Prostanoids exert their effects through respective receptors. On the basis of pharmacological characterization, which was confirmed biochemically, distinct receptors have been identified for prostanoids. A classification for prostanoid receptors was proposed and adopted such that for PGD₂, PGE₂, PGF_{2 a}, PGI₂, and TXA₂, they are classified, respectively, as DP, EP, FP, IP, and TP; EP receptors are further divided into EP₁, EP₂, EP₃, and EP₄ (16,17). The eight known types of prostanoid receptors are each encoded by an individual gene. The cloning of the prostanoid receptors identified another degree of heterogeneity secondary to mRNA splicing. Splice variants have been identified for the EP₁, EP₃, FP, and TP receptor homologues of various species. There are currently nine known subtypes of the human EP₃ receptor: EP_3-1a, EP_3-1b, EP_3-II, EP_3-III, EP_3-IV, EP_3-V, EP_3-VI, EP_3-e, and EP_3-f (18,19,20); subtypes of the EP₃ receptors are distinguished by variances in the tail of the carboxy-terminal portion. Human subtypes also exist for the TP receptor (21), specifically TP_a and TP_b, which as for EP₃ subtypes vary by the tail of their carboxy-terminal end. Although splice variants have been identified for the rat EP₁ (22) and the ovine FP (23) receptors, which also differ by their carboxyl-terminal portions, human homologues to EP₁ and FP subtypes have not been detected.

Sequence homology is mainly based on signaling pathway than on preferential ligand (24,25,26). The effects of prostanoid receptors on smooth muscle reflect this relationship. Thus, EP₂, EP₄, DP, and IP induce smooth muscle relaxation and are more closely related to each other than to the other prostanoid receptors. Similarly, EP₁, FP, and TP receptors cause smooth muscle contraction and form another group based on sequence homology.

Prostanoid receptors are rhodopsin-type containing seven transmembrane domains, an extracellular amino- and intracellular carboxy-terminus, and belong to the superfamily of G protein-coupled receptors. There are 28 amino acid residues conserved within all prostanoid receptor sequences, and 8 of these are shared with other G protein-coupled receptors. These conserved regions are thought to play fundamental roles in the structure of the prostanoid binding domains. These residues are believed to be particularly important in receptor structure and/or function. For instance, an arginine in the seventh transmembrane domain conserved between all prostanoid receptors was proposed to be the binding site for the carboxyl moiety of the prostanoids (27,28); the conserved motif in the second extracellular loop may also function in this regard (27). In addition, glycosylation is required for ligand binding of certain prostanoid receptors (29).

Three clusters of related receptors have been defined based on their signaling: (i) DP, IP, EP₂, and EP₄; (ii) EP₁, FP, and TP; and (iii) EP₃. Prostanoid receptors in group (i) are linked to heterotrimeric G proteins that are composed of a G_a subunit that generally stimulates adenylate cyclase (designated G_{a s}) to produce cyclic AMP. Accordingly, its dominant effect on smooth muscle is relaxation. Prostanoid receptors in group (ii) couple mostly to increases in intracellular free Ca²⁺ through the activation by G_{a q} of phospholipase C, with subsequent inositol phosphate liberation. In smooth muscle, stimulation of this group of receptors leads to contraction. Group (iii), which constitutes the EP₃ subtypes of the prostanoid receptor family, employs as its primary effector pathway inhibition of adenylate cyclase through the G_{a i} family (30). However, because of the variant molecular nature of EP₃, the latter can couple to a variety of G proteins.

The effects of PGE₂ and PGD₂ in inflammation are well established (31). PGE₂ through its EP₃ receptor is also significantly implicated in pyrexia (32), whereas PGD₂ via its DP receptor seems to contribute to allergen-evoked bronchoconstriction (33); moreover, the PGD₂ metabolite 15-deoxy-Δ-PGJ₂ (12,14) is a potent immune modulator.

A detailed review on pharmacokinetics of NSAIDs in children is reported (46). Pharmacokinetics in children is notable by interindividual differences. In general, NSAIDs are rapidly absorbed from the intestine to reach maximal plasma concentrations within 1 to 2 hours. They tend to distribute in a small volume of distribution and are highly bound to plasma proteins; but in children, the apparent volume of distribution is greater than that in adults as shown for diclofenac, ibuprofen, ketorolac, and nimesulide for reasons that are not yet clear. Assuming, a comparable concentration–efficacy relationship, children may require higher loading doses. NSAIDs are metabolized via phase I and II biotransformations. Conjugation occurs mostly with glucuronic acid and sulfate producing mostly inactive compounds. Approximately 60% to 70% of metabolized agents are excreted in urine and the rest in feces.

Aspirin is rapidly absorbed enterally with a t_max of 2 hours. It is readily deacetylated by intestinal, hepatic, and blood esterases. Aspirin is metabolized by liver enzymes mostly into salicyluric acid, salicyl phenolic glucuronide, and salicyl acyl glucuronide and altogether account for 90% of metabolites which are inactive and eliminated by the kidneys; because of the ionized form of this acid, its renal elimination is favored in alkaline urine. Interestingly, aspirin metabolism is relatively rapidly saturated, such that its kinetics proceeds from first to zero order; accordingly, the half-life of aspirin changes as a function of dose.

