Glossary 2
C, Cx:
The concentration (in units of mass/volume) of a chemical in a body fluid such as blood, plasma, serum, urine, etc.; the specific fluid may be indicated by a subscript, i.e. CU, the concentration of drug in the urine; when no subscript is used, C is commonly taken to be the concentration in the plasma.
C0:
The fictive concentration of a drug or chemical in the plasma at the time (in theory) of an instantaneous intravenous injection of a drug that is instantaneously distributed to its volume of distribution. C0 is determined by extrapolating, to zero-time, the plot of log C against t (for apparently “first-order ” decline of C) or of C against t (for apparently “zero-order” decline of C).
Cf. Volume of Distribution, Cmax, Css, First-Order Kinetics, Zero-Order Kinetics
Cmax, Cmin:
The maximum or “peak” concentration (Cmax) of a drug observed after its administration; the minimum or “trough” concentration (Cmin) of a drug observed after its administration and just prior to the administration of a subsequent dose. For drugs eliminated by first-order kinetics from a single-compartment system, Cmax, after n equal doses given at equal intervals is given by C0(1 – fn )/(1 – f) = Cmax, and Cmin = Cmax – C0.
The time following drug administration at which the peak concentration of Cmax occurs, tp (for any route of administration but the intravenous), is given by tp = (ln ka – ln kel )/(ka – kel). (Remember that ln is the natural logarithm, to the base e, rather than the common logarithm or logarithm to the base 10; ln X=2.303 log X.)
Cf. Css , f , Multiple Dose Regimens
Css:
The concentration of a drug or chemical in a body fluid – usually plasma – at the time a “steady state” has been achieved, and rates of drug administration and drug elimination are equal. Css is a value approached as a limit and is achieved, theoretically, following the last of an infinite number of equal doses given at equal intervals. The maximum value under such conditions (Css,max) is given by Css,max = C0/(1 -f), for a drug eliminated by first-order kinetics from a single compartment system. The ratio Css,max/C0 indicates the extent to which drug accumulates under the conditions of a particular dose regimen of, theoretically, an infinitely long duration; the corresponding ratio 1/(1 – f) is sometimes called the Accumulation Ratio, R. Css is also the limit achieved, theoretically, at the “end” of an infusion of infinite duration, at a constant rate.
Cf. Multiple Dose Regimens , Infusion Kinetics, First-Order Kinetics
Cl, Clx:
Clearance – in volume/unit time – of a drug or chemical from a body fluid, usually plasma or blood, by specified route(s) and mechanism(s) of elimination, as indicated by a subscript, e.g., ClR, urinary clearance; ClH, hepatic clearance, etc. ClT, total clearance, indicates clearance by all routes and mechanisms of biotransformation and excretion, operating simultaneously. ClT = kel · Vd. Following intravenous administration, ClT = D/AUC; following administration of drug by any route other than the intravenous, ClT = F D/AUC.
Ceiling:
The maximum biological effect that can be induced in a tissue by a given drug, regardless of how large a dose is administered. The maximum effect produced by a given drug may be less than the maximum response of which the reacting tissue is capable, and less than the maximum response that can be induced by another drug of greater intrinsic activity. “Ceiling” is analogous to the maximum reaction velocity of an enzymatic reaction when the enzyme is saturated with substrate.
Chemotherapy:
Drug treatment of parasitic or neoplastic disease in which the drug has a selective effect on the invading cells or organisms.
Clearance:
The clearance of a chemical is the volume of body fluid from which the chemical is, apparently, completely removed by biotransformation and/or excretion, per unit time. In fact, the chemical is only partially removed from each unit volume of the total volume in which it is dissolved. Since the concentration of the chemical in its volume of distribution is most commonly sampled by analysis of blood or plasma, clearances are most commonly described as the “plasma clearance” or ” blood clearance” of a substance.
For a single compartment system, total clearance, by all routes (ClT), is estimated as the product of the elimination constant and the volume of distribution, in liters: ClT = kel · Vd the dimensions of ClT are, of course, volume/time.
Renal Clearance:
Renal plasma (or blood) clearance ClR is the volume of plasma (or blood) freed of a substance by only renal mechanisms, per unit time. The amount of drug (AU) excreted in the urine during the time interval t – t’ is determined; the plasma (or blood) concentration at the mid-point of the interval (Cp) is found by interpolation on the line relating log C and t. The urinary excretion rate of the drug,
AU/(t – t’), divided by Cp is the renal clearance.
