Glossary 4
ka:
The “absorption rate constant” for a drug administered by a route other than the intravenous. The rate of absorption of a drug absorbed from its site of application according to first-order kinetics. ka is determined directly, or indirectly, as the slope of the linear relationship between the logarithm of the amount un absorbed and t, when natural logarithms, i.e. logarithms to the base e, are used. The half-time for absorption is computed as 0.693/ka, i.e. ln 2/ka.
Cf. kel, k0, t1/2, Half-Life, First-Order Kinetics, Cmax
kel:
The “elimination rate constant” for a drug eliminated according to the laws of first-order reaction kinetics; the slope of the plot of the logarithm of concentration against time, when natural logarithms, i.e. logarithms to the base e, are used.
t1/2 = 0.693/kel. kel = 2.303b. ClT = kel Vd. AUC from Tn to infinity = Cn/Kel.
Cf. b, t1/2, Half-Life, ka, First-Order Kinetics
k0:
The “absorption rate constant” when rate of absorption (D/T) does not vary. k0 describes the rate at which drug enters the body during constant-rate intravenous infusions, or during use of “sustained” release preparations for oral or transdermal drug administration.
Latent Period or Latency:
The period of time that must elapse between the time at which a dose of drug is applied to a biologic system and the time at which a specified pharmacologic effect is produced. In general, the latent period varies inversely with dose; the relationship between dose and latent period for a given agent is described by a time-dose or time-concentration curve.
Cf. Time-Concentration Curve, CT Index
LD50:
Loading Dose:
A larger than normal dose (D*) administered as the first in a series of doses, the others of which are smaller than D* but equal to each other. The loading dose is administered in order to achieve a therapeutic amount in the body more rapidly than would occur only by accumulation of the repeated smaller doses. The smaller doses (D) which are given after D* are called “maintenance doses”. The effect of D* on C becomes relatively less with each succeeding maintenance dose; finally Css,max and Css,min are determined by D, and are uninfluenced by D*.
The relative sizes of D and D* can be adjusted so that peak plasma concentrations (Cmax) are the same following every dose, including the first with D*, and all are equal to Css,max. These conditions are met when D/D* = 1-f.
Cf. Dose, Cmax, Css, F, Multiple Dose Regimens
Maintenance Dose:
See Loading Dose.
Median Effective Dose:
The dose of a drug predicted (by statistical techniques) to produce a characteristic effect in 50 percent of the subjects to whom the dose is given. The median effective dose (usually abbreviated ED50) is found by interpolation from a dose-effect curve. The ED50 is the most frequently used standardized dose by means of which the potencies of drugs are compared. Although one can determine the dose of drug predicted to be effective in one percent (ED1) or 99 percent (ED99) of a population, the ED50 can be determined more precisely than other similar values. An ED50 can be determined only from data involving all or none (quantal) response; for quantal response data, values for ED0 and ED100 cannot be determined. In analogy to the median effective dose, the pharmacologist speaks of a median lethal dose (LD50), a median anesthetic dose(AD50), a median convulsive dose (CD50), etc.
Cf. Dose-Effect Curve, Therapeutic Index, Standardized Safety Margin, Bioassay, Metameter
Metameter:
A term used to designate “the measurement or transformation of the measurement used in evaluating biological tests.” Examples of metameters of dose include “milligrams,” “moles,” “log milligrams,” “log milligrams per kilogram of body weight,” etc. Metameters of response include “increase in blood pressure, in mmHg,” “Maximum blood pressure achieved, in mmHg,” and “percent increase in blood pressure.” Metameters are frequently and erroneously chosen only to facilitate statistical summary and analysis of data; the metameter used may also obscure or influence the biological interpretation of the data in a manner not intended or expected by the investigator. For example, implicit in the calculation of “percent change in blood pressure ” is the statement that the final state of the system is a function of the initial state that may or may not be true.
