Pharmacokinetics and Pharmacodynamics

4 Pharmacokinetics and Pharmacodynamics








Principles of pharmacokinetics


The effects of drug administration vary with both the drug and the patient. There have been many attempts to model these processes using mathematical equations to guide clinical therapy. In addition, understanding of developmental changes in drug metabolism and excretion and emerging information about pharmacogenetics enable more accurate prediction of pediatric drug dosing and effects.25



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).





Drug Distribution


Drug distribution is affected by factors such as protein binding, lipid solubility, and ionization state, and by conditions such as blood pH, temperature, and other substances in the blood (e.g., blood urea nitrogen [BUN], other drugs). The volume of distribution is the ratio of the concentration of drug in the blood to the total amount of drug in the body. For example, gentamicin has a small volume of distribution; it is principally found in the blood. In contrast, digoxin undergoes widespread distribution to tissues, so the concentration in the blood represents only a fraction of the total body stores (i.e., it has a large volume of distribution). Gentamicin and digoxin are both removed by similar processes in the kidney, but the rates of elimination of the two drugs differ because the amount that is present in the blood affects how quickly the kidneys can remove the drug.


The drug’s site of action can also help predict how drug distribution will affect its efficacy and safety. Shortly after the intravenous administration of digoxin, blood concentrations can be extremely high, but the patient will not exhibit toxicity because digoxin acts on the cardiac muscle. As the blood drug concentration decreases and concentrations in the tissue (including the heart muscle) increase, the likelihood of a toxic effect increases. It is only after the drug is distributed into tissue that blood concentrations can be used to predict the likelihood of a beneficial or toxic effect.




Mathematical modeling of drug paths


Mathematical models of drug kinetics (including elimination), called kinetic modeling, have identified several general patterns of drug behavior. The Michaelis-Menten equation describes drug kinetics, including drug elimination. According to the Michaelis-Menten equation, when the enzyme that metabolizes a drug is not saturated (i.e., there is plenty of enzyme still available to metabolize even more drug than is present), drug elimination will vary based on how quickly the drug is presented to the enzyme. If the enzyme is fully saturated (i.e., all available enzyme is being used to metabolize the drug), then drug elimination will occur at a fixed rate.



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.




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 (t1/2). 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.



Box 4-1 Metaphor for Understanding First Order and Zero-Order Kinetics


Another way to conceptualize first-order kinetics for drug elimination is to compare drug metabolism to customers going through checkout lanes at a store. A group of cashiers has a certain capacity to process customers, much as the liver processes or metabolizes a drug. If the number of cashiers is sufficiently high, when a customer appears that customer will be processed immediately. As long as the number of cashiers exceeds the number of customers presenting at the checkout lanes, the number of customers processed through the checkout lanes will be determined by the number of customers who are present at the checkout lanes. Renal filtration or excretion and liver metabolism typically have sufficient capacity, so they have capacity (“cashiers”) available at all times to eliminate many drugs. This is called first-order kinetics.


If the capacity to process or metabolize the drug is saturated, then the rate of drug metabolism will become constant and if drug administration exceeds the rate of metabolism, the drug will begin to accumulate. Using the cashier metaphor, if the number of customers exceeds the available cashiers, the rate that customers are processed will become constant (for example, 10 customers/h), regardless of how many customers are waiting. The customers will accumulate if the number of customers exceeds the number of cashiers and the customers appear at the checkout line at a rate that is faster than they can be processed. If the capacity to metabolize the drug is saturated (zero-order kinetics) drug concentrations will increase in a manner similar to customer accumulation at the cashiers.



Volume of Distribution


Volume of distribution can be used to predict the drug concentration achieved with a drug loading dose. As noted previously, a drug like gentamicin has a low volume of distribution (it remains in the blood), so effective blood concentrations are quickly established without the need for a loading dose. By comparison, when administering a drug like digoxin, with a high volume of distribution, a relatively large initial loading dose must be given to achieve reasonable blood concentration after tissue distribution.


The volume of distribution is generally expressed as a liquid volume per body weight, such as liters per kilogram (L/kg) or milliliters per kilogram (mL/kg). The volume of distribution is used to calculate loading doses for drugs such as phenytoin, for which a loading dose of 20   mg/kg is administered to occupy the volume of distribution (0.7   L/kg) and achieve a therapeutic blood (serum) concentration.


Although it is tempting to relate anatomic places to the mathematical concept of compartments for drug distribution, the characterization is not entirely accurate. In general, we consider the group of tissues into which the drug distributes at a similar rate as occupying the same compartment, because the tissues all receive the drug at the same time.


Generally speaking, when injecting an intravenous drug, the first compartment it occupies is the blood. If the drug is primarily distributed in the blood (e.g., gentamicin), that is where the drug remains until it is eliminated; these kinetics are described as one-compartment kinetics. The graph of the logarithm of blood concentration over time shows a rise when the drug is administered and a straight line as the drug is eliminated (see Fig. 4-2, curve B).


If a drug is distributed in the blood and the tissues (e.g., vancomycin), intravenous administration temporarily increases the concentration of the drug in the blood. Initially, blood levels decline rapidly as the drug moves into tissue, and then a more gradual decline occurs as the drug is eliminated. This drug activity is called two-compartment kinetics (see Fig. 4-2, curve C).



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).



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.



Dec 3, 2016 | Posted by in NURSING | Comments Off on Pharmacokinetics and Pharmacodynamics

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