Glossary 1
A:
An amount of drug or chemical in units of mass such as milligrams. Special attributes of the amount are indicated by subscripts: A0, the amount of drug in the body at “zero-time;” AB, the amount of drug in the body; AU, the amount of drug recovered in the urine, etc. The amount of drug in the drug’s volume of distribution is equal to the concentration of the drug times the volume: A = C · Vd.
a:
The earlier segment of a biphasic plot of log C against t (following intravenous injection of a drug) represents the “distributive phase” of a drug’s sojourn in the body. a is used as a subscript for pharmacokinetic parameters appropriate to the distributive phase, e.g., t1/2a, Vda, etc.
Cf. b, Compartments, Volume of Distribution, Half-Life
Absorption Rate Constant:
See ka
Accumulation, Accumulation Ratio:
See Css
Accuracy:
The use of the word “accurate” – free of error – in referring to a scientific observation or scientific method sometimes obscures the fact that even the best methods and observations are only relatively free from error. The use of the single word “accurate” also hides the fact that a number of separate elements contribute to over-all freedom from error. “Accurate” is frequently used to refer indiscriminately to the effect of any of these elements, or to the combined effects of all of them on the freedom from error of a system. Effective use of a method or observation requires that we know the ways and degrees to which the data are free of error, not that we know only that the data are “accurate” or “inaccurate”.
The elements to be taken into account in a complete evaluation of a method or system can be derived from the properties of the quantitative relationship between the “input” and the “output” for the system. The input-output relationship, for all its generality, has specific application–and specific names–in different scientific fields and for different kinds of experimental or observational systems. In physics and engineering, the “stress-strain diagram” is a special representation of the input-output relationship; in pharmacology, the “dose-effect curve” is an example of the input-output relationship. In quantitative chemical analyses, the “calibration curve” is an example of the input-output relationship. Generally, “input” can be looked on as the measured value of an independent variable or “measurand”; “output” can be viewed as a measurement made under non-standard or test conditions.
“Accuracy”, as formally defined, and the elements that contribute to it can be only briefly outlined here.
- Accuracy
- In engineering, “accuracy” is the ratio of the “error” of a system to the range of values for output that are possible, i.e., the ratio of error to so-called Full-Scale Output. Error is defined as the algebraic difference between an indicated output value and the true measure of the input or measurand. Error, as defined by the engineer, is most like “precision” as defined below.
- Validity
- The degree to which output reflects what it purports to reflect, i.e., input; the degree to which output is a function of known input and it alone. For example, does an essay examination validly measure a student’s knowledge of material, or is it invalid, actually measuring his literary skill or the state of the grader’s digestion?
- Reliability
- The degree to which the input-output relationship is reproducible if the relationship is studied repeatedly under comparable conditions. For example, if a student took the same examination twice, or in two forms, would he get the same grade both times? If the same work were reviewed by two graders, would they both assign the same mark?
- Sensitivity
- The lowest value of input that can be inferred with a given degree of validity and reliability from measurements of output. Analogous to the usage for the word “threshold” is the phrase “threshold dose”. The engineer uses the word “threshold”, however, to mean the smallest change in input that will result in change in output.
- Amplification
- The amount of change in measured output per unit change in input. The slope of the input-output, or dose-effect, curve. (Engineers sometimes refer to “amplification” as “sensitivity”.)
- 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.
- Comparability
- The ability of a system to deliver data that can be compared in standard units of measurement and by standard statistical techniques with the data delivered by other systems. While not a critical component of accuracy, comparability of data generated by a system is critical to evaluating its accuracy and usefulness.
- Economy
- The ability of a system to deliver data of high information content at a low overall cost per item of data; economy does not, of course, contribute to ” accuracy” but is an important determinant of the practical usefulness of a system or method.
