1437CHAPTER 122 Principles of Drug Disposition reaches adult levels by puberty The higher fluid composition of younger children indicates that they could have higher volumes of distribution for hydrop[.]
CHAPTER 122 Principles of Drug Disposition TABLE a 122.5 Fluid Compartment Size as a Function of Age Total Body Water Extracellular Fluid Intracellular Fluid Fetus ,3 mo 92 65 25 Term gestation 75 35–44 33 4–6 mo 60 ≈23 37 12 mo 26–30 Puberty 60 ≈20 40 50–60 20 40 Adult a Presented as percentage of body weight reaches adult levels by puberty The higher fluid composition of younger children indicates that they could have higher volumes of distribution for hydrophilic drugs, including salicylate, digoxin, and phenytoin.95 The drugs that extensively distribute into extracellular fluid require higher doses per kilogram body weight to achieve comparable drug concentrations Furthermore, total body fat can be as low as 1% in the premature infant compared with 15% in a full-term infant.7 Disease-Dependent Changes Affecting Drug Distribution Critical illness affects all of the major organ systems—the immune, cardiac, hepatic, renal, and circulatory systems—and can lead to multiorgan dysfunction.7 Changes in blood pH, hypoproteinemia, increased hydrostatic pressure, concomitant medications, and increased capillary permeability are a few examples that can have profound effects on drug distribution.8–10 In critically ill patients, fluid volume status must be assessed for each patient Blood volume is composed of red blood cell volume and plasma volume Hypervolemia leads to edema, hypertension, and cardiovascular changes Hypovolemia can lead to poor organ perfusion and damage as well as shock Intravascular hypovolemia has multiple etiologies, including capillary leak, hemorrhage, gastrointestinal fluid losses (e.g., vomiting, diarrhea), renal dysfunction, and burns For acute bleeds or loss of fluids in the hypovolemic state, the volume of both the red blood cells and plasma are reduced Fluid resuscitation is commonly administered to patients with low blood volume to restore normal cardiovascular physiology However, transfusions are restricted to patients with active bleeds or severe anemia Therefore, fluid resuscitation can result in hypervolemic anemia or a large plasma volume with little to no change in red blood cell volume and therefore an overall decrease in hemoglobin concentration Any accumulation in extravascular fluid, such as ascites, will result in development of an additional reservoir for drugs and increase volume of distribution, especially for hydrophilic compounds Ascites has multiple etiologies, including bile duct trauma, Budd-Chiari syndrome, congestive heart failure, and liver failure.96 In the case of liver failure, the concentration of plasma-binding proteins decreases enough to alter the hydrostatic pressure in the vasculature, promoting shifts in fluid out of the vasculature and into the abdominal space.97 Other disease states can also affect plasma protein concentrations; for instance, AAG concentrations can increase during times of inflammation, infection, or cancer.98 1437 Extracorporeal membrane oxygenation (ECMO) is another medical intervention that affects drug pharmacokinetics The ECMO circuit requires a large volume of blood to prime the tubing and circuit, thus, increasing the total amount of blood volume For hydrophilic drugs, this extra volume of blood and plasma can increase the volume of distribution, as was shown for drugs such as gentamycin and vancomycin.99–101 For lipophilic drugs, such as fentanyl and midazolam, volume of distribution can be increased, as there is a potential that the drug can be sequestered by the circuit tubing.102,103 In critically ill patients, changes in hemoglobin and hematocrit are common Blood volume is composed of red blood cell volume and plasma volume Hemoglobin and hematocrit are both values representing the red blood cell concentration; therefore, they are dependent on the amount of red blood cells compared to the total plasma volume A reduction in red blood cell concentration or volume or an increase in plasma volume can result in anemia Overall fluid volume must be assessed for each patient because hypervolemia can lead to edema, hypertension, and cardiovascular changes, while hypovolemia can lead to poor organ perfusion and damage as well as shock Intravascular hypovolemia has multiple etiologies, including capillary leak, hemorrhage, gastrointestinal fluid losses (e.g., vomiting, diarrhea), renal dysfunction, and burns For acute bleeds or loss of fluids in the hypovolemic state, the volumes of both red blood cells and plasma are reduced Fluid resuscitation is commonly administered to patients with low blood volume to restore normal