Effective:

Under the Kefauver-Harris Drug Amendments of 1962 (amending the Food, Drug, and Cosmetic Act of 1938), a drug is considered to be effective that has been designated as such by the Food and Drug Administration on the basis of "substantial evidence." Such evidence was defined by Congress as "... adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved."

Equipotent:

Equally potent, or equally capable of producing a pharmacologic effect of a specified intensity. The masses of the drugs required to produce this degree of effect may be compared, quantitatively, to yield estimates of "potency" of the drugs. Obviously, if two drugs are not both capable of producing an effect of a given intensity, they cannot be compared with respect to potency; i.e., drugs with different intrinsic activities or ceiling effects cannot be compared with respect to potency in doses close to those producing the ceiling effect of the drug with the greater intrinsic activity.

Equivalence:

In 1969, a federal Task Force on Prescription Drugs recommended that the words "generic equivalents" no longer be used in describing and comparing drug preparations. The Task Force recommended that an appropriate nomenclature should take into account three kinds of equivalence of drug preparations:

Chemical Equivalents:

Those multiple-source drug products which contain essentially identical amounts of the identical active ingredients, in identical dosage forms, and which meet existing physicochemical standards in the official compendia.

Biological Equivalents:

Those chemical equivalents which, when administered in the same amounts, will provide essentially the same biological or physiological availability, as measured by blood levels, etc.

Clinical Equivalents:

Those chemical equivalents which, when administered in the same amounts, will provide essentially the same therapeutic effect as measured by the control of a symptom or a disease.

f:

The fraction of C₀ remaining at some specified time after drug administration; more generally, the fraction of C, or A_B, remaining after some specified time interval. For first-order, single compartment systems (i.e. those yielding a single straight line when log C is plotted against t), f can be determined from the relationship: log C = log C₀ - b t. When t is the time after drug administration, or the interval between two administrations, and t_1/2 is the elimination half-life of the drug, f is 0.5 raised to a power which is the ratio of the time interval to the elimination half-life, i.e., 0.5^t/t1/2.

F:

The fraction of a dose which is absorbed and enters the systemic circulation following administration of a drug by any route other than the intravenous route; the availability of drug to tissues of the body, generally. When the total clearance and the dose of drug administered are known, F can be determined from the relationship: (AUC x Cl_T)/D = F. When identical doses of a drug have been given by the intravenous and by some other route (x), and the AUCs have been determined, the availability of the drug after administration by route X can be determined: F=AUC_x/AUC_iv. The amount of free drug recovered in the urine (A_U) after administration of identical doses given intravenously and by route X can also be used to determine availability: F=A_U,x/A_U,iv

First-Order Kinetics:

According to the law of mass action, the velocity of a chemical reaction is proportional to the product of the active masses (concentrations) of the reactants. In a monomolecular reaction, i.e., one in which only a single molecular species reacts, the velocity of the reaction is proportional to the concentration of the unreacted substance (C). The change in concentration (dC) over a time interval (dT) is the velocity of the reaction (dC/dT) and is proportional to C. For infinitely small changes of concentration over infinitely small periods of time, the reaction velocity can be written in the form of a differential equation: -dC/dt=kC. Here, dC/dt is the reaction velocity, C is concentration, and k is the constant of proportionality, or monomolecular velocity constant, which uniquely characterizes the reaction. The minus sign indicates that the velocity decreases with the passage of time, as the concentration of unreacted substance decreases; a plot of C against time would yield a curve of progressively decreasing slope. The mechanisms, the kinetics, described by the differential equation are termed first order kinetics because - although the exponent is not written - concentration (C) is raised to only the first power (C¹). The differential equation above may be integrated and rearranged to yield: ln(C/C₀)= k t, where ln indicates use of the natural logarithm, to the base e; C₀ is the concentration of unreacted substance at the beginning of an observation period; t is the duration of the observation period; and k is the familiar proportionality or velocity constant. The units of k are independent of the units in which C is expressed; indeed, since a logarithm is dimensionless, and t has the dimension of time, the integrated equation balances, dimensionally, because k has the dimension of reciprocal time, t^-1. Notice that for observation periods of equal length, the ratio C/C₀ is always the same; after equal intervals, the final concentration is a constant fraction of the starting concentration, or, in equal time intervals, constant fractions of the starting concentration are lost, even though absolute decreases in concentration become progressively less as time passes and C becomes smaller and smaller.

