Pharmacokinetics Of Non-steroidal Anti-inflammatory Drugs Research Articles

Role for Carboxylic Acid Moiety in NSAIDs: Favoring the Binding at Site II of Bovine Serum Albumin.

The molecular structures of nonsteroidal anti-inflammatory drugs (NSAIDs) vary, but most contain a carboxylic acid functional group (RCOOH). This functional group is known to be related to the mechanism of cyclooxygenase inhibition and also causes side effects, such as gastrointestinal bleeding. This study proposes a new role for RCOOH in NSAIDs: facilitating the interaction at the binding site II of serum albumins. We used bovine serum albumin (BSA) as a model to investigate the interactions with ligands at site II. Using dansyl-proline (DP) as a fluorescent site II marker, we demonstrated that only negatively charged NSAIDs such as ibuprofen (IBP), naproxen (NPX), diflunisal (DFS), and ketoprofen (KTP) can efficiently displace DP from the albumin binding site. We confirmed the importance of RCOO by neutralizing IBP and NPX through esterification, which reduced the displacement of DP. The competition was also monitored by stopped-flow experiments. While IBP and NPX displaced DP in less than 1 s, the ester derivatives were ineffective. We also observed a higher affinity of negatively charged NSAIDs using DFS as a probe and ultrafiltration experiments. Molecular docking simulations showed an essential salt bridge between the positively charged residues Arg409 and Lys413 with RCOO-, consistent with the experimental findings. We performed a ligand dissociation pathway and corresponding energy analysis by applying molecular dynamics. The dissociation of NPX showed a higher free energy barrier than its ester. Apart from BSA, we conducted some experimental studies with human serum albumin, and similar results were obtained, suggesting a general effect for other mammalian serum albumins. Our findings support that the RCOOH moiety affects not only the mechanism of action and side effects but also the pharmacokinetics of NSAIDs.

Gender characteristics of hematuria during lithokinetic therapy in patients with nephrolithiasis

Purpose. To study gender characteristics of the severity of hematuria and compensatory mechanisms of the proaggregant component of hemostasis in patients with nephrolithiasis when prescribing litokinetic therapy (LCT), including nonsteroidal anti-inflammatory drugs (NSAIDs). Material and methods. The prospective study included 60 patients (group 1 – 30 men; group 2 – 30 women) with imaging signs of the presence of stones in the urinary tract. For 7 days, patients underwent standard LCT, including NSAIDs, an α1A-blocker (tamsulosin) and antibiotics. In vitro, the activity of the TP receptor for TxA2 and purine P2Y receptors (P2Y1 and P2Y12) was studied on a platelet suspension after 24, 48, 72 hours, 5 and 7 days. Platelet aggregation was assessed using the turbidimetric method using a ChronoLog analyzer (USA). Results. At the hospitalization stage, in both groups (before the introduction of NSAIDs), hyperreactivity of the TP-receptor was observed, and in men the activity of the TP receptor was lower, and hematuria (p<0.05) was higher than in women. The pharmacokinetics of NSAIDs in men was characterized by inhibition of cyclooxygenase (COX) in two time periods – 72 hours and 7 days, as a result of which the synthesis of TхA2 in platelets decreased and hematuria increased 4.4 times (p<0.001) compared with the hospitalization stage. In women, COX inhibition occurred within 5 days; At the same time, the preservation of normal reactivity of the TP-receptor and purine P2Y receptors ensured the implementation of a compensatory platelet response, limiting the severity of hematuria. Conclusion. Analysis of the mechanisms of gender differences in hematuria in nephrolithiasis is important for developing a personalized medicine strategy when prescribing NSAIDs.