cardiovascular physiology However, transfusions are restricted to patients with active bleeds or severe anemia Therefore, fluid resuscitation can result in a hypervolemic anemia or a large plasma volume with little to no change in red blood cell volume and therefore an overall decrease in hemoglobin concentration These potential volume changes will alter the pharmacokinetic parameters, such as an increase in volume of distribution as hydrophilic drugs move with water content or with lowered red blood cell binding of tacrolimus These changes affect drug disposition Metabolism Metabolism refers to the body’s process of transforming the chemical structure of the administered drug to facilitate detoxification and elimination Usually, this biotransformation process uses the addition of a more polar chemical group, such as –OH or –NH2, or the removal of hydrophobic groups, thereby increasing water solubility The liver is the predominant organ for drug metabolism, but the intestine can also metabolize drugs before they reach the liver First-pass metabolism, impacted by both hepatic and intestinal enzymes, is critical in the determination of the bioavailability of orally administered medications Other organs, such as the blood and lungs, can also metabolize drugs to a lesser extent Metabolic enzyme proteins are classified by their family denoted by an Arabic number, subfamily denoted by a capital letter, and gene isoform denoted by an Arabic number.104 However, each enzymatic pathway has its own maturational profile specific to the organ in which it is located and its own substrate specificity (Table 122.6) Genetics plays a large role in the activity of enzymes Patients expressing the normal genotype are known as extensive metabolizers Altered genotypes are denoted by an asterisk and an Arabic numeral and code for either poor metabolizers or ultra-rapid metabolizers Poor metabolizers can either have an altered protein or absent protein, leading to slow or no metabolism Ultra-rapid metabolizers have a higher expression and activity of enzyme that leads to a faster and more thorough metabolism 1438 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology TABLE 122.6 Representative Hepatic Enzyme Substrates Enzyme Representative Substrates Phase I CYP1A2 Acetaminophen, caffeine, theophylline, warfarin CYP2B6 Methadone, tramadol, valproic acid CYP2C9 Phenytoin, S-warfarin, diclofenac CYP2C19 Diazepam, omeprazole, propranolol, voriconazole, lansoprazole CYP2D6 Clozapine, codeine, flecainide, haloperidol, oxycodone CYP2E1 Acetaminophen, enflurane, halothane CYP3A Cyclosporine, diazepam, methadone, midazolam, spironolactone, and tacrolimus Phase II UGTs Acetaminophen, bilirubin, chloramphenicol, dextromethorphan, morphine N-acetyltransferase-2 (NAT2) Caffeine, clonazepam, hydralazine Methyltransferase Catecholamines, captopril, serotonin Sulfotransferases Acetaminophen, bile acids, chloramphenicol, dopamine UGTs, Uridine 59-diphosphate glucuronosyltransferases Drug-drug interactions (DDIs) are another issue to consider aside from age- and disease-dependent changes in metabolism Polypharmacy is common in critically ill children; consequently, the potential for interactions between concomitant medications needs to be monitored Enzyme activity can be affected by inhibition or induction Enzyme expression can be increased by induction, meaning a higher abundance of metabolizing enzymes and therefore higher clearance and lower concentrations of the drugs metabolized by these enzymes A few drugs are known to induce enzyme expression, including rifampicin, phenobarbital, phenytoin, and carbamazepine Over-the-counter medications, such as St John’s Wort, also induce enzyme expression Finally, environmental and nutritional factors can act as enzyme inducers, such as cigarette smoke and charcoal-broiled meat, which induce CYP1A2 Enzyme inducers act within the cell nucleus by promoting transcription and translation of proteins Consequently, the maximum effect of enzyme induction will be observed to days after the start of the inducing agent The exact time to reach maximum effect will depend on the affected enzyme and its turnover rate These interactions are important, as these enzymeinducing drugs can act as autoinducers For example, carbamazepine induces CYP3A4 but is also metabolized by the same enzyme As such, when dosing carbamazepine, a dose increase might be warranted within to weeks after initiating therapy, as its clearance will likely increase and concentration will decrease due to induction Contrary to the relatively long time course for induction, inhibition can be observed within the first dosing interval, where enzyme metabolism is blocked, resulting in decreased clearance Inhibition can either be reversible