Clinical Pharmacology and Use of Nonsteroidal Anti-Inflammatory Drugs

Clinical Pharmacology

0031-3955/89 $0.00

+ .20

Clinical Pharmacology and Use of Nonsteroidal Anti-Inflammatory Drugs

Mary Ellen Mortensen, MD, * and Robert M. Rennebohm, MDt

Nonsteroidal anti-inflammatory drug (NSAID) usage has expanded to numerous conditions known or believed to be mediated by prostaglandins. This review summarizes arachidonic acid metabolism and the role of prostaglandins in chronic inflammation as background for understanding NSAID actions. NSAID pharmacokinetics, stereochemical considerations, and usage in pediatrics are discussed. Although differences among NSAIDs are pointed out, the lack of dear evidence for therapeutic superiority of any currently available NSAID is emphasized.

ARACHIDONIC ACID METABOLISM products of arachidonic acid metabolism (e. g., prostaglandins, thromboxanes, and leukotrienes) play important roles as mediators and modulators of inflammation65 . 102. 105. 119. 125. 139 (Fig. 1, Table 1). Normally stored in cell membranes, arachidonic acid is released when membranes are perturbed. Metabolism of arachidonic acid via the cydooxygenase pathway leads to prostaglandins and thromboxanes. Metabolism via the lipoxygenase pathway results in the production of various leukotrienes (Fig. 1). Collectively, the prostaglandins, thromboxanes, and leukotrienes are called eicosanoids. Of the cydo-oxygenase products, PGE 2 and prostacydin play the most important roles in inflammation. Both are potent vasodilators and hyperalgesic agents and are presumed to contribute significantly to the erythema, swelling, and pain associated with inflammation. Prostaglandins not only have direct proinflammatory effects but also synergize with other

*Assistant

Professor, Clinical Pediatrics, Section of Clinical Pharmacology/Toxicology, The Ohio State University, Columbus, Ohio t Associate Professor, Clinical Pediatrics, Pediatric Rheumatology, The Ohio State University, Columbus, Ohio

Pediatric Clinics of North America-Vol. 36, No.5, October 1989

1113

...... ...... ......

"'"

MERaRANE

PHOSPHOLI PI DS

PHOSPHO"I.""SJ:

ARACHIIKMtIC ACID

1.1 POXVGDMSE

- - - - - - - . . . •• 11. 12 OR 15 .PEtE

PEROXIDASE

tHROHBOXAto:

,,~

tHROIIBOXIIIINJ: SVNTHASIE

PROST.eveLl" SyNtHASE

PROSt.eveLI" ePGI.;!;)

t

IL'C'~ LTD. PII08rANOID8

H LTE.

I

LI:UICO'lIlII:"1:1

(PlIOSrAGLANDINS. PJIOS'IAcYLJN. 'IHJIOIImOXANES)

Figure 1. Arachidonic acid metabolism. (Key: PC for prostaglandin, followed by a class [0, E, F, H, I] and subclass [subclass 2] designation; LT for leukotriene, followed by a class [B, C, 0, E] and subclass designation [subscript 4]; HPETE is hydroperoxyeicosatetraenoic acid.)

1115

NSAID PHARMACOLOGY

Table 1. Important Biological Effects of Eicosanoids PGE,

PGI, (Prostacyclin)

PGD,

Thromboxane A,

LTB,

LTC" LTD" LTE,

Vasodilation, increased vascular permeability, hyperalgesia Fever Bronchodilation Stimulation of bone resorption Gastric mucosal cytoprotection Induces diuresis and natriuresis Vasodilation, increased vascular permeability, hyperalgesia Bronchodilation Inhibition of platelet aggregation (PGI, is the principal cyclo-oxygenase product of endothelial cells) Stimulates release of renin Systemic vascodilation, increased vascular permeability Bronchoconstriction, pulmonary artery vasoconstriction (PGD, is the major cyclo-oxygenase product of mast cells) Promotes platelet activation and aggregation Vasoconstriction, bronchoconstriction (TXA, is the principal cyclo-oxygenase product in platelets) Potent chemotactic agent for neutrophils, eosinophils and monocytes Promotes leukocyte adherence to endothelial cells Promotes secretion of oxygen radicals and hydrolytic enzymes by neutrophils Acts synergistically with other mediators to increase vascular permeability Bronchoconstriction Augments bronchial mucous secretion Vasoconstriction, increased vascular permeability SRS-A activity

inflammatory mediators such as bradykinin and histamine. Of the leukotrienes, LTB4 appears to be particularly important, in large part because of its potent chemotactic property. All cells (except non-nucleated erythrocytes) are capable of producing cyclo-oxygenase products, but cells differ regarding the predominant product they synthesize. In blood platelets, for example, PGH 2 is metabolized primarily by thromboxane synthase, so thromboxane A2 is the primary cyclo-oxygenase product. In endothelial cells prostacyclin synthase predominates, so that PGI 2 is primarily produced. Mast cells primarily produce PGD z because of predominance of endoperoxide-D isomerase. There is some evidence that the preferred cyclo-oxygenase product(s) of a given cell may change depending on clinical circumstances. After immune complex damage, for example, the renal glomeruli may selectively increase renal production of thromboxane A2 instead of the usually predominant PGE 2 and PGF Z • 105• 124 Unlike the ubiquitous cyclo-oxygenase, the lipoxygenase pathway that leads to leukotriene formation has so far been noted primarily in leukocytes (neutrophils, eosinophils, monocytes, macrophages, and mast cells).l1O Indeed, the leukotrienes were originally so named because they appeared to be produced primarily by leukocytes. The extent to which lymphocytes synthesize leukotrienes is unknown.

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MARY ELLEN MORTENSEN AND ROBERT M. RENNEBOHM

MECHANISM OF ACTION OF NSAIDS NSAIDs appear to act primarily through inhibition of cyclo-oxygenase, thereby inhibiting prostaglandin and thromboxane synthesis. Symptomatic relief experienced by rheumatoid arthritis (RA) patients treated with NSAIDs is associated with reduced prostaglandin levels and their proinflammatory effects. 65 Indeed, the synovial fluids of untreated RA patients contain high levels of PGE 2, which are lower after treatment with NSAIDs. 45.65 Currently available NSAIDs do not appreciably inhibit the lipoxygenase pathway. Some undesirable NSAID effects may occur when arachidonic acid metabolism is shunted through the lipoxygenase pathway, thereby creating excessive leukotriene levels. 120 For example, it has been hypothesized that accumulation ofbronchoconstricting LTC 4, LTD4, and LTE4 may be responsible for aspirin-induced asthma. 105 Unfortunately, all currently available NSAIDs appear to be nonselective inhibitors of cyclo-oxygenase, at least clinically.ll2 In addition to inhibiting unwanted prostaglandin synthesis (as in rheumatoid synovial tissue), they also inhibit desirable prostaglandin synthesis (as in gastric mucosa and the renal medulla). There may be a few exceptions to this generalization: in very low dosages aspirin inhibits platelet thromboxane A2 production without significantly affecting prostaglandin synthesis in other cells. 107 This "selectivity," however, is probably relative rather than absolute. 106 Sulindac relatively may spare the kidney because sulindac sulfide, the active metabolite, is oxidized back to its inactive prodrug by the kidney. 99 Potency of prostaglandin biosynthesis inhibition varies among NSAIDs. The nonacetylated salicylates weakly inhibit cyclo-oxygenase in vitro. 34 Even within a specific NSAID chemical class potency can vary. Using in vitro data from several studies, Brogden ranked arylpropionic derivatives in decreasing order of potency: ketoprofen, fenoprofen, naproxen, and ibuprofen. 22 Such potency rankings are of unknown clinical relevance because they are based on in vitro animal studies in diverse tissues. NSAIDs capable of inhibiting both the cyclo-oxygenase and lipoxygenase pathway are currently under development. Timegadine appears to be such a dual inhibitor in vitro and has been shown in one study to be superior to naproxen in controlling disease activity in RA.47 An ideal NSAID would inhibit cyclo-oxygenase and lipoxygenase in only the desired tissue (e. g., synovial tissue) without affecting eicosanoid synthesis in other tissues. Currently available NSAIDs may act through mechanisms other than inhibition of eicosanoid synthesis. NSAIDs may inactivate tissue damaging oxidants or prevent their formation. 63 NSAIDs may differ in their ability to affect leukocyte chemotaxis, migration, aggregation, and release of destructive products. I Whether such effects are clinically valuable or independent of inhibition of eicosanoid synthesis remains to be established. EICOSANOIDS, CYTOKINES, AND CHRONIC RHEUMATOID INFLAMMATION Figure 2 is a schematic model of eicosanoid and cytokine participation in chronic rheumatoid inflammation. 35 An early central event in the devel-

r SYNOVIAL FLUID

SYNOVIAL TISSUE

CARTILAGE AND BONE

~~--------------------

..... ..... .....

~

Figure 2. Immunopathogenesis of rheumatoid arthritis. (From Cush JJ, Lipsky PE: The immunopathogenesis of rheumatoid arthritis: The role of cytokines. Clin Aspects Autoimmunity 1(4):2-13, 1987; with permission.)