A Critical Review on the Pharmacodynamics and Pharmacokinetics of Non-steroidal Anti-inflammatory Drugs and Opioid Drugs Used in Reptiles

Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are analgesics used for moderate to severe pain in many animals, including reptiles. However, reptilian dosing regimens are often extrapolated from other animal species. This is not ideal as inter- and intra-species variability in physiology may result in varied drug disposition. Therefore, this critical review aims to collate data from pharmacological studies of selected NSAIDs and opioids performed in reptile and provide an analysis and discussion on the existing pharmacodynamic knowledge and pharmacokinetic data of NSAIDs and opioids use in reptiles. Additionally, key pharmacokinetic trends that may aid dosing of NSAIDs and opioids in reptiles will also be highlighted. Most of the existing reports of NSAID used in reptiles did not observe any adverse effects directly associated to the respective NSAID used, with meloxicam being the most well-studied. Despite the current absence of analgesic efficacy studies for NSAIDs in reptiles, most reports observed behavioural improvements in reptiles after NSAID treatment. Fentanyl and morphine were studied in the greatest number of reptile species with analgesic effects observed with the doses used, while adverse effects such as sedation were observed most with butorphanol use. While pharmacokinetic trends were drug- and species-specific, it was observed that clearance (CL) of drugs tended to be higher in squamates compared to chelonians. The half-life (t1/2) of meloxicam also appeared to be longer when dosed orally compared to other routes of drug administration. This could have been due to absorption-rate limited disposition. Although current data provided beneficial information, there is an urgent need for future research on NSAID and opioid pharmacology to ensure the safe and effective use of opioids in reptiles.

Prospective Randomized Study Using Pharmacogenetics to Customize Postoperative Pain Medication Following Hip and Knee Arthroplasty.

The purpose of this study is to determine whether pharmacogenetic testing could be used to effectively customize postoperative pain medicine following total joint replacement. Buccal swabs were collected preoperatively from 107 patients. Pharmacogenetic testing was performed for genetic variants on a panel of 16 genes, including CYP2D6, CYP2C9, OPRM1, and CYP1A2, which affect the pharmacodynamics and pharmacokinetics of non-steroidal anti-inflammatory drugs and many opioids. Patients were randomized to a control group or custom group and blinded to their group. The control group was prescribed oxycodone, tramadol, and celecoxib for postoperative pain management. If any of those were not normally metabolized, they were not prescribed to the patients in the custom group, who were given an alternative drug (hydromorphone for narcotics, meloxicam for non-steroidal anti-inflammatory drugs). Patients recorded their pain level (0-10 numeric scale) and all medications taken daily for the first 10 days following surgery. Medication was converted to milligram morphine equivalents (MMEs). Genetic variations to medications in our standard postoperative pain management protocol occurred in 24 of the 107 patients (22.4%). The 10-day MME consumed by patients in the control group with genetic variants was 162.6 mg. Patients with variants who had custom postoperative medication consumed only 86.7 MME in the same timeframe (P= .126). The control group demonstrated a higher 10-day average pain level of 4.2 vs the custom group pain level of only 3.1 (P < .05). With custom postoperative pain prescriptions based on pharmacogenetic testing, patients were able to achieve lower pain levels while reducing the consumption of pain medication.

Features of NSAIDs' use in pandemic. Gastroenterologist's view

Non-steroidal anti-inflammatory drugs (NSAIDs) are drugs used to treat acute and chronic pain associated primarily with inflammatory changes. This group of drugs is widely used in neurology, rheumatology, traumatology, etc. The main mechanism of action of the drugs is associated with the effect on cyclooxygenase-2 (COX-2) and blockade of the synthesis of pro-inflammatory prostaglandins (PG), as well as the effect on COX-1 and suppression of the synthesis of cytoprotective PG, which determines the possibility of side effects from the gastrointestinal tract. In the pandemic, the use of this group of drugs has increased many times over. Features of the clinical course of both the viral infection itself and the use of other drugs leads to a significant change in the pharmacodynamics and pharmacokinetics of NSAIDs, which may lead to the development of undesirable side effects.