or irreversible—the main difference is the capability of the inhibitor to dissociate from the enzyme Irreversible inhibition is characterized by the inhibitor covalently binding to the active site Many poisons are irreversible inhibitors, such as sarin The oncology agent, 5-fluorouracil, is another example of irreversible inhibition Penicillin is also an example of irreversible inhibition, as it binds irreversibly in the cell wall of a bacterium to inhibit its growth, killing the bacterium Reversible inhibition is further broken down into competitive, uncompetitive, or noncompetitive inhibition Noncompetitive inhibition involves the inhibitor binding to the enzyme at a location other than the active site, which can cause conformational changes and/or reduce the activity of the enzyme Nonnucleoside reverse transcriptase inhibitors are examples of noncompetitive inhibition Uncompetitive inhibitors require substrate to bind to the enzyme before the inhibitor can bind and reduce the catalytic activity of the enzyme Competitive inhibition is the most common form of inhibition seen with drug-drug interactions It involves two compounds competing for the active site on an enzyme Increasing substrate concentrations relative to inhibitor concentrations will reduce the effect of inhibition An example of inhibition is the coadministration of ranitidine and midazolam Ranitidine inhibits CYP3A4 and therefore hepatic metabolism of midazolam, resulting in higher systemic concentrations of midazolam In general, clinicians need to be aware of clearance pathways and the possibility of drug-drug interactions, as they could result in reduced efficacy, higher toxicity, or, conversely, could be used to improve efficacy or toxicity profiles Hepatic Phase I Metabolism Approximately 70% of the top 200 drugs prescribed in the United States are cleared by hepatic metabolism.105 Phase I metabolism converts the parent compound into metabolites by oxidation, reduction, or hydrolysis reactions The enzymes primarily responsible for phase I reactions are within the cytochrome P450 (CYP) class of proteins Of these, phase I oxidative enzymes account for 78% of the drugs that are metabolized via hepatic enzymes.105 In adults, the most common hepatic CYP family and subfamilies are the 3A, 2C, 1A, 2E, 2D, and 2B, which account for 68% of all hepatic enzymes.106 However, each of these enzymes exhibits its own unique ontogeny pattern that affects drug clearance throughout development CYP3A e most abundant hepatic CYP enzyme is a member of the Th CYP3A family, accounting for approximately 30% of hepatic enzymes The three principal isoforms are 3A4, 3A5, and 3A7 Approximately 37% of the top 200 drugs are metabolized by this family, including midazolam (and most benzodiazepines to some extent), barbiturates, sildenafil, dexamethasone, and endogenous substrates such as testosterone and other steroids.105 CYP3A7 is the predominant isoform expressed during gestation, with expression over 100-fold higher than either 3A4 or 3A5.107 At birth, the predominant CYP3A isoform transitions from 3A7 to 3A4 While the expression of CYP3A7 declines, the expression of CYP3A4 increases by over 200-fold until it reaches mature adult levels at approximately to 12 months after birth.107,108 In contrast to these two isoforms, the expression of 3A5 remains relatively stable from birth throughout adulthood.107,109 The expression of 3A5 is CHAPTER 122 Principles of Drug Disposition influenced by genetic polymorphisms, in which some alleles code for nonfunctional protein, leading to large intraindividual variability in expression.105 Therefore, the expression of 3A4 is anywhere between 2- to 50-fold higher than that of 3A5.107,110 Overall, clearance of substrates metabolized through the 3A pathway is lower in neonates than in children and adults CYP2C e second most abundant hepatic phase I enzymes are in the Th CYP2C family, accounting for approximately 20% of all hepatic enzymes.106 The main isoform is 2C9, followed by 2C19 Both isoforms are detectable at very low to almost undetectable levels during gestation.107,111 The expression of 2C9 increases after birth to levels comparable to adults In vitro studies show that the probe substrate for 2C9, diclofenac, is metabolized at very low levels in fetal liver tissue but at comparable levels in children and adults.107,111 The expression of 2C19 also increases after birth, but the expression and activity in children is higher than that of adults.107 Applying these in vitro results to clinical scenarios suggests that drugs metabolized by 2C9 will have little to no difference in children compared with adults, but neonates might have lower clearance In contrast, drugs metabolized through 2C19 might have a lower clearance