1432 SECTION XII I Pediatric Critical Care Pharmacology and Toxicology changes to therapeutic decision making Understanding the fac tors that affect pharmacokinetics and pharmacodynamics—and therefore[.]
1432 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology Parent Ontogeny Absorption Phase I metabolism Phase II metabolism Distribution in systemic circulation Pharmacodynamics Pharmacokinetics Phase I metabolism Phase II metabolism Elimination Pathophysiology • Fig 122.5 Determinants of effective therapy changes to therapeutic decision-making Understanding the factors that affect pharmacokinetics and pharmacodynamics—and therefore drug disposition and effective therapy (Fig 122.5)—can facilitate optimal drug choice and dosing recommendations Parent Metabolites • Fig 122.6 Absorption, distribution, metabolism, and elimination pathway Movement of drug through the body depends on its physicochemical properties, which regulate absorption, distribution, metabolism, and elimination Movement can be linear or nonlinear through these processes Metabolism can occur before or after distribution or not at all A drug can be metabolized solely through the phase I or phase II pathway or through both After metabolism, drug or metabolite can be excreted into the biliary system or distributed back into the systemic circulation to exert an effect or be eliminated Pharmacokinetic Processes Pharmacokinetics can be explained by four main processes: absorption, distribution, metabolism, and elimination (ADME) A drug’s pathway through each of these processes can be linear or circular, depending on its physicochemical properties (Fig 122.6) For instance, metabolism can occur immediately following absorption or metabolites can be distributed back into the systemic circulation before elimination Each of these processes is affected by developmental and physiologic changes These age- and disease-dependent changes in the ADME processes can inform the changes of the clinical pharmacokinetic parameters of clearance, volume of distribution, half-life, and exposure TABLE 122.1 Factors Affecting Drug Absorption Physicochemical Factors Patient Factors Disintegration of tablets or solid phase Surface area for absorption Dissolution in gastric or intestinal fluids pH of gastrointestinal tract Lipophilicity/hydrophilicity Gastric emptying and intestinal transit times Molecular weight Stomach and duodenal volume Absorption Drug ionization Bile salt concentration One of the most common forms of drug administration is through the intravenous route This ensures complete administration of the drug into the bloodstream All other forms of administration not guarantee complete delivery into the blood and rely on the process of absorption Absorption refers to the movement of drug from the site of administration to the bloodstream Depending on the site of administration, absorption can vary greatly across different types of formulations for the same drug Absorption is regulated by the site of administration, the composition of the tissues involved, the drug physicochemical properties (Table 122.1), and disease states (Box 122.2) The physicochemical properties of a drug influence the absorption profile and solubility of the drug in biological fluids For formulations not already in solution, such as a tablet or capsule, the first step of absorption is the process of disintegration to Particle size Bacterial colonization Osmolality Disease states release the drug After disintegration, the drug is available to dissolve into the biological fluid, which is dependent on its physicochemical properties The molecular weight and ionization of the compound, as well as the pH of the organ where it dissolves, affect its overall solubility Next, the drug must be relatively permeable in order to cross biological membranes to access the systemic circulation or small enough to fit between the cells, which are known as transcellular or paracellular transport, respectively (Fig 122.7) Paracellular transport is limited usually to small hydrophilic drugs, such as metformin and CHAPTER 122 Principles of Drug Disposition desmopressin.22,23 However, the vast majority of drugs are absorbed through the transcellular pathway and must cross biological membranes Cell membranes consist of a lipid bilayer enclosing the intracellular space Depending on the size, ionization, and lipophilicity of the compound, it can cross membranes passively through diffusion or using active uptake and efflux processes, such as transporters Each route of administration involves different types of tissues that have their own pH profile and permeability factors • BOX 122.2 Selected Disease States Affecting Gastrointestinal Absorption of Drug Gastric Acid Secretion Bile Salt Excretion Proximal small bowel resection Cholestatic liver disease Extrahepatic biliary obstruction Delayed Gastric Emptying Pyloric stenosis Congestive heart failure Protein calorie malnutrition Decreased Surface Area Short bowel syndrome Intestinal Transit Time Protein/calorie malnutrition Thyroid disease Diarrheal disease Paracellular Passive diffusion Active transport Efflux Uptake Efflux • Fig 122.7 Absorption and transport processes across the cell membrane The lines show the movement of drugs across the cell membrane 1433 Enteral Absorption Enteral administration is the next most common route after intravenous administration Enteral administration includes