Safety and Efficacy of Topical Diclofenac and Subcutaneous Firocoxib, Ketoprofen, and Meloxicam in Smoky Jungle Frogs (Leptodactylus pentadactylus )

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are often used in anurans, limited pharmacodynamic data are available regarding their value, particularly with regards to repeated dosing. This study investigated the efficacy and safety of serial, once-daily NSAID dosing in smoky jungle frogs (Leptodactylus pentadactylus). Twenty frogs were randomly assigned to receive one of five treatments, once daily for six consecutive days: topical diclofenac (1 mg/kg) or subcutaneous firocoxib (5 mg/kg), ketoprofen (1 mg/kg), meloxicam (0.2 mg/kg), or an equal volume 0.9% saline (control). An acetic acid test was used to determine the nociceptive threshold for each frog 2, 8, 24, 48, and 144 h after initial drug administration. All frogs were euthanized on day 7 for gross examination and histopathology. No significant difference in response was noted for any drug at any time point compared with saline. Mean or median test response for NSAID groups was greater than or equal to saline in 3/4, 2/4, 4/4, 4/4, and 3/4 frogs at 2, 8, 24, 48, and 144 h, respectively. Significant necropsy findings included epidermal necrosis of the hindlimbs in 7/20 frogs (NSAID groups), gastric ulceration in 6/ 20 frogs (NSAID and saline groups), and renal tubular degeneration in 1/20 frogs (NSAID group). None of the aforementioned pathologies were suspected to be secondary to NSAID administration. Further research regarding NSAID pharmacokinetics and pharmacodynamics in anurans is warranted. Topical acetic acid is correlated with epidermal necrosis in smoky jungle frogs.

Using pharmacogenetics to structure individual pain management protocols in total knee arthroplasty

The purpose of this study was to use pharmacogenetics to determine the frequency of genetic variants in our total knee arthroplasty (TKA) patients that could affect postoperative pain medications. Pharmacogenetic testing evaluates patient DNA to determine if a drug is expected to have a normal clinical effect, heightened effect, or no effect at all on the patient. It also predicts whether patients are likely to experience side effects from medicine. We further sought to determine if changing the multimodal programme based on these results would improve pain control or reduce side effects. In this pilot study, buccal samples were collected from 31 primary TKA patients. Pharmacogenetics testing examined genetic variants in genes OPRM1, CYP1A2, CYP2B6, CYP2C19, CYP3A4, CYP2C9, and CYP2D6. These genes affect the pharmacodynamics and pharmacokinetics of non-steroidal anti-inflammatory drugs and opioids. We examined the frequency of genetic variants to any of the medications we prescribed including celecoxib, hydrocodone, and tramadol. Patients were randomized to one of two groups: the control group received the standard postoperative pain regimen, and the study group received a customized regimen based on the pharmacogenetic results. For the first ten postoperative days, patients recorded pain scores, medication, and side effects. Genetic variants involving one or more medications in the multimodal pain protocol occurred in 13 of the 31 patients (42%). In total, eight patients (26%) had variants affecting more than one of the medications. For the 25 patients who recorded pain and medication logs, the mean pain levels and morphine equivalents (MEQs) consumed in the first ten days were higher in the control group than in the custom-guided group (p = 0.019 for pain and p = 0.655 for MEQ). Overall, 42% of patients had a variant involving one of the pain medications prescribed in our perioperative pain program for TKA. Ongoing research will help determine if using these data to modify a patient's medication will improve outcomes. Cite this article: Bone Joint J 2020;102-B(6 Supple A):73-78.

Rectal indometacin dose escalation for prevention of pancreatitis after endoscopic retrograde cholangiopancreatography in high-risk patients: a double-blind, randomised controlled trial

