1427CHAPTER 122 Principles of Drug Disposition saturated, and the amount of drug metabolized is constant and at its maximum In this event, the drugs follow zero order or satura tion elimination kineti[.]
CHAPTER 122 Principles of Drug Disposition always easy or practical Therefore, clearance can also be estimated after the first dose of drug is administered by the following equation: CL Dose F AUC where dose is in units of mass, such as grams or milligrams, F is the bioavailability, and AUC is in the units of mass time/ volume Deriving clearance from these equations does not necessitate an understanding of where and how the drug is metabolized and/or cleared from the body (i.e., metabolized in the liver or cleared through the kidneys) It does, however, present an overall understanding of the time it takes to clear the body of the drug The two main organs of drug clearance are the liver and kidneys Drugs may be bound or unbound to plasma or tissue proteins and establish an equilibrium within the body Since only unbound drug can distribute throughout the body, be metabolized or cleared, and, usually, effect a response at the target, the ratio between bound to unbound drug is important Overall, total body clearance of unbound drug (fu) is equal to the sum of the clearances from all clearance mechanisms In other words, CLTotal CLH CLR CLO, where CLH is the hepatic clearance, CLR is renal clearance, and CLO is the total clearance from elimination pathways other than the liver and kidney Renal clearance is the sum of glomerular filtration and tubular secretion minus tubular resorption, represented by the equation: CLR fu GFR Secretion Resorption Hepatic clearance relies on drug metabolism due to liver enzyme activity and impacted by the drug’s intrinsic clearance (CLint), which is the ability of drug-metabolizing enzymes to clear the drug Hepatic CL also relies on hepatic blood flow (QH) to deliver drugs to the sites of metabolism Hepatic blood flow can be calculated using the following equation: CL H Q H f u CL int Q H f u CL int Drugs can be further defined by the extraction ratio (E), which is the fraction of drug removed during one pass through the liver The hepatic clearance of high extraction ratio drugs ranges from 0.7 to 1.0 In this case, CLint is much larger than QH; thus, the equation for hepatic clearance simplifies to CLH QH In summary, the CL of drugs with high extraction ratios is dependent primarily on hepatic blood flow The hepatic clearance of low extraction ratio drugs, or those ranging from 0.01 to 0.30, simplifies down to CLH fu CLint, since CLint is much smaller than QH The metabolic transformation of drugs that drives the intrinsic clearance is catalyzed by enzymes; most reactions follow Michaelis Menten kinetics In this case, the rate of drug metabolism is defined as Vmax [ S] V K m [ S] where Vmax is the maximal rate of drug metabolism, S is the concentration of the drug or substrate, and Km is half the maximal rate of metabolism When the drug concentration is much less than the Km (Km [S]), then the rate of drug metabolism is proportional to the concentration of the free drug, also known as first-order elimination kinetics Most drugs are eliminated via linear first-order kinetics However, if the drug concentration is much higher than the Km ([S] Km), then the enzyme system is 1427 • BOX 122.1 Examples of Drugs Demonstrating Saturation Kinetics Furosemide Indomethacin Phenytoin Caffeine Chloramphenicol Diazepam Ethanol saturated, and the amount of drug metabolized is constant and at its maximum In this event, the drugs follow zero-order or saturation elimination kinetics In children, a number of important compounds demonstrate zero-order kinetics at clinically useful doses (Box 122.1) Drugs can sometimes follow zero-order kinetics and, ultimately, when the concentration is less than the Km, transition to first order Understanding the mechanisms of elimination can clarify how this parameter can change with age and disease since renal function, hepatic blood flow, and enzyme abundance change over time and are susceptible to pathophysiologic changes Volume of Distribution After administration, the drug disseminates throughout the body where it can remain solely in the blood or plasma (central compartment) or can distribute extensively throughout the body into tissue compartments (peripheral compartments) The extent of distribution is represented by the volume of distribution, which is the theoretical volume of fluid that contains the compound The units are volume, such as mL or L, and are often normalized to weight (L/kg) The volume of distribution does not explicitly correspond to physiologic space, which is why it can exceed the total volume of body water (0.5–0.6 L/kg).11,12 However, the Vd correlates with how much of the body the drug partitions into For instance, a drug with a low volume of distribution distributes minimally, if at all, into tissues or compartments other than blood or plasma Examples, such as sulfamethoxazole or aspirin, both have an apparent volume of distribution of approximately 0.2 to 0.5 L/kg.13,14 Conversely, a large volume of distribution suggests extensive distribution into tissues or compartments other than the central compartment, such as chloroquine and labetalol, which both have an apparent volume of distribution of greater than to L/kg.15,16 The apparent volume of distribution can be calculated after the administration of an intravenous bolus using the following concentration: Vd