What is the term for taking two drugs at the same time with similar effects?
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The medicines might be taken for the same illness, such as quinsy (an abscess in the throat), for which a person needs antibiotics and painkillers. Or it may be because they suffer from two different diseases at the same time, such as high blood pressure and arthritis, for which they need antihypertensives and anti-inflammatories. Show
Medicines can sometimes influence each other inside the body, producing an increased effect, extra side effects, or decreased effectiveness of one or more of the drugs. This is called a drug interaction. How can two different drugs influence each other's effect?Nearly all medicines are broken down by specific enzymes in the liver, and are then excreted as smaller molecules through the kidneys. Some medicines can affect the way other medicines are broken down in the liver, or are filtered into the urine by the kidneys. If medicine A inhibits the enzyme responsible for breaking down medicine B, the result can be an excessive amount of medicine B in the bloodstream. This can increase the chance of serious side effects. If a doctor thinks that both medicines are necessary at the same time, they will ensure that the dose of medicine B is reduced, to avoid any adverse effects. If, on the other hand, medicine A increases the activity of the enzyme responsible for breaking down medicine B, the breakdown will occur much faster and the effect of medicine B will be decreased or lost. In that case, a doctor will increase the dose of medicine B. Medicines can also influence each other in other ways; for instance, they can affect absorption from the intestines or excretion by the kidneys. In both instances, this can result in effects similar to those described above - too much or too little medicine in the bloodstream, which may lead to serious side effects or little or no effect at all. If medicines that can have similar side effects are taken together, there may also be a chance that the side effects will be additive. For example, if an antihistamine that can make you sleepy is taken by someone who is also taking a strong painkiller that can cause drowsiness, for example morphine, then any drowsiness is likely to be increased. Do I have to tell my doctor about all the medicines I am using?As long as a doctor or pharmacist has taken into account the effect of taking two or more medicines at the same time it should be perfectly safe. This is why you should always tell your doctor or pharmacist about all the medicines you are using, including herbal remedies and those bought without a prescription, since drug interactions can occur with these too. When buying over-the-counter medicines from a chemist you should also remember to check with the pharmacist whether the new medicine is safe to take with any other medicines you are currently using. When children have complex psychiatric symptoms, or aren’t responding adequately to a medication they are taking, doctors often recommend adding another medication. Taking multiple psychoactive medications is called “polypharmacy.” And studies show that the number of children taking more than one medication is soaring. Combining medications can be effective when they’re prescribed and monitored carefully by a doctor expert in using them with children. But it’s important for parents to know the risks inherent in adding medications, and how to tell if you should be concerned about what a doctor is recommending. The risk in combining medications is that they can interact in ways that increase unwanted or harmful side effects. Let’s say your child is prescribed one medication that causes mild sedation, and a second does the same thing. The result can be so much sedation that the child isn’t herself and can’t stay awake, explains Dr. Ron Steingard, a child and adolescent psychiatrist at the Child Mind Institute. Another medication interaction that can be problematic is if two medications use the same metabolic pathway—the mechanism in the body that breaks them down and delivers them to the target. In some cases these medications, taken together, can overwhelm that pathway and create a buildup of medication, Dr. Steingard says, and that can cause the kind of side effects you’d see with a much higher dose of one of the meds. Finally, there’s a risk that a child is prescribed multiple medications when he would benefit more from other supports, including behavioral treatments that have been shown to be effective for kids with many issues, including ADHD, anxiety and depression. 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. , , , Absorption Rate Constant:See Accumulation, Accumulation Ratio:See 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. AccuracyIn 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.ValidityThe 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?ReliabilityThe 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?SensitivityThe 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.AmplificationThe 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”.)PrecisionThe 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.ComparabilityThe 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.EconomyThe 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:See 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: Cf. , , , . 