in neonates, but children will have a higher clearance than adults This phenomenon can be observed with voriconazole, in which the clearance in children is threefold higher than that of adults and thus requires a higher weight-based dosing.112,113 Higher clearances are also observed in children compared with adults for proton pump inhibitors, such as lansoprazole.114 CYP2D6 YP2D6 accounts for approximately 2% of hepatic enzyme expresC sion It is present at very low to almost undetectable levels during the first half of gestation but increases during the last few weeks until birth.115 The time that it takes to mature to adult levels varies in the literature from week to year.115,116 It was the first family of enzymes that had genetic polymorphisms associated with pharmacokinetic and pharmacodynamic outcomes Codeine is a prodrug that needs to be metabolized by CYP2D6 to be converted to morphine, the active form Poor metabolizers are unable to break down codeine sufficiently enough to produce an effect, while ultrarapid metabolizers break it down rapidly, forming more morphine than expected and leading to potentially life-threatening toxicities Codeine should be avoided in both populations owing to the lack of efficacy or increased risk of toxicity Otherwise, codeine is most likely ineffective and has variable efficacy in neonates owing to the low expression of CYP2D6 and the lack of confidence in the maturational profile of when it reaches adult expression Aside from the normal metabolizers, there are genetic variants that code for 2D6 proteins that metabolize very slowly, resulting in ineffective treatment, and that metabolize very quickly, resulting in increased effectiveness and toxicity.105 CYP2B6 YP2B6 accounts for less than 1% of hepatic enzyme expression C but metabolizes over 90 drugs, including bupropion, propofol, and efavirenz Protein expression and activity is very low in neonates but increases over the first year of life until it reaches adult levels.117 Of all the CYP 450 enzymes, CYP2B6 is one that is associated with the most polymorphisms.105 Many of these alleles decrease enzyme expression and activity Since these alleles are still 1439 being elucidated, careful monitoring should be taken when administering drugs metabolized by this pathway Other ther hepatic enzymes important to drug metabolism in children O include CYP1A2, 2A6, and 2E1 All three of these enzymes are undetectable in fetal liver tissues but are detectable in neonatal liver samples and reach adult levels by approximately year of age CYP1A2 is responsible for caffeine and theophylline metabolism CYP2A6 is responsible for metabolism of dexmedetomidine and 2E1 for substrates such as acetaminophen Substrates of these enzymes will have low clearance in neonates, which will increase over the first year of life until reaching adult levels, as is observed with dexmedetomidine and caffeine.118,119 Acetaminophen is metabolized by both phase I and phase II pathways, with CYP2E1 being the predominant phase I metabolizing enzyme and producing the toxic metabolite N-acetyl-p-benzoquinone imine, which produces hepatotoxicity Due to maturational changes, production of this toxic metabolite is reduced in neonates, but is varied, leading to differences in toxicologic implications of acetaminophen dosing Hepatic Phase II Metabolism Phase II, or conjugation, reactions convert the parent compound by attaching a small hydrophilic group, such as a glucuronic acid, sulfate, amino acid, glutathione, and so on Drugs predisposed to undergo conjugation are those with functional groups—such as a hydroxyl, amino, or carboxyl group—which are there originally on the parent drug or acquired through phase I metabolism It is important to note that it is not necessary for a drug to go through phase I metabolism before it undergoes phase II Developmental profiles of phase II metabolic enzymes have not been as extensively studied as phase I enzymes Hence, data on maturation of most of these pathways is limited Glucuronidation is the most common conjugation pathway, accounting for up to 35% of all phase II reactions, and is carried out by uridine 59-diphosphate glucuronosyltransferases (UGTs).120 It is involved in metabolism of approximately 10% of the top 200 prescribed drugs, as well as bilirubin, steroids, and other endogenous compounds.121 In the pediatric population, it is the primary pathway for important and frequently administered drugs, such as acetaminophen, morphine, lorazepam, furosemide, and valproic acid.122 There are two main families, the UGT1 and UGT2 families, with a total of and 10 functional isoforms, respectively.120 Due to overlapping specificities of the UGT isoforms, it is difficult to determine exact maturation profiles using