Dose/C0 where C0 is the initial concentration at time zero, or its peak immediately after administration This equation can also be used to calculate the volume of distribution in the central compartment (Vc), which represents an instantaneous, rapid equilibration in the blood, plasma, and potentially any other fast-equilibrating tissue compartments Compounds that distribute into other tissue compartments that equilibrate slower than the central compartment have both a central (Vc) and peripheral (Vp) volume of distribution When the rates of distribution in and out of the peripheral compartment are at equilibrium, the steady-state volume of distribution is reached and can be defined using the following equation: Vss Vc Vp fup/fut 1428 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology where fup is the unbound fraction in the plasma and fut is the unbound fraction in the tissue This ratio of the unbound fraction in the plasma to the tissue is also referred to as the partition coefficient, or Kp Half-Life Elimination half-life of a drug represents the amount of time it takes for half the concentration to be cleared from the body The amount of time for half of the drug to distribute into the tissues represents the distribution half-life While it may seem that the drug is being cleared during distribution, it is still in the body and should not be confused with the elimination half-life When percent of drug remaining in the body is plotted on a semi-logarithmic plot against the number of half-lives, the slope of the resulting line generates a slope of 20.693, or ln(0.5) (Fig 122.1) The absolute value of Ln(0.5) equals Ln(2) Therefore, the specific half-life of a drug can be estimated by dividing the natural log of by the elimination rate, ke, or substituting CL and Vd in for ke, as shown: t1 Ln(2) ke Vd Ln(2) CL Therefore, changes in volume of distribution and/or clearance alter the elimination half-life Elimination half-life guides the dosing interval and schedule of peak and trough sampling for therapeutic drug monitoring (TDM) For multiple dosing or drug infusions, the elimination half-life is essentially when the rate of drug entering the body is equal to the rate of drug exiting the body It takes approximately to half-lives for 90% to 95% of the drug to be eliminated from the body A drug dosed at a regular interval based on the half-life achieves steady state after to doses In order to achieve Bioavailability Pharmacokinetic parameters are based on intravenous administration, which is considered the reference standard for absorption After intravenous administration, 100% (F 1) of the drug is available in the body and can reach the target site For compounds that are administered by other nonintravenous routes, the drug must be absorbed and the amount available to reach the target site can range anywhere from 0% to 100% (0.01 , F , 1.0) The barriers to complete absorption can be due to factors such as low permeability, low solubility, first-pass metabolism, and changes in transporters First-pass metabolism refers to the metabolism of the drug before it enters the systemic circulation This results in loss of drug before it can reach the target site In order to calculate absolute bioavailability, the AUC after intravenous administration must be compared to that of the AUC after nonintravenous administration, normalizing for dose For instance, relative bioavailability of an orally administered drug can be calculated using the following equation: F AUC oral AUC IV Dose IV Dose oral However, if a direct comparison to an intravenous formulation is not possible, then the relative bioavailability can be calculated by comparing the exposure to another nonintravenous formulation Relative bioavailability is important when comparing a newer formulation to an existing formulation to calculate the need for a dosage adjustment It is also important to note that if an intravenous y = 100 e–0.693x 100.0 Percent of drug remaining in body a steady-state concentration faster than to half-lives, a loading dose can be administered Steady state cannot be achieved by increasing the dose or rate of infusion, as these methods only achieve a higher steady state in to half-lives, and the initial target steady-state concentration will be exceeded 10.0 Number of half-lives 10 1.0 Percent of drug remaining in body 100 50 25 12.5 6.3 3.1 1.6 0.8 0.4 0.2 0.1 Percent of drug eliminated 50 75 87.5 93.7 96.9 98.4 99.2 99.6 99.8 99.9 0.1 Number of half-lives • Fig 122.1 Percent of drug remaining in the body and derivation of the half-life equation (semi-log plot) 10 CHAPTER 122 Principles of Drug Disposition formulation is unavailable and relative F is unknown or incalculable, then only apparent clearance (CL/F) and apparent volume of distribution (Vd/F) can be calculated When clearance or volume parameters are shown divided by F, it implies that these are not absolute values of the parameters and that the values are reliable only for that route of administration For compounds with a bioavailability of 1, no dosage adjustment is required when switching between intravenous and nonintravenous administration However, doses must be increased when the bioavailability of the nonintravenous route of administration is less than Examples of lowered bioavailability have been demonstrated in critically ill patients for oral and subcutaneous medications The bioavailability of both moxifloxacin and lansoprazole, administered as an oral and an orally disintegrating