Glossary 5
R:
Accumulation Ratio, see Css.
Receptors:
Actual or hypothetical “…small, chemically defined areas (of a cell) which give (initiate) a biological response upon uniting with chemically complementary areas of natural or foreign molecules (drugs)”. The receptor hypothesis is indispensable to pharmacologists in analyzing and interpreting the actions of some drugs; however, reasonable care should be exercised that “receptor” does not become a catch-all phrase used to explain all drug actions or the actions of all drugs.
Cf. Intrinsic Activity, Affinity, Antagonism
Reference Standard:
A drug, chemical, or dosage form, etc., of specified properties used as the basis for quantitative comparison with other materials of qualitatively similar properties. The purpose of such a comparison is to express the amount or degree of the designated property in the “other “material as a fraction or multiple of the amount or degree of the property contained in the standard. The reference standard serves as a unit of measurement for the properties of the other, or “unknown,” material.
Even physical systems of measurement are based on reference standards. The use of reference standards is of particularly great importance to the design and interpretation of biological experiments. In biological experiments, particularly, variability and instability of the biological test system can markedly influence the apparent effects and effectiveness of substances being tested.
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?
See Accuracy.
Risk:
The likelihood that harm will result from exposure to a hazard. More generally, the probability that an event has occurred, or will occur, in members of a population under specified conditions, e.g., of exposure to a hazardous chemical; the “population at risk” consists of the subjects who could experience the event, e.g., who were exposed to the chemical. Risk is calculated by dividing the number of subjects who experience an event by the number of subjects in the population at risk. The risk, so calculated, is one of the bases used to estimate the likelihood that the event will occur in the future, the predicted risk. Risk, calculated as described, also indicates the probability that any individual subject in the population at risk experienced the event. (Formally, the idea of “risk” is applicable to the study of both desirable and undesirable events.)
For a meaningful estimate of risk (following exposure of subjects to some hazard), it is necessary to have carefully defined the harm that was done, to have characterized the population at risk, and to have specified the conditions of exposure. Interpreting an estimate of risk requires comparing the data with those from a “control” population, ideally one never exposed to the hazard. The statistical techniques used to estimate risks and to compare them are, generally, the techniques used in epidemiology.
Perceived risk is the subjective assessment of the importance of a hazard to individuals or to groups of individuals, For example, hazards that affect children generally have higher perceived risks than those that tend to affect adults. Hazards viewed as under a person’s control (e.g., driving a car) generally have lower perceived risks than those viewed as not under such control (e.g., riding in a aircraft piloted by someone else). Hazards that produce fatalities grouped in time and space (e.g., airplane crashes) generally have higher perceived risks than those which produce fatalities scattered in time and space (e.g., automobile accidents), etc. Perceived risks are not necessarily correlated with the risks, for the same hazards, measures by epidemiologic techniques.
Risk management is the effort to reduce the likelihood that a hazard will produce harm. Risk management may involve decreasing the size of the population at risk (e.g., by prohibiting the use of a chemical as a food additive), altering the conditions of exposure (e.g., requiring adequate ventilation in an industrial environment), developing and using therapeutic regimens to minimize the consequences of exposure, etc.
Cf. Hazard, Toxicology
Selectivity:
The capacity or propensity of a drug to affect one cell population in preference to others, i.e., the ability of a drug to affect one kind of cell, and produce effects, in doses lower than those required to affect other cells. Selectivity can be measured or described by means of such numbers as the Therapeutic Index, or the Standardized Safety Margin: not infrequently one wishes to express selectivity of drug action with respect to two potentially beneficial effects, or two potentially toxic doses, or two toxic doses, instead of one each.
“Selectivity” is not to be confused with ” potency”; a potent drug may be non-selective or a selective drug may be impotent. “Selectivity” is however, a measure of the relative potency of a drug in producing different effects.
