Paths of Drugs in the Body

The path of a drug in the body from administration and distribution to elimination is complex. We can break this path into individual components for better understanding (Fig. 4-1).

Fig. 4-1 Possible paths of drugs in the body from entry to distribution and elimination. A drug will follow some of these pathways. Drug effects are caused by blood concentration, tissue concentrations, or both.

(Courtesy William Banner, Jr.)

Michaelis-Menten Kinetics

A common drug governed by Michaelis-Menten kinetics is phenytoin. With even a single dose of phenytoin, the enzymes that metabolize the drug (the cytochrome P450 enzymes) are typically saturated, so the phenytoin blood concentration will initially fall slowly after administration. However, once the blood concentration falls sufficiently, the enzymes responsible for metabolism are no longer saturated and the blood concentration will then fall quickly (Fig. 4-2, curve A). Giving too much of a drug initially or giving additional doses too soon can increase the drug concentration and risk of toxicity and prolong effects and elimination time. Implications of phenytoin kinetics with repeated dosing are discussed in the next section.

Fig. 4-2 Three general models of drug elimination. After a single dose of a drug is given, the graph of the logarithm (log) of blood concentration produced over time varies based on drug distribution and elimination (kinetics). Curve A: If the drug is primarily distributed in the blood (e.g., phenytoin) and is eliminated by enzyme systems, it demonstrates one-compartment Michaelis-Menten kinetics as shown. The log of the blood concentration over time initially declines slowly until some enzyme systems are no longer saturated. From that time, the concentration will fall more rapidly. Curve B: If the drug is largely distributed in the blood (one compartment) and the elimination systems have plenty of capacity (first-order kinetics), the graph of the log of blood concentration over time will be an inverted V. The concentration rises in a straight line and then declines in a straight line. The log of the drug concentration will fall by half during each half-life of the drug. Curve C: Drugs distributed in the tissues (e.g., vancomycin) typically demonstrate two-compartment kinetics. Immediately after administration the concentration rises. As the drug is distributed into the tissues the drug concentration falls rapidly (the first part of the downward curve). As the drug is eliminated, the drug level falls more gradually.

(Courtesy William Banner, Jr.)

First Order Kinetics

One extreme of the Michaelis-Menten equation occurs when the kidney or the liver is functioning well below its capacity to remove the drug and there is little risk of overloading the system. This extreme is referred to as first-order kinetics.

With first-order kinetics, drugs behave similarly to radioactive decay, and elimination is described in terms of the drug’s half-life (t_1/2). The drug half-life is the time it takes for half of the drug to be eliminated from the body. When a half-life is listed in a drug database, the drug has first-order kinetics (see section, Half-life). See Box 4-1 for a metaphor to further explain first- and zero-order kinetics. Many of the principles described in the following sections (e.g., time to study state, volume of distribution, filtration rates) apply chiefly to drugs with first-order kinetics.

Implications of Multicompartment Distribution

Drugs can disappear rapidly from the blood if they are distributed in the tissue. The best example of this is sodium thiopental (Pentothal). In clinical practice, a single dose of intravenous thiopental has a short effect. However, the drug has a long final half-life. The explanation for this apparent contradiction is that most thiopental elimination occurs after the drug concentration is below the level needed to keep the patient asleep (i.e., anesthetized). If several doses of thiopental are administered in a short period of time in an attempt to produce anesthesia, the tissues will become saturated and no distribution will occur. If the drug concentration increases to sufficiently high levels, the clinical effect (i.e., anesthesia) may last a long time (see Fig. 4-3).

Fig. 4-3 Thiopental accumulation in body compartments: single versus multiple doses. Drugs that appear to have a short duration of action may simply be rapidly distributed into tissue, allowing patients to recover from the drug effects. When pentothal is given in a single dose (solid curve), the drug concentration rises rapidly and then falls rapidly as the drug is distributed into the tissues; as a result, the patient will wake in a short time. If an additional dose is given within a short time (dotted curve), the drug effects last for a longer time. If several doses are administered over a short time, the tissues can become saturated and the drug does not have a rapid distribution phase (dashed curve). The drug accumulates in the blood (i.e., concentration is high), elimination takes more time, and the patient will take much longer to wake. The kinetics of fentanyl are similar.

(Courtesy William Banner, Jr.)