1118

MARY ELLEN MORTENSEN AND ROBERT M. RENNEBOHM

opment and perpetuation of chronic rheumatoid arthritis is activation of macrophages within synovial tissue. Key products released by activated macrophages include IL-1 (interleukin-1), TNF (tissue necrosis factor), LTB 4 , PGE z, toxic oxygen radicals, and destructive hydrolases. IL-1 participates in the activation of T and B cells. Activated T cells release a variety of cytokines, and activated B cells produce antibodies including rheumatoid factor. Subsequent immune complex formation and complement activation further amplify the inflammatory cascade. The LTB4 released by macrophages is powerfully chemotactic for polymorphonuclear cells, which release proinflammatory and tissue-destructive compounds in the synovial fluid. IL-1 and TNF stimulate PGE 2 and protease production by synovial tissue cells, which along with other factors adversely affect cartilage and bone. IL-1 and TNF also cause a variety of systemic manifestations, some of which are mediated by prostaglandins. In summary, eicosanoids and cytokines work together to amplify and perpetuate the inflammatory reaction. For more detailed discussion of these interactions the reader is referred to several excellent reviews. 7. 41. 42, 50, 51, 153 With Figures 1 and 2 in mind, imagine how NSAIDs might suppress the immune-inflammatory reaction, Cyclo-oxygenase inhibiting NSAIDs blunt PGE 2 production at several sites, Lipoxygenase-inhibiting NSAIDs blunt LTB4 production, thereby diminishing polymorphonuclear cell mediated inflammation and destruction, NSAIDs may also scavenge oxygen radicals, Ideal would be NSAIDs capable of inhibiting IL-1 or other specific cytokines,

USE OF NSAIDS IN PEDIATRICS The NSAIDs are classified by chemical group (Table 2). Although the use of a variety of NSAIDs has been studied in children, only aspirin, tolmetin, and naproxen have so far been approved by the FDA for pediatric use. Indomethacin is approved only for use in neonates for closure of the ductus arteriosus. Other pediatric indications for indomethacin were withdrawn following reports of sudden death and fatal hepatitis. 72, 74 Currently, the primary FDA-approved use of NSAIDs in pediatrics is for treatment of rheumatic conditions, particularly juvenile rheumatoid arthritis (JRA). The antiplatelet effect of low-dose aspirin has been used in conditions to prevent thrombotic complications, as in Kawasaki disease. Nonaspirin NSAIDs (NANSAIDs) currently are not approved as analgesic or antipyretic agents in pediatrics.

PHARMACOKINETICS OF NSAIDS Absorption All the NSAIDs are absorbed rapidly and almost completely following oral administration. Absorption occurs by passive diffusion in the stomach and upper small intestine and is influenced by pH. 22 Since NSAIDs are

1119

NSAID PHARMACOLOGY

Table 2. FDA-Approved Nonsteroidal Anti-Inflammatory Drugs DOSAGE CLASS AND GENERIC NAMES

Salicylates Aspirin Nonacetylated salicylates: Salicylsalicylate Choline magnesium trisalicylate Diflunisal Indoles Indomethacin Sulindac Tolmetin Propionic acid derivatives Ibuprofen Naproxen Fenoprofen Ketoprofen Carprofen Phenylacetic acid derivative Diclofenac Fenamates Meclofenamate Oxicams Piroxicam Pyrazoles Phenylbutazone

(mg/kg/day)

DOSES/DAY

Aspirin*

so

3-4

Disalicid Trilisatet

§

50

2-3 2-3

Dolobid

10-20

2

Indocin:j: Clinoril Tolectin*

1-2.5

3-4

TRADE NAME

Motrin, Rufen Naprosyn*t Nalfon Orudis Rimadyl Voltaren Meclomen

§

2

20-30

3-4

30-40 10-20

3-4 2 3-4

1200-1S00/m2 § §

4

§

4-7.5

Feldene

§

Butazolidin

§

3-4

3-4

* Approved by FDA for use in children. t Available in liquid form. :j: Approved only for neonatal use. § Not established for children.

weak acids (range of pKa 2.5-4.7), they are un-ionized in the highly acid gastric environment. In this state NSAIDs are lipid soluble and easily diffuse into gastric cells, where the pH is higher and the drug dissociates. In this manner NSAIDs become "ion-trapped" within the gastric cells. Such locally high concentrations contribute to the gastrointestinal side effects of NSAIDs. 64,71 Co-administration of aluminum or magnesium antacid may delay absorption of NSAIDs. Although prior antacid or food ingestion may delay NSAID absorption, the same amount of drug is absorbed. A larger fraction of the NSAID dose is absorbed in the small intestine under these circumstances. Rectal suppositories of NSAIDs do not confer any advantage because absorption is erratic and incomplete. 22 , 93 Gastric side effects are still possible through systemic mechanisms. Distribution All NSAIDs have relatively small volumes of distribution. Except for salicylate, NSAIDs are extensively bound (>90 per cent) to serum albumin (Table 3). At least two binding sites are available on human serum albumin, and NSAIDs have differing affinities for binding to one, the other, or both sites. 87

I-' I-'

I'Q

= Table 3. NSAID Pharmacokinetics

DRUG

Aspirin

TIME TO PEAK

ELIMINATION HALF-LIFE

VOLUME OF DISTRIBUTION

PROTEIN BINDING

(hr)

(hr)

(liter/kg)

(%)

ELIMINATION ROUTE(S)

0.5-1

0.25

0.15-0.2

3-6

0.13-0.18

80-90

Hydrolyzed to salicylic acid; renal excretion Mainly hepatic, some renal metabolism; Renal excretion is urine pH-dependent.

2-3

2-3 11-14

0.16-0.34 0.11

80-90 98-99

0.5-2

1.2-1.8

0.12-0.17

>99

1-2

2-3

0.08-0.11

>99

1.5-2 2-4

2 12-14

0.14 0.1

99 >99

1.7

7 (sulindac) 18 (sulfide)

0.5-1

1

Salicylate (infant)

Salicylate* (child). DiHunisal Nonsalicylates Diclofenac*

Fenoprofen* Ibuprofen* Naproxen Sulindac

Tolmetin*

93 98 0.04

*Pharmacokinetics have been studied in children with juvenile rheumatoid' arthritis.

>99

>90% hepatic metabolism; renal excretion First-pass metabolism up to 40% of dose; >90% hepatic metabolism; some bile, mainly renal excretion 95% hepatic metabolism; renal excretion

90% hepatic metabolism; renal excretion' >80% hepatic metabolism; renal biliary excretion (active metabolite) >80% hepatic metabolism

NSAID PHARMACOLOGY

1121

Protein binding serves as a reservoir, and only unbound ("free") drug is active, that is, able to produce therapeutic or toxic effect and available for metabolism or elimination. For highly protein bound drugs such as the NANSAIDs, a small change in binding may substantially affect unbound drug concentration. For example, a doubling of unbound naproxen concentration occurs when protein binding decreases by less than 1 per cent, from 99 to 98 per cent. However, clinical effect of the increased active drug concentration may not be detectable because of the simultaneous increase in metabolism of unbound NSAID.87 The extent of salicylate protein binding depends on serum pH and salicylate concentration. 37 At therapeutic concentrations, about 80 to 85 per cent of salicylate is protein bound. In general, unbound fraction of salicylate increases with rising total salicylate concentration. 34 Such concentrationdependent protein binding has been observed for naproxen and phenylbutazone. 106,123 The weak acidity of NSAIDs affects the differential concentrations in plasma and tissues. Only un-ionized molecules are lipid soluble and able to diffuse through biologic membranes, so that a decrease in serum pH increases the fraction of un-ionized NSAID and the movement of drug from plasma into tissues. Salicylate distribution is related inversely to serum pH. 34 A change in serum pH from 7.4 to 7.2 will double the fraction of unionized salicylate and increase salicylate tissue-to-plasma ratio,67 In particular, cerebrospinal fluid (CSF) and brain salicylate concentrations rise during systemic acidosis, The unbound un-ionized NSAID is able to diffuse through biologic membranes but may become ionized ("trapped") if a higher pH is encountered. This principle of "ion-trapping" in the presence of systemic acidosis accounts for the increased CSF:plasma salicylate ratio observed in salicylate poisoning. Awareness of such pH-dependent changes in ionization and distribution is vital to understanding the rationale for alkaline therapy of aspirin overdose. Several excellent reviews are available.34, 85, 131 Because only unbound drug is available for moving between tissue and plasma, one would predict that serum pH changes would not substantially alter the distribution of the highly protein-bound NANSAIDs. Synovial Fluid Distribution Synovial fluid concentrations of ibuprofen and naproxen are 20 to 70 per cent of simultaneously determined serum concentrations. 142 In a study of children with JRA, peak synovial fluid ibuprofen concentration occurred later and was 50 per cent of the serum peak in serum, but drug was eliminated more slowly from synovial fluid than from plasma. 91 NSAID diffusion into synovial tissue and fluid is favored by the greater acidity of the joint. 58, 87 In addition to "ion-trapping" of drug in the more highly acidic synovial fluid, NSAIDs are bound to proteins in synOVial fluid. 87 Equilibration between plasma and synovial tissue or fluid is slower than plasma elimination, Factors influenCing equilibration include synovial blood flow, tissue and protein binding, and local pH. 58, 87