Selectivity is generally a desirable property in a drug, e.g., it is desirable that an antibacterial agent affect parasites in doses too small to affect host cells. Sometimes, selectivity of action is virtually precluded by the nature of the drug, e.g., in the case of analogs of hormones that have many target cells or tissues. Sometimes selectivity of action for cells within an organism is not necessarily desirable, as in the case of certain economic poisons, i.e., pesticides, herbicides, rodenticides; even in this case, however, it is desirable to have a drug selective for cells of a particular species, and this criterion can most easily be met by drugs selective for certain cell types in the organisms of the target species.
“Selectivity” and “specificity” are, unfortunately, frequently used as synonyms for each other. They describe separate phenomena, each of which deserves an unambiguous name.
Cf. Specificity, Therapeutic Index
Sensitivity:
The ability of a population, an individual or a tissue, relative to the abilities of others, to respond in a qualitatively normal fashion to a particular drug dose. The smaller the dose required to produce an effect, the more sensitive is the responding system. A patient would be considered abnormally sensitive to aspirin if a small fraction of the normal analgesic dose gave adequate pain relief; or, were an abnormally large dose of aspirin required to afford pain relief, the subject would be said to be “insensitive” to aspirin. Conversely, the drug would appear to be extraordinarily potent or impotent in such a patient. If a patient manifested an allergic response after raking aspirin, he would be considered hypersensitive to aspirin, regardless of whether the aspirin afforded him relief from pain, and regardless of the size of the dose required to elicit the allergic response. Such a patient might be simultaneously hypersensitive to aspirin, and insensitive to aspirin, acting as an analgesic agent.
Every subject is sensitive to a drug; the question of importance is “how sensitive?” In any event sensitivity is a property ascribed to the organism; potency is a property ascribed to the drug. Hypersensitivity is a property ascribed to a subject in a particular immunologic state.
Sensitivity may be measured or described quantitatively in terms of the point of intersection of a dose-effect curve with the axis of abscissal values or a line parallel to it; such a point corresponds to the dose just required to produce a given degree of effect (see Threshold”). In analogy to this, the “sensitivity” of a measuring system is defined as the lowest input (smallest dose) required to produce a given degree of output (effect).
Cf. Supersensitivity, Hypersensitivity, Allergic Response, Potency, Accuracy
Side Effects:
Drug effects which are not desirable or are not part of a therapeutic effect; effects other than those intended. For instance, in the treatment of peptic ulcer with atropine, dryness of the mouth is a side effect and decreased gastric secretion is the desired drug effect. If the same drug were being used to inhibit salivation, dryness of the mouth would be the therapeutic effect and decreased gastric secretion would be a side effect.
Pharmacological side effects are true drug effects. With increasing doses of a drug, the intensity of pharmacological side effects in individuals, and/or the frequency with which a pharmacological side effect is observed in a population is increased.
Cf. Idiosyncratic Response, Toxic Effects, Allergic Response
Spare Receptors:
A pharmacological system has spare receptors (a receptor reserve), if an agonist can induce a maximum response when occupying less than 100% of the available receptors. The existence of spare receptors reflects a circumstance in which the maximum effect produced by an agonist is limited by some factor other than the number of activated receptors. Whether or not a system has spare receptors depends upon the nature of the receptor and its coupling to the measured response, the number of receptors, and the intrinsic activity of the agonist.
Specificity:
The capacity of a drug to manifest only one kind of action. A drug of perfect specificity of action might increase, or decrease, a specific function of a given cell type, but it would not do both. Nicotine is not specific in its actions in autonomic ganglia; it both stimulates and depresses ganglionic function by a number of means. Atropine is quite specific in only blocking the actions of acetylcholine at certain receptors; in general atropine does not stimulate cellular activity when it combines with receptors, nor does it block interaction with receptors of agonists other than acetylcholine. In affecting exocrine glands, acetylcholine itself is very specific, in that it causes only stimulation or secretion; acetylcholine, at the same time, is non-selective in its action, in that stimulation of all exocrine glands is produced by about the same dose of acetylcholine.
Selectivity is concerned with site of action; specificity, with the kinds of action at a site.
Cf. Selectivity
Standard Drug:
See Bioassay, Positive Control Drug.