Activity, Intrinsic:
Addiction:
According to DSM-IV (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Washington, D.C., 1994):
“A maladaptive pattern of substance use leading to clinically significant impairment or distress as manifested by three (or more) of the following, occurring at any time in the same 12-month period:
* Substance is often taken in larger amounts or over longer period than intended
* Persistent desire or unsuccessful efforts to cut down or control substance use
* A great deal of time is spent in activities necessary to obtain the substance (e.g., visiting multiple doctors or driving long distances), use the substance (e.g., chain smoking), or recovering from its effects
* Important social, occupational or recreational activities given up or reduced because of substance abuse
* Continued substance use despite knowledge of having a persistent or recurrent psychological, or physical problem that is caused or exacerbated by use of the substance
* Tolerance, as defined by either: (a) need for increased amounts of the substance in order to achieve intoxication or desired effect; or (b) markedly diminished effect with continued use of the same amount
* Withdrawal, as manifested by either: (a) characteristic withdrawal syndrome for the substance; or (b) the same (or closely related) substance is taken to relieve or avoid withdrawal symptoms”
Cf. Dependence, Drug Dependence, Habituation, Tolerance.
Affinity:
The equilibrium constant of the reversible reaction of a drug with a receptor to form a drug-receptor complex; the reciprocal of the dissociation constant of a drug-receptor complex. Under the most general conditions, where there is a 1:1 binding interaction, at equilibrium the number of receptors engaged by a drug at a given drug concentration is directly proportional to their affinity for each other and inversely related to the tendency of the drug-receptor complex to dissociate. Obviously, affinity depends on the chemical natures of both the drug and the receptor. (See: Ariens, E.D. et al., Pharmacol. Rev. 9: 218, 1957).
Agonist:
A ligand that binds to a receptor and alters the receptor state resulting in a biological response.
Agonist, Partial:
A partial agonist is an agonist that produces a maximal response that is less than the maximal response produced by another agonist acting at the same receptors on the same tissue, as a result of lower intrinsic activity. See also Agonist, Full.
Agonist, Full:
A full agonist is an agonist that produces the largest maximal response of any known agonist that acts on the same receptor.
Agonist, Inverse:
An inverse agonist is a ligand that by binding to a receptor reduces the fraction of receptors in an active conformation, thereby reducing basal activity. This can occur if some of the receptors are in the active form in the absence of a conventional agonist.
Allergic Response:
Some drugs may act as haptens or allergens in susceptible individuals; re-administration of the hapten to such an individual results in an allergic response that may be sufficiently intense to call itself to the attention of the patient or the physician. The response may be so severe as to endanger the patient’s life. The symptomatology of the allergic response is the result of the complex mechanism that is only “triggered” by the hapten. Hence, allergic responses to different haptens are fundamentally alike and qualitatively different from the pharmacologic effects the hapten-drugs manifest in normal subjects, i.e., patients not hypersensitive to the drug. Dose-effect curves obtained after administration of antigen to sensitized subjects usually reflect the dose-effect curves of the products of the allergic reaction even though the severity of the effects measured is proportional to the amount of antigen administered. Positive identification of a response as being allergic in nature depends on the demonstration of an antigen-antibody reaction underlying the response. In the case of specific patients, presumptive diagnoses of an allergic response must sometimes be made since no opportunity exists for formal identification of an antigen-antibody reaction; such diagnoses can be made and justified since the clinical symptomatology of allergic responses is usually characteristic and clear. Obviously, not all untoward effects of drugs are allergic in nature.
Cf. Side-effect, Idiosyncratic Response, Hypersensitivity, Sensitivity
Amplification:
The amount of change in measured output per unit change in input. The slope of the input-output, or dose-effect, curve. (Engineers sometimes refer to “amplification” as “sensitivity”.)
Cf. Accuracy
Analgesic:
A drug that dulls the sense of pain. It differs from an anesthetic agent in that it relieves pain without loss of consciousness.
Cf. Anesthetic, Narcotic
Anesthetic:
Literally: an – without + aisthesis – perception by the senses (Gr.) A drug that causes loss of sensation. General anesthetics cause not only loss of sensation, but also loss of consciousness. Local anesthetics cause loss of sensation by blocking nerve conduction only in the particular area where they are applied.
Antagonism:
The joint effect of two or more drugs such that the combined effect is less than the sum of the effects produced by each agent separately. The agonist is the agent producing the effect that is diminished by the administration of the antagonist. Antagonisms may be any of three general types:
- Chemical
- caused by combination of agonist with antagonist, with resulting inactivation of the agonist, e.g., dimercaprol and mercuric ion.