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MARY ELLEN MORTENSEN AND ROBERT M. RENNEBOHM

Practical Implications Absorption rate and elimination half-life are important determinants of oral dosing schedules. For rapidly absorbed drugs with inactive metabolites, a dosing interval no less than 5 times the elimination half-life is typically recommended to maintain therapeutic or detectable serum concentrations. (A longer time between doses results in elimination of >99 per cent of the dose by the end of the interval.) Based on this premise, NSAIDs with short half-lives «4 hours) should require at least six-times-daily dosing. In clinical practice, dosing intervals of 6 to 8 hours provide adequate and sustained anti-inflammatory effect. 57. 58 In fact, ibuprofen (T1I2 1.5-2 hours) has been administered every 12 hours with similar clinical efficacy to a 6-hourly schedule. 28 One explanation is that NSAID accumulates in synovial fluid and cells and is more slowly eliminated from inflamed joints and tissues. This results in a longer duration of anti-inflammatory effect and less fluctuation of NSAID concentration in synovial fluid than in serum. 29. 58. 130 Such delayed synovial fluid elimination has been documented for ibuprofen, diclofenac, naproxen, and indomethacin. 22.23.90.91 Another possibility is that the minimal levels of NSAID remaining at the end of a dosing interval are sufficient to inhibit prostaglandin production. Evidence for this is the persistence of low prostaglandin E concentration in synovial fluid up to 24 hours after the last dose of tolmetin, a rapidly eliminated NSAID.45 Elimination With two exceptions, NSAIDs are administered in active form and inactivated by hepatic metabolism. Sulindac is a pro-drug that is converted by liver to the active sulfide form. 25 Aspirin is rapidly hydrolyzed primarily by plasma esterases but also in gastric mucosa to salicylate, the active form. Diclofenac and sulindac are the only NSAIDs that undergo appreciable enterohepatic recirculation. As much as 40 to 60 per cent of a diclofenac dose may be excreted into bile and feces. 136 The pattern of hepatic metabolism based upon urinary recovery studies appears to be similar for all the NANSAIDs. The parent drug and various hepatic metabolites are conjugated to glucuronic acid. Only a small fraction «10 per cent) of a dose is eliminated as unchanged drug, except for tolmetin (up to 17 per cent). 22. 26 Salicylate is metabolized by several conjugation and oxidation pathways in liver and to a lesser extent, in kidney.141 At therapeutic doses, less than 5 per cent is eliminated in urine as unchanged salicylate. Raising urinary pH to 8 can substantially increase the fraction of salicylate eliminated unchanged. 85 Salicylate and diflunisal are metabolized by hepatic enzyme systems that may become saturated within the therapeutic dosing range. 24. 86 Such metabolism is described as zero-order. Once the enzymatic capacity is reached, only this maximum (fixed) amount of drug per unit time can be metabolized. Beyond this saturation point, any increase in dose produces a disproportionate rise in serum drug concentration. For salicylate this occurs at relatively low dosages when the two major metabolic pathways become

NSAID PHARMACOLOGY

1123

saturated-conjugation with glucuronide and with glycine. 85, 86 The saturable process in diflunisal metabolism is not known. 24 Metabolism of other NSAIDs follows first-order kinetics; that is, a constant fraction is metabolized per unit time. One would expect an increase in serum NSAID concentration that is directly proportional to the dosage increase. However, the rise in serum concentration is smaller than predicted because of concentration-dependent changes in protein binding. 87, 123 Hepatic metabolites of NSAIDs used in pediatrics are inactive and eliminated by urinary excretion. An increase in urinary pH will increase renal clearance of NSAIDs. This effect is clinically unimportant with the NANSAIDs because of the extensive protein binding and because such a small fraction of a dose is excreted as unchanged drug. In contrast, increasing urinary pH can significantly increase the fraction of unmetabolized salicylate that becomes "ion-trapped" in urine. 85, 131

INFLUENCE OF AGE AND DISEASE STATES Although few pediatric studies have been published, pharmacokinetics of naproxen, ibuprofen, fenoprofen, tolmetin, and diclofenac appear to be similar in healthy children and adults. 26, 27, 73, 91, 122, 147 Pharmacokinetics of ibuprofen, fenoprofen, diclofenac, and tolmetin do not appear to be altered in JRA. 26 , 61, 92, 122 NAN SAID clearance is characterized as restrictive, that is, relatively small in comparison to liver blood flow. The limiting factors in NSAID metabolism are unbound drug concentration and hepatic enzyme activity. Decreased protein binding that is accompanied by increased metabolism is unlikely to be clinically significant despite changes in pharmacokinetic parameters (volume of distribution, clearance, or both).87 Altered albumin and decreased plasma protein concentrations have been noted in rheumatoid disorders.87 Nonetheless, average pharmacokinetics of ibuprofen, naproxen, diclofenac, and tolmetin in subjects with RA do not differ substantially from values determined in healthy volunteers.22 Individual patients with RA may show changes in pharmacokinetics, with increased metabolism during periods of hypoalbuminemia and disease activity.138 Nephrotic syndrome and protein-calorie malnutrition are associated with hypoproteinemia and presumably decreased NSAID protein binding and increased metabolism. Other conditions associated with decreased protein binding are listed in Table 4. In contrast, a decrease in both protein binding and liver metabolism may considerably alter NSAID pharmacokinetics. The most clinically important conditions in Table 4 are those that also are associated with decreased hepatic metabolism. Prolonged half-life and clearance of salicylate and indomethacin occur in neonates. 93, 118 Patients with chronic hepatic insufficiency should probably not be treated with NSAIDs because liver is the site of metabolism, and the degree of metabolic impairment may be unpredictable. Children with cystic fibrosis theoretically may have diminished metabolism, but in one study pharmacokinetics were unaltered, possibly because drug absorption was erratic and incomplete. 53

1124

MARY ELLEN MORTENSEN AND ROBERT M. RENNEBOHM

Table 4. Conditions Associated with Diminished or Altered Serum Albumin That May Decrease NSAID Protein Binding Age (neonate) Congestive heart failure Chronic inflammatory diseases Chronic bronchitis Cystic fibrosis Immobilization Liver disease (chronic) Malignancy

Malnutrition Nephrotic syndrome Pancreatitis Pregnancy Renal failure Sepsis Surgery Trauma

Note: These conditions may result in altered pharmacokinetics and exaggerated response to therapy. Increased unbound NSAID concentration and risk of toxicity are most likely to occur in conditions accompanied by decreased hepatic metabolism.

In renal failure, the presence of binding inhibitors and altered albumin structure decreases protein binding. Increased volume of distribution has been noted in uremic patients treated with naproxen, diflunisal, or salicylate. 24, 87 Prolonged elimination half-life has been shown with diclofenac and diflunisal, roughly proportional to the degree of renal impairment. 23, 24 Reabsorption of glucuronide metabolites may contribute to the slower fall in plasma NSAID concentration. Metabolite accumulation also occurs because urine is the primary route of excretion. Only sulindac has active metabolites, so that prolonged drug effect might be anticipated in patients with renal failure. Sulindac and diflunisal also are excreted into bile. In patients with renal failure, biliary excretion may account for a larger fraction of dose eliminated. 24, 25

PHARMACODYNAMICS AND MONITORING PLASMA CONCENTRATIONS Despite extensive use of NSAIDs in arthritis, the therapeutic range of plasma concentrations has not been clearly established for any of the NSAIDs, including aspirin. Whether the maximal recommended dosages of different NSAIDs truly provide comparable anti-inflammatory activity has not been established. Furthermore, it has not been established whether plasma or synovial fluid pharmacokinetics are the most appropriate parameter by which to determine optimal daily dosage and frequency of administration. Monitoring serum or plasma NANSAID concentrations is neither clinically useful nor feasible at present. In the few studies published, dose or serum concentration correlates weakly or not at all with anti-inflammatory effect. 38. 80 Delineating the relationship between plasma concentration and antiinflammatory response will require measurement of unbound NSAID (active drug), perhaps closer to the site of action. Even unbound plasma NSAID concentrations may not be indicative of anti-inflammatory effect. Repeated determinations of unbound NSAID in synovial fluid or tissue may correlate best with anti-inflammatory effect. The need for stereospecific assays of propionic acid derivatives further

1125

NSAID PHARMACOLOGY

complicates the study of ibuprofen, naproxen, and fenoprofen pharmacodynamics. Assays that do not distinguish enantiomers of these NSAIDs will measure both therapeutically inactive and active drug.

