Evidence-based use of indomethacin and ibuprofen in the neonatal intensive care unit

Abstract

Indomethacin and ibuprofen are potent inhibitors of prostaglandin synthesis. Neonates have been exposed to these compounds for more than 3 decades. Indomethacin is commonly used to prevent intraventricular hemorrhage (IVH), and both drugs are prescribed for the treatment or prevention of patent ductus arteriosus (PDA). This review examines the basis for indomethacin and ibuprofen use in the neonatal intensive care population. Despite the call for restrained use of each drug, the most immature infants are likely to need pharmacologic approaches to reduce high-grade IVH, avoid the need for PDA ligation, and preserve the opportunity for an optimal outcome.

Fig. 1

Structure of common NSAIDs. The NSAID parent compound, salicylic acid, was purified in 1829 and commercially synthesized in the mid-1800s. By 1897, salicylic acid had been successfully acetylated and was marketed as aspirin in 1899. Subsequent NSAID development led to the production of phenacetin (1887), acetaminophen (1888), phenylbutazone (1949), the fenamates (1950s), ibuprofen (1961), and indomethacin (1963).

Fig. 2

Structure of COX-1 and COX-2 substrate binding channels. Amino acid residues, Val 434, Arg 513, and Val 523, create a side pocket in COX-2, whereas the larger residues, Ile 434, His 513, and Ile 532, in the COX-1 channel block the bulky side chains of selective COX-2 inhibitors. (Adapted from Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 2006;116(1):4–15; with permission.)

Fig. 3

Relative selectivity of different NSAIDs for COX-1 or COX-2. Values were extrapolated from inhibition curves for each compound against COX-1 and COX-2 that were generated in a human modified whole blood assay. Bars represent the ratio of IC₈₀ concentrations, plotted logarithmically. (Adapted from Warner TD, Mitchell JA. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J 2004;18(7):790–804; with permission.)