Let t_1/2 represent the length of time required for C₀ to be halved, so that C=0.5 C₀. Then, substituting in the integrated equation above, ln 0.5 = -kt_1/2, or, since -0.693 is the natural logarithm of 0.5: -0.693 = kt_1/2. Multiplying both sides of the equation by -1 yields 0.693 = kt_1/2 or 0.693/k = t_1/2: the natural logarithm of 2 (0.693) divided by the monomolecular velocity constant yields the time required for the concentration to be halved, the "half-life" or "half-time" of the reaction.

Since ln (C/C₀) may be rewritten (lnC - lnC₀), the integrated equation may be rewritten and given the form of a linear equation: ln C = ln C₀ -kt. The existence of a monomolecular reaction can be established by plotting ln C, for unreacted material, against t and finding the relationship to be linear; the slope of the line is the original proportionality or velocity constant, and the intercept of the line with the ordinate is the natural logarithm of the original concentration of unreacted material. Since natural logarithms have a fixed relationship to common logarithms, i.e., logarithms to the base 10 (lnX =2.303 log X), one may write: 2.303 log C =2.303 log C - kt. When common logarithms of C are plotted against t, a first order reaction yields a straight line with a slope of k/2.303, and an intercept which is the common logarithm of C₀.

When two molecular species react with each other (a bimolecular reaction), but one of the substances is present in a concentration greatly in excess of the concentration of the other and/or does not change in concentration during the reaction, the velocity of the reaction at any time is really determined only by the concentration of the other substance. Such a pseudo-monomolecular reaction, because the velocity is determined by the concentration of only one of the two reactants, still follows first order kinetics.

Following administration of a drug, it may be eliminated from the body only after "reacting " with tissue components which are present in high concentrations and which are not used up to any degree during the drug's stay in the body. Such eliminative processes mimic pseudo-monomolecular reactions, and the drug is eliminated from the body according to first order kinetics,. The apparent velocity constant determined for such a process is called the elimination rate constant, kel, and the elimination half-life can be computed as 0.693/k_el.

First Pass Effect:

The biotransformation and/or excretion of a drug by hepatic, including biliary, mechanisms following absorption of the drug from the gastrointestinal tract, before drug gains access to the systemic circulation.

Generic Drugs:

Drug formulations of identical composition with respect to the active ingredient, i.e., drugs that meet current official standards of identity, purity, and quality of active ingredient. Drug dosage forms considered as "generically equivalent" are more properly considered as "chemically equivalent" in that they contain a designated quantity of drug chemical in specified stable condition and meet pharmacopoeial requirements for chemical and physical properties. Each of a number of preparations of a given drug entity may carry a different "proprietary name" or "trademark"; such a name is registered with the U.S. Patent Office and identifies the special brand of the drug with the firm owning the name. All such preparations - identical with respect to content and specification of active ingredient - may be looked upon as comprising a "genus"; they are generically equivalent and are generic drugs. It is well recognized that a number of factors other than quantity of drug present in a dose can determine the ultimate therapeutic usefulness of the drug preparation, and even the availability of drug to the site of action once the preparation has been given. Drugs may be generically equivalent but not therapeutically equivalent. Factors which affect therapeutic usefulness or efficacy of drug preparations include appearance, taste, disintegration and dissolution properties of the preparation, interaction of active materials with other ingredients including binders and solvents, pH, particle size, age of preparation, conditions of manufacture such as degree of tablet compression, and the nature and amount of coating of enteric-coated tablets.

Habituation:

A condition characterized by a psychological craving for the effects produced by the administration of a drug.

The Expert Committee on Addiction-Producing Drugs of the World Health Organization defines habituation (1957) as: "...a condition resulting from the repeated consumption of a drug. Its characteristics include: (1) a desire (but not compulsion) to continue taking the drug for the sense of improved well-being which it engenders; (2) little or no tendency to increase the dose; (3) some degree of psychic dependence on the effect of drug; but absence of physical dependence and hence of the abstinency syndrome; (4) detrimental effects, if any, primarily on the individual.