NSAID ENANTIOMERS Terminology An enantiomer, or optical isomer, is a molecule that rotates polarized light to the right (the S or [ + 1isomer) or to the left (the R or [ - 1isomer). The two enantiomers are superimposable mirror images with the same molecular formula. Stereoselectivity refers to the preference of one isomer over the other. A racemate is a 50:50 mixture of enantiomers. Pharmacologic Relevance Therapeutic effects, as well as absorption, distribution, protein binding, metabolism, and excretion, may be stereoselective.145 Of the NSAIDs, the arylpropionic acid derivatives (see Table 2) exist as enantiomers. The (+) enantiomer inhibits prostaglandin synthesis in vitro; S ( + ) ibuprofen is 150 times more active than the (-) enantiomer.3 The R (-) enantiomer may contribute to toxicity. 145 Ibuprofen is administered as a racemate but the ratio of S (+): R ( - ) urinary metabolites is not 1:1, as might be expected. Metabolic inversion occurs, with about 60 per cent of the R ( - ) converted to S (+ ) ibuprofen. 2, 82 Pharmacokinetic differences also have been demonstrated, with more rapid absorption and plasma disappearance of the R (-) isomer relative to the active S (+) isomer. 40, 140 These differences may vary substantially among study subjects. 4o In the most recent of these studies, Day et al. determined ibuprofen enantiomer concentrations in synovial fluid simultaneously with serum.40 Isomer concentrations were lower in synovial fluid but fluctuated far less than in serum, but no correlation was evident between concentrations in the two compartments. At all times the concentration of S (+) ibuprofen was about twice that of R ( - ) ibuprofen. 40

EFFICACY OF NSAIDS IN TREATMENT OF JUVENILE ARTHRITIS Aspirin, ibuprofen, 5, 92. 128 tolmetin,83 naproxen,l00, 146 meclofenamate,19 piroxicam,146 fenoprofen,20 ketoprofen,15. 21 sulindac,18 diclofenac,61 flurbiprofen,lO oxaprozin,l1 pirprofen,12 and indomethacin 15 have been shown to be effective in at least the short-term treatment of JRA. Of the NANSAIDs only diclofenac has been tested in a placebo-controlled study of children with JRA. 61 In that study 45 hospitalized children with JRA were studied in a randomized, double-blind 2-week trial comparing diclofenac, aspirin, and placebo. Global evaluation of therapeutic efficacy showed improvement in 73, 50, and 27 per cent in the diclofenac, aspirin, and placebo groups,

1126

MARY ELLEN MORTENSEN AND ROBERT M. RENNEBOHM

respectively. Efficacy of diclofenac and aspirin was not different when assessed by other parameters. Several other NSAIDs have been compared to aspirin in the treatment of JRA. In double-blind studies, tolmetin,83 naproxen,78, 90, 100 fenoprofen,20 and sulindac 18 all have been shown to be as effective as aspirin. No NAN SAID has been shown to be clearly more effective than aspirin. Few studies in children have compared one NANSAID to another. Piroxicam compared favorably to naproxen in an 8-week double-blind crossover study.146 In a double-blind crossover trial indomethacin was superior to ketoprofen in several efficacy parameters. 1.; There have been no studies comparing naproxen and tolmetin in the treatment of JRA. NSAIDs traditionally have not been classified as remittive or diseasemodifying agents for arthritis. They do, however, decrease joint swelling, tenderness, pain on motion, morning stiffness, or limitation of motion while disease remains active. In addition, patients feel more comfortable and are better able to carry out physical therapy programs while on NSAIDs. There is no consistent evidence that NSAIDs impede erosive disease. Although the sedimentation rate may fall during NSAID therapy, it is difficult to know whether this is due to NSAID therapy or is part of the natural course of the disease.

EFFICACY OF NSAIDS AS ANTIPYRETIC AGENTS The antipyretic efficacy of aspirin is well demonstrated and appears to be mediated centrally through prostaglandin inhibition. 13, 43 Concerns about the association between Reye's syndrome and aspirin undoubtedly have motivated clinical trials of several NANSAIDs, Ibuprofen (6 mg per kg) appears to be equally effective as aspirin (10 mgper kg) and acetaminophen (12.5 mg per kg). ISO In the United States antipyretic evaluations of ibuprofen and naproxen are in progress. Antipyretic efficacy of various NSAIDs has been recently reviewed. 149, 150

EFFICACY OF NSAIDS AS ANTIPLATELET DRUGS Aspirin inhibits platelet cyclo-oxygenase (and, hence, thromboxane A2 production) irreversibly so that platelet aggregation is impaired for as long as 10 days after aspirin has been discontinued. 105. 134 Results of platelet antiaggregation studies have led to the recommendation that low-dose aspirin (5-10 mg per kg per day) be administered to patients with Kawasaki disease. 66, lOB However, the optimal dosage for such therapy has not been established and may be lower.105 Cyclo-oxygenase inhibition by other NANSAIDs is reversible, so that platelet aggregation returns to normal as soon as such NSAIDs have been fully excreted (e.g., within 24-48 hours for tolmetin or ibuprofen). 95, 96 The nonacetylated salicylates are poor inhibitors of cyclo-oxygenase and, at usual dosages, have little or no effect on platelets. 59

1127

NSAID PHARMACOLOGY

EFFICACY OF NSAIDS AS ANALGESIC AGENTS The efficacy of various NSAIDs as analgesic agents for children has not been adequately studied. Due to differences in lipophilicity and tissue specificity, some NSAIDs may penetrate CNS and affected tissues to a greater extent than others. 52 This appeared to account for a superior analgesic effect for Zomepirac, but it was taken off the market because of unacceptable side effects. ll3

SIDE EFFECTS OF NSAIDS Side effects of NSAIDs are largely consequences of prostaglandin inhibition (Table 5). Affected tissues are those in which NSAIDs tend to accumulate. 64 , 71, ll5 The true incidence of pediatric side effects associated with individual NANSAIDs has not been established. There are little relevant pediatric data regarding comparative toxicity among NANSAIDs. Barron et al. have reported the most extensive retrospective review of side effects during NSAID therapy of JRA (Table 6).9 Several double-blind trials in children with JRA and numerous studies in adults support the contention that NANSAIDs are better tolerated and less likely to prompt discontinuation than aspirin. 20. 33, 55, 61. 78, 148 Gastrointestinal Gastrointestinal (GI) symptoms are the most common adverse effects reported in children treated with NSAIDs. Fortunately, most GI side effects are mild, consisting of nausea, vomiting, abdominal pain, or upset. However, acute ulcer disease and massive life-threatening bleeding can occur, even without warning symptoms. 3 ! The potential for clinically important, even catastrophic, GI side effects has become a major, growing concern in NSAID therapy of adults. 31. 70 It is unclear whether children are at less risk, have greater tolerance, or adapt to NSAIDs more effectively than do adults. Table 5. Summary of Nontherapeutic NSAID Actions TARGET TISSUE

Gastric mucosa

Kidney Central Nervous System Platelets

Liver

EFFECT

Diminished production and alteration of mucosal barrier (aspirin) Direct irritation and erosion Inhibition of prostaglandin synthetase Diminished renal perfusion and glomerular filtration Sodium and water retention Prostaglandin synthesis inhibition Aggregation inhibited Reversible (nonsalicylate NSAID) Irreversible (aspirin) Interference with glucose metabolism Krebs cycle enzyme inhibition Increased aminotransferase enzymes (aspirin)

I-" I-"

t.:I 00

Table 6. Symptoms Prompting Discontinuation of Various NSAID Treatment Courses of 101 NO. OF TRIALS

ASPIRIN 147

TOLMETIN90

NAI'ROXEN 53

FENOPROFEN 46

IBUPROFEN 33

IRA

Patients

OTHER NSAID 58

TOTALS 427

(% of the above trials discontinued because of the following symptoms) Abdominal pain Headache Nausea/vomiting Tinnitus

Rash Change in personality Mouth ulcers Fatigue/Malaise Decreased hearing Alopecia Easy bruisability Dizziness Blurred vision Anorexia Edema Constipation/diarrhea

19.7 2.7 4.8 8.2 2.7 5.4 2.7 3.4

3.3 4.4 1.1 2.2 1.1 3.3 1.1

1.9 5.7 5.7 1.9 2.9 3.8

8.7 6.5

0.7 1.4 0.7

3.0

7.1 4.8 7.1 2.4 9.5

3.0

4.8

2.2 2.2

3.8 0.7

9.1

1.1 1.1 1.1

2.2 2.2 2.2

1.1

2.2 2.2

3.0 2.2

10.1 3.7 3.3 3.3 2.6 2.3 1.4 1.2 1.2 1.2 0.7 0.7· 0.7 0.5 0.5 0.5

- = Side effect did not cause discontinuation of drug in any patient. This study included only patients treated with more than one NSAID. Since only side effects that prompted NSAID discontinuation were reported, actual side effects incidence cannot be determined. Data from Barron KS, Person DA, Brewer EJ: J RheumatoI9:149, 1982; with permission.