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 . See also 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. , , , 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. 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: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: Chemicalcaused by combination of agonist with antagonist, with resulting inactivation of the agonist, e.g., dimercaprol and mercuric ion.Physiologicalcaused by agonist and antagonist acting at two independent sites and inducing independent, but opposite effects.Pharmacologicalcaused 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. , , , Area Under the Curve:Abbreviated as (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. , , , Availability:See B 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. Cf. , , 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. , , , 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:
(See: Bliss, C.I., American Scientist, 45: 499, 1957). Cf. , , , 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. , , , , , , , 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: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. , 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. , , , , , 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. Cf. , , C C, Cx:The concentration (in units of mass/volume) of a chemical in a body fluid such as blood, plasma, serum, urine, etc.; the specific fluid may be indicated by a subscript, i.e. CU, the concentration of drug in the urine; when no subscript is used, C is commonly taken to be the concentration in the plasma. C0:The fictive concentration of a drug or chemical in the plasma at the time (in theory) of an instantaneous intravenous injection of a drug that is instantaneously distributed to its volume of distribution. C0 is determined by extrapolating, to zero-time, the plot of log C against t (for apparently “first-order ” decline of C) or of C against t (for apparently “zero-order” decline of C). Cf. , , , , Cmax, Cmin:The maximum or “peak” concentration (Cmax) of a drug observed after its administration; the minimum or “trough” concentration (Cmin) of a drug observed after its administration and just prior to the administration of a subsequent dose. For drugs eliminated by first-order kinetics from a single-compartment system, Cmax, after n equal doses given at equal intervals is given by C0(1 – fn )/(1 – f) = Cmax, and Cmin = Cmax – C0. The time following drug administration at which the peak concentration of Cmax occurs, tp (for any route of administration but the intravenous), is given by tp = (ln ka – ln kel )/(ka – kel). (Remember that ln is the natural logarithm, to the base e, rather than the common logarithm or logarithm to the base 10; ln X=2.303 log X.) Cf. , , Css:The concentration of a drug or chemical in a body fluid – usually plasma – at the time a “steady state” has been achieved, and rates of drug administration and drug elimination are equal. Css is a value approached as a limit and is achieved, theoretically, following the last of an infinite number of equal doses given at equal intervals. The maximum value under such conditions (Css,max) is given by Css,max = C0/(1 -f), for a drug eliminated by first-order kinetics from a single compartment system. The ratio Css,max/C0 indicates the extent to which drug accumulates under the conditions of a particular dose regimen of, theoretically, an infinitely long duration; the corresponding ratio 1/(1 – f) is sometimes called the Accumulation Ratio, R. Css is also the limit achieved, theoretically, at the “end” of an infusion of infinite duration, at a constant rate. Cf. , , Cl, Clx:Clearance – in volume/unit time – of a drug or chemical from a body fluid, usually plasma or blood, by specified route(s) and mechanism(s) of elimination, as indicated by a subscript, e.g., ClR, urinary clearance; ClH, hepatic clearance, etc. ClT, total clearance, indicates clearance by all routes and mechanisms of biotransformation and excretion, operating simultaneously. ClT = kel · Vd. Following intravenous administration, ClT = D/AUC; following administration of drug by any route other than the intravenous, ClT = F D/AUC. Cf. , , Ceiling:The maximum biological effect that can be induced in a tissue by a given drug, regardless of how large a dose is administered. The maximum effect produced by a given drug may be less than the maximum response of which the reacting tissue is capable, and less than the maximum response that can be induced by another drug of greater intrinsic activity. “Ceiling” is analogous to the maximum reaction velocity of an enzymatic reaction when the enzyme is saturated with substrate. Cf. Chemotherapy:Drug treatment of parasitic or neoplastic disease in which the drug has a selective effect on the invading cells or organisms. Clearance:The clearance of a chemical is the volume of body fluid from which the chemical is, apparently, completely removed by biotransformation and/or