Distribution of drugs Developmental changes in body composition are primarily respon- sible for the age-associated diff erences in drug distribution. As neonates and infants have rel atively larger extracellular and total- body water, coupled with smaller fat and muscle sto res compared to adults, when water-soluble drugs are administered, plasma lev- els in these compartments may be lower (i.e. larger volume of dis- tribution; Echeverria et al., 1975 ; Siber et al., 1975 ). Additionally, neonates and young infants have lower amounts of total circulat- ing plasma proteins, such as albumin and 1 -acid glycoprotein, resulting in a n increase in the free fraction of drugs, which infl u- ences the availability of the activ e moiety of drugs (Ehrnebo et al., 1971 ). Th e free fraction of highly protein-bound drugs is higher in neonates compared to older children and adults, as fetal albumin has lower bi nding affi nity for weak acids, and there is an increase in endogenous substances (e.g. fre e fatty acids) with a high affi nity for displacing drugs from albumin binding sites (Ehrne bo et al., 1971 ; Windorfer et al., 1974 ). Other age-related physiological changes, such a s diff erences in organ perfusion, regional blood fl ow, and permeability of cell membranes , can also dramatically infl uence drug binding and distribution. Following birth, neonates experience a marked increase in gas- tric emptying due to the imp rovement of the coordination of antral contractions (Gupta and Brans, 1978 ; Ittmann et al. , 1992 ). Th is is clinically signifi cant as the rate of drug exposure along the mucosal s urface of the small intestine is determined by the transit time of the drug within the gast rointestinal tract. As a result of increased gastric emptying in neonates, orally administe red drugs are less well absorbed and more time is required to achieve therapeutic plasma le vels of drugs in neonates compared to older children and adults (Heimann, 1980 ). Although few bioavailability studies have examined the absorption of drugs in infants and older chil dren, it has been suggested that both passive and active transportation are fully mature in infants by approximately 4 months of age (Anderson and Holford, 2008 ; Heimann, 1980 ). Drug metabolism Compared to older children and adults, neonates and infants exhibit distinc t developmental immaturity of many phase I (oxida- tion; Hines and McCarver, 2002 ) and pha se II (conjugation) drug- metabolizing enzymes (McCarver and Hines, 2002 ; Tateishi et al., 1997 ), which can contribute to observed drug toxicities in this age group (Weiss et al., 1960 ). During postnatal development, distinct patterns of change are observed in the isofo rm-specifi c expression Delayed maturation or developmental diff erences in the activity of intestinal drug-metabol izing enzymes in neonates and infants may aff ect the bioavailability of drugs (Hines and M cCarver, 2002 ), and can alter the systemic absorption of therapeutically active metabolite s of certain drugs, such as theophylline. For example, CHAPTER 42 principles of pain pharmacology in pediatrics 431 and activity of phase I enzymes, such as the cytochrome P450 fam- ily of drug-metabolizing enzymes: in children under 6 years of age even when acetaminophen plasma levels are within the range that is toxic at older ages (Rumore and Blaiklock, 1992 ). \231 Th e activity of CYP2E1 surges within hours aft er birth (Vieira et al., 1996 ). Elimination of drugs Beginning at 9 weeks of age, there is a developmental increase in the glomerular fi ltration rate, a process that is dependent on nor- mal nephrogenesis but is c omplete by 36 weeks of gestation, and then infl uenced by postnatal changes in renal and in trarenal blood fl ow (Robillard et al., 1988 ). During the fi rst 2 weeks of life, there is a rapid and marked increase in the glomerular fi ltration rate, which reaches its peak adu lt values by 8 to 12 months of age (Arant, 1978 ; van den Anker et al., 1995 ). Correspondi ngly, delayed maturation of tubular secretion is observed following birth; however, it reac hes adult capacity by the fi rst year of life (Arant, 1978 ). \231 Th is is