Pharmacokinetics and Pharmacology of Drugs Used in Children
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Drug and Fluid Th erapy SECTION II Pharmacokinetics and Pharmacology of Drugs Used CHAPTER 6 in Children Charles J. Coté, Jerrold Lerman, Robert M. Ward, Ralph A. Lugo, and Nishan Goudsouzian Drug Distribution Propofol Protein Binding Ketamine Body Composition Etomidate Metabolism and Excretion Muscle Relaxants Hepatic Blood Flow Succinylcholine Renal Excretion Intermediate-Acting Nondepolarizing Relaxants Pharmacokinetic Principles and Calculations Atracurium First-Order Kinetics Cisatracurium Half-Life Vecuronium First-Order Single-Compartment Kinetics Rocuronium First-Order Multiple-Compartment Kinetics Clinical Implications When Using Short- and Zero-Order Kinetics Intermediate-Acting Relaxants Apparent Volume of Distribution Long-Acting Nondepolarizing Relaxants Repetitive Dosing and Drug Accumulation Pancuronium Steady State Antagonism of Muscle Relaxants Loading Dose General Principles Central Nervous System Effects Suggamadex The Drug Approval Process, the Package Insert, and Relaxants in Special Situations Drug Labeling Opioids Inhalation Anesthetic Agents Morphine Physicochemical Properties Meperidine Pharmacokinetics of Inhaled Anesthetics Hydromorphone Pharmacodynamics of Inhaled Anesthetics Oxycodone Clinical Effects Methadone Nitrous Oxide Fentanyl Environmental Impact Alfentanil Oxygen Sufentanil Intravenous Anesthetic Agents Remifentanil Barbiturates Butorphanol and Nalbuphine 89 A Practice of Anesthesia for Infants and Children Codeine Antiemetics Tramadol Metoclopramide Nonsteroidal Anti-infl ammatory Agents 5-Hydroxytryptamine Type 3 Receptor Ketorolac (5-HT3) Antagonists Acetaminophen Anticholinergics Sedatives Atropine and Scopolamine Diazepam Glycopyrrolate Midazolam Antagonists Dexmedetomidine Naloxone Chloral Hydrate Naltrexone Antihistamines Methylnaltrexone Diphenhydramine Flumazenil Cimetidine, Ranitidine, and Famotidine Physostigmine THE PHARMACOKINETICS AND PHARMACODYNAMICS of most medica- antibiotics, theophylline, and diazepam).17 In addition, some tions, when used in children, especially neonates, diff er from medications, such as phenytoin, salicylate, sulfi soxazole, caf- those in adults.1-11 Children exhibit diff erent pharmacokinetics feine, ceftriaxone, diatrizoate (Hypaque), and sodium benzoate, from adults because of their altered protein binding, larger compete with bilirubin for binding to albumin (see Fig. 6-3 on volume of distribution (Vd), smaller proportion of fat and website). If large amounts of bilirubin are displaced, particularly muscle stores, and immature renal and hepatic function.2,3,12-19 in the presence of hypoxemia and acidosis, which open the Th ese factors and individual diff erences in drug metabolic blood/brain barrier, kernicterus may result.24,25,30,33-35 Because enzymes may reduce a drug’s metabolism and/or delay elimina- these metabolic derangements often occur in sick neonates tion and, in some cases, may increase metabolism.7,20-22 Th is coming to surgery, special care must be taken when selecting necessitates modifi cation of the dose and the interval between doses to achieve the desired clinical response and avoid toxicity.7 8 In addition, some medications may displace bilirubin from its Fetus protein binding sites and possibly predispose an infant to ker- Neonate nicterus.23-28 Th e capacity of the end organ, such as the heart or 7 Adult bronchial smooth muscle, to respond to medications may also diff er in children compared with adults. In this chapter we 6 discuss basic pharmacologic principles as they relate to drugs commonly used by anesthesiologists. 5 Drug Distribution 4 Protein Binding 3 Th e degree of protein binding is usually less in preterm and term infants than in older children and adults. Th is may be attributed Serum protein (grams/100 mL) 2 in part to the lower concentrations of total protein and albumin (Fig. 6-1).29 Many drugs that are highly protein bound in adults have less of an affi nity for protein in neonates (Fig. 6-2, see 1 website).29-33 Lower protein binding results in a greater free frac- tion of medications, thus providing more free medication and 0 greater pharmacologic eff ect.2,3,12,14,17 Th is eff ect is particularly Total protein Albumin important for medications that are highly protein bound because the reduced protein binding increases the free fraction of the Figure 6-1. The changes in total serum protein and albumin medication. For example, phenytoin is 85% protein bound in values with maturation. Note that total protein and albumin are less in preterm than term infants and less in term infants than healthy infants but only 80% in those who are jaundiced. Th is adults. The result may be altered pharmacokinetics and pharmaco- equates to a 33% increase in the free fraction of phenytoin when dynamics for drugs with a high degree of protein binding because jaundice occurs (Fig. 6-3, see website). Diff erences in protein less drug is protein bound and more is available for clinical effect. binding may have considerable infl uence on the response to (Data from Ehrnebo M, Agurell S, Jalling B, et al: Age differences medications that are acidic and are, therefore, highly protein in drug binding by plasma proteins: studies on human fetuses, bound (e.g., phenytoin, salicylate, bupivacaine, barbiturates, neonates and adults. Eur J Clin Pharmacol 1971; 3:189-193.) 