If The Rate Of Absorption Of A Drug Is Increased, Which Of The Following Statements Would Be True?

Principles of Drug Therapy

Lee Goldman Medico , in Goldman-Cecil Medicine , 2022

Problems with Interpreting Drug Concentration

The fourth dimension of blood collection, perhaps more whatsoever other factor, contributes to the misinterpretation of drug levels. Every bit tin can be seen inFigure 26-2 , if sampling is performed besides early, while the drug is still in the distribution phase, the drug level may be loftier and not reflect drug concentration at the site of activeness. It is therefore important to sample afterwards the distribution phase.

For many drugs administered intermittently, a trough level, obtained immediately before the next dose is administered, is most useful for making decisions about dose adjustments (seeTable 26-one). For drugs administered by infusion or intermittently at short intervals (run intoFig. 26-4), the all-time time to describe blood is during steady state.

Poly peptide binding is another major factor that contributes to the misinterpretation of drug levels. Free drug (not bound to poly peptide and able to equilibrate with tissues and to interact with the site of action) is the critical drug concentration when therapeutic decisions are being made. Many drugs are tightly bound to plasma poly peptide, however.Tabular array 26-ane shows that many commonly used drugs, such equally aspirin, carbamazepine, phenytoin, and glimepiride, have poly peptide bounden of more 75%. Because many of the unremarkably used drug assays decide total drug concentration (which includes poly peptide-jump drug and free drug), cess of the "true" free drug concentration may be inaccurate, particularly if the fraction of drug jump to protein varies. In improver, the drug'southward binding may exist decreased past disease or by other drugs, leading to increased unbound drug levels that modify the interpretation of the measured drug concentrations. Kidney and liver disease can alter the binding of certain drugs (due east.g., phenytoin) to protein because of a decrease in protein (eastward.chiliad., decreased albumin, equally in nephrotic syndrome or liver disease) or every bit a result of competition for poly peptide bounden by endogenously produced substances (e.1000., uremia in kidney disease, hyperbilirubinemia in liver disease). Similarly, other drugs existence administered may compete for bounden to protein. A major problem secondary to these changes in protein binding is that free drug is not typically measured in many of the common drug assays used by clinical laboratories. Lastly, changes in drug binding to protein tin can bear upon the pharmacokinetics of the drug, the main effect being on the VD, which increases equally poly peptide binding decreases.

The usefulness of a drug assay is also limited by physiologic changes that may modify the response at a particular drug concentration. An instance of this pharmacodynamic change is the response produced past a certain level of digoxin in the presence of altered electrolyte concentrations (eastward.grand., potassium, calcium, and/or magnesium). Tolerance, a reduced response to a given concentration of drug with continued use, is another pharmacodynamic change that may alter how a drug concentration is interpreted. Tolerance is usually observed with the continued use of narcotics (e.one thousand., in terminal cancer patients); initially, adequate pain command is noted at a given drug concentration, but afterward long-term administration, the same drug concentration is no longer associated with pain relief. Positive (placebo) or negative (nocebo) effects may also exist associated with many drugs and may mimic their known benefits or toxicities. ^1c

Clinical Utility of Gratis Drug Monitoring

Florin Marcel Musteata , in Therapeutic Drug Monitoring, 2022

Conclusions

Free drug concentrations correlate to therapeutic effects amend than total drug concentrations, for both minor and big molecules. Unfortunately, electric current technical difficulties in accurately measuring free concentrations prevent full clinical awarding, and further enquiry in this field is needed. Nevertheless, in clinical laboratories ultrafiltration followed by measurement of the drug in the poly peptide-complimentary ultrafiltrate using a commercially available immunoassay or a chromatographic method is routinely used for free drug monitoring of phenytoin, valproic acid, carbamazepine and mycophenolic acrid. Such routine monitoring of complimentary drug concentrations certainly has demonstrated clinical usefulness. Every bit bioanalytical methods become more sensitive, accurate and precise we will certainly witness an increase in monitoring of gratuitous drug concentrations, which represent the "agile" fraction of the drug.

As an alternative, when costless drug concentrations are likewise complicated to monitor or the procedure is too costly, the full drug concentration can exist normalized by using equation iv.6, or specific equations such as those proposed for phenytoin [i, 8] or testosterone [54]. However, direct measurement of free drug is certainly superior to indirect estimation of costless drug using a mathematical equation.

An important tendency in the next decade volition be the development of new analytical methods based on in vivo microextraction and biosensors. These new approaches will naturally decide gratis drug concentrations, and will also allow investigation of pharmacokinetics in target tissues, further expanding the utility of free drug monitoring.