Acetaminophen is very commonly used in the pediatric population. Orally administered acetaminophen is rapidly (t_max = 1 hour) and nearly fully absorbed (>90%). In contrast, rectally administered acetaminophen is variable with mean bioavailability of 47% in children. Contrary to most NSAIDs, this drug has low protein binding. Its elimination occurs by conjugation to glucuronide and sulfates, the latter being the dominant form in children up to 9 years of age. A small amount of acetaminophen is oxidized by CYP enzymes. This latter pathway generates electrophilic compounds which require glutathione for detoxification; in overdose, this pathway is overutilized resulting in glutathione depletion and hepatic toxicity.

Specific COX-2 inhibitors have been approved by the Food and Drug Administration (United States) for a number of inflammatory and nociceptive indications; however, increased cardiovascular morbidity (and mortality) with a number of recently developed COX-2 inhibitors has resulted in limiting their applications particularly in adult patients (47,48). Selective COX-2 inhibitors, such as celecoxib,
rofecoxib, valdecoxib, as well as meloxicam (semi-selective COX-2 inhibitor), are readily absorbed enterally within 2 to 3 hours for the coxibs and 5 to 6 hours for meloxicam. Celecoxib, valdecoxib, and meloxicam are mainly metabolized by CYP2C9 and to some extent by CYP3A4 (49) and exhibit in the adult a t_1/2 of 11 and 20 hours, respectively. In children, celecoxib is also well absorbed orally but is cleared much faster with a t_1/2 of approximately 4 hours (50). Rofecoxib is metabolized by CYP1A2 and cytosolic liver enzymes (51) and has a t_1/2 of 17 hours; its disposition in children is reported to be similar to that in adults (52).

Fever represents the major indication of NSAIDs and acetaminophen in children. Of the NSAIDs, ibuprofen, approved in the United States for this indication, is by far the most commonly utilized in developed countries; aspirin, which has been mostly abandoned because of the risk of Reye syndrome, is still used in underdeveloped parts of the world. Doses of 10 mg per kg ibuprofen and 15 mg per kg acetaminophen have been found to exert similar antipyretic efficacy (53). Higher doses of ibuprofen (specifically 10 compared to 5 mg per kg) were more effective in lowering higher core temperatures (54).

A number of randomized trials have evaluated the efficacy of NSAIDs in juvenile rheumatoid arthritis [for review, see reference no. (46)]. Overall diverse NSAIDs have been found to be equivalently effective, consistent with observations in the adult. Response is also dependent upon duration of therapy and increases with the latter to achieve approximately 80% efficacy after 8 weeks of treatment. Prolonged treatment with NSAIDs as needed for juvenile rheumatoid arthritis seems to augment the risk of gastroduodenal injury to a prevalence of 50% or more (19). On the other hand, significant renal complications are uncommon (55). Pseudoporphyria is an infrequent complication of NSAIDs, essentially limited to naproxen; the condition resolves upon drug discontinuation. Selective COX-2 inhibitors seem to be as effective as nonselective COX inhibitors, but exert fewer gastrointestinal complications (56,57). Although acetaminophen acts principally via COX-2 (14,15), its anti-inflammatory properties are limited as is its efficacy in severe rheumatoid arthritis (1,24,58).

Aspirin is commonly utilized in Kawasaki disease, but its efficacy remains controversial; however, aspirin combined with intravenous immunoglobulins is effective in this condition (59), but in acute Kawasaki it may cause thromboembolism (60). Similarly, the benefits of ibuprofen on lung function in cystic fibrosis have been confirmed in randomized trials (61,62).

Adverse effects of NSAIDs in children are similar in nature to those described in adults. Ibuprofen seems to exert a 7.2/100,000 risk of gastrointestinal bleeding (63). Mild reversible renal impairment is also observed in 8% to 10% of patients (64); dehydration doubles the risk. Other potential adverse effects of ibuprofen include aseptic meningitis and increased susceptibility of enhanced infections associated with group A β-hemolytic streptococci in children with varicella.

Acetaminophen is relatively safe. High doses are associated with hepatotoxicity. Limitation of acetaminophen doses to less than 60 mg per kg per day virtually abolishes the risk of hepatotoxicity, unless used with other hepatotoxic agents (65).

Overall, NSAIDs have a good tolerance record. None-theless, in certain cases, they should be contraindicated (Table 48.2). In light of the cardiovascular effects recently associated with long-term COX-2 inhibitors use in adult, the dosing, tolerance, and safety of selective COX-2 inhibitors in children may need to be revisited.

Patent ductus arteriosus (PDA) is a common complication of the preterm infant. Its incidence is inversely related to gestational age. A patent DA is essential for fetal well-being because it allows 90% of the right ventricular output to bypass the high-resistance pulmonary vascular bed in utero. Prostaglandins play a major role in maintaining ductal patency during fetal life (66). Of the prostaglandins, PGE₂ is the most important ductus arteriosus (DA) relaxant. Accordingly, inhibition in prostaglandin formation favors ductal constriction. Two COX inhibitors, indomethacin and, more recently, ibuprofen (2006), have been approved for the treatment of ductal patency in North America.