Chapter 17.pdf

PharmacologyIIP A R T17CHAPTERAn Introduction to the Intricaciesof Pharmacology in PediatricsBrian J. AndersonINTRODUCTIONChildren have been labeled “therapeutic orphans” in the past. 1 Theywere involved in all of the major therapeutic catastrophes that haveshaped modern drug development, 2,3 and as a consequence,pharmacokinetic (PK) and pharmacodynamic (PD) studies werenot performed in children for many years because it was consideredunethical. Unmonitored off-label use of medicines in children,extrapolated from adult data, has resulted in significant morbiditythat could have been avoided or minimized by appropriate testingin children. 4–7 This morbidity extended to the practice of pediatricanesthesia; neonates and infants given continuous-infusion epidu -ral analgesia suffered seizures attributable to high serum bupiva -caine concentrations, and these high concentrations were a directconsequence of a failure to appreciate reduced clearance in theneonatal age group. 5 Licensing laws that encourage pediatricstudies, 8,9 improvements in drug assay techniques that allow smallvolumesamples, and population modeling have dramaticallyaltered the scene for pediatric pharmacologic studies.PEDIATRIC DIFFERENCESSubsequent chapters detail current knowledge of pediatricanesthetic pharmacology. A recurring theme is the impact growthand development has on PK and PD in children. Disease type,presentation, and progression are different from those in adults.Pediatric anesthesiologists have always sought detailed insight ofthe drugs they use and have been at the forefront of such researchin order to best serve their patients. The effect of some of thesedifferences is highlighted in this chapter.Pharmacokinetic ConsiderationsAbsorptionThe majority of drugs used in anesthesia are administered eitherintravenously or through the lungs. Pulmonary absorption isgenerally more rapid in infants and children than in adults. 10 Thegreater fraction of the cardiac output distributed to the vessel-richtissue group (i.e., a clearance factor) and the lower tissue/bloodsolubility (i.e., a volume factor) also affect the more rapid wash-inof inhalational anesthetics in the younger age group. 11 Solubilitydetermines volume of distribution. An inhalational agent witha greater volume of distribution will take longer to reach a steadystateconcentration when delivered at a constant rate. Thesolubilities in blood of halothane, isoflurane, enflurane, andmethoxyflurane are 18% less in neonates than in adults. 12 Infants,with their decreased solubility, would be expected to have a shortertime to reach a predetermined FE/FI (fraction of expired gas–to–fraction of inspired gas) ratio because of a smaller volume ofdis tribution. Decreased solubility (i.e., smaller volume of dis -tribution) and size factors (i.e., faster physiologic processes)increase speed of onset. The increased minimum alveolar con -centration (MAC; i.e., a pharmacodynamic difference) and a ratedependentcardiac output set the scene for a relative overdose withhalothane. A lack of awareness of what constitutes bradycardia inneonates and infants completes the recipe. Age has little effect onthe solubility of the less-soluble agents nitrous oxide and sevo -flurane. 13 Reduced solubility and the reduced cardiac effects ofsevoflurane guaranteed its superiority over halothane for manyindications.The rate at which most drugs are absorbed when given by theoral route is slower in neonates and young infants than in olderchildren because gastric emptying is delayed; normal adult ratesmay not be reached until 6 to 8 months. 14–17 The larger relativeskin surface area, increased cutaneous perfusion, and thinnerstratum corneum in neonates increase absorption and exposureof topically applied drugs (corticosteroids, local anesthetic creams,antiseptics). Neonates have a tendency to form methemoglobinbecause they have reduced levels of methemoglobin reductase andfetal hemoglobin is more readily oxidized than adult hemoglobin.This, combined with increased absorption through the neonatalepidermis, resulted in reluctance to use lidocaine-prilocaine creamfor repeat use in this age group. 18,19