Although rectal indometacin 100 mg is effective in reducing the frequency and severity of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients, the optimal dose is unknown, and pancreatitis incidence remains high. The aim of this study was to compare the efficacy of two dose regimens of rectal indometacin on the frequency and severity of pancreatitis after ERCP in high-risk patients. In this randomised, double-blind, comparative effectiveness trial, we enrolled patients from six tertiary medical centres in the USA. Eligible patients were those at high risk for the development of pancreatitis after ERCP. We randomly assigned eligible patients (1:1) immediately after ERCP to receive either two 50 mg indometacin suppositories and a placebo suppository (standard-dose group) or three 50 mg indometacin suppositories (high-dose group). 4 h after the procedure, patients assigned to the high-dose group received an additional 50 mg indometacin suppository, whereas patients in the standard-dose group received an additional placebo suppository. The randomisation schedule, stratified according to study centre and with no other restrictions, was computer generated by an investigator who was uninvolved in the clinical care of any participants, distributed to the sites, and kept by personnel not directly involved with the study. These same personnel were responsible for packaging the drug and placebo in opaque envelopes. Patients, study personnel, and treating physicians were masked to study group assignment. The primary outcome of the study was the development of pancreatitis after ERCP. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01912716, and enrolment is complete. Between July 9, 2013, and March 22, 2018, 1037 eligible patients were enrolled and randomly assigned to receive either standard-dose (n=515) or high-dose indometacin (n=522). Pancreatitis after ERCP occurred in 141 (14%) of 1037 patients-76 (15%) of 515 patients in the standard-dose indometacin group and 65 (12%) of 522 patients in the high-dose indometacin group (risk ratio [RR] 1·19, 95% CI 0·87-1·61; p=0·32). We observed 19 adverse events that were potentially attributable to study drug. Clinically significant bleeding occurred in 14 (1%) of 1037 patients-six (1%) of 515 patients in the standard-dose indometacin group and eight (2%) of 522 patients in the high-dose indometacin group (p=0·79). Three (1%) of 522 patients in the high-dose indometacin group developed acute kidney injury versus none in the standard-dose group (p=0·25). A non-ST elevation myocardial infarction occurred in the standard-dose indometacin group 2 days after ERCP. A transient ischaemic attack occurred in the high-dose indometacin group 5 days after ERCP. All 19 adverse events, in addition to the 141 patients who developed pancreatitis after ERCP, were considered serious as all required admission to hospital. We observed no allergic reactions or deaths at 30 day follow-up. Dose escalation to rectal indometacin 200 mg did not confer any advantage compared with the standard 100 mg regimen, with pancreatitis incidence remaining high in high-risk patients. Current practice should continue unchanged. Further research should consider the pharmacokinetics of non-steroidal anti-inflammatory drugs to determine the optimal timing of their administration to prevent pancreatitis after ERCP. American College of Gastroenterology.

Plasma Concentrations of Ketoprofen and Meloxicam after Subcutaneous and Topical Administration in the Smoky Jungle Frog (Leptodactylus pentadactylus)

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for analgesia in veterinary patients; however, evaluation of NSAID pharmacokinetics in amphibians is limited. A wide variety of pharmacotherapeutics have been administered topically to the skin of anurans with limited empirical evidence of absorption or efficacy. Systemic absorptions of two NSAIDs, meloxicam and ketoprofen, were evaluated after subcutaneous and topical cutaneous administration in smoky jungle frogs (Leptodactylus pentadactylus). Eighty-four, 8 month old, 38.0 g (26.1–56.6 g) (median [range]) frogs were randomly assigned to receive one of four treatments, with 21 animals in each group: 1 mg/kg racemic ketoprofen administered either subcutaneously (SK) or topically (TK) or 0.2 mg/kg meloxicam administered either subcutaneously or topically. Plasma concentrations of meloxicam and the R- and S-enantiomers of ketoprofen were quantified at 3, 8, and 24 h after administration. At each time point, seven frogs per group were anesthetized for blood collection and then euthanized. Plasma samples were pooled within each group for drug quantification. Both enantiomers of ketoprofen were detectable in groups SK and TK, and plasma concentrations decreased from 3 to 24 h. The drop in concentration was less predictable for TK than for SK. Plasma concentrations of meloxicam were nondetectable at most time points by both routes. Topical absorption of ketoprofen is possible in frogs, although therapeutic levels have not been determined for this species.