Standardized Safety Margin:
A number, LD1-ED99/ED99 x 100%, which is a measure of the selectivity of action or relative “safety” of a drug. The standardized safety margin indicates by what percentage of itself a dose effective in virtually all (99%) of a population must be exceeded in order to produce a lethal effect in a minimum number (1%) in the population. The therapeutic index (q.v.) measures by what factor an effective dose must be increased to produce a standard lethal effect in a population. Clinically, the standardized safety margin probably has greater practical meaning than does the therapeutic index, and, unlike the therapeutic index, the meaningfulness of the standardized safety margin does not depend on the parallelism of the dose effect curves from which the LD1 and ED99 are inferred. The standardized safety margin (more frequently than the therapeutic index) can sometimes be computed from clinical data not involving lethal effects, e.g., the ED99 for control of epileptic seizures and the ED1 for the production of drowsiness or ataxia, in a population of patients with epilepsy. See: Foster, R.H.K., J. Pharmacol. 65: 1, 1939.
Cf. Therapeutic Index, Median Effective Dose, Selectivity, Clinical Therapeutic Index
Supersensitivity:
An extreme and high degree of sensitivity to a drug or chemical. Usually a high degree of sensitivity induced by some specific procedure such as denervation, administration of another drug, etc. Sensitivity to a drug, of some degree, is inherent in every organism; supersensitivity is a state that has had to be produced in the organism. In the supersensitive subject, the actions of the drug are qualitatively like those observed in a subject of normal sensitivity, and unlike those produced in a subject who is hypersensitive to the drug.
Cf. Hypersensitivity, Sensitivity
Synergy:
A mutually reinforcing drug interaction such that the joint effect of two drugs administered simultaneously is greater than the sum of their individual effects. Synergism is distinguished from additivity, in which the joint effect of two drugs is equal to the sum of their individual effects. If the joint effect is less than the sum of the two drugs’ independent effects, the interaction is said to be antagonistic.
Cf. Antagonism, Potentiation
T or ?:
A point in time or a time interval; frequently a time interval following administration of a drug or the time interval between doses of a drug. The definition of a specific T or ? may be explicit or may be inferred from the context in which it is found. Specific times of interest may be indicated by subscripts, e.g., T0 is the time of drug administration; Tn is the time of administration of the nth dose in a series.
t½:
The “half-life” of a drug; the amount of time required for the concentration of a drug in, e.g., a body fluid such as plasma, serum, or blood, to be halved. The idea of half-life is legitimately applied only to the case of a drug eliminated from body fluid according to the laws of first-order reaction kinetics. t½ = 0.301/b = 0.693/kel, where 0.301 and 0.693 are the logarithms of 2 to the bases 10 and e, respectively.
Cf. Half-Life, b, kel, First-Order Kinetics
Tachyphylaxis:
A decline in the response to repeated applications of agonist, typically occurring over a relatively short time scale (seconds to hours). See also Desensitization, Tolerance.
Therapeutic Index:
A number, LD50/ED50, which is a measure of the approximate “safety factor” for a drug; a drug with a high index can presumably be administered with greater safety than one with a low index. The therapeutic index is ordinarily calculated from data obtained from experiments with animals. As in comparing ED50s from two different drugs, the comparison of the LD50 and ED50 (therapeutic index) is most meaningful when the dose-effect curves from which the ED50 and LD50 are inferred are parallel.
The therapeutic index is a measure of drug selectivity, and analogous index numbers are frequently computed to measure selectivity that does not involve lethal effects. For example, to measure the selectivity of a drug potentially useful in the treatment of epilepsy, the ED50 for producing ataxia in mice might be compared to the ED50 for abolishing electrically-induced convulsions in mice.