tablet, respectively, are reduced compared with intravenous administration by approximately 25%.17–19 A comparison of enoxaparin bioavailability after intravenous and subcutaneous administration indicates that critical illness reduces bioavailability of the subcutaneous route by almost 40%.20 Morphine, a commonly administered medication in critically ill patients, has a low oral bioavailability of 20% to 30% but is metabolized into two metabolites, morphine3-glucuronide (M3G) and morphine-6-glucuronide (M6G) The M6G metabolite is pharmacologically active; thus, differences in metabolism could change the ratio of parent to active metabolite For diazepam, oral and rectal bioavailability is approximately 80% to 90% compared with intravenous bioavailability These examples provide evidence that if a nonintravenous route of administration is considered, clinicians need to understand that route of administration will impact the total amount delivered to the systemic circulation, and dosage adjustments will likely be needed Applied Pharmacokinetics Each pharmacokinetic parameter can be derived from plotting the drug concentration versus time The total exposure to drug over time, also known as the area under the concentration-time curve (AUC), can be calculated by dividing the curve into trapezoids and summing the area of each Additionally, these types of plots can provide information on the number of compartments in which the drug distributes, which can be determined when the concentration on the y-axis is converted into a logarithmic scale (Fig 122.2) The drug is said to distribute into one compartment if the drug concentration decreases in a proportional linear manner after converting the y-axis (Fig 122.2A) The negative slope of the line represents the elimination rate constant, or ke In contrast, the drug distributes into two compartments if the drug concentration decreases exponentially (Fig 122.2B) The exponential decay of a two-compartment drug is classified as the alpha (a) phase (green line) and the beta (b) phase (purple line) and correspond to the distribution and elimination phases, respectively If these lines are extended as shown in the figure, the intercepts (A and B) and slopes (a and b) for both lines can be identified 100 100 Logarithmic concentration A 10 10 B 1 A 12 Time (hours) • Fig 122.2 Plasma 16 20 1429 24 B 12 16 20 Time (hours) concentration vs time curves presented on semilogarithmic graphs (A) Onecompartment model with linear elimination (B) Biphasic, two-compartment model The distribution phase, or a phase, is the first part of the curve, and the elimination phase, or b phase, is the second part of the curve Extrapolating for both phases gives the intercepts and slopes of both phases 24 1430 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology Using the slopes and intercepts, plasma concentration can be determined at any time after administration using the following equation: C Ae2at Be2bt where t is the time after administration For two-compartment drugs, b refers to the rate of elimination, or ke; thus, elimination half-life can be determined by substituting the b value for the ke Distribution half-life can be calculated by substituting the a value for the ke and represents the time it takes for half of the drug to distribute throughout the body Applying these pharmacokinetic principles can facilitate therapeutic choices To target a specific concentration, clinicians can use loading and maintenance doses Loading doses facilitate faster attainment of the target concentration if it is necessary to achieve that concentration immediately Loading doses can be calculated using the following equation: Loading dose C p Vd F where Cp is the target concentration Maintenance doses sustain the target concentration at a steady state and can be calculated using the following equation: Maintenance dose C p Vd F where t is the dosing interval Ultimately, these pharmacokinetic parameters can be used to determine dose, dosing interval, time to steady state, and other important factors influencing therapeutic choices Clinical Pharmacodynamics Pharmacodynamics in simple terms is the effect that the drug has on the body and involves biochemical, physiologic, and molecular effects Overall, it encompasses mechanism of action, safety profiles, drug-receptor interactions, and receptor-effector coupling Pharmacodynamic responses can be characterized as either agonists or antagonists depending on the response after administration (Fig 122.3) Drugs that can produce a 100% response at the highest doses are labeled as full agonists whereas those that can produce only a fraction of the full response at the highest doses are partial agonists Drugs that occupy the receptor and not produce an effect or block an effect are labeled as antagonists Examples of each of these effects can be seen with opioids: morphine is a full agonist, buprenorphine is a partial agonist, and naloxone is an antagonist The extent of response can be characterized as linear, hyperbolic (Emax), or sigmoid (as shown in Fig 122.3) Linear relationships have a direct relationship between concentration and effect; thus, a doubling of concentration will result in doubled response Conversely, hyperbolic and sigmoid responses plateau at a certain point, and additional drug will not exert additional effect Pharmacodynamic response can be linked to the pharmacokinetics, as the exposure influences the amount of drug available to produce an effect After understanding the