Recommendation for the substantial choice between various nonsteroidal antiinflammatory drugs based on their safety profile

Nonsteroidal antiinflammatory drugs are the most commonly used painkillers. Both analgetic and antiinflammatory effects of these medications are important in the treatment of rheumatic diseases. Despite their well-recognized efficacy, professional societies recommend using nonsteroidal antiinflammatory drugs with caution, balancing the various potential gastrointestinal, cardiovascular and renal adverse events. Clinicians should consider advanced age and history of concomitant diseases even in younger patients when considering treatment choice. As our Hungarian society is aging, prescribers must be aware of the basic pharmacodynamics and pharmacokinetics of nonsteroidal antiinflammatory drugs as well as drug interactions and potential adverse effects should be taken into consideration when using them according to the latest professional guidelines. Orv Hetil. 2018; 159(44): 1783-1788.

Prediction of the effect of voriconazole on the pharmacokinetics of non-steroidal anti-inflammatory drugs

To evaluate the impact of voriconazole on the pharmacokinetics of Non-steroidal anti-inflammatory drugs (NSAIDs). Pharmacokinetic and physiochemical properties of voriconazole and NSAIDs are applied to build physiologically based pharmacokinetic (PBPK) models using GastroplusTM. The PBPK models of voriconazole and NSAIDs are verified by published studies, respectively. After the successful verification, DDI simulations are applied to predict the effect of voriconazole on the pharmacokinetics of NSAIDs. The area under the plasma concentration-time curves extrapolated to infinity (AUC0-inf) of celecoxib, ibuprofen, tenoxicam and piroxicam are increased by 51%, 7%, 2% and 1% in concurrent use with voriconazole, respectively. The maximum concentration (Cmax) of celecoxib, ibuprofen, tenoxicam and piroxicam are increased by 21%, 1%, 1% and 1% in the presence of concomitant voriconazole, respectively. Considering the inter-patient variability, changes in AUC or Cmax are not clinically meaningful. Therefore, adverse events and toxicity that are associated with celecoxib should be closely monitored when in combination with voriconazole, and this result can provide guidance for clinical DDI studies.

Penetration and pharmacokinetics of non-steroidal anti-inflammatory drugs in rat prostate tissue.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) involves inflammation of the prostate and affects the quality of life of men of all ages. It is well reported in clinical studies that the treatment for CP/CPPS using nonsteroidal anti-inflammatory drugs (NSAIDs) produced favorable outcomes. However, currently, there are no guidelines on choice of the NSAIDs for the treatment of CP/CPPS. Therefore, in the current research study, we evaluated the prostate tissue penetration of four NSAIDs in rats to provide guidance on choice of NSAIDs for the treatment of CP/CPPS. Male Sprague-Dawley rats were administered orally with four NSAIDs viz. celecoxib, diclofenac, ibuprofen, and naproxen at 500 mg/kg dose. The animals were then sacrificed at various time points, and their prostate tissues were harvested. The NSAIDs were then extracted from the prostate tissues using liquid extraction technique, and their concentration in prostate tissue was quantified using high-performance liquid chromatography (HPLC). The prostate tissue penetration and related pharmacokinetic parameters were evaluated by non-compartmental analysis. The HPLC method for quantifying NSAIDs in prostate tissue resulted in single, sharp peaks without any interference and all validation parameters were within limits. Celecoxib showed the highest area under the curve (AUC) [146.50 ± 2.75 μg/mL*h] of all NSAID's. A two-factor analysis of variance (ANOVA) with replication indicated an overall statistically significant difference in the pharmacokinetic parameters for celecoxib, diclofenac, ibuprofen, and naproxen. This study for the first time reported the relative prostate tissue penetration of four NSAIDs. The pharmacokinetic data indicated that celecoxib has the highest penetration and retention in rat prostate tissues. Therefore, celecoxib may be considered as a better choice for the treatment CP/CPPS involving NSAIDs.