Cf. Parameter, Bioassay, Dose-Effect Curve
Multiple Dose Regimens:
The pharmacokinetic aspects of treatment schedules that involve more than one dose of a drug are discussed below. The relationships described involve assumptions of instantaneous intravenous administration and distribution of a drug that is eliminated by first-order kinetics from a single-compartment system, and is given in equal doses at equal time intervals. The relationships become less accurate in describing real situations to the extent that the real systems depart from the ideal model, i.e. to the extent that ka is not much greater than kel, and to the extent that Vda is not much smaller than Vdb.
When equal doses are administered at equal intervals, the peak plasma concentration after the nth dose, Cmax,n is given by the relationship:
Cmax,n = C0 (1 – f n)/( l- f)
The “trough” concentrations (Cmin) for the two conditions are:
Cmin,n = Cmax,n – C0, and
Css,min = Css,max – C0, respectively.
Knowing the half-life of a drug and the Css,max and Css,min desired to produce optimum therapy, the dose interval, ? (tau), necessary to achieve and maintain these maximum and minimum concentrations can be determined from the relationship:
?= 1.443 (t1/2) ln(Css,max/Css, min).
(Remember that ln X = 2.303 log X, that t1/2 = 0.693/kel, and that 1/0.693 = 1.443.)
The doses to be administered at intervals, ?, to produce the desired Css,max and Css,min are inferred from experimental data relating the size of single doses to the peak plasma concentrations (Cmax) each produces, or are estimated from the relationship F · D/Vd = C, when the Vdand F of the drug are known. (The relationship among Css,max, Css,min and expected therapeutic outcome, including occurrence of side effects, are inferred from dose-effect relationships established in clinical pharmacologic experiments.)
With repeated doses, at equal intervals, peak plasma concentrations (Cmax) approach but, in theory, never reach Css,max. In practice, it is useful to know how long it takes for Cmaxto reach some specified level with respect to Css,max, i.e., how long it takes for Cmax/Css,max to reach, say, 0.95. Knowing the expected value of Css,max and the fractional achievement desired, e.g. 0.95, it is easy to compute the desired Cmax. Then, knowing the dose interval, ?, and the half-life of the drug, the time required to reach the desired Cmax is given by the relationship:
n? = 1.443 ( t1/2) ln [(Css,max - Cmax)/Css,max]
where the time required (n?) is expressed as the product of the number of doses and the duration of the dose interval (?). The number of doses required to achieve the desired ratio of Cmax to Css,max may be determined by dividing the right hand member of the equation by the length of the dose interval.
When ? is long, relative to t1/2, many doses may have to be given, and much time may have to pass if a reasonable fraction of Css,max is to be achieved by administering identical doses at equal interval. Under such circumstances, prompt achievement of therapeutically effective blood levels may require beginning the treatment regimen with a “loading dose” (q.v.).
Cf. Cmax, Css, Infusion Kinetics, First-Order Kinetics, Compartment
N:
The number of doses in a series; as a subscript, the last dose in a series or the number of the last dose.
Cf. Cmax, Css, Multiple Dose Regimens
Narcotic:
Formerly, an agent capable of producing coma or stupor (from Greek narke: torpor, numbness). Now, usually, any drug which produces analgesia and is capable of producing stupor: pain is relieved by a dose or narcotic before the occurrence of sleep or unconsciousness. Legally, the tern “narcotic ” is applied only to those drugs the sale and use of which is regulated by the Harrison Narcotic Act.
Cf. Addiction, Anesthetic, Analgesic
National Formulary (N.F.):
A reference volume published formerly by the American Pharmaceutical Association containing standards of purity and methods of assay for some drugs, and formulae and methods of manufacture for a variety of pharmaceutical preparations. Drugs were included on the basis of demand as well as therapeutic value. The N.F. and the U.S.P. are recognized by the F.D.A. as official standards, and the two are now published as a single volume.