immediately followed by the detection of CYP2D6 (Treluyer et al., 1991 ). \231 By the fi rst week of life, the expression of CYP3A4 (Lacroix et al., 1997 ) and CYP 2C (CYP2C9 and CYP2C19; Treluyer et al., 1997 ) become detectable. \231 By 1 to 3 months of life, CYP1A2 begins to appear (Sonnier and Cresteil, 1998 ). Th e cytochrome P450 superfamily of enzymes catalyzes the oxi- dation of opioids, convertin g the parent opioid to a more polar metabolite to facilitate its excretion. Of importance i n opioid metabolism are CYP3A4 and CYP2D6. Relatively low levels of P450s are expressed in the fetal liver; the level of CYP2D6 expres- sion reaches only 3% to 5% of adult expression in the third trimes- ter (Ladona et al., 1991 ). However, expression and activity level of CYP2D6 approaches 95% of adult capacity by 2 weeks of life (Blake et al., 2007 ). In compa rison, the expression of CYP3A4/5 begins to increase at 1 week of life reaching 30% of adul t levels by the age of 1 month. As developmental diff erences in the maturation of renal function can signifi cantly infl u ence the plasma clearance of drugs extensively eliminated by the kidneys (e.g. ceft azidime and famotidine; James et al., 1998 ), consideration of the ontogeny of renal function and age-appropriate dosing regimens for infants is necessary to avoid potential toxicity. Developmental pediatric pharmacodynamics It is well-established that physiological developm ent plays an important role in the mechanism of action of, and the response to, a drug. How ever, the eff ect of ontogeny on the interactions between a drug within the human body and the consequence of these inter- actions are still incompletely understood. Certain drugs, s uch as cyclosporine (Marshall and Kearns, 1999 ) and warfarin (Takahashi et al., 2000 ), de monstrate developmental diff erences in the interac- tion between a drug and the targeted r eceptor. Whereas, drugs such as midazolam show a clearer relationship between plasma level and the pharmacological eff ect of the drug (e.g. sedative eff ect; Marshall et al., 2000 ) . Although the ontogeny of phase II drug-metabolizing enzymes is less well established than p hase I drug-metabolizing enzymes, available data suggests that specifi c isoforms of uridin e diphosphate (UDP)-glucuronosyltransferase (UGT) display distinct patterns of maturation, which can markedly aff ect the pharmacokinetics of drugs (Barrett et al., 1996 ): \231 Th e expression and activity of the isoforms UGT1A6 and UGT1A9, are lower in neonate s and infants, and the glucuro- nidation of acetaminophen by UGT1A6 and, to a lesser extent , UGT1A9, is markedly decreased relative to adolescents and adults (Miller et al., 1976 ) \231 Th e isoform UGT2B7 can be detected from 24 weeks of gesta- tional age, and glucuron idation of morphine can occur in prema- ture infants (Barrett et al., 1996 ). As the expres sion and activity of UGT2B7 markedly increases between 27 and 40 weeks postcon- ceptual age , increases in morphine dose are necessary to main- tain therapeutic plasma levels of morph ine (Scott et al., 1999 ). Functionally and morphologically, the human brain is imma- ture at birth, which contributes to the variability in opioid-related analgesia and respiratory depression. Moreover, the o ntogeny of the BBB, drug metabolizing enzymes, and transporters also alter the pharmacodyna mics of opioids in neonates. Opioids must travel across the BBB in order to elicit their th erapeutic eff ect; therefore, the amount of opioid that an infant brain is exposed to is in part dependent on the maturity of the BBB. For example, neonates are more sensitive to the respiratory eff ects of morphine and merpe- ridine compared to older children and adults ( Way et al., 1965 ), and the greater permeability of neonatal brain to opioids (Koren et al. , 1985 ) is one contributing factor. Additionally, human new- borns display age-related dif f erences in morphine requirement, and full-term neonates aged 7 days or younger require si gnifi cantly less morphine to achieve an analgesic eff ect compared to older children (Bouw meester et al., 2003 ; see also Hathway, Chapter44; Strassels, Chapter 45 , this