Half-Life:

The period of time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount. The given concentration or amount need not be the maximum observed during the course of the experiment, or the concentration or amount present at the beginning of an experiment, since the half-life is completely independent of the concentration or amount chosen as the "starting point". Half-lives can be computed and interpreted legitimately only when concentration or amount varies with time according to the law appropriate to the kinetics of a first order reaction: the common logarithm of the concentration or amount is related linearly to time, e.g.:

where C is concentration at time t, a (in logarithmic units) is the intercept of the line with the ordinate, and b (which has a negative sign) is the slope of the line. The parameters of the equation can be estimated from the plot of experimental values of log C and t. The half-life can be computed simply by dividing the slope of the curve into 0.301, the difference between the logarithm of a number (C) and the logarithm of number half as large (C/2); the symbol for half-life is t_1/2.

The half-life of a drug in plasma or serum is frequently taken as indicating the persistence of the drug in its volume of distribution; this interpretation may be incorrect unless the material can move freely and rapidly from one fluid compartment of the body to another, and is not bound or stored in one or another tissue. The term "biological half-life" should not be used instead of the specific terms "plasma half-life" or "serum half-life". The tissue for which the half-life of a drug is determined should always be specified, e.g., "serum half-life"; the half-life of a drug in muscle, kidney, etc., or in the whole organism can be determined. Drug half-lives are frequently based on the results of chemical analyses, i.e., the results of the reaction of a reagent with a specific chemical group of a drug molecule; it should be remembered that detection of the group per se does not necessarily imply its continuous existence as part of a biologically active drug molecule.

A drug molecule that leaves the plasma may have any of several fates: it can be destroyed in the blood; it can be eliminated from the body; or it can be translocated to a body fluid compartment other than the intravascular to be stored, biotransformed, or to exert its pharmacodynamic effects.

When the plot of log plasma or serum concentration (during the period of its decline) against time is composed of two straight line segments, the inference may be made that two first order processes are involved in the distribution and biotransformation and elimination of the drug. The earlier phase - represented by the line segment of greater slope - is termed the distributive phase, and corresponds to the period during which translocation of the drug to its ultimate volume of distribution occurs and is the dominant process; the later phase - represented by the line of lesser slope - is termed the eliminative phase, and corresponds to the period when biotransformation and elimination of drug are dominant processes. For two-phase systems, three phase systems, etc., half-lives of the drugs in the various phases can be determined only after more sophisticated analysis of the data than that described above.

Harrison Act:

A federal law passed in 1916 which regulated the manufacture, importation, transportation, and distribution (wholesale, retail, dispensing) of all "narcotics" defined by the act. Coca leaves and derivatives, opium and derivatives, and various synthetic agents were subject to the act and are officially designated as "narcotics". The effect of the law was to regulate possession and use of the materials designated as narcotics. Since regulation was achieved through taxation, the law was enforced by the Treasury Department, Bureau of Internal Revenue. Traffic in marihuana was first controlled by the Marijuana Tax Act of 1937. More recently, additional materials, e.g., barbiturates, amphetamines, etc., were recognized by Congress as requiring legal control, and were included with narcotics and marihuana in the Controlled Substances Act of 1970. The law is implemented by placing a nominal tax on certain materials under the law, and by requiring that physicians, dentists, etc., be specially licensed, annually, to legally prescribe materials covered by the law. The Act of 1970 is enforced by the Drug Enforcement Administration of the U.S. Department of Justice.

Hazard:

The potential for causing harm; that which is a potential cause of harm. With respect to chemicals which are capable of causing harm, "hazard" is about equivalent in meaning to "toxicity"; measuring the hazard or toxicity of a chemical is to measure its potency in producing harm: the lower the dose required to produce harm, the greater the hazard or toxicity, the more hazardous or toxic is the substance.

Since the time of Paracelsus, in the early 16th century, it has been recognized that all chemicals, given in sufficient doses, are capable of producing harm. Therefore, it is not very meaningful simply to call a chemical a hazard, or to speak of a chemical as hazardous, without qualification or definition. Three categories of information are needed to define a hazard: specific descriptions of the harms it can produce, specific identification of the species or kinds of subjects that can be harmed, and specification of the kinds of exposure to the chemical (including dose) which can result in the respective harms.

Observe that hazard is the potential for causing harm. However hazardous a chemical might be, it may present no risk if potential victims are not exposed to it! Risk management is the effort to limit the likelihood that the hazard of a chemical will be realized or manifested.