Fentanyl also has a relatively short clinical half-life when administered as a single injection. However, if continuous infusions are used over a period of days, the drug will soon have an elimination half-life of 24   hours, meaning that it will take an extended period of time for the drug levels to decrease sufficiently so the patient wakes up. This long ultimate half-life is sometimes referred to as the beta half-life.

Frequently Used Terms

Drug concentration is affected by drug administration rate and dose, drug absorption and drug elimination. To evaluate a drug concentration, providers must be familiar with common terms such as half-life, steady state, and loading dose, and they must be familiar with drug metabolism and excretion patterns.

Steady State

When multiple doses of any medication are given, there is a period of accumulation before the drug reaches what is referred to as steady state. The steady state is a state of equilibrium between the amount of drug administered and the amount of drug being removed from the body. In drugs with first-order kinetics (i.e., the systems that eliminate the drug are not saturated), steady state can be predicted from the drug half-life. When a drug is administered as a continuous infusion, 50% of steady state is achieved during the first half-life of the drug. By the end of the second half-life of the drug, 75% of steady state will be achieved. If there is a need to achieve steady state more rapidly, administer a bolus prior to initiation of the drug infusion (see section, Bolus Plus Infusion Kinetics). Note that the average blood concentration at which steady state ultimately is achieved is the same regardless of whether the drug is given by continuous infusion or intermittent dosing (see Fig. 4-4).

Fig. 4-4 Time to steady-state concentration. Steady-state concentration is achieved after four to five half-lives of the drug (each vertical hatch mark on the time line represents one half-life of the drug) whether the drug is administered by continuous infusion (solid line) or intermittently (dashed line). The time to equilibrium and the blood concentration associated with steady state varies as the result of the drug actions, distribution, interactions, and factors affecting drug elimination.

(Courtesy William Banner, Jr.)

Clinical Examples

Several clinical examples demonstrate the range of time to steady state in drugs given by continuous infusion. Dopamine has a half-life of 1 to 2   minutes. During continuous infusion, dopamine reaches a steady-state value in the first 4 to 10   minutes of administration (four to five times the half-life of 1 to 2   minutes). By comparison, phenobarbital has a half-life of approximately 30 to 60   hours. Therefore, if phenobarbital is given by continuous infusion without a loading dose, it may take days or weeks to reach a steady-state concentration.

In patients with normal renal function, drugs such as aminoglycosides (e.g., gentamicin) have a half-life of approximately 2   hours; such drugs reach a steady state at around 8 to 10   hours, or by about the time of the second dose. However, in a patient with renal failure, the half-life of gentamicin can increase beyond 10   hours; it may take several days to achieve steady state.

Bolus Plus Infusion Kinetics

Critical care nurses often administer analgesics, sedatives, and vasoactive agents by continuous infusion, and these drugs are titrated to clinical effect. As a result, nurses should be familiar with the effects of continuous infusions and loading doses on drug concentration, as shown in Fig. 4-5.

Fig. 4-5 Bolus plus infusion kinetics. The concentration of drug reaches steady state (in this case, synonymous with therapeutic level shaded in grey) in several different ways over different time courses. When a continuous infusion is provided without a loading dose (dotted line), the drug will achieve steady state over approximately four to five half-lives of the drug. The solid line depicts the relationship of the logarithm (log) of blood concentration over time when a bolus dose plus continuous infusion is provided. The bolus dose helps to rapidly achieve steady state (in this example, synonymous with therapeutic drug concentration), and the continuous infusion has been calculated to keep the blood concentration within the therapeutic ranges. If two boluses are given (such as in the operating room to produce deep sedation) before the continuous infusion is provided (see dashed line), the initial concentration will be higher than after a single dose, and it will remain elevated for a longer period of time. The final steady-state concentration is the same whether one or more boluses are administered, provided the clearance is equal.

(Courtesy William Banner, Jr.)

As noted previously, if a drug is administered by either loading dose or continuous infusion, drug concentration will increase over time and achieve 90% of steady state over approximately four to five half-lives of the drug.

To avoid a delay in the onset of effective therapy by continuous infusion, a bolus dose can be given. The bolus dose is followed by the continuous infusion. Note that the same steady-state concentration will ultimately be achieved whether or not a bolus is given; the bolus shortens the time required to achieve this steady state.