- Physiological
- caused by agonist and antagonist acting at two independent sites and inducing independent, but opposite effects.
- Pharmacological
- caused by action of the agonist and antagonist at the same site.
In the case of pharmacological antagonisms, the terms competitive and non-competitive antagonism are used with meanings analogous to competitive and non-competitive enzyme inhibition as used in enzymology. (See Symposium on Drug Antagonism, Pharm. Rev. 9: 211, 1952).
Cf. Synergy, Potentiation, Intrinsic Activity, Affinity
Area Under the Curve:
Abbreviated as AUC (q.v.)
AUC:
The area under the plot of plasma concentration of drug (not logarithm of the concentration) against time after drug administration. The area is conveniently determined by the “trapezoidal rule”: the data points are connected by straight line segments, perpendiculars are erected from the abscissa to each data point, and the sum of the areas of the triangles and trapezoids so constructed is computed. When the last measured concentration (Cn, at time tn) is not zero, the AUC from tn to infinite time is estimated by Cn/kel.
The AUC is of particular use in estimating bioavailability of drugs, and in estimating total clearance of drugs (ClT). Following single intravenous doses, AUC = D/ClT, for single compartment systems obeying first-order elimination kinetics; alternatively, AUC = C0/kel. With routes other than the intravenous, for such systems, AUC = F · D/ClT, where F is the bioavailability of the drug. The ratio of the AUC after oral administration of a drug formulation to that after the intravenous injection of the same dose to the same subject is used during drug development to assess a drug’s oral bioavailability.
Cf. Clearance, Bioavailability, Compartments, F
Availability:
See Bioavailability
B:
Body weight. Sometimes, as a subscript, to indicate “of, or in, the body”; thus, A B is the amount of drug in the body.
b:
The slope of a linear plot of log C against t, when logarithms to the base 10, common logarithms, are used; the slope of the linear, semi-logarithmic, plot of a first-order reaction when common logarithms are used. k el = 2.303b; t 1/2 = 0.301/b.
b0:
The slope of a linear plot of C (not the logarithm of C) against t; the slope of the linear plot of a zero-order reaction, in which, in equal time intervals, equal amounts of chemical undergo reaction.
b:
The later segment of a biphasic plot of log C against t (following intravenous injection of a drug) represents the “elimination phase” of the drug’s sojourn in the body, when eliminative, rather than distributive, processes dominate the rate at which plasma concentrations of drug decrease with the passage of time. b is used as a subscript for pharmacokinetic parameters appropriate to the elimination phase, e.g. t1/2b, Vdb, etc. For systems with more than two phases, the lower case Greek letters following b are used, in order, to designate the third, fourth, etc., phases.
Cf. a, Compartments, Volume of Distribution, Half-Life
Bioassay or Biological Assay:
“The determination of the potency of a physical, chemical or biological agent, by means of a biological indicator . . . The biological indicators in bioassay are the reactions of living organisms or tissues.” Principles characterizing a bioassay include:
- Potency is a property of the material to be measured, e.g., the drug, not a property of the response. Ordinarily, the relationship between changes in behavior of the indicator and differences in drug dose – (a dose-effect curve) – must be determined as a part of each assay.
- Potency is relative, not absolute. The potency of one preparation (the “unknown”) can be measured only in relationship to the potency of a second preparation (the “standard” or “reference drug”) that elicits a similar biologic response. When the absolute amounts of standard used in the assay are known, the results of the assay can be used to estimate the amount – in absolute units – of biologically active material contained in the unknown preparation.
- A bioassay provides only an estimate of the potency of the unknown; the precision of the estimate should always be determined, using the data of the assay.
(See: Bliss, C.I., American Scientist, 45: 499, 1957).
Cf. Positive Control Drug, Negative Control Drug, Dose-Effect Curve, Time-Concentration Curve
Bioavailability:
The percent of dose entering the systemic circulation after administration of a given dosage form. More explicitly, the ratio of the amount of drug “absorbed” from a test formulation to the amount “absorbed” after administration of a standard formulation. Frequently, the “standard formulation” used in assessing bioavailability is the aqueous solution of the drug, given intravenously.