oral, sublingual, or gastrostomy/jejunostomy tube administration Enteral administration involves the mouth, salivary glands, esophagus, stomach, small intestines, and large intestines The pH profile changes throughout the gastrointestinal tract and is age dependent (Table 122.2) The upper and lower sections of the gastrointestinal tract are closer to a neutral pH (6.7–7.4) However, the pH of the stomach is significantly more acidic (1.4–2.5) in subjects older than month, but closer to neutral (2–8) in neonates.24,25 Other than water, little absorption occurs in the stomach, but the extreme acidity can alter the solubility of drugs or change the absorption profile for drugs that are acid labile For instance, the acid-labile drug penicillin has a markedly increased absorption profile in full-term and preterm neonates owing to the higher pH of the stomach.26 Weak bases and strong acids have an increased solubility in more acidic conditions and precipitate out in more basic environments; therefore, they have higher solubility in the stomach than the intestine However, the addition of acidsuppressing agents, such as proton pump inhibitors, can decrease the solubility—and therefore the absorption—of weak bases Studies have shown up to 40% to 90% reductions in drug exposure of atazanavir, mycophenolic acid, and posaconazole when coadministered with proton pump inhibitors.27–29 Additionally, if the solubility of a drug is pH dependent, then administration in the fasted state might become increasingly important This factor could become an issue if a continuous feed is implemented in those with tube feedings and drug administration The majority of absorption occurs in the small intestine owing to the high surface area The lumen of the small intestine is folded along the entire length into circular folds The luminal wall is then folded into finger-like projections called villi that contain blood vessels and lacteal ducts Each villus is covered in enterocytes, the epithelial cells of the intestine, and covered in microvilli, also known as the brush border, which contains digestive enzymes Each of these folds and projections increase the surface area substantially If the small intestine were able to be spread flat, it would be the size of half a badminton court in an adult.30 After digestion in the acidic environment of the stomach, the contents move to the duodenum and small intestine, which the pH increases due to the secretion of sodium bicarbonate from the pancreas along with other digestive enzymes In conjunction with these pancreatic secretions, the liver and gallbladder excrete bile and bile salts, especially in conjunction with high-fat meals Bile salts emulsify and surround fats to create micelles that increase hydrophilicity until they can be absorbed Along with bile salts, digestive enzymes on the brush border and secreted from the TABLE 122.2 Age-Dependent Changes in Gastrointestinal Physiology Neonate Mouth pH Infant Adult 7.1–7.4 6–7.4 Stomach pH 2–8 1.4 1.5 1–2.5 Small intestine pH — — 6.3–6.4 5–6.5 Rectum pH 4.4–7.2 5.9–10.9 6.5–12.1 6.7–7.8 Stomach volume (mL) 10–100 90–500 750–1500 2000–3000 275 380 450 575 Small intestine length (cm) Child 1434 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology pancreas break down the contents from the stomach At this point, drugs can be absorbed through the mechanisms discussed earlier through the enterocytes If drugs are absorbed through the transcellular route, they can potentially undergo metabolism via intestinal metabolic enzymes Drugs are then transported into the hepatic portal circulation to be delivered to the liver for further metabolism Both the metabolism in the intestine and liver compromise what is known as first-pass metabolism after enteral administration, since a portion of a drug can be broken down and eliminated before it ever reaches the systemic circulation Contents from the liver are then deposited into the hepatic vein and then the systemic circulation Many age- and disease-dependent changes affect absorption through the small intestine, including the abundance of metabolic enzymes (discussed in detail in a later section), bile salt concentration, and the microbiome The concentration of bile salts is lower in full-term neonates and infants than in healthy adult subjects.31,32 Furthermore, reabsorption of bile salts seems to be limited to passive diffusion and matures to adult levels within the first months of life.33,34 Lower concentrations of bile salts can affect fat absorption and has been linked with steatorrhea in neonates Bile salt concentration can also alter the solubility and absorption of lipophilic drugs.35,36 Whether the bile salt concentration is lower due to disease, such as cholestasis, or age, pharmacokinetic differences have been found, such as with vitamin E and pleconaril.37,38 The lumen of the small intestine is sterile in utero and at birth However, within a few hours, colonization has occurred and can differ depending on delivery method (e.g., cesarean vs natural) and food source (e.g., breast vs formula milk).39–42 Sublingual/Buccal Absorption Sublingual and buccal administrations refer to drugs for which the main absorption is located under the tongue or at the cheek, respectively Following absorption through the mucosal layers of the mouth, drugs distribute into the internal jugular vein, subclavian vein, and brachiocephalic vein These veins deposit the drug into