Cf. Median Effective Dose, Selectivity, Standardized Safety Margin, Clinical Therapeutic Index
Therapeutics:
The science and techniques of restoring patients to health. Properly, therapeutics has many branches, any or all of which may be needed in the treatment of a specific patient. In addition to pharmacotherapeutics or drug therapy, there exist coordinate fields of therapeutics such as surgical therapy, psychotherapy, physical therapy, occupational therapy, dietotherapy, etc. Drugs are commonly considered capable of participating in one or more of the following general kinds of therapy:
- Curative or specific therapy:
- treatment directed toward eradication of one or more of the agencies etiologic to the patient’s condition. Antimicrobial drugs such as penicillin have specific or curative effects.
- Palliative or symptomatic therapy
- treatment directed only toward relief of the patient’s symptoms, toward making the patient feel better without necessarily altering the natural course of the disease. Analgesic agents such as aspirin or morphine have obvious palliative effects.
- Supportive therapy
- treatment directed toward maintaining the patient’s physiological or functional integrity until more definitive treatment can be carried out, or until the patient’s recuperative powers function to obviate the need for further treatment. Many drugs can provide supportive therapy; even in a single patient supportive therapy can be provided from agents of such different classes as sedatives, diuretics, antihypertensives, etc.
- Substitutive or replacement therapy
- treatment directed toward supplying a material normally present in the body, but absent in a specific patient because of disease, injury, congenital deficiencies, etc. Adrenocortical hormones used in the treatment of a patient with Addison’s Disease are used as substitutive therapy.
- Restorative therapy
- therapy directed at rapid restoration of health, usually regardless of the nature of the original disease; restorative therapy is most frequently given during convalescence. Vitamin supplements or sex hormones used for their anabolic effects might be considered as providing restorative therapy.
A single drug may have two or more therapeutic effects in the same patient at the same or different times, or in different patients. A patient may require more than one kind of therapy at a given time, or in the course of his/her disease.
Drugs may be used prophylactically to prevent disease or to diminish the severity of a disease should it occur subsequent to or during treatment; with a fine disregard for precision of definition, such a use of drugs is commonly called “prophylactic therapy”. Drugs are sometimes used to measure bodily function and contribute toward the diagnosis of disease; such diagnostic agents have not yet been accused of participating in “diagnostic therapy“.
Threshold Dose:
A dose of drug just sufficient to produce a pre-selected effect. Frequently, and improperly, restricted to the dose just sufficient to produce a minimal detectable effect. In fact, an LD50 is a threshold dose if the pre-selected effect is “death in 50% of a population”.
Cf. Median Effective Dose, Sensitivity, Potency
Time-Concentration Curve:
The graphical representation of the relationship – for a given drug and a given biological system – between concentration (or dose) and latency or latent period: the period of time elapsing between the time the dose is administered and the time a given effect is produced. Time-concentration curves tend to be hyperbolic in form: as dose increases latency decreases and vice versa. Latency is an inverse function of concentration. But the hyperbolic relationship never approaches the axes as asymptotes; there is always a concentration below which the drug is ineffective, regardless of the duration of exposure of the tissue to the drug, and there is always a finite interval between the time of exposure to the drug and the time the response occurs. The time-concentration curve is analogous to the strength-duration curve that the physiologist uses to determine rheobase and chronaxie. It is characteristic of true drug effects that a generally hyperbolic relationship exists between dose and latency. If, with increasing doses of material, a time-concentration curve and a dose-effect curve cannot be demonstrated, one cannot conclude that the material is responsible for the effects observed.
Cf. Dose-Effect Curve, CT Index, Latent Period
Tolerance:
A condition characterized by a reduced effect of a drug upon repeated administration. In some cases, it may be necessary to increase the dose of the drug to attain the same effect, or the original level of effect may be unattainable. Tolerance typically develops over days to weeks, and is distinguished from tachyphylaxis, a more rapid decline in the effect of a drug. Tolerance can result from multiple mechanisms, including changes in drug metabolism and alteration in the number or responsiveness of receptors (see desensitization). “Tolerance” should not be used to mean “lack of sensitivity” manifested toward a single dose of a drug. A non-habitual drinker who is unaffected by several drinks of whisky downed in rapid succession is probably insensitive to alcohol rather than tolerant to its effects.