Renal plasma clearance will vary with such factors as age, weight, and sex of subject, the state of cardiovascular and renal function, the nature of the material being excreted, species, etc. Renal clearance by only glomerular filtration is defined and measured as the clearance of the sugar inulin, which is eliminated from the body by no route other than glomerular filtration. Total renal clearance is defined and measured by clearance of para-amino-hippurate (PAH), a substance that is eliminated by both glomerular filtration and tubular excretion (at the maximum rate of which the tubular mass is capable). Neither inulin nor PAH undergoes reabsorption by the tubules as some materials do. (N.B.: Blood and plasma are completely cleared of PAH by a single “pass” through the kidney; PAH clearance is therefore, the standard measure of renal plasma, or blood, flow).
In normal adult human males, plasma clearance of inulin is about 130 ml plasma/min; of PAH, about 700 ml plasma/min. In normal adult human females, clearance of inulin is about 115 ml plasma/min; of PAH, about 600 ml plasma/min. The relationship between clearance of blood and clearance of plasma is given by the relationship ClR (blood) = ClR (plasma)/(1-Hct), where “Hct” is the hematocrit, the proportion, as a fraction – of the blood which consists of cells, not plasma; on the average, normal adult human subjects can be assumed to have a hematocrit of about 0.45.
Like
many other physiological “constants,” renal plasma clearance varies regularly and exponentially with body weight, across mammalian species ( Science 109: 757, 1949). Renal plasma clearances, in normal animals, can be predicted using the following relationships, where Cl R is in ml/hr, and body weight (B) is in grams:
ClR (inulin) = 1.74B0.77
ClR (PAH) = 5.40B0.80
Nonrenal Clearance:
Clearance by the fecal route (ClF), respiratory route (ClL), salivary route (ClS), biliary route (ClB), can be computed in a fashion analogous to computation of ClR: measuring the amount of substance excreted in the feces, expired air, saliva, etc., over an interval and dividing by the plasma concentration at mid-interval and the length of the interval. Following oral administration of a substance, measurement of fecal clearance may be confounded by the presence, in feces, of unabsorbed substance or of substance absorbed but excreted into the lumen of the gastrointestinal tract in, e.g., bile. Specialized techniques exist for estimating clearance of substances by the liver (ClH), by biotransformation and/or biliary excretion.
Unlike half-lives, clearances are directly additive and for any substance:
ClT = ClR + ClL + ClH + ClS + ClF + . . . etc.
Clinical Therapeutic Index:
Some indices of relative safety or relative effectiveness cannot be defined explicitly and uniquely, although it is presumed that the same quantifiable and precise criteria of efficacy and safety will be used in comparing drugs of similar kinds. The Food and Drug Administration has considered the following definition of an improved Clinical Therapeutic Index to be used in comparing different drug combinations or formulations; the assumption is retained that an improved or ” better” drug has a higher Clinical Therapeutic Index ” (1) increased safety (or patient acceptance) at an accepted level of efficacy within the recommended dosage range, or (2) increased efficacy at equivalent levels of safety (or patient acceptance) within the recommended dosage range.”
Cf. Food and Drug Administration, Therapeutic Index, Standardized Safety Margin, Effective
Compartment(s):
The space or spaces in the body, which a drug appears to occupy after it has been absorbed. Pharmacokinetic compartments are mathematical constructs and need not correspond to the fluid volumes of the body which are defined physiologically and anatomically, i.e., the intravascular, extracellular and intracellular volumes.
Some drugs make the body “behave” as if it consisted of only a single pharmacokinetic compartment. Tissue and plasma concentrations of the drug rapidly and simultaneously reach equilibrium in all the tissues to which the drug is distributed. A plot of plasma concentration against time after intravenous administration can be rectified into only a single straight line of negative slope, which can intersect the ordinate at only one point; only one volume of distribution can be calculated. Hence, the existence of only one compartment or volume of distribution can be inferred.
Some drugs make the body appear to consist of two or more pharmacokinetic compartments, since tissue/plasma equilibrium is achieved at different times in different tissues or groups of tissues. A plot of plasma concentration against time after intravenous administration can, at best, be resolved into a series of connected straight-line segments with progressively decreasing slopes. Each of these segments may be extrapolated to intersect the ordinate, and one may infer the existence of as many pharmacokinetic compartments, of volumes of distribution, for the drug as there are intersections or segments.
Compartments in which equilibrium is achieved relatively late are referred to as “deep” compartments; compartments in which equilibrium is achieved early – and from which drug is redistributed to other sites – are referred to as “shallow” or “superficial” compartments.
Cf. a, b, Volume of Distribution, Vd
Compliance:
The extent to which a patient agrees to and follows a prescribed treatment regimen.