NSAID PHARMACOLOGY

1129

There have been no published endoscopic studies of NSAID-treated children. Endoscopic studies performed in adults after both acute and chronic administration of NSAIDs consistently have shown a high incidence of gastric lesions, especially with aspirin. 32. 79. 129 Enteric coating of aspirin reduces the incidence of gastropathy. 13 It was hoped that sulindac, administered as inactive pro-drug, might not cause CI side effects. While gastric irritation may occur less frequently with sulindac, the effect is not absent. 25 Furthermore, drugs absorbed in the small intestine still may cause gastric mucosal injuryY Nonaspirin salicylates may prove to be less toxic to the CI tract than other NSAIDs.6 Hepatic Abnormalities Associated with NSAIDs Elevations of serum transaminases (SCOT and SCPT) occur in more than 50 per cent of children receiving aspirin therapy for rheumatic disease and are a common reason for discontinuation of the drug. 14. 89, 98 In one study, hepatotoxicity was more frequent in younger children and those with systemic-onset JRA. 14 Some children developed elevated SCOT values despite receiving relatively small doses of aspirin, even with serum salicylate levels within the "safe" range (less than 25 mg per 100 ml).14 Transaminase elevation may produce no symptoms and spontaneously resolve despite unaltered aspirin therapy. 8, 98 However, a significant percentage of children may develop nausea, vomiting, malaise, and right upper-quadrant abdominal pain and tenderness, requiring hospitalization. Aspirin-associated hepatopathy may be clinically and histologically indistinguishable from Reye's syndrome. 117 The incidence of hepatopathy associated with NANSAIDs appears to be far less, and to date, Reye's syndrome has not been associated with NANSAID therapy. There were no instances of SCOT elevation in shortterm prospective trials of naproxen lOO , 103, 146 (involving a total of 96 patients), ketoprofen 15 (30 patients), indomethacin 15 (30 patients), fenoprofen 20 (49 patients), and diclofenac61 (15 patients). In an ibuprofen trial, 2 (3 per cent) of 62 patients developed SCOT elevation. 92 SCOT elevations associated with aspirin were reported in three of the above studies, and were 9, 12, and 7 per cent, respectively.20, 61,100 Central Nervous System (CNS) Headache appears to be the most common neurologic side effect. 9 Tinnitus and decreased hearing have been reported primarily but not exclusively with aspirin therapy. 54, 90 Rare but important adverse effects include dizziness, blurred vision, and personality changes (irritability, hyperactivity, nervousness, drowsiness, and depression). There is need for further study of possible personality changes, including assessment of cognitive and school performance, in view of cognitive dysfunction reported in adults. 56. 60 Indomethacin has the reputation for causing the highest incidence of CNS effects, usually headache, dizziness, and confusion and occasionally vertigo, somnolence, and depression. 54 In one report, 47 per cent of patients taking indomethacin complained of CNS side effects; 20 per cent stopped the drug because of this. 121

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MARY ELLEN MORTENSEN AND ROBERT M. RENNEBOHM

Renal Prostaglandins play an important role in modulating renal blood flow, glomerular filtration rate, renin release, tubular ion transport, and water exchange. 94. 104. 105. III Such modulation, however, is primarily important during significant transient renal compromise or chronic renal insufficiency. The incidence of renal toxicity appears to be low in the pediatric population. A few cases of reversible renal papillary necrosis and irreversible acute renal failure and interstitial nephritis have been reported in chronically treated children and overdosed adults. 4. 81. 101. 116. 151 Hematuria and proteinuria preceded renal papillary necrosis and have led to the recommendation that during long-term NSAID therapy, urinalysis should be monitored and abnormal results be closely evaluated. 4 Factors that may increase the risk for NSAID nephrotoxicity are reviewed more extensively by others.46. 75 Sulindac has been considered the NSAID of first choice for patients with renal insufficiency or hypertension because its inhibition of renal prostaglandins appears to be less than that of other NSAIDs. Controversy about this exists, however. lOS Cutaneous The frequency and types of cutaneous reactions vary among different NSAIDs.16 Allergic manifestations are noted most often. 54 Three to nine per cent of adults treated with sulindac may have skin reactions, the most serious being erythema multiforme and toxic epidermal necrolysis. 69, 84 Pruritus has been reported with tolmetin, ibuprofen, and naproxen. 16 At least seven cases of Stevens-Johnson syndrome have been associated with diflunisal. 68 Photosensitivity reactions are unusual except with piroxicam. 54, 127 These differences emphasize the fact that not all NSAIDs are the same. Overdosage Overdosage with NSAIDs may exaggerate some side effects and produce other pathophysiologic effects. The clinical presentation and the management of various NSAID overdoses have been reviewed elsewhere.30, 44. 62, 88. 97. 131, 135, 137, 143

USE OF SPECIFIC NSAIDS IN JUVENILE ARTHRITIS Many pediatric rheumatologists still consider aspirin to be the first choice in the treatment of JRA: none of the other NSAIDs have been conclusively shown to be more effective than aspirin; aspirin is the least expensive NSAID; physicians have had experience with aspirin longer than with any other NSAID; and salicylate levels are widely available. A standard initial dosage is 80 mg per kg per day in three to four divided doses. The dosage is then adjusted to maintain a 2-hour post-morning dose serum salicylate level of 20 to 30 mg per dl. Aspirin therapy has lost popularity in recent years, however, for several reasons. Transaminase elevation is common, aspirin is associated with Reye's syndrome, and several studies have suggested that NANSAIDs may be safer.

1131

NSAID PHARMACOLOGY

Tolmetin and naproxen are widely used for therapy of JRA. Tolmetin is the NAN SAID in the United States that has been approved for pediatric use for the longest time, and efficacy and safety are somewhat better known. Naproxen has a long half-life, is dosed twice daily, and is available in liquid form. There have been no studies comparing tolmetin with naproxen for efficacy and safety. Therapy with NANSAIDs is initiated at the average recommended dosage (see Table 2) and cautiously increased toward the maximal recommended dosage, until either clinical benefits or unacceptable side effects occur. Although beneficial effects may become apparent within a few days, it may take several weeks before a beneficial response can be documented. In a study of response of JRA patients to aspirin, tolmetin, and fenoprofen, the mean response time was approximately 1 month. 89 It may be that an adequate therapeutic trial of a given NSAID should last at least 8 weeks. 89 If a patient does not respond to one NSAID, many clinicians may switch to a different NSAID. The value of such a switch has not been well documented, however. It is conceivable that differences in NSAIDs, host differences, or differences in disease subsets may result in a different response to an alternative NSAID.39 There is no convincing evidence that combination therapy is superior to use of a single agent. In fact, combination therapy may be countertherapeutic and increases the risk of drug toxicity due to drug interactions (Table 7). When therapy is begun, potential side effects of NSAIDs should be reviewed thoroughly with the family. Blood test monitoring (CBC, SCOT, SCPT, BUN, creatinine, and urinalysis) should be performed every 3 to 6 months during chronic therapy.

DRUG INTERACTIONS Numerous drug interactions with NSAIDs may be expected as a result of competition for protein binding sites or NSAID reduction in renal function or urine output (Table 7). During indomethacin therapy for patent ductus closure, serum digoxin and aminoglycoside concentrations may rise to potentially toxic levels.77, 152 Decreased renal function due to indomethacin is the most likely explanation. The antihypertensive effects of thiazides and beta-blockers (propranolol, pindolol, atenolol, and oxyprenolol) are reduced when indomethacin or ibuprofen are administered. 14. 144 A similar interaction can be expected with other NSAIDs. Sulindac does not alter the effects of beta-blockers, however. 144 NSAIDs may interfere with the action of diuretics in several ways. Proposed mechanisms include salt and water retention, alteration of prostaglandin-mediated renal blood flow, and interference with renal tubular water and salt excretion. 144 NSAID-induced salt and water retention and renal effects tend to counteract therapeutic effects of any antihypertensive. That NSAID therapy can precipitate decompensation in patients with

1132

MARY ELLEN MORTENSEN AND ROBERT M. RENNEBOHM

Table 7. Expected or Known Drug Interactions with NSAIDS NSAID

Any NSAID

Ibuprofen

Naproxen

Tolmetin Fenoprofen Salicylates Aspirin Diclofenac Indomethacin

INTERACTING DRUG

Lasix* Thiazides* Propranolol* Antihypertensives* Digoxin* Methotrexate* Probenecid Salicylates Aspirin Antacids (AI, Mg) Probenecid Aspirin Aspirin Antacids Diflunisal, Fenoprofen Methotrexate* Digoxin* Aminoglycosides*

COMMENT

Decreased antihypertensive effect

Increased digoxin plasma concentration Increased methotrexate plasma concentrations Decreased ibuprofen clearance Decreased ibuprofen clearances (metabolism) Decreased ASA and naproxen plasma concentration Decreased naproxen absorption Decreased naproxen clearance metabolism Decreased tolmetin plasma protein binding Decreased fenoprofen plasma concentration Decreased salicylate concentration Decreased aspirin NSAID plasma concentration Increased methotrexate plasma concentration Increased digoxin plasma concentration Increased aminoglycoside plasma concentration

*Drug interactions that may be clinically significant. Note: Theoretically, highly protein-bound drugs may competitively displace NSAID from albumin and increase unbound (active) NSAID in plasma. Enhanced NSAID effect would be expected, along with a change in NSAID plasma concentration. However, increased NSAID metabolism accompanies the rise in plasma concentration. Reduced renal function and urine output with NSAID may be an important mechanism of interaction for drugs that are renally eliminated and have narrow margins of safety (digoxin, methotrexate). congestive heart failure has been known for some time and may result at least in part from prostaglandin inhibition. 144 Several NSAIDs have led to fatal toxicity in patients on chronic methotrexate therapy for RA or tumors. 36. 49 Diclofenac, ibuprofen, and indomethacin have been reported to increase methotrexate concentrations. Concurrent use of NSAIDs with methotrexate should be done with caution. The mechanism is unknown, but renal elimination of methotrexate may be inhibited by NSAIDs.136 Few clinically significant interactions result solely from competition for protein binding sites. Increased unbound drug concentration is often compensated by increased clearance (metabolism). For example, naproxen displaces warfarin from albumin, but plasma warfarin concentrations and prothrombin time are unaffected because warfarin clearance increases. 126 If the compensatory change in clearance is prevented, however, significant clinical effects may result. Phenylbutazone displaces warfarin from albumin and inhibits warfarin metabolism. 76 Life-threatening bleeding diathesis was reported before this drug interaction was widely recognized. 48 Regardless, NSAIDs probably should be avoided in patients who are anticoagulated or otherwise at risk for bleeding. In healthy volunteers, probenecid prolongs naproxen half-life, apparently by interfering with metabolism. 126 Probenecid has very limited pediatric usage, but naproxen dosage may need to be reduced ifboth drugs are given.