A continuous infusion may be erroneously referred to as a maintenance dose. However, the continuous infusion will not maintain the therapeutic level if the infusion is not correctly calculated in light of elimination and other factors affecting blood concentration.

If the patient is unable to eliminate a drug normally (i.e., the patient has a decrease in clearance), a continuous infusion can contribute to drug accumulation (i.e., an elevated steady-state concentration) and toxicity. This can occur, for example, when a neonate is given the same bolus plus infusion dose as an older child. See section, Additional Factors Affecting Drug Elimination for further information.

Michaelis-Menten or Non-linear Kinetics and Dosing

A few common drugs do not obey the basic rules of steady-state equilibrium and can produce toxicity in unexpected ways. The most common of these is phenytoin and its precursor fosphenytoin. At low concentrations, phenytoin has a predictable relationship of dose to steady-state concentration (Fig. 4-6). However, as the dose increases, enzymes that normally inactivate the drug eventually become saturated. At that point, the steady-state concentration begins to rise out of proportion to the increase in dose, and even small increases in dose are then likely to substantially increase drug concentration and produce toxicity.

Fig. 4-6 Phenytoin Michaelis-Menten kinetics. This graph depicts the relationship between maintenance dose and steady state dose with phenytoin, a drug with Michaelis-Menten kinetics. For drugs with first-order kinetics (i.e., enzymes or systems that metabolize or inactivate the drug are not saturated), an increase in maintenance dose will produce a linear increase in steady-state concentration (see initial portion of solid line and continuation in dashed line). This is not the case for phenytoin and other drugs that demonstrate Michaelis-Menten kinetics. Once the enzymes that metabolize the drug are fully saturated (arrow), any increase in maintenance dose will produce a significant rise in steady-state concentration (solid line above grey therapeutic level). Other drugs such as salicylate and theophylline demonstrate similar kinetics.

(Courtesy William Banner, Jr.)

Maturation of Kinetic Processes

Developmental changes associated with hepatic drug metabolism and renal secretion or filtration can accelerate or decelerate drug elimination. Several metabolic processes mature during the first months of life (Fig. 4-7); many drug elimination pathways continue to mature during the first years of life. Failure to recognize these developmental changes in children can lead to drug complications.

Fig. 4-7 Maturation of drug elimination in infants. Drug elimination in newborns changes rapidly as a result of maturation in liver and kidney function. Providers must consider the immaturity of the newborn’s drug elimination systems when drugs are prescribed.

(Courtesy William Banner, Jr.)

By the end of the first year of life, liver metabolism and drug clearance is similar to that reported in older children and adults. The child’s glomerular filtration rate does not reach adult levels (in mL/min per m² body surface area) until approximately 3 years of age (Table 4-1)^1,6.

Table 4-1 Changes in Glomerular Filtration Rate with Age

Consistent with values from Barakat AY, Ichikawa I: Laboratory data. In Ichikawa I, editor: Pediatric textbook of fluids and electrolytes, Baltimore, 1990, Williams and Wilkins; and Tan JM: Nephrology. In Custer JW, Rau RE, editors: The Johns Hopkins Hospital Harriet Lane Handbook, ed 18, Philadelphia, 2009, Mosby-Elsevier.

Clinical Factors Affecting Drug Metabolism

Many factors affect drug metabolism. Metabolism of one drug can slow when other drugs interact or interfere with the enzyme systems that normally inactivate that drug. Drug metabolism is also likely to be slowed if the liver is injured or if it is involved in other processes, such as handling bilirubin. For drugs to be metabolized by the liver, they have to circulate to and through the liver. Fentanyl toxicity can occur when increased intraabdominal pressure decreases blood flow to the liver; the decreased liver circulation slows metabolism and prolongs the terminal half-life of the drug.

Drug elimination can be accelerated by the introduction of drugs such as phenobarbital that induce metabolism. As a result, it can be challenging to regulate levels of drugs such as anticonvulsants that are administered simultaneous with phenobarbital.

Pharmacogenetics

The emerging field of pharmacogenetics is adding new information that is critical to our understanding of drugs. Cells of the liver use the cytochrome P450 system to metabolize drugs. This cytochrome P450 system collaborates with many other systems, such as glucuronidation and acetylation, to metabolize drugs, and it initially breaks down a drug to allow the other enzymes to attack it.