excretion, per unit time. In fact, the chemical is only partially removed from each unit volume of the total volume in which it is dissolved. Since the concentration of the chemical in its volume of distribution is most commonly sampled by analysis of blood or plasma, clearances are most commonly described as the “plasma clearance” or ” blood clearance” of a substance. For a single compartment system, total clearance, by all routes (ClT), is estimated as the product of the elimination constant and the volume of distribution, in liters: ClT = kel · Vd the dimensions of ClT are, of course, volume/time. Renal Clearance:Renal plasma (or blood) clearance ClR is the volume of plasma (or blood) freed of a substance by only renal mechanisms, per unit time. The amount of drug (AU) excreted in the urine during the time interval t – t’ is determined; the plasma (or blood) concentration at the mid-point of the interval (Cp) is found by interpolation on the line relating log C and t. The urinary excretion rate of the drug, Renal plasma clearance will vary with such factors as age, weight, and sex of subject, the state of cardiovascular and renal function, the nature of the material being excreted, species, etc. Renal clearance by only glomerular filtration is defined and measured as the clearance of the sugar inulin, which is eliminated from the body by no route other than glomerular filtration. Total renal clearance is defined and measured by clearance of para-amino-hippurate (PAH), a substance that is eliminated by both glomerular filtration and tubular excretion (at the maximum rate of which the tubular mass is capable). Neither inulin nor PAH undergoes reabsorption by the tubules as some materials do. (N.B.: Blood and plasma are completely cleared of PAH by a single “pass” through the kidney; PAH clearance is therefore, the standard measure of renal plasma, or blood, flow). In normal adult human males, plasma clearance of inulin is about 130 ml plasma/min; of PAH, about 700 ml plasma/min. In normal adult human females, clearance of inulin is about 115 ml plasma/min; of PAH, about 600 ml plasma/min. The relationship between clearance of blood and clearance of plasma is given by the relationship ClR (blood) = ClR (plasma)/(1-Hct), where “Hct” is the hematocrit, the proportion, as a fraction – of the blood which consists of cells, not plasma; on the average, normal adult human subjects can be assumed to have a hematocrit of about 0.45. Like many other physiological “constants,” renal plasma clearance varies regularly and exponentially with body weight, across mammalian species ( Science 109: 757, 1949). Renal plasma clearances, in normal animals, can be predicted using the following relationships, where Cl R is in ml/hr, and body weight (B) is in grams: ClR (inulin) = 1.74B0.77 ClR (PAH) = 5.40B0.80 Nonrenal Clearance:Clearance by the fecal route (ClF), respiratory route (ClL), salivary route (ClS), biliary route (ClB), can be computed in a fashion analogous to computation of ClR: measuring the amount of substance excreted in the feces, expired air, saliva, etc., over an interval and dividing by the plasma concentration at mid-interval and the length of the interval. Following oral administration of a substance, measurement of fecal clearance may be confounded by the presence, in feces, of unabsorbed substance or of substance absorbed but excreted into the lumen of the gastrointestinal tract in, e.g., bile. Specialized techniques exist for estimating clearance of substances by the liver (ClH), by biotransformation and/or biliary excretion. Unlike half-lives, clearances are directly additive and for any substance: ClT = ClR + ClL + ClH + ClS + ClF + . . . etc. Clinical Therapeutic Index:Some indices of relative safety or relative effectiveness cannot be defined explicitly and uniquely, although it is presumed that the same quantifiable and precise criteria of efficacy and safety will be used in comparing drugs of similar kinds. The Food and Drug Administration has considered the following definition of an improved Clinical Therapeutic Index to be used in comparing different drug combinations or formulations; the assumption is retained that an improved or ” better” drug has a higher Clinical Therapeutic Index ” (1) increased safety (or patient acceptance) at an accepted level of efficacy within the recommended dosage range, or (2) increased efficacy at equivalent levels of safety (or patient acceptance) within the recommended dosage range.” Cf. , , , Compartment(s):The space or spaces in the body, which a drug appears to occupy after it has been absorbed. Pharmacokinetic compartments are mathematical constructs and need not correspond to the fluid volumes of the body which are defined physiologically and anatomically, i.e., the intravascular, extracellular and intracellular volumes. Some drugs make the body “behave” as if it consisted of only a single pharmacokinetic compartment. Tissue and plasma concentrations of the drug rapidly and simultaneously reach equilibrium in all the tissues to which the drug is distributed. A plot of plasma concentration against time after intravenous administration can be rectified into only a single straight