Cf. Addiction, Sensitivity, Habituation, Dependence
Toxic Effects:
Responses to drug that are harmful to the health or life of the individual. Almost by definition, toxic effects are “side effects” when diagnosis, prevention, or treatment of disease is the goal of drug administration. Toxic effects are not side-effects in the case of pesticides and chemical warfare agents. Toxic effects may be idiosyncratic or allergic in nature, may be pharmacologic side effects, or may be an extension of therapeutic effect produced by overdosage. An example of the last of these is the apnea produced by an anesthetic agent.
Cf. Idiosyncratic Response, Side Effects, Allergic Response, Therapeutic Index, Standardized Safety Margin, Clinical Therapeutic Index
Toxicology:
The scientific discipline concerned with understanding the mechanisms by which chemicals produce noxious effects on living tissues or organisms; the study of the conditions (including dose) under which exposure of living systems to chemicals is hazardous.
Cf. Hazard, Pharmacology, Toxic Effects
Two-state model:
A simplified model of receptor activation by agonists. The receptor is hypothesized to be in conformational equilibrium between an inactive conformation R and an active conformation R*, with the equilibrium in the absence of agonist normally favoring the inactive state. Agonists bind preferentially (i.e. with greater affinity) to the active state, and by mass action shift the conformational equilibrium such that a greater proportion of receptors are in the active R* conformation. Inverse agonists shift the conformational equilibrium such that a greater proportion of receptors are in the inactive R* conformation.
United States Pharmacopoeia (U.S.P.):
The United States Pharmacopoeia is a reference volume, published every five years by the U.S. Pharmacopoeial Convention, which describes and defines approved therapeutic agents, as well as sets standards for purity, assay, etc. Agents are included on the basis of their therapeutic value. The U.S.P. is recognized by the F.D.A. as the official standard for the agents described therein.
The purposes of the Pharmacopoeia, as described in the Preface to the first edition in 1820 by Dr. Jacob Bigelow, are to :
- Select the best, established drugs (those “the utility of which is most fully established and best understood”).
- Set standards of pharmaceutical quality for them (” form from them preparations and compositions in which their powers may be exerted to the greatest advantage “).
- Name them (”distinguish those articles by convenient and definite names, such as may prevent trouble or uncertainty in the intercourse of physicians and apothecaries”).
- Encourage their use (”the value of a Pharmacopoeia depends upon the fidelity with which it conforms to the best state of medical knowledge of the day. Its usefulness depends upon the sanction it receives from the medical community and the public; and the extent to which it governs the language and practice of those for whose use it is intended:).
Vd:
The volume of distribution of a drug; the size of the “compartment” into which a drug apparently has been distributed following absorption. Computed as D/C0 for a one-compartment system, i.e. one yielding a single straight line when log C, or C, is plotted against time after drug administration. Using absolute dose to compute Vd yields Vd in units of volume, i.e. liters. Using relative dose (D/B) to compute Vd yields Vd in relative units, e.g. liters per kilogram, the volume of distribution as a fraction of body weight. When the plot of log C against t yields a biphasic relationship (a two compartment system), Vd is computed by a different method, such as one based on the area under the C vs. t curve.
Cf. Volume of Distribution, Compartment
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?
See Accuracy
Volume of Distribution:
The volume, in an organism, throughout which a drug appears to have been distributed; the volume into which a drug appears to have been dissolved after administration to an organism. Symbolized by Vd.
Suppose a drug has been completely absorbed from its site of application, has reached an equilibrium in its distribution among the several tissues of the body, and that no biotransformation or excretion of the drug has occurred. If one knew the mass (dose) of drug administered and the average concentration of the drug in the body, the apparent volume into which the drug had been dissolved could be determined from the relationship or definition: concentration = mass/volume. Since these idealized conditions are unobtainable in practice, the volume of distribution of a drug can only be approximated using experimental data.