292 PART 2 ■ PharmacologyDistributionBODY COMPOSITION: Total body water and extracellular fluid(ECF) 20 decrease dramatically in the first year of life. Polar drugssuch as aminoglycosides and nondepolarizing neuromuscularblocking drugs (NMBDs) distribute rapidly into the ECF, but entercells more slowly. The initial dose of such drugs is consequentlyhigher in the infant than in older children and adults. The 90%effective dose (ED 90) of succinylcholine (mg/kg) is greater ininfants than in children and adults.Body fat, protein mass, and relative body proportions changedramatically over the first few years of life and similarly affectvolumes of distribution of drugs. These volumes will affect initialdose estimates. Reduction of propofol concentrations after induc -tion is attributable to redistribution. Neonates have low body fatand muscle content and, therefore, less propofol is apportioned tothese tissues. Delayed awakening occurs because central nervoussystem concentration remains higher than that observed in olderchildren as a consequence of reduced redistribution and reducedclearance.PLASMA PROTEINS: Albumen and α 1-acid glycoprotein (AAG)concentrations are reduced in neonates but are similar to those inadults by 6 months. Other endogenous compounds (e.g., biliru -bin) also compete with drugs for binding sites. AAG is an acutephasereactant that increases after surgical stress. This causes anincrease in total plasma concentrations for low to intermediateextraction drugs such as bupivacaine. 21 The unbound concentra -tion, however, will not change because clearance of the unbounddrug is affected only by the intrinsic metabolizing capacity of theliver. Any increase in unbound concentrations observed duringlong-term epidural administration is attributable to reducedclearance rather than AAG concentration. 22Total bupivacaine concentrations increase in the first 24 hoursafter surgery in neonates given analgesia by continuous epiduralinfusion. This increase is attributable to an increase of AAG, whichis an acute-phase reactant. This increase, combined with reportsof seizures in infants given epidural bupivacaine infusion, has ledto recommendations to stop epidural infusion at 24 hours.However, it is the unbound bupivacaine that is responsible for theeffect and this unbound concentration may not change, implyingthat the infusion could be run for a longer duration. Clearance isthe key parameter. Unfortunately, clearance is associated with alarge between-subject variability, meaning that unbound bupiva -caine concentrations may continue to rise in those individualswith very low clearance. Infusion rates for continuous amide localanesthetic regional blockade may be safely predicted based onclearance and its variability estimates and these infusions may berun for longer than 24 hours.Drug MetabolismThe main routes by which drugs and their metabolites leave thebody are the hepatobiliary system, the kidneys, and the lungs. Theliver is the primary organ for clearance of most drugs. Nonpolar,lipid-soluble drugs are converted to more-polar and water-solublecompounds. Water-soluble drugs are excreted unchanged in thekidneys by glomerular filtration and/or renal tubular secretion.Many of these processes are immature in the neonate and maturewithin the first year of life.HEPATIC ELIMINATION: The mixed function oxidases (phase I)are reduced. Some appear to be switched on by birth, whereas inothers, birth is necessary but not sufficient for the onset of ex -pression. 23,24 Cytochrome P (CYP) 2E1 activity surges after birth, 25CYP2D6 becomes detectable soon thereafter, the CYP3A4 andCYP2C families appear during the first week, whereas CYP1A2 isthe last to appear. 26 Neonates are dependent on the immatureCYP3A4 for levobupivacaine clearance and CYP1A2 for ropiva -caine clearance, dictating reduced epidural infusion rates in thisage group. 5,27,28If a drug has a high extraction ratio, then intrinsic clearancemay be very much greater than liver blood flow, and in thesesituations, hepatic clearance is primarily determined by liver bloodflow characteristics. Fentanyl clearance (CYP3A4) is 70 to 80% ofadult values in term neonates and, standardized to a 70-kg person,reaches adult values within the first few weeks of life. Omphalo -coele repair may be associated with raised intra-abdominal pres -sure (a covariate effect), resulting in reduced fentanyl clearanceattributable to both decreased hepatic blood flow and reducedhepatic function (decreased fentanyl extraction).Some phase II pathways are mature in term neonates atbirth (sulfate conjugation), whereas others are not (acetylation,glycina tion, glucuronidation). 