the superior vena cava and then into the systemic circulation These routes of administration avoid any metabolism or clearance before reaching the systemic circulation and therefore avoid firstpass metabolism A variety of drugs are administered via these routes, including nitroglycerin, ondansetron, and buprenorphine Transdermal Absorption Transdermal (topical) administration is one of the most noninvasive methods of drug administration As the largest organ in the body, the skin provides a physical barrier to the body as well as temperature and water control The skin has multiple segments, including the epidermis, dermis, and hypodermis/subcutaneous tissue (Fig 122.8) The stratum corneum contains the top layers of the dermis to which drugs are applied and is composed of multiple layers of corneocytes The thickness of this section varies based on location on the body (e.g., the stratum corneum is thicker on the palms of the hands than the eyelids) and will influence the degree of absorption As with other routes of administration, the molecular weight, lipophilicity, hydrophilicity, and partition coefficient all affect absorption through the stratum corneum The optimal physicochemical properties are essential, as the drug must move from the top layer through multiple tortuous layers to reach the blood vessels beneath in the dermis layer Drugs must be relatively small (#500 Da) and have a balance between lipophilicity and hydrophilicity in order to cross these Epidermis • Barrier Dermis • Strength and elasticity • Thermoregulation Subcutaneous fat • Nutrition • Insulation • Fig 122.8 Layers of the skin, including their functions: epidermis, dermis, and hypodermis/subcutaneous tissue biological membranes.43 Additionally, the drug must be reasonably potent so that even a little absorption produces a response, such as fentanyl, nitroglycerin, or clonidine.44 Finally, for optimal absorption, the stratum corneum must be well hydrated.45 However, if the transdermal route is available, one advantage is that it does not involve the gastrointestinal tract or breaking the skin barrier and therefore can avoid hepatic first-pass metabolism.44 Nevertheless, there are transporters and enzymes on the skin capable of metabolizing drugs, both of which can be affected by genetic factors.45 The stratum corneum develops in utero and is fully mature by approximately 34 weeks’ gestation; thus, full-term neonates have a similar thickness to adults.46–48 At birth, the pH of the skin of a full-term neonate is more alkaline (6.2–7.5) and slowly lowers to levels observed on adult skin (5.0–5.5) within the first month of life.46,47 The last major difference is skin hydration After birth, skin hydration drops within the first day or two, then reaches a peak at months.46 After 12 months, the skin hydration becomes more like that of an adult.47 In contrast, preterm neonates not have a fully formed epidermal layer at birth Studies have shown that the skin of premature neonates (,30 weeks’ gestation) has an increased hydration compared with full-term neonates or those born after 30 weeks’ gestation, which leads to an increased permeability and infections.49,50 For preterm neonates, time for the skin to fully mature depends on the gestational age and can take between weeks to more than weeks.51,52 These changes suggest that neonates, especially preterm neonates, will have a greater amount of transdermal absorption This has been shown for lignocaine, for which there was an inverse correlation between absorption and gestational and postnatal age.53 The same results were found in preterm neonates after application of caffeine for apnea, leading to the conclusion that this might be an effective route of administration.54 However, owing to the higher skin permeability in premature neonates, clinicians must be careful to consider the dose or higher-than-expected concentrations could CHAPTER 122 Principles of Drug Disposition be reached, leading to toxicity, as was shown in a case report of a premature infant who went into a coma after administration of propylene glycol during burn treatments.55 There are a few different transdermal formulation options Liquids, creams, gels, ointments, and transdermal patches are all options for topical administration of drugs Many of these formulations are used for dermatologic issues However, transdermal patches are often used to deliver drugs to the systemic circulation Transdermal patches can have drugs in reservoirs or matrix systems Matrix system transdermal patches are evenly distributed throughout the patch Reservoir system patches not have drug evenly distributed throughout the patch Examples of the reservoir system are fentanyl and clonidine Doses cannot be adjusted by cutting the patch If the patches are cut, it can deliver an incorrect dosage at an uneven rate or available immediately, leading to potentially toxic effects Intramuscular and Subcutaneous Absorption If the intravenous route is unavailable, intramuscular and subcutaneous administration can be used as alternatives Drugs absorbed through these routes enter the bloodstream from the circulation surrounding the tissue at the site of administration, meaning that both avoid first-pass metabolism The absorption from these two routes is guided by the physicochemical properties of the drug and relative blood flow from the site of administration There are a few main differences between the two