concentration versus time profile, it is important to understand the concentration versus effect/response profile There are direct or indirect responses (Fig 122.4).7 Drugs exhibiting a direct response demonstrate concentration and effect that peak simultaneously with an effect that is proportional to the drug concentration Examples of these drugs include blood pressure medication and muscle relaxants Direct effects signify that drugs rapidly equilibrate to site of 100 90 80 Response (%) 70 60 50 40 30 20 10 0.001 0.01 0.1 Full agonist Log[Drug] Partial agonist 10 100 Antagonist • Fig 122.3 Pharmacodynamic responses: agonists versus antagonists 1000 CHAPTER 122 Principles of Drug Disposition 80 80 2.5 Drug 2.5 40 2.0 Response % 40 60 3.0 Response % Drug 60 3.0 1431 1.5 2.0 20 1.5 1.0 20 1.0 0.5 0.5 0.0 10 12 14 16 Time (hours) 18 20 22 24 A 0.0 10 12 14 16 Time (hours) 18 20 22 24 B • Fig 122.4 Indirect vs direct pharmacodynamic responses The concentration of drug is shown on the left axis and red lines The percent of drug response is shown on the right axis and blue lines (A) Representation of a direct pharmacodynamic response model in which the maximum concentration peaks at the same time as the maximum response (Tmax represented by black dotted vertical line) (B) Representation of an indirect pharmacodynamic response model in which there is a time delay for the effect as the maximum concentration peaks before the maximum response (Tmax of drug concentration represented by red dotted vertical line and Tmax of percent response represented by blue dotted vertical line) action Drugs exhibiting an indirect response demonstrate a temporal delay between the maximum drug concentration and effect Indirect responses are characterized by the requirement to transport the drug to the site of action or the response requires downstream synthesis or demolition of a factor controlling response Examples of these include warfarin, interferon-a2a, and cimetidine.21 Aside from understanding the mechanism of action for producing a response, clinicians should also recognize the methods of assessing the clinical outcomes For practical reasons, the intended clinical end point might develop or occur in the future, rendering measurement of pharmacodynamic response infeasible In these cases, alternative methods are required to measure the efficacy of therapeutic interventions to prevent long-term sequelae Biomarkers are surrogate end points used as indicators of normal physiologic processes, pathogenic processes, or pharmacologic responses to therapeutic interventions Optimally, biomarkers must be easily identifiable and quantifiable physiologic effects validated as reliable predictors of a clinical end point Examples of biomarkers are blood pressure, cholesterol, HbA1c, tumor shrinkage, or human immunodeficiency virus (HIV) viral load, which help clinicians predict the clinical end points of stroke, coronary artery disease, diabetes-related morbidity, overall survival or progression-free survival in cancer, or HIV/AIDS (acquired immunodeficiency syndrome), respectively Measuring the timing and percent of change in these biomarkers helps clinicians chose appropriate therapies If there is a clear relationship between the concentration and response, then this information can be used to target a desired effect Therapeutic drug monitoring (TDM) is when drug concentrations in the blood or plasma are measured at specific intervals TDM can also be used to assess the concentration of drug over time and the individual subject’s pharmacokinetic parameters to alter or continue dosing to reach the target concentration TDM has been used to confirm that specific drug concentrations known to be associated with safety and efficacy are achieved, especially for drugs with a narrow therapeutic index The therapeutic index is the range of concentrations considered to be efficacious, with an acceptable toxicity and safety profile A narrow therapeutic index refers to drugs for which the range is small, which increases the difficulty of dosing these medications to achieve efficacy while avoiding toxicity It is important to understand the targeted pharmacodynamic response and its temporal relationship with pharmacokinetics to optimize dosing, especially with dynamic age- and disease-dependent changes impacting pharmacokinetics Determinants of Effective Therapy Therapeutic choices are based on the five Rs: the right drug, right time, right dose, right duration, and right route Age-dependent changes in physiology can affect the pharmacokinetic parameters, such as clearance, volume of distribution, bioavailability, and halflife Additionally, in the setting of critical illness, pathophysiologic changes can complicate these choices as they, too, alter pharmacokinetic parameters Consequently, choosing a safe and efficacious dose in children entails recognizing and applying these developmental ... Toxicology where fup is the unbound fraction in the plasma and fut is the unbound fraction in the tissue This ratio of the unbound fraction in the plasma to the tissue is also referred to as the partition... First-pass metabolism refers to the metabolism of the drug before it enters the systemic circulation This results in loss of drug before it can reach the target site In order to calculate absolute... appropriate therapies If there is a clear relationship between the concentration and response, then this information can be used to target a desired effect Therapeutic drug monitoring (TDM) is when