The amount of drug absorbed is taken as a measure of the ability of the formulation to deliver drug to the sites of drug action; obviously – depending on such factors as disintegration and dissolution properties of the dosage form, and the rate of biotransformation relative to rate of absorption – dosage forms containing identical amounts of active drug may differ markedly in their abilities to make drug available, and therefore, in their abilities to permit the drug to manifest its expected pharmacodynamic and therapeutic properties.
“Amount absorbed” is conventionally measured by one of two criteria, either the area under the time-plasma concentration curve (AUC) or the total (cumulative) amount of drug excreted in the urine following drug administration. A linear relationship exists between “area under the curve” and dose when the fraction of drug absorbed is independent of dose, and elimination rate (half-life) and volume of distribution are independent of dose and dosage form. Alinearity of the relationship between area under the curve and dose may occur if, for example, the absorption process is a saturable one, or if drug fails to reach the systemic circulation because of, e.g., binding of drug in the intestine or biotransformation in the liver during the drug’s first transit through the portal system.
Cf. F, Disintegration Time, Dissolution Time, Generic Drugs, Reference Standard, Equivalence, First Pass Effect, AUC
Biopharmaceutics:
The science and study of the ways in which the pharmaceutical formulation of administered agents can influence their pharmacodynamic and pharmacokinetic behavior. Differences in pharmaceutical properties can cause substantial differences in the biologic properties – and therapeutic usefulness – of preparations which are identical with respect to their content of active ingredient. Pharmaceutical properties known to influence the therapeutic efficacy of drugs include: appearance and taste of the dosage form, solubility of the drug form used in the preparation, the nature of “fillers”, binders, or menstrua in the dosage form, particle size, stability of the active ingredient, age of the preparation, thickness and type of coating of a dosage form for oral administration, the presence of impurities, etc.
Cf. Biotransformation, Biotranslocation, Pharmacokinetics, Bioavailability
Biotransformation:
Chemical alteration of an agent (drug) that occurs by virtue of the sojourn of the agent in a biological system. Spontaneous decay of radium would not be considered a biotransformation even if it occurred within the body; chemical alteration of a chemical by enzymatic attack would be considered a biotransformation even if it occurred in a model system, in vitro. Pharmacodynamics involves the chemical effects of a drug on the body; biotransformation involves the chemical effect of the body on a drug! “Biotransformation ” should be used in preference to “drug metabolism”, and the word “metabolism” should probably be reserved to denote the biotransformation of materials essential to an adequate nutritional state. “Biotransformation” and “detoxication” are not synonyms: the product of a biotransformation may be more, not less, biologically active, or potent, than the starting material.
Cf. Pharmacokinetics, Biopharmaceutics
Biotranslocation:
The movement of chemicals (drugs) into, through, and out of biological organisms or their parts. In studying biotranslocation one is concerned with the identification and description of such movement, elucidation of the mechanisms by which they occur, and investigation of the factors which control them. Ultimately, the study of biotranslocation involves consideration of how chemicals cross cellular membranes and other biological barriers.
Cf. Pharmacokinetics, Half-Life, Volume of Distribution, Biopharmaceutics, ka, kel
Blind Experiment:
A form of experiment in which the participants are, to some degree, kept ignorant of the nature and doses of materials administered as specific parts of the experiment. The purpose of the device is, obviously to prevent a prejudiced interpretation of the drug effects observed, and to prevent a presumed knowledge of effects to be expected from influencing the kinds of effects manifested by a subject. Blind experiments are not limited in use to experiments involving only human subjects. Needless to say, both experimenters and subjects may have general knowledge of the purpose, materials and design of the experiment; their ignorance is limited to the nature of individual drug administrations.
In a “single-blind” experiment, one participant – usually the subject – is left uninformed. In a “double-blind” experiment two participants – usually the subject and observer – are uninformed, and in a “triple-blind” experiment the subject, the observer, and the person responsible for the actual administration of the drug are left unaware of the nature of the material administered.
In clinical experimentation, particularly, the use of blind experimentation is frequently associated with the use of dummy or placebo medication as part of the experimental design, and the use of a “cross-over” experimental design.