routes of administration that might make one more preferable than the other Drugs administered intramuscularly bypass the skin and subcutaneous tissue layer to reach the muscle layer beneath (see Fig 122.8) These drugs must be relatively lipophilic in order to cross membranes but must also retain some hydrophilicity at physiologic pH in order to prevent precipitation They have a relatively rapid uptake (≈15–20 minutes), but this can vary depending on the location of the injection site.56 For instance, blood flow to the deltoid muscle is 7% and 17% greater than either the side of the thigh (vastus lateralis) or gluteal muscles, respectively.57 Therefore, absorption will take longer in muscles with slower blood flow Furthermore, the amount of major nerves or blood vessels can affect patient perception—and therefore acceptance— of the injection For instance, the gluteal sites have fewer nerves and blood vessels than either the deltoid or vastus lateralis sites, meaning that injections into the gluteal muscles are less painful than the other two sites or subcutaneous injections.57 Finally, the injection volume ranges from 0.1 to 5.0 mL in adults in sites below the waist but is limited to a maximum of mL for the deltoid muscle.56,57 Overall, intramuscular administration allows a greater amount of drug to be delivered during one administration with a relatively rapid onset and prolonged duration of action However, for pediatric subjects, the age of the child is important because this will dictate the size and length of the needle used as well as the site of injection The vastus lateralis is the preferred site for intramuscular injections in children younger than 24 to 36 months, depending on the muscle mass in the deltoid.58,59 The size and length of the needle for intramuscular injections in children range from five-eighths of an inch to 1.25 inches and will be based on location (e.g., thigh versus deltoid) and age of the child.60 Finally, the activity of the muscle at the injection site must also be considered If there is limited muscle activity due to sedation, neuromuscular blockades, paralysis, poor muscle mass, or damaged or scarred tissues, then absorption could be reduced, resulting in ineffective therapy.61 Intramuscular injections are 1435 • BOX 122.3 Examples of Drugs Approved for Intramuscular Administration Ceftriaxone Atropine Dexamethasone Digoxin Diphenhydramine Fosphenytoin Furosemide Glucagon Haloperidol Ketamine Lorazepam Meperidine Morphine Naloxone Succinylcholine Thiopental Data from Drugs for pediatric emergencies Committee on Drugs, Committee on Drugs, 1996 to 1997, Liaison Representatives, and AAP Section Liaisons Pediatrics 1998;101(1):E13 used commonly for vaccinations and other drugs when intravenous access is limited or a longer absorption period with a rapid onset is required (Box 122.3).62 Subcutaneous injections are administered into the subcutaneous tissue below the dermis (see Fig 122.8) Owing to the lower blood flow to this region, there is a prolonged and sustained absorption, leading to longer dosing intervals The injection volume ranges from 0.1 to 1.0 mL.56,57 Traditionally, subcutaneous administration has been used for insulin and heparin However, with recent advances in biologicals, there has been a growing number of drugs administered through this route.63 Rectal Absorption For patients who cannot tolerate enteral administration, rectal administration is another option Rectal absorption is variable and, at times, unpredictable Absorption through the rectum is facilitated by passive diffusion, which is similar to absorption through the small intestine.64 The main difference between the small intestine and rectum is surface area, as the rectum does not have microvilli and villi.65 Another physiologic difference is the vasculature of the rectum The lower part of the rectum is connected to the systemic circulation, but the upper part of the rectum is connected with the portal vein.64,65 This difference in physiology determines whether the drug is delivered to the liver and is subject to first-pass metabolism or whether it can avoid first-pass metabolism altogether.66 Additionally, the formulation of the medication can alter the pharmacokinetics Since the water content of the rectum is lower than that in the upper gastrointestinal tract, dissolution of medications could be slower Thus, solid or semisolid rectal formulations, such as suppositories, could produce slower absorption.67,68 However, rectal solutions could produce fast absorption, which may be ideal for a situation requiring fast onset of action, for example, epilepsy medications such as diazepam While rectal administration is not the most common route, it has been shown effective for a number of indications Rectal diazepam has demonstrated quick onset and efficacy for both epilepsy and febrile seizures.69 There is conflicting and inconsistent data in the literature about the efficacy and pharmacokinetics of rectal administration of acetaminophen, but it has shown superior efficacy to intravenous acetaminophen after surgery and also demonstrated efficacy in preterm neonates.70–72 Rectal administration has been studied for other medications for sedation, analgesia, and seizures, including topiramate, carbamazepine, morphine, tramadol, valproic acid, and ibuprofen.73–78 This route is effective for patients with emesis who cannot tolerate oral antiemetics