Because the cytochrome P450 system works in the first stage of drug metabolism, its activity can become a critical rate-limiting step in drug metabolism. The capacity and characteristics of the cytochrome P450 system are determined by genetics; many genetically determined subtypes of the system can cause variability in drug kinetics and elimination. Dosing of warfarin can be predicted by monitoring one genetic variant of the cytochrome P450 system, and further individualization of drug therapy might be possible in the future.

Drug Excretion

The kidney can remove drugs from the body through either filtration or secretion. The most common method of renal elimination is filtration through the glomerulus, with passive elimination in the urine. Drugs removed by filtration demonstrate first-order kinetics—the more filtration that occurs, the more drug is removed.

Active transport mechanisms in the renal tubules can secrete some drugs (e.g., penicillin) directly into the urine. Cells lining the tubules actively transport the drug from the blood into the urine. This tubular active transport system is inhibited by a drug called probenecid, which can be used to prolong the effects of penicillin and ampicillin.

Altered renal function will change elimination kinetics for drugs that are filtered or secreted by the kidney. The dose of aminoglycosides such as gentamicin has to be based on the clearance or filtration of these drugs, as estimated by serum creatinine or calculated creatinine clearance.

The premature infant has markedly reduced renal function, glomerular filtration rate, and drug clearance, even when compared with a full-term infant. These renal dynamics improve significantly during the first 3 years of life (see Table 4-1). Dosing requirements for a number of drugs change during infancy, even from week to week during the first months of life. In general, for seriously ill or injured infants, the combination of immature renal function and disease state will likely slow drug elimination.

Dosing Changes

Providers must be aware of drug kinetics and elimination when adjusting drug dose. For a drug with first-order kinetics, an increase in dose will increase steady-state concentration proportionately. Providers can use that proportional increase to calculate a change in drug dose to reach a given drug concentration: to increase the drug concentration by 20%, increase the dose by 20%.

If the drug has Michaelis-Menten kinetics, any increase in dose will result in a more substantial increase in the drug concentration. For example, a 20% increase in dose may produce a 50% increase in concentration.

Drugs often demonstrate a variety of kinetics and compartments of distribution. Table 4-2 includes a short list of common pediatric critical care drugs with different kinetics and distribution.

Table 4-2 Common Drugs and Kinetic Models

Bayes’ Theorem

Bayes’ theorem is used to analyze complex clinical situations to give more credibility or weight to the most important variables that will influence the situation. When interpreting any laboratory value, providers make judgments based on the absolute value in addition to other patient variables. One example is analysis of the serum potassium concentration. The clinician should react differently to an elevated potassium concentration obtained from a heelstick sample in a child with a normal electrocardiogram (ECG) than to an elevated potassium concentration obtained by venipuncture in the child with acute renal failure, an elevated serum creatinine, and peaked T waves on the ECG. In the child with the heelstick sample, providers should give less weight to potassium concentration and more weight to the clinical findings and the conditions under which the sample was obtained. The provider should be concerned, however, about the elevated potassium concentration in the child with renal failure, because other indicators suggest that it is clinically significant. Drug level monitoring should use such analysis. Computer programs using mathematical regression analysis models are available to aid in the interpretation of drug levels.

Drug Monitoring and Dosing

Although it is important to understand principles of pharmacokinetics to interpret drug concentrations, few clinicians understand the actual mathematical theories and calculations underpinning the kinetics. Fortunately, most drug databases provide relatively simple dosing recommendations and equations that factor in the kinetics. Recommended drug doses often differ based on postconceptual age, weight, and parameters of renal function.

There are two basic reasons to determine drug levels or concentration: to judge safety or efficacy, and to predict future dosing. Drug levels are most often used to monitor for safety and efficacy and are rarely used to attempt to calculate future dosing.

When a sample is obtained to evaluate drug concentration, it is critical to know the timing of the sampling in regard to drug administration. For drugs that require a timed infusion, failure to accurately time both the drug administration and the blood sampling can yield a falsely high or low drug concentration that can cause erroneous decisions about future dosing. The following general approaches to drug dosing and monitoring form a basis for drug use.

Indications, Contraindications, and Mechanisms of Action

Nurses should be aware of a drug’s mechanism of action and contraindications, particularly if such contraindications are designated by a black box (indicating a warning from the U.S. Food and Drug Administration). The nurse should discuss concerns regarding potential contraindications with the provider who has ordered the drug.