Negative Control Drug or Negative Control Procedure:
A treatment incorporated into an experiment with the intention that it have no effects on the experimental system like those expected of the independent variable. In a pharmacologic experiment, the negative control drug mimics in every way the drug preparation under investigation (including identity of dosage form, vehicle, mode of application, etc.) except that the negative control drug lacks the ingredient that is expected to be responsible for the biological effect of the test preparation. The negative control drug has two functions in an experiment: 1.) To permit ascribing a causal relationship between treatment with the independent variable and changes in the experimental system which follow treatment. If the experimental system responds to both the negative control drug and the drug preparation under test, one cannot – in the absence of other information – legitimately infer that the effects of the test preparation are caused by the supposedly pharmacodynamically active test preparation. 2.) To serve as a basis for quantitative estimation of the effects of the independent variable in excess of those effects produced by non-specific changes in the environment or the experimental system. A test drug preparation may have non-specific effects like those of the negative control drug, but may also have specific effects that can be attributed to the ingredient that is unique to the test preparation.
Careful use of a negative control drug in an experiment prevents erroneous conclusions about the apparent activity of a test preparation; use of a positive control drug prevents making erroneous conclusions about apparent inactivity of a test preparation.
Cf. Positive Control Drug, Dummy, Placebo, Bioassay, Cross-Over Experiment
Parameter:
1. One of the elements of an experiment which can be varied, but which the experimenter tries to control or maintain constant during the course of a specific experiment, while intentionally altering the independent variable and observing changes in the dependent variable. Parameters in one experiment (stimulus strength, for example) might well be independent variables in another.
2. Terms of an equation that do not vary within the context of an experiment, but may be different under different circumstances. Parameter should be distinguished from the independent and dependent variables. For example, in the equation of a straight line, y = mx + b, x is normally the independent variable (the variable under experimental control), y is the dependent (measured) variable, and the slope m and intercept b are parameters, which are the same for a given line, but may be different for a different line.
Pharmacodynamics:
The science and study of the biological effects produced by chemical agents; more specifically, the science and study of how chemical agents produce their biological effects. In medical pharmacology, the science and study of how drugs produce their effects.
Cf. Pharmacology, Pharmacokinetics, Therapeutics, Pharmacogenetics
Pharmacogenetics:
The science and study of the inheritance of characteristic patterns of interaction between chemicals (drugs) and organisms. Pharmacogenetics involves identification and description of such patterns, discriminating them from non-heritable patterns, and elucidation of the mechanism of inheritance. Pharmacogenetic studies illuminate many intraspecific and interspecific similarities, and differences in pharmacodynamic and pharmacokinetic mechanisms.
Cf. Pharmacodynamics, Pharmacology
Pharmacokinetics:
The science and study of the factors which determine the amount of chemical agents at their sites of biological effect at various times after the application of an agent or drug to biological systems. Pharmacokinetics includes study of drug absorption and distribution (”biotranslocation”), study of the chemical alterations a drug may undergo in the body, (”biotransformation”), and study of the means by which drugs are stored in the body and eliminated from it.
Cf. Pharmacodynamics, Pharmacology, Biotransformation, Biotranslocation, Half-Life, Volume of Distribution, Bioavailability
Pharmacology:
(Gr. Pharmakon – drug, and Logos – word) is the study of drugs in all their aspects. Pharmacy, although often confused with pharmacology, is, in fact, an independent discipline concerned with the art and science of the preparation, compounding, and dispensing of drugs. Pharmacognosy is a branch of pharmacy that deals with the identification and analysis of the plant and animal tissues from which drugs may be extracted. Pharmacodynamics, which in common usage is usually termed “pharmacology”, is concerned with the study of drug effects and how they are produced. The pharmacodynamicist, or pharmacologist, identifies the effects produced by drugs, and determines the sites and mechanisms of their action in the body. The pharmacologist studies the physiological or biochemical mechanisms by which drug actions are produced. The pharmacologist also investigates those factors that modify the effects of drugs, i.e. the routes of administration, influence of rates of absorption, differential distribution, and the body’s mechanisms of excretion and detoxification, on the total effect of a drug. Pharmacotherapeutics is the study of the use of drugs in the diagnosis, prevention, and treatment of disease states. Toxicology is the study of drug effects that are inimical to health. The toxicologist may investigate such diverse problems as the effects of overdoses of pharmacotherapeutic agents; the diagnosis, treatment, and prevention of lead poisoning in the paint manufacturing industry; the possibility that criminal poisoning was the cause of an otherwise inexplicable death, etc.