1133

NSAID PHARMACOLOGY

Most studies show antacid effects on NSAID absorption that are variable and more pronounced in the fasting state. 57 Aluminum hydroxide reduces naproxen absorption, but magnesium aluminum hydroxide antacids have little effect. 57 Such studies of healthy volunteers using single antacid doses may not be applicable to typical clinical situations. Multiple antacid dosing usually is prescribed, and under this circumstance, NSAID absorption may be decreased significantly. The H 2-antagonists used to reduce gastric acidity and promote ulcer healing, cimetidine and ranitidine, appear not to alter ibuprofen pharmacokinetics. 132 Pharmacodynamic interactions between these two drug classes have not been studied.

CONCLUSIONS In recent years NANSAIDs have challenged aspirin as the drug of first choice for therapy of pediatric chronic inflammatory disease. Although the mechanism(s) of action of NSAIDs is incompletely understood, a primary mechanism involves inhibition of cyclo-oxygenase. Currently available NSAIDs do not significantly inhibit lipoxygenase and are nonselective cyclo-oxygenase inhibitors. Many NSAID side effects are due to interference with desirable prostaglandin actions. NSAIDs differ in a variety of ways: potency of cyclo-oxygenase inhibition, lipophilicity, pKa, absorption characteristics, half-life, and side effect profiles. Despite these differences, no one NAN SAID has been shown to be therapeutically superior. NANSAIDs do appear to be superior to aspirin in terms of GI toxicity and hepatotoxicity. . For a given patient one NANSAlD may be preferable to another for various reasons: interindividual variability in pharmacokinetics, pharmacodynamics and susceptibility to side effects, differences in disease or disease subset, presence of other clinical problems (e.g., hypertension or renal insufficiency), and difference~ in dose schedule preference. In studies of NSAID use for arthritis there is need to compare the efficacy and safety of NANSAIDs with each other, rather than to aspirin. Published data regarding antipyretic efficacy of NANSAIDs in pediatric subjects is limited and for analgesia is virtually nonexistent. The optimal dosage of aspirin for its therapeutic antiplatelet effect remains to be established. There is need to advance the sophistication of NAN SAID plasma concentration monitoring before it will become clinically useful. Most current assays measure total concentration rather than unbound (active) drug. In addition, stereospecific assays are necessary to distinguish between therapeutically active and inactive isomers of arylpropionic derivatives. Future directions in NSAID development will include development of dual cyclo-oxygenase and lipoxygenase inhibitors (ideally, tissue specific); inhibitors or antagonists of only certain specific eicosanoids (e.g., selective LTB4 or thromboxane antagonists); and specific inhibitors or antagonists of IL-l or other cytokines. There also is need to study further the effects of current and future NSAIDs on polymorphonuclear cell functions, tissue. destructive enzymes, and toxic oxygen radicals.

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MARY ELLEN MORTENSEN AND ROBERT M. RENNEBOHM

REFERENCES 1. Abramson S, Korchak H, Ludewig R, et al: Modes of action of aspirin-like drugs. Proc Nat! Acad Sci USA 82:7227, 1985 2. Adams SS, Bresloff P, Mason CG: Pharmacological differences between the optical isomers of ibuprofen. Evidence for metabolic inversion of the (- )-isomer. J Pharm Pharmacol 28:256, 1976 3. Adams SS, McCullough KF, Nicholson JS: The pharmacological properties of ibuprofen, an anti-inflammatory, analgesic and antipyretic agent. Arch Int Pharmacodyn 178:115, 1976 4. Allen RC, Petty RE, Lirenman OS, et al: Renal papillary necrosis in children with chronic arthritis. Am J Dis Child 140:20, 1986 5. Ansell BM: Ibuprofen in the management of Still's disease. Practitioner 211:659, 1973 6. April PA, Curran NJ, Ekholm BP, et al: Multicenter comparative study of salsalate vs. aspirin in rheumatoid arthritis (abstr). Arthritis Rheum 30:593, 1987 7. Arenzana-Seisdedos F, Teyton L, Virelizier JL: Immunoregulatory mediators in the pathogenesis of rheumatoid arthritis. Scand J Rheumatol (Suppl) 66:13, 1987 8. Athreya BH, Moser G, Cecil HS, et al: Aspirin-induced hepatoxicity in juvenile rheumatoid arthritis. Arthritis Rheum 18:347, 1975 9. Barron KS, Person DA, Brewer EJ: The toxicity of nonsteroidal anti-inflammatory drugs in juvenile rheumatoid arthritis. J Rheumatol 9:149, 1982 10. Bass J, Athreya B, Brandstrup N, et al: Flurbiprofen in the treatment of juvenile rheumatoid arthritis. J Rheumatol 13:1081, 1986 11. Bass J, Athreya B, Brewer E, et al: A once-daily anti-inflammatory drug, oxaprozin, in the treatment of juvenile rheumatoid arthritis. J Rheumatol 12:384, 1985 12. Bass J, Giannini E, Brewer E, et al: Pirprofen (Rengasil) in the treatment of juvenile rheumatoid arthritis. J Rheumatol 9:140, 1982 13. Baum J (editorial): Enteric-coated aspirin today. J Rheumatol 12:829, 1985 14. Bernstein BH, Singsen BH, Koster King K, et al: Aspirin induced hepatoxicity and its effect on juvenile rheumatoid arthritis. Am J Dis Child 131:659, 1977 15. Bhettay E, Thomson AJ: Double-blind study of ketoprofen and indomethacin in juvenile chronic arthritis. S Afr Med J 54:276, 1978 16. Bigby M, Stern R: Cutaneous reactions to nonsteroidal anti-inflammatory drugs. J Am Acad Dermatol 12:866, 1985 17. Bjarnason I, Zanelli G, Smith T, et al: The pathogenesis and consequence of nonsteroidal anti-inflammatory drug induced small intestinal inflammation in man. Scand J Rheumatol 64(suppl):55, 1987 18. Bjettau E: Double-blind study of sulindac and aspirin in juvenile chronic arthritis. S Afr Med J 70:724, 1986 19. Brewer E, Giannini E, Baum J, et al: Sodium meclofenamate (Meclomen) in the treatment of juvenile rheumatoid arthritis. J Rheumatol 9:129, 1982 20. Brewer E, Giannini E, Baum J, et al: Aspirin and fenoprofen (Nalfon) in the treatment of juvenile rheumatoid arthritis: results of the double-blind trial. J Rheumatol 9:123, 1982 21. Brewer E, Giannini E, Baum J, et al: Ketoprofen (Orudis) in the treatment of juvenile rheumatoid arthritis. J Rheumatol 9:144, 1982 22. Brogden RN: Nonsteroidal anti-inflammatory analgesics other than salicylates. Drugs 32:27, 1986 23. Brogden RN, Heel RC, Pakes GE, et al: Diclofenac sodium: A review of its pharmacological properties and therapeutic use in rheumatic diseases and pain in varying origin. Drugs 20:24, 1980 24. Brogden RN, Heel RC, Pakes GE, et al: Diflunisal: A review of its pharmacological properties and therapeutic use in pain and musculoskeletal strains and sprains and pain in osteoarthritis. Drugs 19:84, 1980 25. Brogden RN, Heel RC, Speight TM, et al: Sulindac: A review of its pharmacological properties and therapeutic efficacy in rheumatic diseases. Drugs 16:97, 1978 26. Brogden RN, Heel RC, Speight TM, et al: Tolmetin: A review of its pharmacological properties and therapeutic efficacy in rheumatic diseases. Drugs 15:429, 1978 27. Brogden RN, Pinder RM, Speight TM, et al: Fenoprofen: A review of its pharmacological properties and therapeutic efficacy in rheumatic diseases. Drugs 13:241, 1977