Effect of Amoxicillin And Cefalexin on The Pharmacokinetics of Diclofenac Sodium in Healthy Volunteers

Background: Studies investigating the effect of antibiotics on the pharmacokinetics of non-steroidal anti-inflammatory drugs are few. Such interaction could be clinically significant in conditions like diabetic nephropathy. Objectives: To study the effect of amoxicillin and cefalexin on the pharmacokinetics of diclofenac sodium when taken concomitantly. Subjects and Methods: Eleven healthy subjects participated in this single dose cross-over study. Each volunteer randomly joined one of the three treatment groups and received a single dose of diclofenac sodium (50mg enteric-coated tablet), diclofenac sodium + amoxicillin 500mg capsule, and diclofenac sodium + cefalexin 500mg capsule successively with one week washout interval. Blood samples were taken immediately before, at 30 minutes and at 1, 1.5, 2, 2.5, 3, 4 and 6 hours after drug administration and analyzed using high performance liquid chromatography (HPLC) system with ibuprofen as internal standard. Results: Diclofenac sodium produced a maximum concentration of 1.34 µg/ml with a half life of 0.5 hour and area under plasma concentration versus time curve up to 6 hours (AUC0-6) of 1.24 µg.h/ml. Although the AUC0-6 and maximum plasma concentration of diclofenac sodium increased by more than 20% after co-administration of amoxicillin, this increase is not statistically significant. Cefalexin, on the other hand, when given with diclofenac sodium significantly increased the AUC0-6 and maximum plasma concentration of diclofenac by 51.9% and 68.5% respectively. Conclusion: Amoxicillin and cefalexin can change some of the pharmacokinetic parameters of diclofenac tablet when administered concomitantly and cefalexin did that to a greater extent. Such interaction must, therefore, be considered in conditions where diclofenac might be harmful.

Abstract 349: Measurement of Platelet Cyclooxygenase-1 Acetylation Quantifies Interaction of Nonsteroidal Anti-Inflammatory Drugs with Aspirin in vivo

Aspirin prevents heart attack and stroke by irreversibly acetylating serine-529 in human platelet cyclooxygenase-1 (COX-1) and thereby inhibiting the biosynthesis of thromboxane (Tx). We hypothesized that precise quantification of COX-1 acetylation would allow the direct detection of drug-drug interactions between reversible COX inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and aspirin, which may abrogate its cardio-protective effect. We developed a stable isotope dilution liquid chromatography multiple reaction monitoring/mass spectrometry (LC-MRM/MS) method for measurement of platelet COX-1 acetylation. Serine-529 acetylation reflected faithfully aspirin pharmacology determined with conventional markers (serum TxB2 formation, urinary excretion of 11-dehydro-TxB2, and arachidonic acid induced platelet aggregation), but showed lower technical (CV% 3.7±2.7) and inter-individual variability (CV% 3.7). Oral administration of 325 mg of plain aspirin resulted in complete acetylation of platelet COX-1 within 2 hours and sustained maximal acetylation (71 ± 3% of total COX-1 amount) for up to two days in health volunteers (n=8). Recovery from acetylation, which reflects platelet turn-over, occurred at a rate of 7.2 ± 0.2 % per day. We compared the potential of five NSAIDs to block aspirin from acetylating platelet COX-1 in healthy volunteers (n=7 for each NSAID). Single doses of naproxen (500 mg), ibuprofen (600 mg), and diclofenac (100 mg) but not celecoxib (200 mg) and acetaminophen (1000 mg) prevented complete COX-1 acetylation by 325 mg aspirin administered 2 hours after the NSAID. The competition of NSAIDs with aspirin was conditioned by NSAID pharmacokinetics, potency, and COX isoform selectivity, suggesting variability in the likelihood of the drug-drug interaction between compounds and between patients. Monitoring platelet COX-1 acetylation may have utility in the identification of drug interactions that may limit the cardio-protective effect of low dose aspirin.

Polymorphisms of the CYP2C19 gene in Japanese patients with aspirin-exacerbated respiratory disease

Polymorphisms of the CYP2C19 gene in Japanese patients with aspirin-exacerbated respiratory disease

Pharmacology of drugs used to treat osteoarthritis in veterinary practice.