probe substrates However, many clinical examples demonstrate that glucuronidation activity is low at birth and in infants yielding low clearances compared with that of adults One very well-known example is chloramphenicol, which, if administered to newborns, especially premature newborns, accumulates and produces gray baby syndrome Another example is morphine, for which studies have demonstrated very low conversion of morphine to its metabolites, M3G and M6G, in neonates compared with children.123–125 Additionally, pharmacokinetic analyses have established a relationship between postnatal age and morphine clearance, with clearance increasing from preterm neonates to full-term neonates to infants and children.124,126 Furthermore, analyses have established that morphine clearance is not fully mature until after year of age.127,128 This trend toward lower 1440 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology glucuronidation activity and enzyme abundance is also observed with other substrates (tramadol, acetaminophen, propofol, and so on) across all UGT isoforms.122,129 Intestinal Metabolism The intestine was not identified as a major clearance organ until the 1990s, when cyclosporine metabolism still occurred during the anhepatic phase of liver transplantation, demonstrating that the intestines must have metabolic capacity.130 Today, the intestine is known as a critical component of first-pass metabolism since it is the first barrier into the systemic circulation encountered by exogenous compounds after oral administration Follow-up studies characterized the enzyme abundance in adult intestines and revealed that, in adults, more CYP3A4 is expressed in the intestines than in the liver (per milligram of tissue and % expressed).131,132 However, pediatric intestinal enzyme characterization remains incomplete One in vitro study suggested that pediatric CYP3A4 mRNA expression is higher in children younger than years of age compared with older children.133 Conversely, these results were not supported by another study that measured CYP3A4 protein levels, and 6b-OH testosterone levels were lower in neonates and younger children than in children older than 12 years.134 Yet, oral midazolam, a CYP3A4 probe, demonstrates a bioavailability of ,36% in adults but a bioavailability between 15% and 32% in children.135–138 Another example is voriconazole, which has a bioavailability of greater than 90% in adults but only 44% to 66% in children.112,139,140 Studies have modeled intestinal metabolism and demonstrated that intestinal first-pass metabolism could be the reason for this age-dependent difference.141 Therefore, it is important to understand the potential impact of age-dependent first-pass hepatic and intestinal metabolism Elimination The final step of the pharmacokinetic profile is elimination The two main organs of elimination are the liver and kidneys, which account for approximately 95% of elimination.105 There are multiple methods in which a drug can be eliminated Hepatic elimination uses the biliary system to expel drugs into the bile and, consequently, into the feces Renal elimination is able to clear the blood of both unchanged drug and metabolites that have been secreted from the liver back into the systemic circulation Each route of elimination has its own maturational profile and impacts based on disease state Renal Excretion By 36 weeks’ gestation, nephrogenesis is complete, and the glomerulus is the same as that of adults.142 Accordingly, for full-term neonates, renal clearance is dictated by renal blood flow and protein binding At birth to the end of the first week of life, only 6% to 10% of cardiac output is distributed to the kidneys compared with 20% to 25% in adults.143 This corresponds to a glomerular filtration rate (GFR) of approximately 20 to 55 mL/ per 1.73 m2 in full-term neonates.144,145 The GFR reaches 90% of adult values at approximately year of life, with complete maturation occurring between to years of life.146,147 Normal adult GFR ranges from 90 to 120 mL/min per 1.73 m2, but GFR in children older than years ranges between 113.6 and 140.6 mL/min per 1.73 m2, which correlates to a GFR 14% to 21% higher than that of adults.148 This could possibly be explained owing to the fact that kidney size normalized as a percentage of body weight is approximately twofold larger in children compared with adults.149 Conversely, for preterm neonates, renal nephrogenesis is incomplete at birth, and GFR is correlated with postmenstrual age (gestational age plus postnatal age) and can be as low as to mL/min per 1.73 m2 Renal function of infants born prematurely was only 65% and 85% of that compared with healthy full-term infants at months and 24 months, respectively.150,151 Children born