Acular - General Information
A pyrrolizine carboxylic acid derivative structurally related to indomethacin. It is an NSAID and is used principally for its analgesic activity. (From Martindale The Extra Pharmacopoeia, 31st ed)
Pharmacology of Acular
Acular, an antiinflammatory agent with analgesic and antipyretic properties, is used to treat osteoarthritis and control acute pain. It is a peripherally acting analgesic. The biological activity of ketorolac tromethamine is associated with the S-form. Acular tromethamine possesses no sedative or anxiolytic properties.
Acular for patients
Ketorolac is highly bound to human plasma protein (mean 99.2%).
Warfarin, Digoxin, Salicylate, and Heparin
The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs 99.3%) when ketorolac plasma concentrations reach 5 to10 m g/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 m g/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin andtolbutamide did not alter ketorolac tromethamine protein binding.
In a study involving 12 adult volunteers, TORADOLORAL was coadministered with a single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, TORADOLIV/IM was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a mean template bleeding time of 6.4 minutes (3.2 to 11.4 min) compared to a mean of 6.0 minutes (3.4 to 7.5 min) for heparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo. Although these results do not indicate a significant interaction between TORADOL and warfarin or heparin, the administration of TORADOL to patients taking anticoagulants should be done extremely cautiously, and patients should be closely monitored.
TORADOLIV/IM reduced the diuretic response to furosemide in normovolemic healthy subjects by approximately 20% (mean sodium and urinary output decreased 17%).
Concomitant administration of TORADOLORAL and probenecid resulted in decreased clearance of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 m g/h/mL) and terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore, concomitant use of TORADOL and probenecid is contraindicated.
Inhibition of renal lithium clearance, leading to an increase in plasma lithium concentration, has been reported with some prostaglandin synthesis-inhibiting drugs. The effect of TORADOL on plasma lithium has not been studied, but cases of increased lithium plasma levels during TORADOL therapy have been reported.
Concomitant administration of methotrexate and some NSAIDs has been reported to reduce the clearance of methotrexate, enhancing the toxicity of methotrexate. The effect of TORADOL on methotrexate clearance has not been studied.
Nondepolarizing Muscle Relaxants
In postmarketing experience there have been reports of a possible interaction between TORADOLIV/IM and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of TORADOL with muscle relaxants has not been formally studied.
Concomitant use of ACE inhibitors may increase the risk of renal impairment, particularly in volume-depleted patients.
Sporadic cases of seizures have been reported during concomitant use of TORADOL and antiepileptic drugs (phenytoin, carbamazepine).
Hallucinations have been reported when TORADOL was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).
TORADOLIV/IM has been administered concurrently with morphine in several clinical trials of postoperative pain without evidence of adverse interactions. Do not mix TORADOL and morphine in the same syringe.
There is no evidence in animal or human studies that TORADOL induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.
TORADOL is CONTRAINDICATED in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation and in patients with a history of peptic ulcer disease or gastrointestinal bleeding.
TORADOL is CONTRAINDICATED in patients with advanced renal impairment or in patients at risk for renal failure due to volume depletion.
TORADOL is CONTRAINDICATED in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage.
The use of TORADOL is CONTRAINDICATED in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.
TORADOL is CONTRAINDICATED in patients with previously demonstrated hypersensitivity to ketorolac tromethamine, allergic manifestations to aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs).
TORADOL is CONTRAINDICATED as prophylactic analgesic before any major surgery and is CONTRAINDICATED intraoperatively when hemostasis is critical because of the increased risk of bleeding.
TORADOL inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding.
TORADOL is CONTRAINDICATED in patients currently receiving ASA or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events.
TORADOLIV/IM is CONTRAINDICATED for neuraxial (epidural or intrathecal) administration due to its alcohol content.
The concomitant use of TORADOL and probenecid is CONTRAINDICATED.
Additional information about Acular
Acular Indication: For the short-term (~5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting.
Mechanism Of Action: Acular is a nonsteroidal anti-inflammatory drug (NSAID) chemically related to indomethacin and tolmetin. Acular tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S-form having analgesic activity. Its antiinflammatory effects are believed to be due to inhibition of both cylooxygenase-1 (COX-1) and cylooxygenase-2 (COX-2) which leads to the inhibition of prostaglandin synthesis leading to decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid. The resultant reduction in prostaglandin synthesis and activity may be at least partially responsible for many of the adverse, as well as the therapeutic, effects of these medications. Analgesia is probably produced via a peripheral action in which blockade of pain impulse generation results from decreased prostaglandin activity. However, inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation may also contribute to the analgesic effect. In terms of the ophthalmic applications of ketorolac - ocular administration of ketorolac reduces prostaglandin E2 levels in aqueous humor, secondary to inhibition of prostaglandin biosynthesis.
Drug Interactions: Alendronate Increased risk of gasrtic toxicity
Methotrexate The NSAID increases the effect and toxicity of methotrexate
Anisindione The NSAID increases the anticoagulant effect
Acenocoumarol The NSAID increases the anticoagulant effect
Dicumarol The NSAID increases the anticoagulant effect
Warfarin The NSAID increases the anticoagulant effect
Lithium The NSAID increases serum levels of lithium
Aspirin ASA increases toxicity of ketorolac
Probenecid Probenecid increases toxicity of ketorolac
Food Interactions: Take with food to reduce GI irritation
Generic Name: Ketorolac
Synonyms: Ketorolaco [Spanish]; Ketorolacum [Latin]; Ketoralac; Ketorolac Tromethamine
Drug Category: Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors
Drug Type: Small Molecule; Approved
Other Brand Names containing Ketorolac: Acular; Acular LS; Acular Preservative Free; Toradol;
Absorption: Rapidly and completely absorbed after oral administration
Toxicity (Overdose): LD50 = 189 mg/kg (rat, oral).
Protein Binding: 99%
Biotransformation: Primarily hepatic. Less than 50% of a dose is metabolized. The major metabolites are a glucuronide conjugate, which may also be formed in the kidney, and p-hydroxy ketorolac. Neither metabolite has significant analgesic activity.
Half Life: 2.5 hours for the S-enantiomer compared with 5 hours for the R-enantiomer
Dosage Forms of Acular: Tablet Oral
Chemical IUPAC Name: 5-(benzoyl)-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
Chemical Formula: C15H13NO3
Ketorolac on Wikipedia: http://en.wikipedia.org/wiki/Ketorolac
Organisms Affected: Humans and other mammals