As in humans, pain in animals may be associated with a wide range of conditions and circumstances, ranging from acute trauma to joint diseases. Joint diseases are common in companion animal medicine (horse, dog, cat) and at least 80% of cases are classified as osteoarthritis (OA). Several drug classes are available for OA therapy, including corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs), agents with potential disease modifying properties and nutraceuticals. For long-term maintenance OA treatment, particularly in the horse and dog, NSAIDs are routinely and extensively used. This review outlines the pharmacokinetics (PK) and pharmacodynamics (PD) of NSAIDs in companion and farm animal species. NSAID PK and PD have been studied in models of acute inflammation, which enable use of PK-PD modeling to facilitate (a) studies of mechanism of action at the molecular level and (b) prediction of dosages for clinical use. The PK-PD approach is a powerful but underutilized tool which also facilitates inter-species comparisons.

Are altered pharmacokinetics of non-steroidal anti-inflammatory drugs (NSAIDs) a risk factor for gastrointestinal bleeding?

Are altered pharmacokinetics of non-steroidal anti-inflammatory drugs (NSAIDs) a risk factor for gastrointestinal bleeding?

Clinical implications of NSAID pharmacokinetics: Special populations, special considerations

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the centerpiece of pharmacologic therapy for most rheumatic disorders and related conditions, and as such are used in great numbers. These drugs are relatively safe and effective, but the pharmacokinetics of NSAIDs can be substantially altered in certain groups of patients, including the elderly and patients with renal and hepatic disease. In these patients, the risk of NSAID toxicity is increased. An understanding of NSAID pharmacokinetics in these groups can help physicians to adjust therapeutic regimens in order to limit the potentially serious complications of long-term NSAID therapy. The author discusses the age-related physiologic changes that may affect the various areas of drug pharmacokinetics and ways in which NSAIDs may interact with other drugs. Risk assessment and monitoring methods are also discussed.

Clinical Pharmacokinetics of Drugs Used in Juvenile Arthritis

Juvenile arthritis is defined as the occurrence of objective evidence of arthritis for a minimum of 6 weeks, in a child 16 years of age or younger. With a reported incidence of 9 to 19.6 per 100,000 children, juvenile arthritis is considered to be a rare disease. There is no known cure; however, up to 75% of patients will undergo remission by late adolescence. Drugs used in the treatment of juvenile arthritis are divided into 2 major classes: (a) the nonsteroidal anti-inflammatory drugs (NSAIDs) including salicylates, naproxen, ibuprofen, fenoprofen, ketoprofen, flurbiprofen, indomethacin, sulindac, tolmetin and diclofenac, and (b) disease modifying agents which encompass drugs such as antimalarial agents, gold, methotrexate, penicillamine and sulfasalazine. In almost all the reports dealing with the pharmacokinetics of NSAIDs, the level of disease activity has not been noted. The level of activity is important since, during a flare, the plasma albumin may fall to the point that it causes a substantial and clinically significant increase in the unbound serum concentration of highly bound drugs. The relationship between the concentration of these drugs in the systemic circulation and their efficacy is not clear. However, for many of them, therapeutic drug monitoring is recommended as a means of reducing the possibility of toxic reactions. Further pharmacokinetic and -dynamic evaluations are needed for many of these drugs in juvenile arthritis.

Toxicology of Nonsteroidal Antiinflammatory Drugs

Nonsteroidal antiinflammatory drugs (NSAIDs) constitute a class of pharmacologically active agents with similar therapeutic actions and side effects, despite diverse chemical structures. NSAIDs inhibit the enzyme cyclo-oxygenase and, thus, decrease inflammation mediated by prostaglandins. Toxicoses due to NSAIDs are manifested primarily by gastrointestinal upset and hemorrhage and by renal damage. Management consists of detoxification measures, in addition to supportive and symptomatic care. The article outlines the incidence, clinical toxicity, mode of action, and pharmacokinetics of nonsteroidal antiinflammatory drugs. The toxic effects of NSAIDs on individual organ systems are described, and general management recommendations for the treatment of NSAID toxicoses are presented.