Cross-Over Experiment:
A form of experiment in which each subject receives the test preparation at least once, and every test preparation is administered to every subject. At successive experimental sessions each preparation is “crossed-over” from one subject to another. The purpose of the cross-over experiment is to permit the effects of every preparation to be studied in every subject, and to permit the data for each preparation to be similarly and equally affected by the peculiarities of each subject. In a well-designed cross-over experiment, if it is at all possible, the sequence in which the test preparations are administered is not the same for all subjects, in order to avoid bias in the experiment as a result of changes in the behavior of the subjects that are a function of time rather than of drug administration, or a function of drug interactions. At least, the cross-over design permits detecting such biases when they occur. The preparations under test in a cross-over experiment may – ideally, should – include one or more doses, of an experimental or “unknown” drug, one or more doses of a dummy or placebo medication (”negative control drugs”), and one or more doses of a standard drug, the actions of which are expected to be similar to those of the “unknown” (”positive control drug”). Even for the investigator with the best knowledge and intentions, the economics and logistics of experimentation may prevent carrying out a complete and perfect cross-over experiment.
Cf. Bioassay, Positive Control Drug, Blind Experiment
Cross-Tolerance:
Tolerance to a drug that generalizes to drugs that are chemically related of that produce similar affects. For example, a patient who is tolerant to heroin will also exhibit cross-tolerance to morphine.
CT Index:
A measure of drug “potency” calculated from data appropriate to the construction of a Time-Concentration curve; the product of the concentration (C) of an agent applied to a biological system to produce a specific effect and the duration (T) of application required to produce the effect. The index is calculated on the assumption that the time-concentration curve is precisely and symmetrically hyperbolic and convex to the origin, and that the products of the coordinates for all points on the line are constant. The time-concentration curve of an agent with high potentiality for producing a specified effect lies closer to the axis than the curve for an agent of lesser potential; the CT index for the agent of greater potential is smaller than the index for the agent of lesser potential, i.e., the smaller the CT index, the more “potent” the compound. CT indices have found their greatest application in toxicology, in assessing the potential for effect of noxious vapors, etc.
Cf. Time-Concentration Curve, Potency, Dose-Effect Curve, Latency
D*:
Loading Dose (q.v.)
D:
Dose (q.v.); also the “maintenance doses” administered after a loading dose (q.v.)
Dependence:
A somatic state which develops after chronic administration of certain drugs; this state is characterized by the necessity to continue administration of the drug in order to avoid the appearance of uncomfortable or dangerous (withdrawal) symptoms. Withdrawal symptoms, when they occur, may be relieved by the administration of the drug upon which the body was “dependent.”
Cf. Addiction, Habituation
Desensitization:
A decline in the response to repeated or sustained application of an agonist that is a consequence of changes at the level of the receptor.
Cf. Tachyphylaxis, Tolerance.
Disintegration Time:
The time required for a tablet to break up into granules of specified size (or smaller), under carefully specified test conditions. The conditions of the laboratory test, in vitro, are set to simulate those that occur in vivo. Factors such as the kind and amount of tablet binders and the degree of compression used in compacting the tablet ingredients help determine disintegration time. The active ingredients in a disintegrated tablet are not necessarily found to be in solution and available for absorption. A long disintegration time is incompatible with rapid drug absorption; a short disintegration time, by itself, does not ensure rapid absorption.
Cf. Dissolution Time , Generic Drugs , Biopharmaceutics
Dissolution Time:
The time required for a given amount (or fraction) of drug to be released into solution from a solid dosage form. Dissolution time is measured in vitro, under conditions that simulate those that occur in vivo, in experiments in which the amount of drug in solution is determined as a function of time. Needless to say, the availability of a drug in solution – rather than as part of insoluble particulate matter – is a necessary preliminary to the drug’s absorption.
Cf. Disintegration Time , Bioavailability , Generic Drug , Biopharmaceutics
Distribution:
See Volume of Distribution , Pharmacokinetics
Dosage Form:
The physical state in which a drug is dispensed for use. For example: a frequent dosage form of procaine is a sterile solution of procaine. The most frequent dosage form of aspirin is a tablet.
Dose:
The quantity of drug, or dosage form, administered to a subject at a given time; for example, the usual dose of aspirin for relief of pain in an adult is 300-600 milligrams. Dose may be expressed in terms appropriate to a specific dosage form, i.e., one teaspoonful of a liquid medication, rather than the weight of drug in the teaspoonful. Dose may be described as an absolute dose (the total amount administered to a subject) or as a relative dose (relative to some property of the subject as body weight or surface area, mg/kg, or mg/m 2).
