The mention of pharmacokinetics and toxicokinetics often provokes anxiety in clinicians. However, knowledge of a few basic principles within this discipline of clinical pharmacology aids in the management of the acutely poisoned patient. Unfortunately, unfamiliarity with these concepts is common. Moreover, sources of self-study such as reference texts and review articles use concepts of calculus foreign to the average clinician. Questions commonly arising in the overdosed patient include the need for the institution of procedures that augment excretion, such as dialysis, hemoperfusion, the timing and interpretation of blood level determinations, and the explanation for prolonged persistence of symptoms in some overdose patients. This article reviews kinetic principles to answer these questions without advanced calculus or a pocket calculator.
"Pharmacokinetics is the study, as a function of time, of all processes which determine the fate of drug in the organism to which it is administered; in order to elaborate a model of predictive value."1 It consists of mathematical concepts derived to explain the rates of absorption, distribution, metabolism, and excretion of drugs within the body. Because groups of drugs behave differently, different models have been developed to explain these variations. The characterization of the kinetics of a particular drug involves the study of clinical doses within animals and humans. Obviously, large doses (overdoses) cannot be similarly studied. Not surprisingly, large doses of drugs can have longer rates of absorption, distribution, metabolism, and excretion compared with therapeutic doses. The term toxicokinetics was coined in recognition of these differences in behavior. However, precise toxicokinetic values for specific drugs are not known because specific experimentation cannot be done. Thus, it is often difficult to predict the duration of clinical intoxication.
AUGMENTATION OF EXCRETION
A cardinal tenet in the management of the acutely poisoned patient is to augment the excretion of the poison from the patient. Interventions aimed at achieving this goal include dialysis and hemoperfusion. These techniques will work only if the active agent, poison, or its biologically active metabolite, is accessible to the intervention. For example, if 99% of the drug is tissue bound, significant amounts would not be removed from the body by the use of a bloodcleansing procedure such as hemodialysis. The pharmacokinetic principle of volume of distribution helps to define accessibility.
The volume of distribution is a mathematical abstraction and can be greater than the total body volume. It is "not a real volume but an artifact - a hypothetical volume of body fluid that would be required to dissolve the total amount of a drug at the same concentration as that found in the blood."1 It is derived from the simple formula of volume equals the total amount of a substance within that volume divided by its concentration. This assumes that the concentration is equal throughout the volume in question, which usually is not the case in biologic systems.
After a drug has been absorbed, it distributes to various areas of the body. The extent of this distribution depends on several factors that include lipid solubility, active transport mechanisms, and tissue and protein binding. Thus, at equilibrium, the concentrations within various organs can differ greatly from the plasma concentration. If the drug has a high degree of tissue binding, it will have a lower plasma concentration. Because the calculation of the volume of distribution assumes that these concentrations are equal, for a constant amount of drug, a low plasma level will result in a large volume of distribution (volume=amount/concentration). Thus, a high volume of distribution indicates that only very little of the drug is within the plasma, making it relatively inaccessible to interventions that augment excretion from the body.
In clinical situations, physicians can predict the likelihood of potential benefit from dialysis or hemoperfusion by referring to the drug's volume of distribution. These values have been established and can be found in most pharmacology texts. For example, the values for acetylsalicylic acid and phénobarbital are 0.15 and 0.54 L/kg. If the volume of distribution is high (>1.0 L/kg is a useful rule of thumb), then the patient is not likely to benefit from these procedures. Unfortunately, this is so for most drugs and explains why these procedures are not generally helpful. On the other hand, a low volume of distribution does not guarantee efficacy of these interventions because other factors such as plasma protein binding, endogenous clearance, and metabolism to nontoxic metabolites are also important.
TIMING OF DRUG LEVEL DETERMINATIONS
The timing of blood sampling for drug levels and the interpretation of the results is aided by the understanding of the pharmacokinetic principle of distribution. This is "the act of apportioning or spreading out of a drug in an orderly manner once it reaches the general circulation. It is a state by which a drug is distributed or apportioned to one or more so called volumes or spaces, tissues, organs, etc."1
Following absorption into the blood, a drug is distributed to the tissues. If a blood level is measured prior to the completion of the distributive phase, it would be high relative to the tissue level. This is commonly seen with digoxin. Levels taken soon after the ingestion of this drug, even routine therapeutic doses, can be well into the toxic range. However, the patient may be asymptomatic because the myocardial concentration has not yet equilibrated with the plasma concentration.
Toxicokinetics are also important when trying to decide the proper timing for taking blood levels after overdose. This is because the absorptive phase can be longer for toxicologic versus therapeutic doses. Therefore, early blood levels may underestimate the severity of the situation. This is why the nomograms for acetaminophen and salicylate begin at 4 and 6 hours post ingestion, respectively. In clinical practice, for many cases of serious overdose, familiarity with kinetics will not enable the physician to choose a specific time to draw one single blood sample from which patient disposition decisions can be made. Serial blood samples are important in this regard, and the understanding of the kinetic principles will contribute greatly to their interpretation.
Occasionally, a seriously poisoned patient demonstrates a seemingly prolonged duration of symptoms. The differential diagnosis for this situation is quite extensive and beyond the scope of this article. However, one factor often not considered involves a toxicokinetic principle. A drug taken in overdose may persist for a disproportionately longer period than if it were taken in a therapeutic amount. A commonly held misconception is that one can predict the duration of symptoms after a drug level is known by continually subtracting the known half-life of the drug from the initial concentration until one arrives at a nontoxic level. However, drug half-lives are derived from studying therapeutic doses of drugs (pharmacokinetics) and not from toxic doses (toxicokinetics). The half-life can be prolonged after an overdose because enzymatic pathways for drug handling (catabolism and excretion) can become saturated. The net effect is an inability to increase the amount of drug excreted from the body despite an increase in the amount of the drug in the body. Thus, the half-life becomes prolonged.
In theory, this prolongation can be predicted using pharmacokinetic principles. However, in practice, this is not the case because much of the required data are not known (eg, amount of overdose and the individual patient's metabolic activity). Thus, we are left in the unsatisfactory situation of knowing that symptoms may persist for longer than expected, but not knowing in which patient and for how long.
Familiarity with a few principles of pharmacokinetics and toxicokinetics will aid the physician's management of the overdose patient. Situations in which such knowledge can be helpful include the decision for the implementation of interventions to augment the excretion of a toxin, the timing and interpretation of drug levels, and the explanation for unexpected prolonged states of clinical intoxication.
1 . Zathurcckv L. Progress in developing a standard terminology in hiopharmaceutics and pharmacokinetics. Drug, lntethgence and Clinical Pharmacy. 1977; 11:281-2%.