prematurely not achieve renal function comparable to those of children born fullterm until approximately years of age.150,152 Owing to the sensitivity of the kidney to hypoxia and is chemia, renal dysfunction is common in the pediatric intensive care setting and many disease-specific pathophysiologic changes can affect renal function In preterm neonates, acute renal failure could be caused by multiple factors, including maternal nonsteroidal antiinflammatory drug usage, intubation at birth, catheterization, mechanical ventilation, low APGAR (appearance, pulse, grimace, activity, and respiration) score, respiratory distress, and administration of ibuprofen Concomitant medications can also alter renal function, such as aminoglycosides and amphotericin B.153,154 ECMO and hypothermia can reduce renal clearance of antimicrobial drugs, such as vancomycin and cefepime.155,156 If renal function decreases enough, renal replacement therapy might be implemented This affects clearance of drugs depending on the type of renal replacement therapy All stages of renal dysfunction can affect drug pharmacokinetics Renal dysfunction impacts the binding of acidic drugs to albumin owing to the increased competition of accumulated organic acids and uremia-induced structural changes altering albumin binding affinity.157 For critically ill children with acute respiratory failure, renal clearance of midazolam glucuronide metabolite is reduced.158 For subjects with chronic renal failure, the accumulation of toxins induces chronic inflammation, which decreases the expression and activity of hepatic enzymes and transporters.159 Overall, renal insufficiency can decrease overall drug clearance for those drugs that have more than 30% of the dose eliminated unchanged through the kidneys and result in up to a 70% decrease in nonrenal clearance from drugs cleared via hepatic metabolism.157,159 Biliary Excretion The liver anatomy and histology are structured so that blood from the portal vein and hepatic artery transport substrates to the hepatocytes of the liver After uptake into the hepatocyte, the drug can undergo phase I or phase II metabolism Parent drug or the resulting metabolites can then be excreted back into the sinusoid leading to the central vein and, eventually, to the inferior vena cava or into the bile canaliculi leading to the bile ducts Bile is produced in the liver, stored in the gallbladder, and released into the small intestine The maturation of biliary excretion is tied to bile salt formation, which was discussed earlier in the Enteral Absorption section However, reduced bile salt formation or changes in the composition of bile salts could affect the types of drugs excreted into bile Disease states, such as biliary atresia, cholestasis, and liver failure, and some drugs, such as ceftriaxone, will all negatively impact biliary excretion Thus, care must be taken when selecting medications for these populations Ceftriaxone, a commonly used third-generation cephalosporin, is associated with biliary sludge in neonates and infants Owing to this problem and its interaction with calcium prompting precipitation, ceftriaxone should not be administered to neonates (#28 days old), especially if born prematurely, or those with hyperbilirubinemia CHAPTER 122 Principles of Drug Disposition The movement of drugs and metabolites from the intracellular hepatocyte into the bile is via efflux transporters There is limited data currently about the ontogeny of transporters However, one of the most common transporters is p-glycoprotein (P-gp) The abundance of P-gp is very low at birth and increases during the first few months of life until it reaches adult levels by years of age The clinical relevance of this maturation profile is unknown, however, because transporters are promiscuous Even if a substrate has a higher affinity for a specific transporter, if that one is unavailable, other transporters can interchange and movement of drug can still be accomplished Further studies are needed to fully understand how maturation of each transporter works together with others and how this affects clinical outcomes Conjugated metabolites eliminated via the biliary system are excreted into the intestine along with bile Within the intestinal lumen, gut bacteria can cleave the conjugate from the metabolite leaving the parent drug This concentration of parent drug can then be reabsorbed from the intestine and back into the systemic circulation in a process known as enterohepatic recirculation Enterohepatic recirculation allows drug to reenter the systemic circulation, increasing the total exposure (AUC) and bioavailability of drug Pharmacodynamics Changes Infants and children have been described to exhibit different clinical responses to