volume). Glucuronidation plays an important role in the metabolism of many opioids and their metabol ites, as the enzyme, uridine 5-diphopho- glucuronosyltransferase, attaches glucuronic acid onto a functional group on the parent opioid to form a highly polar metabolite, which is th en eliminated by the kidneys. For example, codeine is converted into codeine-6-glucuronide via UGT2B7. Although the ontogeny of UGT expression is still incompletely understood, it is known that at 15 weeks of gestational age, glucuronidation activity is present. Immediatel y aft er birth, UGT activity increases to approximately 10% of adult levels and by 3 to 6 m onths of age, neonatal activity level of UGT reaches full adult capacity (Pacifi ci et al., 1982 ). Glucuronidation of acetaminophen to produce its toxic metabolite, N -acetyl-p-benzoquinone- imine (NAPQI), is capa- ble of depleting hepatic glutathione and results in hepatotoxicity (Rumore and Blaiklock, 1992 ). In contrast to sulphation processes, which are more develope d in young children, glucuronidation activity increases with age explaining less hepatotoxi city observed Low expression and function of P-glycoprotein (P-gp), an effl ux transporter, in neonates a lso contributes to heightened central nerv- ous system (CNS) exposure to morphine. Th e loc alization of P-gp along the luminal plasma membrane of the brain capillary endothe- lium is important, as these transporters effl ux xenobiotics to pre- vent entry and accumulation o f neurotoxins or drugs in the brain SECTION 6 pharmacological interventions 432 (de Vries et al., 2007 ; Fellner et al., 2002 ). Although limited data is available regardi ng the developmental diff erences in the expression the P-gp transporter, it is known that neonates express P-gp as early as 22 weeks of gestational age, however, at relatively low l evels com- pared to that of adults (Daood et al., 2008 ). Postmortem analysis of CNS tissue obtained from neonates at 23 to 42 weeks gestational age revealed signifi cantly lower exp ression levels, but with a similar pattern of P-gp localization to that of adults (Tsai et al., 2002 ). As such, it is probable that delayed expression and function of P-gp may contr ibute to a heightened and sustained CNS exposure to morphine (Bouwmeester et al., 2004 ). F urther studies examining the contribution of the ontogeny of P-gp in the analgesic eff ect of opioids, such as morphine, in neonates are required to fully under- stand the impact of age-related diff erences in opioid response. than two functional alleles (Ito et al., 2010 ). In relation to codeine analgesia, metaboli sm of codeine by CYP2D6 to the active metabo- lite, morphine, is necessary to achieve an an algesic eff ect. Th erefore, phenotypes of clinical signifi cance are: \231 PM which are associated with therapeutic failure, as deletion or inactive variants o f CYP2D6 results in reduced formation of morphine and lack of analgesia. Approximately 5% t o 10% of Caucasians are phenotypically classifi ed as PM and thus, are una- ble to make the conversion of codeine to morphine and they fail to elicit analgesic eff ects with codeine (Caraco et al., 1999 ; Madadi and Koren, 2008 ; Madadi et al., 2009 ; Sistonen et al., 2007 ). \231 UM which are associated with severe opioid intoxication, as individuals carrying mor e than two functional CYP2D6 alle- les may produce an excess amount of morphine from codein e (Ciszkowski et al., 2009 ). Approximately 1% to 2% of Caucasians are classifi ed into the UM phenotype and therefore, these indi- viduals very rapidly and readily convert codeine t o morphine resulting in approximately 50% higher plasma concentrations of morphine correspo nding to severe opioid intoxication, which may result in a high incidence of CNS depression (Dalen et al., 1997 ; Kirchheiner et al., 2007 ; Madadi and Koren, 2008 ). Developmental pediatric pharmacogenomics and pharmacogenetics Th ere are a multitude of gen etic factors that can infl uence the dis- position and action of a drug, and these interind ividual diff erences can also elicit very diff erent clinical responses to the same dose of a drug. In addition to physiological