line of negative slope, which can intersect the ordinate at only one point; only one volume of distribution can be calculated. Hence, the existence of only one compartment or volume of distribution can be inferred. Some drugs make the body appear to consist of two or more pharmacokinetic compartments, since tissue/plasma equilibrium is achieved at different times in different tissues or groups of tissues. A plot of plasma concentration against time after intravenous administration can, at best, be resolved into a series of connected straight-line segments with progressively decreasing slopes. Each of these segments may be extrapolated to intersect the ordinate, and one may infer the existence of as many pharmacokinetic compartments, of volumes of distribution, for the drug as there are intersections or segments. Compartments in which equilibrium is achieved relatively late are referred to as “deep” compartments; compartments in which equilibrium is achieved early – and from which drug is redistributed to other sites – are referred to as “shallow” or “superficial” compartments. Cf. , , , Compliance:The extent to which a patient agrees to and follows a prescribed treatment regimen. Cross-Over Experiment:A form of experiment in which each subject receives the test preparation at least once, and every test preparation is administered to every subject. At successive experimental sessions each preparation is “crossed-over” from one subject to another. The purpose of the cross-over experiment is to permit the effects of every preparation to be studied in every subject, and to permit the data for each preparation to be similarly and equally affected by the peculiarities of each subject. In a well-designed cross-over experiment, if it is at all possible, the sequence in which the test preparations are administered is not the same for all subjects, in order to avoid bias in the experiment as a result of changes in the behavior of the subjects that are a function of time rather than of drug administration, or a function of drug interactions. At least, the cross-over design permits detecting such biases when they occur. The preparations under test in a cross-over experiment may – ideally, should – include one or more doses, of an experimental or “unknown” drug, one or more doses of a dummy or placebo medication (“negative control drugs”), and one or more doses of a standard drug, the actions of which are expected to be similar to those of the “unknown” (“positive control drug”). Even for the investigator with the best knowledge and intentions, the economics and logistics of experimentation may prevent carrying out a complete and perfect cross-over experiment. Cf. , , Cross-Tolerance:to a drug that generalizes to drugs that are chemically related of that produce similar affects. For example, a patient who is tolerant to heroin will also exhibit cross-tolerance to morphine. CT Index:A measure of drug “potency” calculated from data appropriate to the construction of a Time-Concentration curve; the product of the concentration (C) of an agent applied to a biological system to produce a specific effect and the duration (T) of application required to produce the effect. The index is calculated on the assumption that the time-concentration curve is precisely and symmetrically hyperbolic and convex to the origin, and that the products of the coordinates for all points on the line are constant. The time-concentration curve of an agent with high potentiality for producing a specified effect lies closer to the axis than the curve for an agent of lesser potential; the CT index for the agent of greater potential is smaller than the index for the agent of lesser potential, i.e., the smaller the CT index, the more “potent” the compound. CT indices have found their greatest application in toxicology, in assessing the potential for effect of noxious vapors, etc. Cf. , , , D D*:(q.v.) D:Dose (q.v.); also the “maintenance doses” administered after a loading dose (q.v.) Dependence:A somatic state which develops after chronic administration of certain drugs; this state is characterized by the necessity to continue administration of the drug in order to avoid the appearance of uncomfortable or dangerous (withdrawal) symptoms. Withdrawal symptoms, when they occur, may be relieved by the administration of the drug upon which the body was “dependent.” Cf. , Desensitization:A decline in the response to repeated or sustained application of an agonist that is a consequence of changes at the level of the receptor. Cf. , Disintegration Time:The time required for a tablet to break up into granules of specified size (or smaller), under carefully specified test conditions. The conditions of the laboratory test, in vitro, are set to simulate those that occur in vivo. Factors such as the kind and amount of tablet binders and the degree of compression used in compacting the tablet ingredients help determine disintegration time. The active ingredients in a disintegrated tablet are not necessarily found to be in solution and available for absorption. A long disintegration time is incompatible with rapid drug absorption; a short disintegration time, by itself, does not