Pharmacokinetics NSAIDs

Herbette, L. G. Vecchiarelli, M. Tmmlitz, G., NSAID Mechanism of Action Membrane Interactions in the Role of Intracellular Pharmacokinetics, Vane, Botting, Botting, pp. 85-102 (1995). 

Pharmacokinetic Parameters/Maximum Dosage Recommendations of NSAIDs ... 

The acidic NSAIDs include the salicylates and an increasing number of other compounds. The latter agents, as a group, share many common properties they may have toxicities, are highly protein bound and have the potential for interacting with other protein-bound drugs. The choice of a particular agent often depends on the reaction of the patient. Table 36.3 illustrates pharmacokinetic properties of selected NSAIDs. 

Mecfianism of Action An NSAID that inhibits prostaglandin synthesis, reducing the inflammatory response and the intensity of pain stimuli reaching the sensory nerve endings. Therapeutic Effect Produces analgesic and anti-inflammatory effects. Pharmacokinetics Rapidly and completely absorbed from the G1 tract. Food delays absorption of salsalate. Protein binding Fligh (to albumin). Metabolized in the liver. Excreted in urine. Removed by hemodialysis. Half-life 1 hr. 

Within the last 10, years several new compounds were launched in the field of non-steroidal antiinflammatory drugs (NSAIDs) with a clear focus on cyclooxygenase type 2 selective compounds. In the field of opioids on the other hand no new drugs have passed phase III clinical trials. In this field innovation has been achieved through new pharmaceutical formulations of known drugs such as transdermal systems, e.g. buprenorphine patch, transmucosal systems, e.g. fentanyl lollipop, or rectal delivery systems containing e.g. morphine. These were developed in order to reduce opioid side effects, but also to overcome pharmacokinetical limitations, in particular to prolong compliance and duration of action. 

Valdecoxib, a diaryl-substituted isoxazole, is a new highly selective COX-2 inhibitor. Pharmacokinetic characteristics and dosage in arthritis are set forth in Table 36-1. In primary dysmenorrhea, dosage is 20 mg twice daily, and the drug is as effective as nonselective NSAIDs for this indication. Gastrointestinal and other toxicities are similar to those of the other coxibs. Valdecoxib has no effect on platelet aggregation or bleeding time. Serious reactions have been reported in sulfonamide-sensitive individuals. 

Ketorolac is an NSAID promoted for systemic use mainly as an analgesic, not as an antiinflammatory drug (though it has typical NSAID properties). Pharmacokinetics are presented in Table 36-1. The drug does appear to have significant analgesic efficacy and has been used... 

Pharmacokinetics Phenylbutazone is rapidly and completely absorbed after oral or rectal administration. Oxyphenbutazone is an active metabolite and contributes to the activity of the parent drug. Like most of the other NSAIDs, phenylbutazone is extensively bound to plasma proteins. This property causes displace-... 

Drug interactions with lithium have been reviewed (569-573) another review focused on interactions in the elderly (573). A review of drug interactions with lithium considered both pharmacokinetic interactions [for example diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs)] and pharmacodynamic interactions (for example antipsychotic drugs, SSRIs) and summarized the most important ones in tabular form (569). 

In a pharmacokinetic study in healthy volunteers ketorolac increased the concentration of lithium in both serum and erythrocytes, which may reflect concentration of the drug in the nervous system more accurately. Ketorolac can therefore increase the risk of adverse reactions of lithium (683), as do many other NSAIDs. 

This chapter concentrates on some drug choices in acute rather than chronic pain, but the same principles can be used to determine the appropriateness of other types of analgesic. The drugs considered in this section are paracetamol, non-steroidal anti-inflammatories (NSAIDs specifically diclofenac, ibuprofen, indometacin, naproxen, sulindac and tenoxicam) and opioids (codeine, dihydrocodeine, morphine, pethidine and tramadol). Unless otherwise stated, all pharmacokinetic data originate from standard reference sources [1-5] and apply to adults only. 

Irrespective of the pharmacokinetics of NSAIDs in patients with liver disease, the risks of adverse effects will outweigh the benefits of treatment in many patients. Side effects of note are gastrointestinal bleeding, reduction in glomerular filtration rate (GFR), inhibition... 

The risk of ciclosporin-induced nephrotoxicity can be increased when NSAIDs are also used (44,45). Diclofenac in particular should be avoided, because it is more likely to cause deterioration of renal function in patients taking ciclosporin (SEDA-15, 100) (SEDA-17, 107). There is also a pharmacokinetic interaction, which may be caused by inhibition by ciclosporin of the first-pass metabolism of diclofenac (SEDA-21,104). 

Co-administration of fenbufen and fluoroquinolones has been associated with seizures (141). The structure at the 7-position greatly affects the risk of NSAID-potentiated nervous system effects. Fluoroquinolones with unsubstituted piperazinyl rings (ciprofloxacin, enox-acin, and norfloxacin) have a strong interaction with NSAIDs (142). The increased risk of seizures is not caused by increased serum concentrations of fluoroquinolones, since their pharmacokinetics are not altered by NSAIDs (143). The mechanism has been suggested to be facilitation by fenbufen of the fluoroquinolone-induced inhibition of GABAa receptor function in the hippocampus and frontal cortex (144). 

Fillastre JP, Leroy A, Borsa-Lebas F, Etienne I, Gy C, Humbert G. Effects of ketoprofen (NSAID) on the pharmacokinetics of pefloxacin and ofloxacin in healthy volunteers. Drugs Exp Clin Res 1992 18(ll-12) 487-92. 

Although the physicochemical features, pharmacokinetics, and pharmacodynamics of individual NSAIDs differ, it is not known to what extent these differences are significant in the benefit-to-harm balance in the individual patient (8). Certainly they influence the adverse reactions and the general pattern of action of a particular subgroup of NSAIDs or a specific compound within a class, but this still provides no reliable prediction of what the individual patient will experience. 

General interactions with NSAIDs are summarized in Table 2 (pharmacokinetic interactions) and Table 3 (pharmacodynamic interactions). 

Pharmacodynamic and pharmacokinetic relationships in NSAID-induced acute kidney injury... 

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