developmental diff erences, genetic polymorphisms in drug metabolizing enzymes and drug transporters also signifi cantly infl uence the pharmaco kinetic and pharmacodynamic responses to certain drugs, such as opioids. In conjunction with genetic polymorphisms in the CYP2D6 gene, ontogeny further contributes to the interindividual variability in CYP2D6 activity. Some studies have demonstrated very low levels of CYP2D6 expression in fetal liver, where only 3% to 5% of adult expression of CYP2D6 is present during the third trimester with a signifi cant increase following the fi rst week of life (Blake et al., 2007 ; Ladona et al., 1991 ; Neville et al., 2011 ). Furthe rmore, in vitro data of CYP2D6 ontogeny demonstrates that CYP2D6 protein expres- sion and a ctivity remain constant aft er 1 week of life up to 18 years (Neville et al., 2011 ; Steven s et al., 2008 ) and that the contribution of CYP2D6 phenotypes in children approaches adul t levels at 10 years of age (Stevens et al., 2008 ). However, signifi cant interindividual varia- bility in CYP2D6 activity is observed during the fi rst year of life (Blake et al., 2007 ) suggesting that both genetic variation in CYP2D6 expres- sion and activity and devel opmental factors involving CYP2D6 matu- rity play important roles in the metabolism of drug s, such as codeine. Of concern, very few studies have investigated the eff ects of phe- not ype, genotype, and adverse events associated with codeine use for infant pain (Williams et al., 2002 , 2004 ). Furthermore, despite several guidelines suggesting a pediatric therapeu tic safe dose of less than 2 mg/kg, a threshold that is unlikely to result in adverse drug reactions (ADRs; American Academy of Pediatrics, 1997 ), there have been reports of severe and life-threatening ADRs associ- ated with the use of codeine at the recommended dose of l ess than 2 mg/kg in infants and children (Meyer and Tobias, 2005 ; Sachdeva and Stadnyk, 20 05 ; von Muhlendahl et al., 1976 ). As such, it is evident that genetic variations, in addi tion to developmental fac- tors, may amplify the risk of ADRs associated with codeine use i n infants and young children and therefore, caution should be taken when prescribing codein e. Polymorphisms in drug metabolizing enzymes Codeine is an alkaloid of the opium poppy Papave r somniferum and its analgesic eff ects are derived from metabolic conversion to mor- phine by demethylase activity (International Narcotic Control Board, United Nations: Narcotic Dr ug, Estimated World Requirements for 2013- Statistics for 2011 and Chen Z.R, Somogyi A.A, R eynolds .G, Bochner .F., 1991). As codeine is considered a \200\230weak \200\231 opioid, i t is understood that use was associated with a low incidence of adverse events when compare d to \200\230stronger \200\231 opioids. As a result, codeine had been the most commonly pr escribed opioid for treatment of mild-to- moderate pain in children (Conroy and Peden, 2001 ; de Lima et al., 1996 ). Codeine is available in an oral elixir form for oral administra- tion to infants and young children, and is oft en used in combination with acetaminophen i n a 10:1 ratio of acetaminophen (120 mg/5 ml) to codeine (12 mg/5 ml) (Reisine and Pasterna k, 1996 ). Recent reports have recognized that genetic factors play a major role in the dis position and analgesic eff ect of codeine (Madadi and Koren, 2008 ; Madadi et al., 2009 ), as the primary enzyme cytochrome P450 2D6 (CYP2D6 ) that O-demethylates codeine to morphine is highly polymorphic (Madadi and Koren, 2008 ; Olkkola et al., 1995 ; Yaster and Deshpand e, 1988 ). Functional polymorphisms in genes encod- ing for metabolic enzymes may lead to a ltered drug response with either a diminished, excessive, or absent metabolism. Th e enzyma tic activity of CYP2D6 is determined by measuring the urinary meta- bolic ratio, which is t he amount of unchanged drug in urine/amount of O -demethylated metabolite in urine, in comp arison with a speci- fi ed known probe substrate, such as dextromethorphan or des- brisoqui nie. Four phenotypic classifi cations have been established: poor metabolizers (PM), interm ediate (IM) or extensive metabo- lizers (EM) and ultrarapid metabolizers (UM) (Ito et al., 2010 ). Genetically, PM exhibit non-functional homozygotes CYP2D6 alle- les, IM displays on e functional allele and one decrease or null func- tion allele, EM have two functional alle les and UM possess more Polymorphisms in opioid transporters Th e P-gp transporter, which is encoded by the ATP-bin ding cassette B1 ( ABCB1 ) gene, is expressed in the BBB at the luminal mem- brane of the b rain endothelial cells where it effl uxes opioids from the brain to the blood (Xie et al., 1999 ). P-gp is a major determinant of opioid bioavailability in the CNS, as it is capable of limiting entry CHAPTER 42 principles of pain pharmacology in pediatrics 433 of opioids into the brain (Wandel et al., 2002 ). Th erefore, functional polymorphisms in A BCB1 may aff ect opioid disposition into the CNS (Kharasch et al., 2003 ; Lee et al., 2005; Xie et al., 1999 ; Zwisler et al., 2010 ). Th ere have been approximately 35 single nucleo tide polymorphisms identifi ed in the coding region of the ABCB1 gene and it has been sugge sted that, of these, homozygous 3435T/T car- riers undergoing chronic oral morphine exposur e may experience greater pain relief than homozygous wild-type 3435C/C (Campa et al., 2008 ); however, the impact of this variant on P-gp expression in the brain remains unknown. of many analgesic agents. Although there has been signifi cant progress, ongoing investigat ion and research is required to achieve a thorough understanding of the impact of developme ntal changes in drug disposition, metabolism and action, to enhance safe and eff ective pha rmacological management of pain in neonates, infants and children. References Agunod , M. , Yamaguchi , N. , Lopez , R. , Luhby , A. L. , and Glass , G. B. ( 1969 ). Correlative study of hydrochloric acid, pepsin, and intrinsic factor secretion in n ewborns and infants . Am J Dig Dis , 14 , 400 \200\223414. American Academy of Pediatrics. ( 1997 ). Use of codeine- and dextromethorphan-containing cough remedies in children. American Academ y of Pediatrics. Committee on Drugs . Pediatrics , 99 , 918 \200\223920. Anand , K. J. , A nderson , B. J. , Holford , N. H. , Hall , R. W. , Young , T. , Shephard , B. , et al . ( 2 008 ). Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: seconda ry results from the NEOPAIN trial . Br J Anaesth , 101 , 680 \200\223689. Analgesic therapy for pediatric patients Most pain medications, which include peripheral (e .g. non- steroidal anti-infl ammatory drugs (NSAIDs)) and centrally (e.g. morphine and rela ted opioid compounds) acting analgesics, are metabolized by several hepatic enzyme systems, including sulpha- tion, glucuronidation, oxidation, and cytochrome P450 subtypes (Tateishi et al., 1997 ). However, delayed functional maturation of these enzyme systems in neonates and infants signifi cantly infl u- ences the pharmacokinetic properties of these agents wi th addi- tional age-dependent changes in pharmacodynamic responses to analgesic drugs. Th e pharmacology of specifi c drug therapies are covered in more detail in other chapters, but are briefl y men- tioned here. Acetaminophen and NSAIDs, frequently used to treat mild to moderate pain, have antipyretic eff ects in infants and young children, and NSAIDs also hav e anti-infl ammatory eff ects (Brooks and Day, 1991 ; Maunuksela and Olkkola, 1993 ; Savvas and Brooks, 1991 ). With the exception of the neonatal period, the pharmacokinetics and ph armacodynamics of NSAIDs in young children are similar to adults (Berde and Sethna, 2002 ; Mak et al., 2011 ) and although there is the potential for gastrointestinal and renal toxic ities, the incidence in infants and older children is less frequent than observed in adults (Szer et al., 1991 ; see Anderson, Chapter 43, this volume). Anderson , B. J. , and Holford , N. H. ( 2008 ). Mechanism-based concepts of size and matur ity in pharmacokinetics . Annu Rev Pharmacol Toxicol , 48 , 303 \200\223332. Anderson , B. J. , and Palmer , G. M. ( 2006 ). Recent pharmacological advances in pediatric analgesics . Biomed Pharmacother , 60 , 303 \200\223309. 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