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Pharmacokinetics in Neonatal Medicine

Richard J. Martin MBBS, FRACP , in Fanaroff and Martin's Neonatal-Perinatal Medicine , 2022

Pharmacokinetic Models Depict Concentration of Drug Over Fourth dimension

Pharmacokinetic models describe the mathematical relationship between the dose of a medication administered to a patient and the drug concentration over fourth dimension later on a given dose ( Figs. 45.4 and45.5). These drug concentration-versus-time curves draw the disposition of drug through the body and are the basis for the mathematical models (kinetics of disuse) that predict private drug concentrations over time in specific patients. Drug concentrations are typically only available from the claret and serve as a surrogate for drug concentration at sites of activity to correlate with pharmacologic response.

Commencement-Order or Zero-Society Kinetics

The drug-concentration-over-time graphs inFig. 45.iv depict the rate of elimination of a drug from the body on a linear and semi-logarithmic plot. Most drugs follow starting time-guild kinetics, and mathematical equations inTable 45.one are advisable for drugs that are eliminated using properties of first-gild kinetics. ^19,twenty For drugs that follow kickoff-gild kinetics, a constant percentage of drug is metabolized over time. Since the rate of elimination (Grand_el ) is proportional to the amount of drug in the torso, and then a large amount of drug is removed per unit of measurement time initially with a small corporeality drug when concentrations are low. When drugs follow commencement-order kinetics, the concentration time bend shows an exponential subtract in the plasma drug concentration over time, and a linear decrease in drug concentration on logarithmic scale (see Fig. 45.5). The half-life of drug emptying is independent of drug dosage. Nigh drugs used in neonates follow first-club kinetic backdrop, including ampicillin, gentamicin, and phenobarbital.

Rarely, drugs may follow what is called aught-order kinetics or nonlinear, saturable kinetics. In drugs that follow nothing-lodge kinetics, a constant amount of drug is metabolized or eliminated per unit of measurement of time regardless of concentration. The drug concentration follows a linear decrease of serum concentration over fourth dimension (seeFig. 45.four). The emptying charge per unit constant (K_el) is highly variable, with a smaller percentage of the drug eliminated at the beginning and a college percentage of the residual drug eliminated toward the terminate, every bit demonstrated on log-transformed calibration. The half-life of drugs whose elimination follows naught-order kinetics is dependent on drug dosage; larger doses yield a longer one-half-life. One example is ethanol. After ingesting alcohol, the liver'south booze dehydrogenase rapidly becomes saturated such that but a fixed amount can be metabolized over a given amount of time. There is a maximum yet constant corporeality that the body can eliminate at any given time. Small increases in dose can yield big increases in levels, because the amount of drug removed is constant and not proportional to the dose. Phenytoin is another zero-order kinetic drug, owing to saturable kinetics of the metabolizing enzymes. ^nine Some drugs that typically follow starting time-lodge kinetics can follow zero-order kinetics when given at a very high dosage if enzymatic metabolism becomes saturated until the drug concentrations decrease to the point that enzymatic reactions are no longer saturated and then start-social club kinetics can resume.

Poly peptide and Peptide Commitment through Respiratory Pathway

Hemal Tandel , ... Ambikanandan Misra , in Challenges in Delivery of Therapeutic Genomics and Proteomics, 2022

9.5.3.2.2.5 Drug Concentration, Dose, and Administered Volume

Drug concentration, dose, and volume of administration are 3 interrelated parameters that impact the performance of the nasal delivery organization. Nasal absorption of 1-tyrosyl- l-tyrosine was shown to increment with drug concentration in nasal perfusion experiments [91,97]. The result of drug dose on nasal absorption has been reported by numerous studies based on molecules similar calcitonin [98], GnRH agonist [99], desmopressin [100,101], and secretin [102–104]. All studies conclude that by increasing the drug dose, greater transnasal absorption was achieved. The optimal formulation book for nasal administration is 25–200 μl per nostril. More than this volume tin lead to anterior leakage or postnasal dripping of the formulation.

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Pare Bulwark and Transdermal Drug Delivery

Jean Fifty. Bolognia MD , in Dermatology , 2022

Drug Concentration

The driving force for percutaneous absorption is the concentration ofsoluble drug in the vehicle. Many older topical drug products were marketed with the expectation that college concentrations were more than potent. Although true for some products such as tretinoin gels and creams (0.01–0.ane%), in which the drug is completely solubilized at all concentrations, for others it is not the example. Hydrocortisone i% and ii.5% in a cream formulation take been shown to be of equal potency, as take triamcinolone acetonide 0.025%, 0.1% and 0.five% creams ⁴⁹ . One of the major advances in formulating glucocorticoids, every bit commencement shown with fluocinonide, came when it was discovered that the addition of propylene glycol to the vehicle could completely solubilize the drug. This led to corticosteroid products with greater potency, as demonstrated in the vasoconstrictor assay.