With the assumption that the concentration of the drug in the plasma (or serum) reflects the average drug concentration in its whole volume of distribution, plasma concentration can be plotted against time after drug administration, and the resulting line can be extrapolated to yield a fictive concentration (C0) “predicted” to have existed at the instant the drug was administered – further assuming instantaneous and complete administration, absorption, and distribution of the drug. Obviously, C0, is the value expected to have occurred at a time when mechanisms of biotransformation and excretion had no significant effect on the amount of drug in the body. Needless to say, it is assumed for proper interpretation of C0, that the drug as measured in the plasma is identical to the agent that was administered, and that the drug underwent no chemical alteration in the course of administration, absorption, or distribution.
When C0 is divided into the mass of the total dose administered, the quotient indicated the volume into which the drug appears to be dissolved. When C0 is divided into dose expressed in terms of body weight (e.g.,mg/kg), the quotient is dimensionless – since kilograms and liters are considered equivalent – and indicates the fraction of body weight into which the drug appears to be dissolved. The volumes, or fractions, can be readily compared with parts of body weight occupied by the various fluid compartments (e.g., intravascular, extracellular, intracellular, etc.), and the approximate locus of drug distribution may be inferable. A volume of distribution corresponding to more than about the volume of total body water is presumptive evidence that the drug is distributed nonuniformly throughout the body, and is concentrated at one or more sites, usually sites of drug storage, biotransformation or elimination, or at a site of drug application when a route of administration other than the intravenous one has been used. Obviously, legitimate and valid interpretation of calculated volume of distribution depends on the degree to which experimental facts are in concordance with the assumption given above. The idealized state is most closely approximated when the drug is given rapidly intravenously, and blood samples for chemical analysis of their drug content are taken at short intervals, beginning very soon after the time of drug administration.
Two more qualifications – first, special account must be taken mathematically, to yield validly interpretable volumes of distribution when binding of drug to plasma protein significantly restricts the mobility of drug molecules. Second, when the plot of plasma concentration against time gives evidence of a system involving two (or more) phases – i.e., two volumes into which drug tends to be distributed to different degrees at different times – special mathematical treatment of the data (more complicated than the treatment described above) is needed to permit calculation of the volumes of the several phases.
Cf. Compartment, Pharmacokinetics, Half-Life, Vd.
Zero-Order Kinetics:
Mechanisms of chemical reaction in which the reaction velocity is apparently independent of the concentration of all the reactants. Typically, in biological systems, one reactant (X) is present in a concentration greatly exceeding that of the other (Y), but is capable of undergoing change, while the concentration of Y, in contrast, does not undergo substantial change during the course of the reaction.
For example, consider the inactivation of a drug (X), present in the body in an overwhelming quantity, by an enzyme (Y) present in a limited concentration in cells and having a specific maximum capacity to inactivate X. A sufficiently high concentration of X would “saturate ” Y and make the system operate at, effectively, its maximum velocity; the amount of X inactivated per unit time would be constant and would depend on the maximum velocity per mass of Y and the total amount of Y present in the body; modest changes in concentration of X would not detectably change the velocity of the system operating at virtually its maximum rate. (Recollect the shape of the velocity – substrate concentration curve.) The reaction velocity would be independent of the concentrations of both X and Y. Eventually, the concentration of X would decrease to the point that it did not saturate Y, and the inactivation would proceed according to first-order kinetics.
For a zero-order reaction, the plot of C (not ln or log C) against t yields a straight line: C = C 0 – b0 t, in which the slope (b0) is in units of concentration per unit time. The amount of change in concentration per unit time is constant; in the case of first-order kinetics, the fractional change in concentration per unit time is constant.
Following administration of a drug eliminated by zero-order kinetics, the linear plot of C against t can be used to infer C0 and C and (if the dose is known) Vd, but no half-life (t1/2) can be determined. The elegant properties of multiple dose regimens (q.v.) for drugs eliminated according to first-order kinetics do not obtain for drugs eliminated by zero-order kinetics: Cmax for “zero-order drugs” does not approach Css,max as an asymptote; for zero-order drugs, Cmax increases progressively without limit with each dose, when equal doses are administered at equal intervals. Drugs that obey first-order kinetics with low doses may obey zero-order kinetics with large doses.
