Absorption

Absorption specifically refers to the process of drug transfer from its site of administration to the bloodstream (see Figure 51-2). Drugs typically enter the body via enteral, intravenous, intramuscular, intrapulmonary, or subcutaneous routes and are then absorbed into the circulation as free drug. Bioavailability of a drug refers to the fraction of the administered dose that reaches the circulation, but does not take into account the rate at which the drug is absorbed. Bioavailability is determined by comparing the respective area under the plasma concentration curves (AUC) after oral or intramuscular administration with the AUC after intravenous administration. Intravenous administration of a drug provides the most consistent, reliable absorption into the circulation and, therefore, defines a bioavailability of 100%. For enteral medications the bioavailability depends on biochemical properties of the drug, the formulation, and patient-specific factors such as gastric acidity, gastric emptying time, and intestinal transit time. Bioavailability is reduced by incomplete absorption and also by first-pass metabolism that takes place as the drug travels through the liver. Neonates have unique absorption properties that differ with maturity because of differences in their gastric acidity, gastric emptying time, intestinal transit time, hepatic blood flow, and rates of drug metabolism. Bioavailability after intramuscular and subcutaneous administration can be affected by tissue perfusion and drug permeability.

Distribution

Distribution refers to the process by which drugs move from vascular space to the site of action and/or extravascular tissues (see Figure 51-2). Distribution depends on cardiac output, protein binding, and tissue permeability. Drugs enter the systemic circulation as free drug, where they can then be bound by plasma proteins, react at the site of action with receptors, or travel to tissue reservoirs. Initially, drugs rapidly diffuse to well-perfused organs such as the heart, liver, and kidneys. Then, in the second phase, drugs distribute into the more peripheral muscle and adipose tissue.

Once in the circulation, drugs can disperse into several compartments, including the extracellular water stores, adipose tissue, brain, and muscle. The apparent volume of distribution (Vd) for a drug is defined as the hypothetical fluid volume through which drug is dispersed. This is a hypothetical Vd because when drug plasma concentrations are very low, the apparent Vd may be more than physiologic. Drugs can have extraordinarily large Vd if they are bound to proteins in the peripheral tissues or sequestered in adipose tissue. For example, digoxin has a very large Vd because of low concentrations in the plasma because it is sequestered in the peripheral tissue where it is bound to proteins in skeletal and cardiac muscle.¹⁵ Drugs that are primarily maintained in the circulation typically have smaller Vd. The variable body composition at different gestational ages affects Vd. Additionally, many physiologic and pathologic factors influence the distribution of drugs in the body.¹⁷ Excess total body water and extracellular fluid volume as is seen with prematurity, congestive heart failure, or anasarca can increase the apparent volume of distribution. Limited adipose tissue in extremely premature infants limits distribution of drugs to adipose tissue. Drug distribution can be dramatically affected by protein binding. Drugs that are highly bound to plasma proteins, such as vancomycin, stay within the circulation, thus limiting their distribution outside the circulation and their volume of distribution. Preterm infants have deficient serum protein concentrations, resulting in an increased fraction of free drug and often an increased distribution of free drug outside the circulation. Factors affecting an individual patient’s volume of distribution, such as fluid status, prematurity, and clinical disease state, need to be taken into account when determining an appropriate drug dose.

Metabolism

Biotransformation is the process that typically converts a drug molecule into a more polar, hydrophilic derivative.1,3 Polar metabolites are less likely to diffuse across cell membranes, less likely to reach receptors at the site of action, and more likely to be eliminated from the body. Drugs undergo metabolism or biotransformation to polar metabolites by endogenous enzymatic pathways in the liver or less often in the kidneys, intestinal mucosa, or lungs (see Figure 51-2). Metabolism of drugs most often produces inactive metabolites, but can also produce active metabolites (theophylline is methylated to caffeine), or even toxic metabolites (acetaminophen toxicity from N-acetyl-p-benzoquinone imine).

The metabolism of drugs is typically classified into two phases, nonsynthetic phase 1 and synthetic or conjugation phase 2.1,3,7 Enzymes responsible for phase 1 metabolism convert a parent drug to a polar metabolite by introducing or unmasking a more polar site typically from oxidation, reduction, hydrolysis, or demethylation. The cytochrome P450 enzymes found in the liver and other tissues are primarily responsible for phase 1 oxidative metabolism.^1,3 The most common cytochrome P450 drug-metabolizing enzymes are the CYP3A4 and CYP3A5 isoforms that together are responsible for metabolism of about 50% of medications. CYP isoforms are differentially expressed across human development; notably, CYP3A4 and 3A5 are only expressed after birth, whereas CYP3A7 is expressed in the fetus but expression declines after birth. Enzymes responsible for phase 2 metabolism typically add an endogenous substance to the drug to form a highly polar metabolite using UDP-glucuronosyltransferase, glutathione S-transferase, or sulfotransferase. Biotransformation may be enhanced or impaired by multiple factors, including maturity, postnatal age, coenzyme induction or inhibition, prostaglandins, hepatic blood flow and function, and even the effects of other disease states.