29 Covariate effects contribute toclearance variability. Maturation of clearance (UGT2B7) occursmore quickly in infants undergoing noncardiac surgery than inthose receiving morphine after cardiac surgery. 30 Similarly,clearance of propofol (UGT, CYP2B6, CYP2C9, CYP2A6) wasreduced after cardiac surgery in children admitted to a pediatricintensive care unit. 31RENAL ELIMINATION: Drugs and their metabolites are excretedby the kidneys by two processes—glomerular filtration andtubular secretion. Glomerular filtration rate (GFR) is only 10%that of mature value at 25 weeks, 35% at term, and 90% of the adultGFR at 1 year of age. 32 Aminoglycosides are almost exclusivelycleared by renal elimination, and the maintenance dose ispredicted by postmenstrual age because it predicts the time courseof development of renal function. 33Immaturity of clearance pathways can be used to our advantagewhen managing apnea after anesthesia in the premature nurserygraduate. N 7-Methylation of theophylline in the newborn toproduce caffeine is well developed, whereas oxidative demethyla -tion (CYP1A2) responsible for caffeine metabolism is deficientand develops over the ensuing months. Theophylline is effectivefor the management of postoperative apnea in the prematureneonate, partly because it is a prodrug of caffeine, which is effec -tive in controlling apnea, in this age group and caffeine can be onlyslowly cleared by the immature kidney.EXTRAHEPATIC ELIMINATION: Many drugs are metabolized atextrahepatic sites. Remifentanil (and atracurium to some extent)are rapidly broken down by nonspecific esterase in tissue anderythrocytes. Clearance (L/h/kg) is increased in the youngerchildren, 34–38 but this may be attributable to size. The half-life offormation of paracetamol by plasma esterase hydrolysis has beeninvestigated. 39 Hydrolysis half-life was the same in all age groupswhen standardized for size using allometry.MetabolitesMany drugs have active metabolites that contribute to effect. Ex -amples include norketamine from ketamine, 40 4-hydroxydiclofenac

CHAPTER 17 ■ An Introduction to the Intricacies of Pharmacology in Pediatrics 293from diclofenac, 41 O-demethyl tramadol from tramadol, 42 andmorphine 6-glucuronide (M6G) from morphine. 43Contributions to both the desired effect (analgesia) and theundesired effects (nausea, respiratory depression) of M6G are thesubject of clinical controversy. 44 M6G PD has been explored inadults using pupil size as a measure of central opioid effect, butresults are confusing. Effect compartment modeling suggested thatM6G was apparently 22 times less potent than morphine. 45,46Contrarily, other authors have suggested that M6G was four timesmore potent than morphine in producing meiosis, 47 half as potentas an analgesic, 48 and with reduced respiratory depressive effects. 49StereoisomerismSome drugs commonly used in anesthetic practice are racemiccompounds, and activity may reside in only one isomer. There isincreasing interest in these isomers (e.g., levobupivacaine, S(+)ketamine) because they may have a greater potency or safetyprofile. 50,51 Interpretation of the pharmacokinetics of racemiccompounds may not be straightforward because clearance of oneenantiomer may be greater than that of the other, whereas thera -peutic activity resides only in one enantiomer (e.g., ibuprofen). 52Enantiomeric PK differences are best explained by stereoselectiveplasma protein binding and metabolism. 53PharmacogenomicsPharmacogenomics (PG) is the investigation of variations of DNAand RNA characteristics as related to drug response that incor -porates both PK and PD. There is large between-individual PKvariability that is contributed to by polymorphisms of the genesencoding for metabolic enzymes. 54 Genetic variability influencingplasma cholinesterase activity and its influence on succinylcholineis a well-known example. Another example is the CYP2D6 singlenuclear polymorphism (SNP) that is inherited as an autosomalrecessive trait. Homozygous individuals are deficient in the meta -bolism of a variety of important groups of drugs—β adrenorecep -tor blocking agents, antidepressants, neurolept agents, and opioids.Poor metabolizers have reduced morphine production fromcodeine. 