ensure rapid absorption. Cf. , , Dissolution Time:The time required for a given amount (or fraction) of drug to be released into solution from a solid dosage form. Dissolution time is measured in vitro, under conditions that simulate those that occur in vivo, in experiments in which the amount of drug in solution is determined as a function of time. Needless to say, the availability of a drug in solution – rather than as part of insoluble particulate matter – is a necessary preliminary to the drug’s absorption. Cf. , , , Distribution:See , Dosage Form:The physical state in which a drug is dispensed for use. For example: a frequent dosage form of procaine is a sterile solution of procaine. The most frequent dosage form of aspirin is a tablet. Dose:The quantity of drug, or dosage form, administered to a subject at a given time; for example, the usual dose of aspirin for relief of pain in an adult is 300-600 milligrams. Dose may be expressed in terms appropriate to a specific dosage form, i.e., one teaspoonful of a liquid medication, rather than the weight of drug in the teaspoonful. Dose may be described as an absolute dose (the total amount administered to a subject) or as a relative dose (relative to some property of the subject as body weight or surface area, mg/kg, or mg/m 2). Cf. , Dose-Duration Curve:The curve describing the relationship between dose (as the independent variable) and duration of drug effect (as the dependent variable, T). The slope of the curve is always positive, in contrast to the slope of the time-concentration curve (q.v.). There has been increased interest in the dose-duration curve as a useful measure of drug action since Levy’s demonstration that the constants describing the straight log dose-duration curve of a drug can be used to infer pharmacokinetic and pharmacodynamic properties of the drug, such as the elimination half-life and the threshold dose. (Clin. Pharmacol. & Therap. 7: 362, 1966). Cf. , , Dose-Effect Curve:A characteristic, even the sine qua non, of a true drug effect is that a larger dose produces a greater effect than does a smaller dose, up to the limit to which the cells affected can respond. While characteristic of a drug effect, this relationship is not unique to active drugs, since increasing doses of placebos (q.v.) can, under certain conditions, result in increasing effects. Distinguishing between ” true” and “inactive” drugs requires more than demonstration of a relationship between “dose” and effect. The curve relating effect (as the dependent variable) to dose (as the independent variable) for a drug-cell system is the “dose-effect curve” for the system. For a unique system, i.e., one involving a single drug and a single effect, such curves have three characteristics, regardless of whether effects are measured as continuous (measurement) or discontinuous (quantal, all-or-none) variates:
Cf. , , , , Drug:A chemical used in the diagnosis, treatment, or prevention of disease. More generally, a chemical, which, in a solution of sufficient concentration, will modify the behavior of cells exposed to the solution. Drugs produce only quantitative changes in the behavior of cells; i.e., drugs increase or decrease the magnitude, frequency, of duration of the normal activities of cells. Drugs used in therapy never produce qualitative changes in cell behavior short of producing death of the cell, e.g., a nerve cell cannot be made to contract or a muscle cell cannot be made to secrete saliva by use of a drug. The degree to which this point of view will be modified by the discovery and development of agents which act on cells at a genetic level remains to be seen. Drug Abuse:Use or misuse of a drug under conditions, or to an extent, considered “more destructive than constructive for society and the individual.” More specifically, the use of drugs for their effects chiefly on the central nervous system, to an extent and/or at a frequency and/or for a duration of time that is inimical to the welfare of the user and/or the total of social groups in which she/he lives. The abuse potential of a drug depends on its capacity to induce compulsive drug-seeking behavior in the user, its capacity to induce acute and chronic toxic effects (and to permit occurrence of associated diseases), and upon social attitudes toward the drug, its use, and its effects. Cf. , , , Drug Dependence:“Drug Dependence” has been recommended as a term to be substituted for such words as “addiction” and “habituation” since it is frequently difficult to classify specific agents as being only addictive, habituating, or non-addicting or non-habituating. It has been suggested that the general term be used and modified, appropriately, in specific instances, e.g., drug dependence of the barbiturate type. Cf. , , , Dummy:“A counterfeit object;” a form of treatment – as in an experimental investigation of drug effects – which is intended to have no effects, to be biologically inert. The dummy treatment should mimic in every way (dosage form, route of administration, etc.) the purportedly active ingredient upon which the effectiveness of the active treatment is expected to depend. In contrast to a dummy, a placebo is expected to have an effect through the agency of “suggestion” or other psychological mechanisms, even though the effects of placebos may be psychological or physical. Dummies may, of course, have the effects of placebos, but it is useful to be aware of the difference expected to exist between the two. According to Gaddum, dummies have two functions: 1) to distinguish between drug effects in a subject and other effects, such as those of suggestion: obviously, an experiment might properly incorporate both a dummy and a placebo. 