Pharmacokinetic Parameters

The drug’s volume of distribution, protein binding, clearance, and drug half-life may be listed. A drug with a volume of distribution less than 1   L/kg is chiefly distributed in the blood, with only a small amount of tissue distribution. Larger volumes of distribution (>1   L/kg) reflect greater tissue distribution. The greater the tissue distribution, the more likely that administration of a loading dose will be needed, if it can be tolerated. If a loading dose is recommended, it should be listed with the dosing information.

Protein binding (listed as a percent of total) and its clinical importance may be noted in this section. Highly bound drugs can be displaced from proteins by other drugs or in some clinical conditions (e.g., a high BUN). Providers should consider the degree of protein binding when evaluating drug levels; measurement of the free (unbound) drug concentration may be needed.

The drug clearance reflects changes that occur with disease and maturation of organ function. Such data should also be included with dosing information. If a drug’s clearance is altered by disease states or organ function, it may be necessary to alter initial doses to avoid toxicity.

As noted previously, the drug half-life is an extremely useful piece of information. The nurse can use the half-life to predict time to steady state and to know when to anticipate drug effects or changes in effects. Estimates of time of achievement of steady state (typically four to five half-lives of the drug, unless a bolus is administered), will help determine when to obtain blood levels and when to expect a response to therapy.

The drug half-life can be used to help the nurse anticipate clinical changes when drugs are initiated or discontinued. Intravenous milrinone has a half-life of approximately 3   hours in infants, whereas dopamine has a half-life of approximately 2   minutes. If milrinone is discontinued, the drug concentration will decrease by half every 3   hours in the infant (and more rapidly in children and adults), so the benefits of the milrinone will likely decrease over the same time period. By comparison, if a dopamine infusion is discontinued, the drug concentration will halve in approximately 2   minutes, so clinical changes can be observed in that time.

Some databases will list a half-life for short-term administration and a half-life for long-term administration; these may also be termed the distributional effect (or t_1/2-alpha) and terminal elimination (or t_1/2-beta), respectively. The terminal elimination half-life will ultimately determine the time to steady state and may be responsible for prolonged effects observed in children after long-term use of sedatives.

Dosing Information

Dosing information is a critical component of any database. Loading dose, if needed, is typically the first parameter listed. The database may list a rapid loading dose, such as with some anticonvulsants, or a divided loading dose to be given over 24   h, such as with digoxin. In general, the loading dose is based on weight and does not factor in disease state or other patient parameters. To determine the loading dose for a patient, providers must identify any constraints (e.g., irritation to veins or maximum rate of infusion) to drug administration.

The initial dosing recommendations are generally divided by age group. For some drugs, dosing can be based on both development (e.g., postconceptual age) and weight (e.g., premature infant weight <1000   g). Note that to increase accuracy, drug orders should include the dose in milligrams per kilogram and the final dose (amount) to be given.

Disease-dependent variables will affect the maintenance but not the loading dose. The database may provide specific recommendations regarding alteration of dose in renal failure or in hepatic dysfunction, but databases often provide only general guidelines. Some drug dosing (e.g., fentanyl) can be affected by technology such as continuous renal replacement therapy or extracorporeal membrane oxygenation (ECMO), so ECMO loading doses and need for increased infusion rates during ECMO therapy may be noted.

Drug Interactions

Most databases list known interactions with food or disease states or other drugs. For example, enteral feedings that are high in calcium concentration (e.g., infant formulas) can interact with and change the bioavailability of some oral medications. Databases can list precautions regarding intravenous administration rate or problems with admixture with other drugs.

Sampling for Monitoring Drug Concentrations

Most drug databases suggest timing for blood sampling to monitor drug concentration. It is important to consider the primary purpose in determining the drug concentration. When monitoring for safety, a blood sample is typically obtained at the end of a dosing interval (i.e., immediately before a dose), and is called a trough level. When monitoring for efficacy, the sample is typically obtained to identify the concentration immediately after a dose (e.g., 30   minutes after a dose is infused), and is called the peak level.

If providers want to perform rigorous pharmacokinetic predictions, both peak and trough levels are evaluated to calculate a half-life and predict future dosing of drugs. Peak and trough levels are evaluated less commonly than in previous years to predict drug dosing, because more accurate information is now available to guide drug dosing.