55,56 Tramadol is also metabolized by O-demethylation inthe liver (CYP2D6) to O-desmethyl tramadol (M1) and the M1metabolite has a µ-opioid affinity approximately 200 times greaterthan that of tramadol.A SNP is important only if it contributes greater than 50%metabolism and has an active metabolite, a steep dose-responserelationship, and a narrow therapeutic index. These polymor -phisms may have little impact during the neonatal period whenmetabolism is developmentally limited. 42,57–59PG differences also have an impact on PD. Candidate genesinvolved in pain perception, pain processing, and pain manage -ment like opioid receptors, transporters, and other targets of phar -macotherapy are under investigation. These genetic differences(G118 allele) may explain why some patients need higher opioiddoses and the adverse effects profile may be modified by thesemutations. 60 Some genes (e.g., fetal hemoglobin) are expressedmuch more in early life than in adults, and gene switching maymean a drug is effective at one age and not another.In adults, gene testing may prove invaluable for reducingadverse drug effects. 61,62 However, most drug responses involvea large number of proteins regulated by multiple genes. Genotypedoes not equate with phenotype; environment, concomitantthe rapy, and disease have impact, and allele prevalence variesamong ethnic groups. The situation in children is more complex.Allelic variants may remain unchanged throughout life, but trans -crip tomonic, proteomic, and metobonomic data in children arecontinuously changing throughout development.Pharmacodynamic ConsiderationsChildren’s responses to drugs have much in common with theresponses in adults. 63 The perception that drug effects differ inchildren arises because the drugs have not been adequately studiedin pediatric populations who have size- and age-related effects aswell as different diseases.There are, however, situations in which age-related PD changeshave been described. Classic examples are MAC age-relatedchanges of anesthetic inhalation agents and NMBD effects. Cal -cium is an effective inotrope in neonates because cardiac calciumstores in the endoplasmic reticulum are reduced. Amide localanesthetic agents induce shorter block duration and require a largerweight-scaled dose to achieve similar dermatomal levels whengiven by subarachnoid block to infants. This may be caused, in part,by myelination, spacing of nodes of Ranvier, and length of nerveexposed as well as size factors. Inhibitory gamma-aminobutyricacid (GABA) receptors, which may not reach maturity until 10years of age, influence the response seen after benzodiaze pines inchildren. The coagulation cascade is immature at birth, influencinganticoagulant effect. There is an age-dependent ex pression of intes -tinal motilin receptors and the modulation of antral contractions inneonates. Prokinetic agents may not be useful in very preterminfants, partially useful in older preterm infants, and useful in fullterminfants. Catecholamine release and response to vasoactivedrugs vary with age.STATE OF THE ARTImproving the PharmacopoeiaThe introduction of a new drug onto the market is extremelycostly for the pharmaceutical industry. Despite this cost, drugs ofvalue to pediatric anesthesia continue to materialize. Improvedlicensing regulations in both Europe and the United States ensurethat these compounds are investigated in children. Our manage -ment of the neuromuscular junction, for example, will improvewith the introduction of sugammadex.The benefits of pure compounds are recognized. The S(+)isomer of ketamine is now widely used and single-isomer nonsteroidalanti-inflammatory drugs (NSAIDs) are appearing for thetreatment of acute pain that may have fewer adverse effects thantraditional NSAIDs. Nitroxyparacetamol (nitroacetaminophen) isa new nitric oxide–releasing version of paracetamol with analgesicand anti-inflammatory properties. Potency is enhanced, and ani -mal models suggest reduced liver damage in overdose situations.Xenon continues to be investigated as an anesthetic agent.Dexmedetomidine, licensed only for adult sedation in the inten -sive care unit, has found a niche with pediatric sedation. Investi -gations in children by clinical anesthesiologists may result inbroadening of the original narrow indication. Old therapies havefound new roles. Intralipid is now used for the management oflocal anesthetic toxicity. Exploration of the PK and PD of old drugssuch as ketamine should refine clinical use. Drug combinationsoften improve the effect seen from one drug alone.