Drug biotransformation is associated with large inter-patient variability.10,20 This variability is explained not only by ontogeny of drug-metabolizing enzymes across development, but also by environmental, genetic, and physiologic factors. Environmental influences include concomitant medications that may induce or inhibit drug-metabolizing enzymes; fluconazole inhibits CYP2C9 and CYP3A4, whereas phenobarbital induces CYP2B and CYP3A. The cytochrome P450 genes also exhibit wide genetic variation explained by numerous single nucleotide polymorphisms that can diminish enzyme activity and significantly affect drug metabolism, most notably seen in CYP2D6 and opiate metabolism.²³ Other factors affecting hepatic metabolism include hepatic blood flow, body temperature, gender, and disease states.

Elimination

The elimination of active drugs or their metabolites is the process by which drugs are removed from the body, primarily through the liver and kidney (see Figure 51-2).^1,7 The kidney uses three mechanisms of drug elimination: glomerular filtration, active secretion through the proximal tubules, or distal tubule reabsorption. Glomerular filtration increases with maturation, with newborns having the lowest glomerular filtration rate compared with children and adults.¹ Disease states common in critically ill newborns such as hypoxic ischemic encephalopathy, severe respiratory insufficiency, renal failure, and congenital heart disease all have been associated with reduced drug excretion. Drug secretion in the proximal tubules uses transport systems that typically eliminate organic anions. Secretion transporters are used to secrete and thus eliminate drugs conjugated with glucuronic acid, glycine, and sulfate, including penicillin and furosemide. The proximal renal tubules also use transport systems for organic cations or peptides. Tubular secretion is lower in newborns, thereby explaining the prolonged half-life of furosemide and penicillin. Membrane transporters in the distal tubule actively reabsorb drugs from the tubular lumen back into the systemic circulation, typically through nonionic diffusion. Tubular reabsorption is also delayed in neonates. Glomerular filtration rate typically improves with maturation faster than tubular mechanisms.

The liver uses four mechanisms of drug elimination: drug metabolism, excretion into bile, fecal elimination, and enterohepatic recirculation.¹ Hepatic drug elimination can be dependent on either hepatic blood flow or the metabolic capacity of liver. Patients with hepatic insufficiency have decreased elimination of drugs because of alterations in protein levels and protein binding, decreased liver blood flow, and altered hepatic enzymatic reaction. Patients with hepatic insufficiency, however, exhibit marked variability in drug metabolism and elimination. Nonetheless, infants with hepatic insufficiency typically benefit from lower doses of drugs that are eliminated by hepatic biotransformation, and when possible, drug plasma concentrations should be monitored.

Regardless of elimination mechanism, the rate at which drugs are eliminated from the circulation can be described by the PK properties of drug clearance (CL), elimination rate constant (K_el), and half-life (). Drug clearance is defined as the amount of blood from which all drug is removed per unit time; K_el represents the elimination rate constant, in other words, the slope of the drug concentration time curve on a logarithmic scale (Figure 51-3); and is defined as the time it takes to clear half of the drug from plasma.

Body Composition and Organ Dysfunction Affect Pharmacokinetics

Body composition, specifically water, protein, and fat, changes dramatically across the gestational age spectrum and impacts both the distribution and elimination characteristics of a drug.7,20 Infants with minimal fat composition will have limited distribution of lipophilic drugs, whereas large for gestational age infants with increased fat stores may sequester lipophilic drugs. Similarly, when infants with low protein stores receive a highly protein-bound medication, they will likely have a higher proportion of active, unbound drug and typically a lower volume of distribution, faster elimination, and shorter half-life. The PK characteristics of drugs need to be studied across a broad range of prematurity, body composition, postnatal age, and disease state.

Organ dysfunction affects both the distribution and elimination of a drug.⁴ Functional immaturity, renal perfusion, or intrinsic renal disease all can decrease elimination of active drug through the kidneys. Patients with significant renal disease also accumulate organic acids in the plasma that can compete with protein-bound drugs for albumin binding, thereby altering the volume of distribution. Patients with liver disease or hepatic congestion accumulate active drugs owing to their diminished metabolic capabilities and decreased first-pass metabolism. Slow gut motility or bowel wall edema can impair enteral absorption. Patients with liver disease typically have low albumin or altered glycoprotein levels that may affect fractional protein binding of drugs, thereby altering volume of distribution. Cardiac dysfunction significant enough to cause altered perfusion, edema, and/or hepatic congestion can affect drug metabolism. Altered tissue perfusion and increased total body water, as is seen in cardiac, renal, or hepatic dysfunction, can unpredictably alter a drug’s volume of distribution.