r

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28. Brugueras NE, LeZotte LA, Moxley TE: Ibuprofen: a double blind comparison of twice a day therapy with four times a day therapy. Clin Ther 2:13, 1978 29. Brune K, Glatt M, Graf P: Mechanisms of action of anti-inflammatory drugs. Gen PharmacoI7:27, 1976 30. Burton BT: Ibuprofen overdose. West J Med 146:604, 1987 31. Butt JH, Barthel JS, Moore RA: Clinical spectrum of the upper gastrointestinal effects of nonsteroidal anti-inflammatory drugs. Am J Med 84(suppl 2A):5, 1988 32. Caruso I, Bianchi Porro G: Gastroscopic evaluation of anti-inflammatory agents. Br Med J 280:75, 1980 33. Catalano MA: Worldwide safety experience with diclofenac. Am J Med 80:81, 1986 34. Clissold SP: Aspirin and related derivatives of salicylic acid. Drugs 32:8, 1986 35. Cush JJ, Lipsky PE: The immunopathogenesis of rheumatoid arthritis. Clin Aspects Autoimmunity 1:4, 1987 36. Daly HM, Boyle J, Roberts qc, et al: Interaction between methotrexate and nonsteroidal anti-inflammatory drugs. Lancet 1:557, 1986 37. Davison C: Salicylate metabolism in man. Ann NY Acad Sci 179:249, 1971 38. Day RO, Furst DE, Dromgoole SH, et al: Relation of serum naproxen concentration to efficacy in rheumatoid arthritis. Clin Pharmacol Ther 31:733, 1982 39. Day RO, Graham GG, Williams KM, et al: Variability in response to NSAIDs-fact or fiction? Drugs 36:643, 1988 40. Day RO, Williams KM, Graham GG, et al: Stereoselective disposition of ibuprofen enantiomers in synovial fluid. Clin Pharmacol Ther 43:480, 1988 41. Dinarello CA: Interleukin-1. Dig Dis Sci 33:25S, 1988 42. Dinarello CA, Mier JW: Lymphokines. N Engl J Med 317:940, 1987 43. Dinarello CA, Wolff SM: Pathogenesis of fever in man. N Engl J Med 293:607, 1978 44. Done AK: Aspirin overdosage: incidence, diagnosis, and management. Pediatrics 62:890, 1978 45. Dromgoole SH, Furst DE, Desiraju RK, et al: Tolmetin kinetics and synovial fluid prostaglandin E levels in rheumatoid arthritis. Clin Pharmacol Ther 32:371, 1982 46. Dunn MJ, Zambraski EJ: Renal effects of drugs that inhibit prostaglandin synthesis. Kidney Int 18:609, 1980 47. Egsmose C, Lund B, Andersen RB: Timegadine: More than a non-steroidal for the treatment of rheumatoid arthritis. Scand J RheumatoI17:103, 1988 48. Eisen MJ: Combined effect of sodium warfarin and phenylbutazone. JAMA 189:64, 1964 49. Ellison NM, Servi RJ: Acute renal failure and death following sequential intermediatedose methotrexate and 5-FU: A possible adverse effect due to concomitant indomethacin administration. Cancer Treat Rep 69:342, 1985 50. Egeland T: Immunological aspects of the rheumatoid synovium. Scand J Rheumatol (Suppl) 66:27, 1987 51. Fauci AS, Rosenberg SA, Sherwin SA: Immunomodulators in clinical medicine. Ann Intern Med 106:421, 1987 52. Flower RJ, Vane JR: Some pharmacologic and biochemical aspects of prostaglandin biosynthesis and its inhibitors. In Robinson HJ, Vane JR (eds): Prostaglandin Synthetase Inhibitors: Their Effects on Physiological Functions and PatholOgical States. New York, Raven Press, 1974, p 9 53. Fonstan MV, Chai B-L, Hoppel CL, et al: Pharmacokinetics of ibuprofen in children with cystic fibrosis. Clin Res 35:843A, 1987 54. Fowler PD: Major toxic reactions associated with NSAIDs. In Hart FD, Klineberg JR (eds): ChOOSing NSAID Therapy: An International Reappraisal. Auckland, AD IS Press, 1985, p 41 55. Fowler PD: Aspirin, paracetamol and non-steroidal anti-inflammatory drugs. A comparative review of side effects. Med Toxicol 2:338, 1987 56. Goodwin JS, Regan M: Cognitive dysfunction associated with naproxen and ibuprofen in the elderly. Arthritis Rheum 25:1013, 1982 57. Graham GG: Pharmacokinetics and metabolism of non-steroidal anti-inflammatory drugs. Med J Aust 147:597, 1987 58. Graham GG, Day RO, Champion CD, et al: Aspects of the clinical pharmacology of non-steroidal antiinflammatory drugs. Clin Rheum Dis 10:229, 1984 59. Green D, Davies RO, Holmes GI, et al: Effects of diHunisal on platelet function and fecal blood loss. Clin Pharmacol Ther 30:378, 1981

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60. Griffith JD, Smith CH, Smith RC: Paranoid psychosis in a patient receiving ibuprofen, a prostaglandin synthesis inhibitor: case report. J Clin Psychiatry 43:499, 1982 61. Haapasaari J, Wuolijoki E, Ylijoki H: Treatment of juvenile rheumatoid arthritis with diclofenac sodium. Scand J Rheumatol 12:325, 1983 62. Hall AH, Smolinske SC, Conrad FL, et al: Ibuprofen overdose: 126 cases. Ann Emerg Med 15:1308, 1986 63. Halliwell B, Hoult JR, Blake DR: Oxidants, inflammation, and anti-inflammatory drugs. FASEB 2:2867, 1988 64. Halter F: Mechanisms of gastrointestinal toxicity of NSAIDs. Scand J Rheumatol (Suppl) 73:16, 1988 65. Henderson B, Pettipher ER, Higgs GA: Mediators of rheumatoid arthritis. Br Med Bull 43:415, 1987 66. Hicks RV, Melish ME: Kawasaki syndrome. Pediatr Clin North Am 33:1151, 1986 67. Hill JB: Salicylate intoxication. N Engl J Med 288:1110, 1973 68. Hunter WJ, Dorward AJ, Knill-Jones R, et al: Diflunisal and Steven's and Johnson's syndrome. Br Med J 2:1088, 1978 69. Husain Z, Runge L, Jabbs J, et al: Sulindac-induced Stevens-Johnson syndrome: Report of 3 cases. J Rheumatol 8:176, 1981 70. Ivey KJ: Gastrointestinal intolerance and bleeding with non-narcotic analgesics. Drugs 32:71, 1986 71. Ivey KJ: Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage. Am J Med 84 (suppl 2A):41, 1988 72. Jacobs JC: Sudden death in arthritic children receiving large doses of indomethacin. JAM A 199:182, 1967 73. Kauffmann RE, Bolliger RO, Han Wan S, et al: Pharmacokinetics and metabolism of naproxen in children. Dev Pharmacol Ther 5:143, 1982 74. Kelsey WM, Scharyi M: Fatal hepatitis probably due to indomethacin. JAMA 199:54, 1967 75. Ki';'caid-Smith P: Effects of non-narcotic analgesics on the kidney. Drugs 32:109, 1986 76. Koch-Weser J, Sellers EM: Drug interactions with coumarin anticoagulants. N Engl J Med 285:487, 1971 77. Koren G, Zarfin Y, Perlman M, et al: Effects of indomethacin on digoxin pharmacokinetics in preterm infants. Pediatr Pharmacol 4:25, 1984 78. Kvien TK, Hoyeraal HM, Sandstad B: Naproxen and acetylsalicylic acid in the treatment of pauciarticular and polyarticular juvenile rheumatoid arthritis. Scand J Rheumatol 13:342,1984 79. Lanza FL: Endoscopic studies of gastric and duodenal injury after the use of ibuprofen, aspirin, and other non-steroid anti-inflammatory agents. Am J Med 77:19, 1984 80. Laska EM, Sunshine A, Marrero I, et al: The correlation between blood levels of ibuprofen and clinical analgesic response. Clin Pharmacol Ther 40:1, 1986 81. Laxer RM, Silverman ED, Balfe JW, et al: Naproxen-associated renal failure in a child with arthritis and inflammatory bowel disease. Pediatrics 80:904, 1987 82. Lee EJD, Williams K, Day R, et al: Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol 19:669, 1985 83. Levinson J, Baum J, Brewer E Jr, et al: Comparison of tolmetin sodium and aspirin in the treatment of juvenile rheumatoid arthritis. J Pediatr 91:799, 1977 84. Levit L, Pearson R: Sulindac-induced Stevens-Johnson toxic epidermal necrolysis syndrome. JAMA 243:1262, 1980 85. Levy G: Clinical pharmacokinetics of aspirin. Pediatrics 62:867, 1978 86. Levy G, Tsuchiya T, Amsel LP: Limited capacity for salicyl phenolic glucuronide formation and its effect on the kinetics of salicylate elimination in man. Clin Pharmacol Ther 13:258, 1971 . 87. Lin JH, Cocchetto DM, Duggan DE: Protein binding as a primary determinant of the clinical pharmacokinetic properties of non-steroidal antiinflammatory drugs. Clin Pharmacokin 12~402, 1987 ' . 88, Linden CH, Townsend PL: Metabolic acidosis after acute ibuprofen overdosage, J Pediatr 111:922, 1987 89, Lovell DJ, Giannini EH, Brewer EJ Jr: Time course of response to nonsteroidal antiinflammatory drugs in juvenile rheumatoid arthritis. Arthritis Rheum 27:1433, 1984