However, this route of administration is contraindicated in 1436 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology TABLE 122.3 Age-Dependent Changes in Serum Binding Proteins Total Protein (g/L) Albumin (g/L) AAG (g/L) D Total Protein (%)a D Albumin (%)b D AAG (%)a Preterm — 32.8 Neonate 55 33.8 0.14 — –23.3 –81.2 0.36 –24.6 –20.9 –52.8 Infants 58.3 36.5 0.62 –20.0 –14.7 –17.5 Children 68.2 38.1 0.74 –6.4 –10.9 –1.7 Adults 72.9 42.76 0.75 0.0 0 AAG, a1 acid glycoprotein Changes in binding protein concentrations are shown as a percent change from adult values a patients who are immunocompromised or neutropenic, owing to the increased susceptibility to infections in the surrounding tissues and mucosa The use of these formulations is rare but can be considered a practical alternative if necessary TABLE 122.4 Differential Protein Binding Drug Acetaminophen Newborn Adults 36.8 0.3 47.5 0.6 9.8 2.2 21.5 2.5 Distribution Ampicillin Drug distribution is altered by age-dependent changes in body composition affecting physiologic spaces.79 These changes can be affected by maturation in factors such as protein binding, organ volumes, blood flow, fluid volumes, fat content, and membrane permeability It can also be affected by disease states in which there are physiologic alterations or the addition of concomitant medications that change these factors Bupivacaine 60.0 10.0 90.0 5.0 Clonazepam 82.7 1.6 86.1 0.5 Cyclosporine 20 2.5 90.0 5.0 Diazepam 85 2.5 97 2.0 Digoxin 20.0 6.0 31.5 8.5 Lidocaine 52.4 5.4 70.1 9.1 Morphine 31.0 1.0 42.1 1.0 Phenobarbital 32.4 0.6 50.7 1.3 Phenytoin 74.4 1.0 85.8 1.0 Sufentanil 80.5 2.7 92.2 1.5 Theophylline 40.0 8.0 59.0 6.0 Age-Dependent Maturation in Protein Binding Protein binding has a significant clinical effect on the distribution of drugs throughout the body The most common binding proteins in the human body are found in the plasma: albumin and a1 acid glycoprotein (AAG).80 Therefore, only unbound concentrations of the drug can distribute throughout the body and effect a response if the target is outside of the blood, while the bound portion stays in the vasculature.81,82 Maturational changes occur from birth to adulthood (Table 122.3) establishing that changes in binding proteins can be reduced by up to 25% to 50% in fullterm neonates and up to 80% in preterm neonates as compared with adults.83–88 While still variable, both proteins start to reach adult values after year of age.89 Since protein binding relies on the affinity constant of the drug for the protein, the number of available binding sites, and the concentration of the plasma binding proteins, younger children have the potential of having higher unbound concentration of drug, allowing more to be cleared or to partition into tissues, resulting in a higher volume of distribution depending on the physicochemical properties of the drug For instance, higher unbound fraction of hydrophilic drugs in the setting of liver failure and ascites will have a much higher volume of distribution If the volume of distribution does not change, then higher unbound concentrations of drugs are likely to have a higher clearance Overall, higher unbound concentrations of drugs could potentially have a more pronounced response This has been shown for a few different medications, as shown in Table 122.4.85–88,90,91 Aside from plasma protein binding, drugs can also bind to red blood cells Binding of drugs to red blood cells is dependent on hematocrit At birth, hematocrit is higher than that of adults but declines progressively from approximately 52% to 37% within the first month of life and remains stable until adolescence At puberty, hematocrit increases to 40% until it reaches normal adult levels of 42% to 47%, depending on gender One example of red blood cell binding is tacrolimus, which has a blood-to-plasma ratio of 15 with a wide range of 14 to 114.92 Dependence on hematocrit as well as drug concentration influences the wide variability of the blood-to-plasma ratio This binding affects volume of distribution; the normal values are 1.0 to 1.5 L/kg in adults and 2.6 to 2.7 L/kg in children Due to hematocrit dependence, erythrocyte binding of tacrolimus will be affected by any disease state, such as anemia, infection, renal failure, liver disease, cancer, and more; drugs affecting red blood cell count or protein binding; or blood product transfusions that affect hematocrit Age-Dependent Maturation in Body Composition Alteration in body water affects the volume of distribution of drugs Age-dependent changes in the various fluid compartments are presented in Table 122.5.93,94 Total body water and extracellular water accounts for a large percentage of body weight in neonates but decreases to adult levels by approximately to months of age However, intracellular fluid increases over time until it ... is composed of multiple layers of corneocytes The thickness of this section varies based on location on the body (e.g., the stratum corneum is thicker on the palms of the hands than the eyelids)... have a similar thickness to adults.46–48 At birth, the pH of the skin of a full-term neonate is more alkaline (6.2–7.5) and slowly lowers to levels observed on adult skin (5.0–5.5) within the first... minutes), but this can vary depending on the location of the injection site.56 For instance, blood flow to the deltoid muscle is 7% and 17% greater than either the side of the thigh (vastus lateralis)