“Experimental pharmacology, in the broadest sense, deals with the reactions of living organisms to chemical agents, or, to put the matter in another way, the behavior of organisms to changes in the chemical environment in which they live. Pharmacology is a part of biology… Of all the vast number of pharmacologic reactions, those that the physician attempts to use for curative purposes are of the greatest interest and most deserved of study. This part of pharmacology, the scientific knowledge of remedial agents, forms the theoretical foundation for therapeutics…” H.H.Meter and R. Gottlieb, Experimental Pharmacology as a Basis for Therapeutics: A Textbook for Students and Physicians, 1910 (trans. by V. E. Henderson).
Cf. Therapeutics, Pharmacodynamics, Pharmacokinetics, Pharmacogenetics, Toxicology
Placebo:
(Latin: I will satisfy). “A medicine or preparation with no inherent pertinent pharmacologic activity that is effective only by virtue of the factor of suggestion attendant upon its administration.” A placebo is frequently used as a negative control in a blind experiment to prevent results from being confounded by the effect of suggestion.
Cf. Dummy, Negative Control Drug, Positive Control Drug
Positive Control Drug:
A drug preparation incorporated into an experiment with the intention that it have effects on the experimental system qualitatively similar to those expected of the independent variable. The positive control drug has two functions in an experiment: 1) to verify that the experimental system is indeed capable of undergoing the changes expected to follow manipulation of the independent variable. If the system fails to respond to the positive control drug, its failure to respond to the independent variable is uninterpretable; 2) to serve as a basis for quantitative estimation of the relative efficacy of the independent variable. In these terms, the positive control drug is a “standard”, and the independent variable may be considered the ” unknown” in a bioassay.
Cf. Negative Control Drug, Bioassay, Cross-Over Experiment, Reference Standard
Potency:
An expression of the activity of a drug, in terms of the concentration or amount needed to produce a defined effect; an imprecise term that should always be further defined (see EC50, ED50).
Cf. Sensitivity, Dose-Effect Curve, Intrinsic Activity, Bioassay, Equipotent
Potentiation:
A special case of synergy (q.v.) in which the effect of one drug is increased by another drug that by itself has no effect. For example, although physostigmine has no acetylcholine-like activity of its own, it potentiates the actions of acetylcholine by inhibiting the enzymes responsible for the destruction of acetylcholine. Intensity of effect may be potentiated, duration of effect may be prolonged: potentiation and prolongation are independent phenomena, but frequently occur together.
Cf. Synergy, Antagonism
Priming Dose:
See Loading Dose.
Prodrug:
A chemical with little or no pharmacologic activity that undergoes change in the body into a more active material. The change may be a result of biotransformation, or may occur spontaneously, in the presence of, e.g., water, an appropriate pH, etc.
Precision:
The capacity of the system to discriminate between different values of input; the “fineness” with which different values for input can be inferred from measured values of output. The pooled deviation of observed from expected values of output, all divided by the amplification, yields the “index of precision”. The square of the reciprocal of the index of precision is the measure of the amount of information that can be delivered by the system.
Specifically, precision is computed in several steps. First, the deviation of each observed value of output from the corresponding predicted value is squared; predicted values are determined from the curve relating input and output for all the data. The squared deviations are summed and divided by N-2, the number of “degrees of freedom”; the square root of the quotient is determined and is a number analogous to the standard deviation. This “root mean square deviation” is then divided by the slope of the input-output curve, i.e., the amplification, to yield the “index of precision “; it is assumed that the input-output relationship is linear.
See Accuracy