294 PART 2 ■ PharmacologyDefining the Required EffectThis target concentration strategy is a powerful tool for deter -mining clinical dose. 64 Anesthesia lends itself to this strategy inwhich we have clearly defined target effects and monitoring ofadverse effects. The key to this approach be able to measure sucheffects. We excel in the fields of neuromuscular, evoked potentials,anesthesia depth, and cardiovascular monitoring. These toolscontinue to be refined and adapted for even the premature neo -nate. Measurement of target concentration in which effect is morecrudely measured is routine for inhalational agents. Anesthesiahas advanced from observing Guedel’s stages 65 and a finger on thepulse. The assessment and measurement of pain and its manysubtleties, however, continue to be a barrier to effective analgesia,although advances are progressive. 66Population ModelingPediatric anesthetists have embraced the population approach forinvestigating PK and PD. This approach is achieved throughnonlinear mixed effects models. They provide a means to studyvariability in drug responses among individuals representative ofthose in whom the drug will be used clinically. Traditionalapproaches to interpretation of time-concentration profiles (e.g.,naive and standard two-stage approaches) relied on “rich” datafrom a small group of subjects. By contrast, mixed effects modelscan be used to analyse “sparse” (two or three samples) data froma large number of subjects. Sampling times are not crucial forpopulation methods and can be fitted around clinical proceduresor outpatient appointments. However, optimal sampling schedulescan be determined through previous information and the FisherInformation Matrix. 67–69 Sampling time bands rather than exacttimes are equally effective 70 and allow flexibility in children.Mixed effects models are “mixed” because they describe thedata using a mixture of fixed and random effects. Fixed effectspredict the average influence of a covariate such as weight as anexplanation of part of the between-subject variability in a para -meter like clearance. Random effects describe the remainingvariability between subjects that is not predictable from the fixedeffect average. Explanatory covariates (e.g., age, size, renalfunction, sex, temperature) can be introduced that explain thepredictable part of the between-individual variability. Nonlinearregression is performed by an iterative process to find the curve ofbest fit by maximizing the likelihood. 71,72Interpretation of truncated individual sets of data or missingdata is also possible with this type of analysis, rendering it usefulfor pediatric studies. The appropriate number of patients for apopulation study is difficult to determine and will depend on thenumber of covariates under examination. 73 Population modelingalso allows pooling of data across studies to provide a single robustPK analysis rather than comparing separate smaller studies thatare complicated by different methods and analyses.FUTURE DIRECTIONSIt is not possible to predict the future. The Bell telephone was onceconsidered such an advance that every town would eventually haveone. Missiles were thought to be the future method of maildelivery and the US Postal Service sent 3,000 letters via missilefrom Virginia to Florida in 1959. Lessons from the past suggestthat the forces driving innovation and change are not alwayspredictable. The most popular analgesics in children, paracetamoland the NSAIDs, were derived almost by accident. Althoughsalicylic acid was used by ancient Egyptians, attempts to revive itsuse in the 18th century failed. Marketing by Bayer took off onlybecause of surreptitious use by local dentists after aspirin charac -terization. Paracetamol and indomethacin were byproducts of coaltar, the substrate that supported the German dye industry, esta -blished Prussian economic power, and caused the loss of GreatBritain’s jewel in the crown, India. 74Future anesthetic benefits for children will come from incen -tives for drug development and investigation (regulatory climate),PKPD understanding, 75 target concentration approaches, 76 stereoi -somer and circadian rhythm investigations, 50–52,77 and understand -ing of metabolites. Investigation of covariate effects influencingPK (e.g., pharmacogenetics 78 ) and PD (e.g., disease processes,maturation) will reduce variability and allow tailoring of drugs toindividual need. 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