For chemicals, such as drugs, it is frequently more informative to consider their hazards relative to their potential for producing benefit, rather than relative to the hazards of other chemicals. An extremely potent therapeutic agent may also be potent in producing harm, but it may be a useful drug because of its large therapeutic index or standardized safety margin.

Hypersensitivity:

The physiological state necessary for a subject's manifesting an allergic response or reaction; the state is dependent on the administration of a haptene or allergen to a susceptible individual, and the development of antibodies and immune mechanisms capable of being activated by a subsequent administration of the haptene. Hypersensitivity may exist but not be manifested until a second administration of haptene occurs. The dose of haptene (or drug) required to produce the allergic response may be smaller, larger, or the same size as the dose required for the drug to produce its characteristic pharmacologic effects; hence hypersensitivity is not the same as sensitivity and the two words should not be used as synonyms. The nature of the response to haptene in a hypersensitive subject is determined by the immune mechanisms and effector organs and is not, in general, related to the nature of the haptene; the allergic response in the hypersensitive subject is qualitatively different from the expected pharmacodynamic response to the haptene or drug.

Hypnotic:

A drug which produces a state clinically indentical to sleep by means of action in the central nervous system.

Idiosyncratic Response:

A qualitatively abnormal or unusual response to a drug which is unique, or virtually so, to the individual who manifests the response. "Idiosyncratic Response" usually applies to a response which is not allergic in nature and cannot be produced with regularity in a substantial number of subjects in the population , and which is ordinarily not produced in a greater intensity in an individual, or in a greater fraction of the population, by the expedient of increase in the dose. In other words, were frequency or intensity of idiosyncratic response used as a measure of effect in constructing a dose-effect curve, a curve might indeed be constructed, but its slope would be found to be 0 (zero), indicating that effect was not significantly a function of dose. In practice, the mechanism of production of an idiosyncratic response is unknown; once the mechanism is known, the response can usually be classified in some other way.

Infusion Kinetics:

Infusion, as a means of drug administration, involves an effectively continuous flow of a drug solution into the blood stream over a relatively long period of time. (Intravascular injections are separate administrations of drug solutions, each over a short period of time.) A major purpose of an infusion is to maintain a steady blood or plasma concentration of drug over a long period of time, i.e. to achieve and maintain Css.

The C_ss achieved during infusion of a drug is directly proportional to the rate of drug administration (D/T, or k₀), and inversely proportional to both the rate of elimination (k_el), and to the volume of body throughout which the drug is distributed: C_ss =D/Tk_elV_d. Since, k_elVd equals total clearance: C_ss = D/TCl_T, or C_ss =k₀/Cl_T. The concentration finally achieved varies directly with the infusion rate and indirectly with the total clearance of the drug (always assuming first-order elimination and a single compartment system).

For a drug given by infusion, and eliminated by first-order kinetics from a one-compartment system, the rate at which C_ss is achieved depends only on the half-life of the drug. In the absence of other doses (such as a loading dose [q.v.]) the plasma concentration at any time after beginning the infusion (C_T), expressed as a fraction of the C_ss to be achieved, is given by (1 - f):

After duration of infusion of one half-life, 50% of the final concentration will have been achieved; after a duration of infusion of 4 half-lives, about 95% of the final concentration will have been achieved.

Intrinsic Activity:

The property of a drug which determines the amount of biological effect produced per unit of drug-receptor complex formed. Two agents combining with equivalent sets of receptors may not produce equal degrees of effect even if both agents are given in maximally effective doses; the agents differ in their intrinsic activities and the one producing the greater maximum effect has the greater intrinsic activity. Intrinsic activity is not the same as "potency" and may be completely independent of it. Meperidine and morphine presumably combine with the same receptors to produce analgesia, but regardless of dose, the maximum degree of analgesia produced by morphine is greater than that produced by meperidine; morphine has the greater intrinsic activity. Intrinsic activity - like affinity - depends on the chemical natures of both the drug and the receptor, but intrinsic activity and affinity apparently can vary independently with changes in the drug molecule.

In analogy to the Lineweaver-Burk plot of the reciprocal of reaction velocity of an enzymatically catalyzed reaction against the reciprocal of the substrate concentration, one may plot the reciprocal of the magnitude of the drug-induced biological effect against the reciprocal of the drug concentration . Under ideal conditions, the slope of the resulting line is a measure of affinity and the point of intersection of the line with the ordinate is a measure of intrinsic activity.