Drug metabolism and elimination from the body exhibit marked complexity and interpatient variability.1,3,20 Variability is greatest in the newborn, given the differences in prematurity, postnatal age, and pathophysiology. In general, the rates of biotransformation and elimination are often slower in the newborn period. The expected changes in drug metabolism with maturation are often extremely variable and depend on both the drug and the metabolic pathways.

First-order or Zero-Order Kinetics

The drug-concentration-over-time graph describes the rate of elimination of a drug from the body (see Figure 51-3). Most drugs follow first-order kinetics, and mathematical equations used from this point forward are appropriate for drugs that are eliminated using properties of first-order kinetics (Table 51-1).²² For drugs that follow first-order kinetics, a constant percentage of drug is metabolized over time; therefore, the rate of elimination is proportional to the amount of drug in the body. Most drugs used in neonates follow first-order kinetic properties, including ampicillin, gentamicin, and phenobarbital. These medications have an exponential decrease in the serum concentration over time and therefore represent a linear relationship on a logarithmic scale. The half-life of drug elimination is independent of drug dosage. The fraction of drug eliminated is constant (K_el). For example, if 50% of the drug is removed per unit of time, then a larger amount of drug is removed in first interval than in last interval.

TABLE 51-1

Mathematical Equations for Bedside PK Analysis: Intravenous Drugs That Follow First-Order Kinetics

PK Parameter	Abbreviation	Units	[#] Equation
Drug Concentration	[Cmax] at end infusion [Ct] at time t	mg/L	[Cmax]=Dose mg/kg÷Vd (L/kg) max concentration after injection [1] [1] [Ct]=[Cmax]×(e−Kt) concentration at time t [2] [2]
Volume of Distribution	Vd	L/kg	Vd=amount drug given (mg/kg)÷(plasma [drug] mg/L) [3a] [3a] Vd=CL÷Kel [3b] [3b]
Elimination rate constant	Kel	hr−1	Kel=(Ln [Ct1]−Ln [Ct2]) ÷Δt or=Ln [Ct1/Ct2]/Δt [4a] [4a] where [Ct1] = conc at Time 1 or Time 2 and Δt is difference in hours between t2-t1 Kel=CL÷Vd [4b] [4b] Kel=0.693÷T12 [4c] [4c]
Half-life		hr	T12 =0.693÷Kel (note that 0.693=Ln2, time for exponential twofold decline) [5a] [5a] T12=(0.693×Vd)÷CL [5b] [5b]
Clearance	CL	L/hr * kg	CL=Kel×Vd [6a] [6a] CL=(0.693×Vd)÷T12 [6b] [6b] CL=(Dose τ)÷average steady-state [drug]ssWhere τ is dose interval in hours [6c] [6c]
Calculations after single dose infusions accounting for drug elimination during infusion
Drug concentration at time t	Ct tinf = infusion time (hr) t is any time after infusion end	mg/L	Cmax=(R0/CL)×(1−e−Ktinf) where R0=(dose​/​infusion time) in units (mg​/​kg  * hr) [7] [7] Ct=(R0/CL)×(1−e−Ktinf)×e−Kt [8] [8] Because CL = Vd × k then rearrange [8] to solve for Vd or dose to achieve [Ct] if [Ct] and tinf are known Vd=(R0/[Ct×K])×(1−e−Ktinf)×e−Kt [9] [9] Dose=( Vd×Tinf×Ct×K)÷([1−e−Ktinf]×e−Kt) [10] [10]
Calculations after (n) multiple doses after bolus injection or short infusion time models
Drug concentration after multiple doses (n)	Cmax (n) Max C after n doses Ct (n) C at time t after infusion after n doses Ct (ss) C at time t after infusion at steady-state	mg/L	For a bolus injection Cmax(n)=(Dose/Vd)×[(1−e−nKτ)÷(1−e−Kτ)] (n =doses, τ=dose interval) [11] [11]
			Ct(n)=(Dose/Vd)×[(1−e−nKτ)÷(1−e−Kτ)]×e−Kt [12] [12] Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Related Related posts: Coding and Reimbursement: Principles and Practices Normal Mother-Infant Attachment Developmental Immunology Role of Positive Pressure Ventilation in Neonatal Resuscitation Stay updated, free articles. Join our Telegram channel Join Tags: Fanaroff and Martins Neonatal-Perinatal Medicine Diseases of the Jun 6, 2017 | Posted by admin in PEDIATRICS | Comments Off on Pharmacokinetics in Neonatal Medicine Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access