90 Pharmacokinetics and Pharmacology of Drugs Used in Children 6 medications for the anesthetic.35 Medications that are basic 90 (e.g., lidocaine or alfentanil) are generally bound to plasma Fat Muscle α -acid glycoprotein; α -acid glycoprotein concentrations in 80 1 1 Water preterm and term infants are less than in older children and adults. Th erefore, for a given dose, the free fraction of a drug is 70 greater in preterm and term infants.36-38 60 Body Composition Volume of Distribution 50 Preterm and term infants have a much greater proportion of body weight in the form of water than older children and adults 40 (Fig. 6-4).19 Th e net eff ect on water-soluble medications is a greater Vd in infants, which in turn increases the initial (loading) 30 dose, based on weight, to achieve the desired serum level and Body composition (percent) clinical response.2,3,14,39,40 Term neonates often require a greater 20 initial loading dose (milligrams per kilogram) for some medica- tions (e.g., digoxin, succinylcholine, and antibiotics), than older 10 children.39-43 However, neonates also tend to be sensitive to the respiratory, neurologic, and circulatory eff ects of many medica- 0 tions and therefore tend to be more responsive to these eff ects Preterm Term Adult at reduced blood concentrations than are children and adults. Neonates Preterm infants are usually more sensitive than term neonates and in general require even lower blood concentrations.2 On the Figure 6-5. Changes in body content for fat, muscle, and water other hand, dopamine may increase blood pressure and urine that occur with maturation. Note the small fat and muscle mass in output in term neonates only at doses as large as 50 μg/kg/min. preterm and term infants. These factors may greatly infl uence the Th is dose, which would induce intense vasoconstriction in pharmacokinetics and pharmacodynamics of medications that adults, suggests that neonates are less sensitive in their cardio- redistribute into fat (e.g., barbiturates) and muscle (e.g., fentanyl) because there is less tissue mass into which the drug may vascular responsiveness.3,41,44-47 It is important to carefully titrate redistribute. (Data from Friis-Hansen B: Body composition during growth: in-vivo measurements and biochemical data correlated to differential anatomical growth. Pediatrics 1971; 47:264-274.) 70 Intracellular fluid Extracellular fluid 60 the doses of all medications that are administered to preterm and term infants to the desired response. 50 Fat and Muscle Content Compared with children and adolescents, preterm and full-term 40 neonates have a smaller proportion of body weight in the form of fat and muscle mass; with growth, the proportion of body weight composed of these tissues increases (Fig. 6-5).2-4,19,45,46,48,49 30 Th erefore, medications that depend on their redistribution into muscle and fat for termination of their clinical eff ects likely have 20 a large initial peak blood concentration. Th ese medications may Body composition (percent) also have a more sustained blood concentration because neo- 10 nates have less tissue for redistribution of these medications. An incorrect dose may result in prolonged undesirable clinical eff ects (e.g. barbiturates and opioids may cause prolonged 0 sedation and respiratory depression). Th e possible infl uence Preterm Term Adult of small muscle mass on the response to muscle relaxants is Neonates exemplifi ed by achieving neuromuscular blockade at lower serum concentrations in infants.41 Figure 6-4. Changes in the intracellular and extracellular compart- ments that occur with maturation. Note the large proportion of extracellular water in preterm and term infants. This large water Metabolism and Excretion compartment creates an increased volume of distribution for highly Hepatic Blood Flow water-soluble medications (e.g., succinylcholine, antibiotics) and may account for the large initial “loading” dose (mg/kg) required Th e liver is one of the most important organs involved in drug for some medications to achieve a satisfactory clinical response. metabolism. Hepatic enzymatic drug metabolism usually con- (Data from Friis-Hansen B: Body composition during growth: in-vivo verts the medication from a less