several medications from those of adults One example of this is the paradoxical excitability that children may experience following exposure to antihistamines and barbiturates in contrast to the sedation normally observed in adults.160,161 Children also have a greater incidence of dystonic reactions following the administration of dopamine antagonists (e.g., haloperidol, chlorpromazine, metoclopramide), potentially due to differences of dopamine receptors in the brain.162 During serious illness, substantial changes may occur in receptor function, tissue architecture, and postreceptor function that ultimately are responsible for changes in drug action These can be caused by imbalances in electrolytes or acid–base status, vascular volume, or conditions such as pulmonary fibrosis and cardiomyopathy Infection with Haemophilus influenzae type B has been associated with decreased pulmonary b2-receptor function with a resultant increase in airway resistance.163,164 Protracted use of catecholamines may result in downregulation of functional b-receptors in target organs, requiring frequent dose increases to achieve the maintained desired pharmacologic effect.164,165 Finally, it is important to remember that subjects in the pediatric intensive care unit receive many medications (Box 122.4), putting them at risk for drug-drug interactions, toxicity, and serious side effects.7,166 Critical Care Therapeutics In the treatment of critically ill children, clinicians must understand the developmental maturation and pathophysiologic changes that affect drug disposition and therefore therapeutic choices Recognizing how the relationship between dynamic pathophysiologic changes and maturational changes affect drug pharmacokinetics and pharmacodynamics will allow clinicians to optimize dosing in critically ill children Antimicrobials Pharmacodynamic biomarkers for antibiotics are difficult and sometimes infeasible to attain A direct count of bacterial load is 1441 • BOX 122.4 Commonly Prescribed Medications in Pediatric Intensive Care Benzodiazepines Sympathomimetics Midazolam Diazepam Oxazepam Lorazepam Flumazenil Barbiturates Dopamine Dobutamine Epinephrine Norepinephrine Isoproterenol Phenylephrine Vasopressin Thiopental Pentobarbital Diuretics Other Sedatives/Analgesics Furosemide Bumetanide Morphine Hydromorphone Fentanyl Naloxone Ketamine Propofol Etomidate Dexmedetomidine Vasodilators Hydralazine Nicardipine Milrinone Neuromuscular Blockers Succinylcholine Pancuronium Vecuronium Atracurium Mivacurium usually unattainable; thus, clinicians use clinical end points to determine the severity of infection Physiologic factors—such as core body temperature, respiratory rate, heart rate, and leukocyte count—are all used as indicators of infection However, while these are useful clinical end points, they not always correlate with bacterial count or eradication Therefore, to assess efficacy, pharmacokinetic markers are used to determine the probability of eradicating infection and antibiotic efficacy Some antibiotics— such as b-lactams, clindamycin, and macrolides—are timedependent, meaning that the time that the drug concentration is above minimum inhibitory concentration (MIC) of the bacteria affects efficacy For these classes of antibiotics, the fraction of time above the MIC is used to determine the probability of eradicating the infection Other antibiotics, such as aminoglycosides and quinolones, are concentration dependent, meaning that the concentration (either the AUC or maximal concentration) above the MIC influences efficacy The peak, or AUC-toMIC ratio, is the most important pharmacokinetic factor to monitor for efficacy This class of medication demonstrates the importance of how the understanding of physiologic conditions and age directly affects pharmacokinetics and therapeutic efficacy Analgesics and Sedatives Analgesics and sedatives are two extremely common medication types administered to critically ill children for pain relief, help with mechanical ventilation, or anxiety The main class of drug for analgesia is opioids, including morphine, oxycodone, hydromorphone, and fentanyl, which bind to either m-, k-, or d-receptors ... these populations Ceftriaxone, a commonly used third-generation cephalosporin, is associated with biliary sludge in neonates and infants Owing to this problem and its interaction with calcium... together with others and how this affects clinical outcomes Conjugated metabolites eliminated via the biliary system are excreted into the intestine along with bile Within the intestinal lumen,... induction Contrary to the relatively long time course for induction, inhibition can be observed within the first dosing interval, where enzyme metabolism is blocked, resulting in decreased clearance