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Makela A: Naproxen in the treatment of juvenile rheumatoid arthritis. Scand J Rheumatol 6:193, 1977 Makela AL, Lempiainen M, Ylijoki H: Ibuprofen levels in serum and synovial fluid. Scand J Rheumatol (Suppl) 39:15, 1981 Makela AL, Lempiainen M, Yrjana T: Ibuprofen in the treatment of juvenile rheumatoid arthritis: Metabolism and concentrations in synovial fluid. Br J Clin Practice 6:23, 1979 Mandelli M, Morselli PL: Antipyretic and nonsteroid antiinflammatory drugs. In Morselli PL (ed): Drug Disposition During Development. New York, Spectrum Publications, 1977, p 271 Marasco W A, Gikas PW, Azziz-Baumgartner R, et al: Ibuprofen-associated renal dysfunction. Pathophysiologic mechanisms of acute renal failure, hyperkalemia, tubular necrosis, and proteinuria. Arch Intern Med 147:2107, 1987 McQueen EG, Facoory B, Faed JM: Non-steroidal anti-inflammatory drugs and platelet function. N Z Med J 99:358, 1986 Meischer PA, Pola W: Hematological effects of non-narcotic analgesics. Drugs 32:90, 1986 Meredith TJ, Vale JA: Non-narcotic analgesics: Problems of overdosage. Drugs 32:177, 1986 Miller JJ, Weissman DB: Correlations between transaminase concentrations and serum salicylate concentration in juvenile rheumatoid arthritis. Arthritis Rheum 19: 115, 1976 Miller MJ, Bednar MM, McGiff JC: Renal metabolism of sulindac, a novel nonsteroidal anti-inflammatory agent. Adv Prostaglandin Thromboxane Leukotriene Res 11:487, 1983 Moran H, Hanna DB, Ansell BM, et al: Naproxen in juvenile chronic polyarthritis. Ann Rheum Dis 38:152, 1979 Moss AH, Riley R, Murgo A, et al: Over-the-counter ibuprofen and acute renal failure. Ann Intern Med 105:1986 Needleman P, Turk J, Jakschik BA, et al: Arachidonic acid metabolism. Ann Rev Biochem 55:69, 1986 Nicholls A, Hazleman B, Todd RM, et al: Long-term evaluation of naproxen suspension in juvenile chronic arthritis. Curr Med Res Opin 8:204, 1982 Oates JA, FitzGerald GA, Branch RA, et al: Clinical implications of prostaglandin and thromboxane A2 formation. N Engl J Med 319:761, 1988 Oates JA, Fitzgerald GA, Branch RA, et al: Clinical implications of prostaglandin and thromboxane A2 formation. N Engl J Med 319:689, 1988 Orme M, Holt PJL, Hughes GRV, et al: Plasma concentration of phenylbutazone and its therapeutic effect-studies in patients with rheumatoid arthritis. Br J Clin Pharmacol 3:185, 1976 Patrignani P, Filabozzi P, Patrono C: Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 69:1366, 1982 Patrona C, Ciabottoni G, Patrignani P, et al: Clinical pharmacology of platelet cyclooxygenase inhibition. Circulation 72:1177, 1985 Patrono C, Dunn MJ (editorial): The clinical significance of inhibition of renal prostaglandin synthesis. Kidney Int 32:1, 1987 Piper pJ, Samhoun MN: Leukotrienes. Br Med Bull 43:297, 1987 Pirson Y, van Ypersele de Strihou C: Renal side effects of nonsteroidal antiinflammatory drugs: Clinical relevance. Am J Kidney Dis 8:338, 1986 Pong SS, Levine L: Prostaglandin biosynthesis and metabolism as measured by radioimmunoassay. Prostaglandins 3:41, 1977 Pruss TP, Gardocki JF, Taylor RJ, et al: Evaluation of the analgesic properties of zomepirac. J Clin Pharmacol 20:216, 1980 Radack KL, Deck CC, Bloomfield SS: Ibuprofen interferes with the efficacy of antihypertensive drugs. Ann Intern Med 107:628, 1987 Rainsford KD, Schweitzer A, Brune K: Autoradiographic and biochemical observations on the distribution of non-steroid antiinflammatory drugs. Arch Int Pharmacodyn 250:180, 1981 Ray PE, Rigolizzo D, Wara DR, et al: Naproxen nephrotoxicity in a 2-year-old child. Am J Dis Child 142:524, 1988

1138

MARY ELLEN MORTENSEN AND ROBERT M. RENNEBOHM

117. Rennebohm RM, Heubi JE, Daugherty CC, et al: Reye syndrome in children receiving salicylate therapy for connective tissue disease. J Pediatr 107:877, 1985 118. Roberts RJ: Drug Therapy in Infants. Pharmacologic Principles and Clinical Experience. Philadelphia, WB Saunders, 1984, p 250 U9. Robinson DR: Lipid mediators of inflammation. Rheum Dis Clin North Am 13:385, 1987 120. Robinson DR, Skoskiewicz M, Bloch KJ, et al: Cyclooxygenase blockade elevates leukotriene E4 production during acute anaphylaxis in sheep. J Exp Med 163:1509, 1986 121. Rothermich N: An extended study of indomethacin. JAMA 195:531, 1966 122. Rubin A, Chernish SM, Crabtree R, et al: A profile of the physiological disposition and gastro-intestinal effects of fenoprofen in man. Curr Med Res Opin 2:529, 1974 123. Runkel R, Chaplin M, Sevelius H, et al: Pharmacokinetics of naproxen overdoses. Clin Pharmacol Ther 20:269, 1976 124. Saito H, Ideura T, Takeuchi J: Effects of a selective thromboxane A2 synthetase inhibitor on immune complex glomerulonephritis. Nephron 36:38, 1984 125. Salmon JA, Higgs CA: Prostaglandins and leukotrienes as inflammatory mediators. Br Med Bull 43:285, 1987 126. Segre EJ: Drug interactions with naproxen. Eur J Rheum Inflamm 2:12, 1979 127. Serrano C, Bonillo J, Aliaga A, et al: Piroxicam-induced photosensitivity. J Am Acad Dermatol U:U3, 1984 128. Sheldrake FE, Ansell BM: The use of "brufen" (ibuprofen) in the treatment of juvenile chronic polyarthritis. Curr Med Res Opin 3:604, 1975 129. Silvoso CR, Ivery KJ, Butt JH, et al: Incidence of gastric lesions in patients with rheumatic disease on chronic aspirin therapy. Ann Intern Med 91:517, 1979 130. Simkin PA: Pharmacokinetic and chemical properties of NSAIDs. In Hart D, Klineberg JR (eds): Choosing NSAID Therapy: An International Appraisal. Langhorne, PA, ADIS Press, 1985, p 69 131. Snodgrass WR: Salicylate toxicity. Pediatr Clin North Am 33:381, 1986 132. Stephenson DW, Small RE, Wood JH, et al: Effect of ranitidine and cimetidine on ibuprofen pharmacokinetics. Clin Pharm 7:317, 1988 133. Stern RC: Pathophysiologic basis for symptomatic treatment of fever. Pediatrics 59:92, 1977 134. Stuart MJ, Murphy S, Oski FA: A simple nonradioisotope technique for the determination of platelet life span. N Engl J Med 292: 1310, 1975 135. Temple AR: Pathophysiology of aspirin overdosage toxicity, with implications for management. Pediatrics 62:873, 1978 136. Todd PA, Sorkin EM: Diclofenac sodium-a reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 35:244, 1988 137. Vale JA, Meredith TJ: Acute poisoning due to non-steroidal anti-inflammatory drugs: Clinical features and management. Med Toxicoll:12, 1986 138. Van Den Ouweland FA, Cribnau FW], Tan Y, et al: Hypoalbuminaemia and naproxen pharmacokinetics in a patient with rheumatoid arthritis. Clin Pharmacokin U:5U, 1986 139. Vane J, Botting R: Inflammation and the mechanism of action of anti-inflammatory drugs. F ASEB J 1:89, 1987 140. VanCiessen CJ, Kaiser DC: CLC determination of ibuprofen [dl-2-(p-isobutylphenyl) propionic acid] enantiomers in biological specimens. J Pharm Sci 64:798, 1975 141. Von Lehmann B, Wan SH, Riegelman S, et al: Renal contribution to overall metabolism of drugs. IV. Biotransformation of salicylic acid to salicyluric acid in man. J Pharm Sci 62:1483, 1973 142. Wallis WJ, Simkin PH: Antirheumatic drug concentrations in human synovial fluid and synovial tissue: Observations on extravascular pharmacokinetics. Clin Pharmacokin 8:492, 1983 143. Walson PD, Mortensen ME: Pharmacokinetics of common analgesics, anti-inflammatories, and antipyretics in children. Clin Pharmacokin (in press) 144. Webster J: Interactions of NSAIDs with diuretics and beta-blockers: Mechanisms and clinical implications. Drugs 30:32, 1985 145. Williams K, Lee E: Importance of drug enantiomers in clinical pharmacology. Drugs 30:333, 1985 146. Williams PL, Ansell BM, Bell A, et al: Multicentre study of piroxicam versus naproxen

NSAID PHARMACOLOGY

147. 148. 149. 150. 151. 152. 153.

1139

in juvenile chronic arthritis, with special reference to problem areas in clinical trials of non-steroidal anti-inflammatory drugs in childhood. Br J Rheumatol 25:67, 1986 Willis JV, Kendall MJ: Pharmacokinetic studies on diclofenac sodium in young and old volunteers. Scand J Rheumatology (Suppl) 22:36, 1978 Wilkens RF: Worldwide clinical safety experience with diclofenac. Semin Arthritis Rheum 15(Suppl1):105, 1985 Wilson JT, Brown RD, Bocchini JA Jr, et al: Efficacy, disposition and pharmacodynamics of aspirin, acetaminophen and choline salicylate in young febrile children. Ther Drug Monitor 4:147, 1982 Wilson JT: Clinical pharmacology of pediatric antipyretic drugs. Ther Drug Monitor 7:2, 1985 Wortmann DW, Kelsch RC, Kuhns L, et al: Renal papillary necrosis in juvenile rheumatoid arthritis. J Pediatr 97:37, 1980 Zarfin Y, Koren G, Maresky D, et al: Possible indomethacin-aminoglycoside interaction in preterm infants. J Pediatr 106:511, 1985 Zvaifler NJ: New perspectives on the pathogenesis of rheumatoid arthritis. Am J Med 85 (Suppl 4A):12, 1988

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