart failure or severe uncontrolled hypertension. May cause dyspepsia, heartburn, nausea, vomiting, anorexia, diarrhea, constipation, stomatitis, flatulence, bloating, epigastric pain, and abdominal pain. Peptic ulcer and GI bleeding have been reported. May also cause dizziness, headache and nervousness. Acute renal failure accompanied by acute tubular necrosis has been reported.

Most common symptoms of overdose are abdominal pain, nausea, vomiting, lethargy, vertigo, drowsiness (somnolence), dizziness and insomnia. Other symptoms of overdose include headache, loss of consciousness, tinnitus, CNS depression, convulsions and seizures. May rarely cause metabolic acidosis, abnormal hepatic function, hyperkalemia, renal failure, dyspnea, respiratory depression, coma, acute renal failure, and apnea (primarily in very young pediatric patients).

LD₅₀=1255mg/kg(orally in mice)

biotransformation

R-enanatiomer undergoes extensive enantiomeric conversion (53-65%) to the more active S-enantiomer in vivo. Metablized by oxidation to 2 inactive metabolites: (+)-2[4´-(2-hydroxy-2-methylpropyl)phenyl]propionic acid and (+)-2-[4´-(2-carboxypropyl)phenyl]propionic acid. Very small amounts of 1-hydroxyibuprofen and 3-hydroxyibuprofen have been recovered from urine. Cytochrome P450 2C9 is the major catalyst in the formation of oxidative metabolites. Oxidative metabolites may be conjugated to glucuronide prior to excretion.

absorption

~ 80% absorbed from GI tract

Time to reach peak plasma concentration = 47 minutes (suspension), 62 minutes (chewable tablets), 120 minutes (conventional tablets)

half life

2-4 hours

route of elimination

Ibuprofen is rapidly metabolized and eliminated in the urine.

drug interactions

Acebutolol: Risk of inhibition of renal prostaglandins

Acenocoumarol: The NSAID, ibuprofen, may increase the anticoagulant effect of acenocoumarol.

Acetylsalicylic acid: Concomitant therapy of the NSAID, ketoprofen, and acetylsalicylic acid may result in additive adverse/toxic effects (e.g. GI bleeding). The NSAID may also limit the cardioprotective effect of acetylsalicylic acid. Occasional concomitant use may not cause clinically significant problems, but regular, frequent concomitant therapy is not recommended.

Alendronate: Increased risk of gastric toxicity

Anisindione: The NSAID, ibuprofen, may increase the anticoagulant effect of anisindione.

Atenolol: Risk of inhibition of renal prostaglandins

Betaxolol: Nonsteroidal Anti-Inflammatory Agents such as ibuprofen may diminish the antihypertensive effect of Beta-Blockers such as betaxolol. Monitor for increases in blood pressure if a nonsteroidal anti-inflammatory agent (NSAID) is initiated/dose increased, or decreases in blood pressure if a NSAID is discontinued/dose decreased; this is particularly important if NSAID treatment is for extended periods of time. Ophthalmic beta-blockers are likely of little concern.

Bevantolol: Risk of inhibition of renal prostaglandins

Bisoprolol: Risk of inhibition of renal prostaglandins

Bumetanide: The NSAID, ibuprofen, may antagonize the diuretic and antihypertensive effects of the loop diuretic, bumetanide.

Carteolol: Risk of inhibition of renal prostaglandins

Carvedilol: Risk of inhibition of renal prostaglandins

Colesevelam: Bile acid sequestrants may decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Monitor for decreased serum concentrations/therapeutic effects of nonsteroidal anti-inflammatory agents (NSAID) if coadministered with bile acid sequestrants. Separating the administration of doses by 2 or more hours may reduce (but not eliminate) the risk of interaction. The manufacturer of colesevelam recommends that drugs should be administered at least 1 hour before or 4 hours after colesevelam.

Cyclosporine: Monitor for nephrotoxicity

Dicumarol: The NSAID, ibuprofen, may increase the anticoagulant effect of dicumarol.

Esmolol: Risk of inhibition of renal prostaglandins

Ethacrynic acid: The NSAID, ibuprofen, may antagonize the diuretic and antihypertensive effects of the loop diuretic, ethacrynic acid.

Furosemide: The NSAID, ibuprofen, may antagonize the diuretic and antihypertensive effects of the loop diuretic, furosemide.

Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.

Labetalol: Risk of inhibition of renal prostaglandins

Lithium: The NSAID, ibuprofen, may decrease the renal excretion of lithium. Increased risk of lithium toxicity.

Methotrexate: The NSAID, ibuprofen, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Metoprolol: Risk of inhibition of renal prostaglandins

Nadolol: Risk of inhibition of renal prostaglandins

Oxprenolol: Risk of inhibition of renal prostaglandins

Penbutolol: Risk of inhibition of renal prostaglandins

Pindolol: Risk of inhibition of renal prostaglandins

Practolol: Risk of inhibition of renal prostaglandins

Propranolol: Risk of inhibition of renal prostaglandins

Sotalol: Risk of inhibition of renal prostaglandins

Tamoxifen: Ibuprofen may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Ibuprofen is initiated, discontinued or dose changed.

Tolbutamide: Ibuprofen, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Ibuprofen is initiated, discontinued or dose changed.

Torasemide: The NSAID, ibuprofen, may decrease the diuretic and antihypertensive effect of the loop diuretic, torasemide.

Trandolapril: The NSAID, Ibuprofen, may reduce the antihypertensive effect of Trandolapril. Consider alternate therapy or monitor for changes in Trandolapril efficacy if Ibuprofen is initiated, discontinued or dose changed.

Treprostinil: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Ibuprofen. Monitor for increased bleeding during concomitant thearpy.

Triflusal: The metabolite of triflusal, 2-hydroxy-4-trifluoro-methyl-benzoic acid (HTB), impairs the serum protein binding of ibuprofen to the same extent as acetylsalisylic acid. Thus, the free fraction of glisentide may be increased. A dosage reduction may be required if used in combination.

Trimethoprim: The strong CYP2C9 inhibitor, Ibuprofen, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Ibuprofen is initiated, discontinued or dose changed.

Vilazodone: Increased risk of bleeding with concomitant use of non-steroidal anti-inflammatory drugs with vilazodone.

Voriconazole: Ibuprofen, a strong CYP2C9 inhibitor, may increase the serum concentration of voriconazole by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of voriconazole if ibuprofen is initiated, discontinued or dose changed.

Warfarin: Ibuprofen, a strong CYP2C9 inhibitor, may decrease the metabolism of warfarin. The antiplatelet effect of ibuprofen may also increase the bleed risk associated with warfarin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of warfarin if ibuprofen is initiated, discontinued or dose changed.