2) to obtain an unbiased assessment of the result of a pharmacologic experiment. (See Gaddum, J.H., Proc. Roy. Soc. Med. 47: 195, 1954). Cf. , , E EC50:The concentration of an agonist that produces 50% of the maximal possible effect of that agonist. Other percentage values (EC10, EC20, etc.) may be specified. Concentration is preferably expressed in molar units, but the mass concentration (g/l) may be used if the molecular weight of the substance is unknown. ED50:1. In a quantal assay, the 2. In a graded (non-quantal) assay, the dose of a drug that produces 50% of the maximal response to that drug. It is preferable, where possible, to express potency in terms of EC50 but ED50 is appropriate for in vivo measurements and for those in vitro experiments where the absolute concentration is uncertain. If the maximum response is unknown, it is acceptable to express the effectiveness of a drug in terms of the dose that produces a particular level of response, for example a certain change in blood pressure or heart rate. In such a case, the appropriate units must be included (e.g. ED20mm) to avoid confusion. 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.” Cf. , Efficacy:Broadly, efficacy refers to the capacity of a drug to produce an alteration in a target cell/organ after binding to its receptor. A competitive antagonist, that occupies a binding site without producing any alteration in the receptor, is considered to have an efficacy of zero. Efficacy is generally independent of potency/affinity, and is related to the maximum effect that a particular drug is capable of producing. As originally formulated by Stephenson (1956), binding of an agonist A to its receptor R is considered to result in a “stimulus” S=? A x P AR where ? A is the efficacy of A and PAR is the proportion of the receptors occupied. The effect of the drug on the cell or tissue is given by Effect = f (S), where f is an unspecified monotonic function that is dependent upon the nature of the receptor and its interaction with the cell or tissue. Efficacy is both agonist and tissue-dependent. Efficacy is related to , which was originally defined by Furchgott (1966) as e=?/R T , i.e. as the efficacy per receptor. In practice, the two terms are sometimes loosely used synonymously. See Elimination Rate Constant:See 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. Cf. , 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.Cf. , Experiment:See , , F f:The fraction of C0 remaining at some specified time after drug administration; more generally, the fraction of C, or AB, 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 t½ is the elimination half-life of the drug, f is 0.5 raised to a power that is the ratio of the time interval to the elimination half-life, i.e., 0.5t/t½. Cf. , , , , , , 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 ClT)/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 bioavailability of the drug after administration by route X can be determined: F=AUCx/AUCiv. The amount of free drug recovered in the urine (AU) after administration of identical doses given intravenously and by route X can also be used to determine bioavailability: F=AU,x/AU,iv Cf. , , 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)= kt, 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 t1/2 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 = -kt1/2, or, since -0.693 is the natural logarithm of 0.5: -0.693 = kt1/2. Multiplying both sides of the equation by -1 yields 0.693 = kt1/2 or 0.693/k = t1/2: 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 that 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 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 (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. What is it called when two drugs have the same clinical effect?Additive effect often occurs when two similar drugs are taken together to achieve the same degree of therapeutic effect while reducing the specific adverse effect of one particular drug.
What is it called when two or more drugs are taken at the same time?The use of more than one drug, also known as polysubstance use, is common. This includes when two or more are taken together or within a short time period, either intentionally or unintentionally.
What is it called when 2 drugs interact?Drug-drug interactions occur when two or more drugs react with each other. This drug-drug interaction may cause you to experience an unexpected side effect.
What is it called when one drug enhances the effect of another?Potentiation: when one drug does not elicit a response on its own but enhances the response to another drug.
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