Cf. Dosage, Multiple Dose Regimens
Dose-Duration Curve:
The curve describing the relationship between dose (as the independent variable) and duration of drug effect (as the dependent variable, T). The slope of the curve is always positive, in contrast to the slope of the time-concentration curve (q.v.). There has been increased interest in the dose-duration curve as a useful measure of drug action since Levy’s demonstration that the constants describing the straight log dose-duration curve of a drug can be used to infer pharmacokinetic and pharmacodynamic properties of the drug, such as the elimination half-life and the threshold dose. (Clin. Pharmacol. & Therap. 7: 362, 1966).
Cf. Dose-effect curve, Time-Concentration Curve, Pharmacokinetics
Dose-Effect Curve:
A characteristic, even the sine qua non, of a true drug effect is that a larger dose produces a greater effect than does a smaller dose, up to the limit to which the cells affected can respond. While characteristic of a drug effect, this relationship is not unique to active drugs, since increasing doses of placebos (q.v.) can, under certain conditions, result in increasing effects. Distinguishing between ” true” and “inactive” drugs requires more than demonstration of a relationship between “dose” and effect.
The curve relating effect (as the dependent variable) to dose (as the independent variable) for a drug-cell system is the “dose-effect curve” for the system. For a unique system, i.e., one involving a single drug and a single effect, such curves have three characteristics, regardless of whether effects are measured as continuous (measurement) or discontinuous (quantal, all-or-none) variates:
- The curves are continuous, i.e. there are no gaps in the curve, and effect is a continuous function of dose. Some effect corresponds to every dose above the threshold dose (q.v.), and every dose has a corresponding effect; there is no inherent invalidity in interpolating doses or effects from a dose-effect curve.
- The curves are “monotonic”. The curve may have a positive slope, or a negative slope, but not both if the system under study is unique. The slope of the curve may show varying degrees of positivity (negativity), but the sign of the slope stays the same throughout the range of testable doses. When monotonicity of a dose-effect curve does not obtain, one may infer that the system under study is not unique or singular: either more than one active agent or more than one effect is under study.
- The curves approach some maximum value as an asymptote, and the asymptote is a measure of the intrinsic activity (q.v.) of the drug in the system.
Cf. Bioassay, Median Effective Dose, Time-Concentration Curve, Dose-Duration Curve, Metameter
Drug:
A chemical used in the diagnosis, treatment, or prevention of disease. More generally, a chemical, which, in a solution of sufficient concentration, will modify the behavior of cells exposed to the solution. Drugs produce only quantitative changes in the behavior of cells; i.e., drugs increase or decrease the magnitude, frequency, of duration of the normal activities of cells. Drugs used in therapy never produce qualitative changes in cell behavior short of producing death of the cell, e.g., a nerve cell cannot be made to contract or a muscle cell cannot be made to secrete saliva by use of a drug. The degree to which this point of view will be modified by the discovery and development of agents which act on cells at a genetic level remains to be seen.
Drug Abuse:
Use or misuse of a drug under conditions, or to an extent, considered “more destructive than constructive for society and the individual.” More specifically, the use of drugs for their effects chiefly on the central nervous system, to an extent and/or at a frequency and/or for a duration of time that is inimical to the welfare of the user and/or the total of social groups in which she/he lives. The abuse potential of a drug depends on its capacity to induce compulsive drug-seeking behavior in the user, its capacity to induce acute and chronic toxic effects (and to permit occurrence of associated diseases), and upon social attitudes toward the drug, its use, and its effects.
Cf. Drug Dependence, Addiction, Habituation, Harrison Act
Drug Dependence:
“Drug Dependence” has been recommended as a term to be substituted for such words as “addiction” and “habituation” since it is frequently difficult to classify specific agents as being only addictive, habituating, or non-addicting or non-habituating. It has been suggested that the general term be used and modified, appropriately, in specific instances, e.g., drug dependence of the barbiturate type.
Cf. Addiction, Habituation, Drug Abuse, Harrison Act
Dummy:
“A counterfeit object;” a form of treatment – as in an experimental investigation of drug effects – which is intended to have no effects, to be biologically inert. The dummy treatment should mimic in every way (dosage form, route of administration, etc.) the purportedly active ingredient upon which the effectiveness of the active treatment is expected to depend. In contrast to a dummy, a placebo is expected to have an effect through the agency of “suggestion” or other psychological mechanisms, even though the effects of placebos may be psychological or physical. Dummies may, of course, have the effects of placebos, but it is useful to be aware of the difference expected to exist between the two.
According to Gaddum, dummies have two functions: 1) to distinguish between drug effects in a subject and other effects, such as those of suggestion: obviously, an experiment might properly incorporate both a dummy and a placebo. 2) to obtain an unbiased assessment of the result of a pharmacologic experiment. (See Gaddum, J.H., Proc. Roy. Soc. Med. 47: 195, 1954).