Newer products are now tested during the development process to ensure that increased drug concentration results in increased bioavailability. Notwithstanding, backlog non-dissolved drug can sometimes be advantageous, especially in transdermal patches worn for prolonged periods of time (eastward.grand. upward to a calendar week). In this situation, as dissolved drug is absorbed into the torso, non-dissolved drug can then become dissolved in society to maintain an equilibrium, thereby maintaining a constant dissolved drug concentration over time and providing a constant charge per unit of commitment ^l .

Antiseizure Drug Therapy in Children

Jeannine M. Conway , ... Angela K. Birnbaum , in Swaiman's Pediatric Neurology (6th Edition), 2022

What to Mensurate

Total drug concentrations generally are measured; all the same, it as well is possible to make up one's mind levels of free or unbound drug, as well as of metabolites of the administered drug. Gratis drug concentrations correlate best with clinical effect and toxicity. In near cases, the ratio of free to bound drug is relatively constant for a particular patient; therefore, total drug concentrations unremarkably are adequate. In certain instances, however, particularly with critically ill patients under intensive care, determination of gratuitous drug levels, especially for phenytoin and valproic acid, is essential. In such patients, many drugs are typically administered, increasing the likelihood that antiseizure drugs will be displaced from protein-binding sites. The per centum of unbound valproic acid increases with college drug concentrations and with comedication, or when valproic acid is speedily administered. When the jump fraction is doubled, the valproic acid free fraction may be 8 times higher.

Occasionally, measurement of antiseizure drug metabolites is useful. With several antiseizure drugs, metabolites are clinically active and contribute to both response and toxicity. Phenobarbital is an active metabolite nowadays during primidone therapy. Carbamazepine-10,11-epoxide is a derivative of carbamazepine and contributes to toxicity. Clinical monitoring of oxcarbazepine and eslicarbazepine acetate treatment is evaluated past measuring their principal metabolites.

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PK Estimation of Drug Distribution: General Concepts and Application to Special Populations

Shinya Ito , in Reference Module in Biomedical Sciences, 2022

2.1.one Concentration-time profile

Drug concentration-fourth dimension profiles in torso fluid are quantitatively analyzed and interpreted using PK concepts, which guide drug development at a population level and pharmacological management of private patients. In other words, PK analyses of concentration—time curves provide information necessary to define the dose-concentration-effect relationship, establishing appropriate dosing schedules.

The trunk fluid for drug concentration measurement is usually plasma, serum or blood (In this affiliate, drug concentrations are assumed to be measured in plasma, unless stated otherwise). Although the time course and fashion of drug administration influences the concentration-fourth dimension curves, a common blueprint emerges later sufficient fourth dimension has elapsed from the last dose. For example, later on intravenous bolus injection of a drug at a therapeutic dose, plasma drug concentration starts decreasing from the initial tiptop, post-obit a design of a curve that can be all-time described by a unmarried exponential decay function with the base e in a course of e ^{− a ∙ x}, or a combination of them.

This observed pattern of decay is a process common to many phenomena in nature, where a quantity of a substance is shrinking at a declining rate proportional to its present quantity equally seen in radioactivity disuse. A general form of such a function equally a plasma drug concentration—fourth dimension curve is given by:

(1) $C = \sum_{i = 1}^{north} A_{i} ∙ e^{- λ_{i} ∙ t}$

A variable C is a plasma drug concentration at fourth dimension t, and − λ _i is a constant that defines a log-linear slope of each exponential function as − λ/Lnx or − λ/2.303 , and has a unit of reciprocal time (e.g., min^{− 1}). A _i corresponds to the Y-intercept of each exponential term. A mono-exponential disuse (n = i in Eq. 1) is the simplest form:

(ii) $C = A ∙ {east}^{- λ ∙ t}$

In Eq. (ane) and Eq. (ii) (as a special example of Eq. 1) describing drug concentration—time profiles, the coefficient and the exponent are defined as mathematical parameters in relation to the curve. As seen below, withal, a more physiologic estimation is besides possible.

Assume a mono-exponential disuse curve (Eq. 2) for simplicity. The derivative of a mono-exponential decay function (Eq. 2) provides the velocity or the rate of concentration change as follows:

(3) $\frac{dC}{dt} = - λ ∙ C$

The minus sign before λ indicates that the change management is quantity reduction as time elapses. In Eq. (iii), the proportionality constant λ determines the reduction rate of the concentration (i.east., dC/dt), which is proportional to C at a given fourth dimension. It is evident from Eq. (3) that the rate or the velocity of concentration decay steadily slows down as time passes because C is declining. Note that Eqs. (1)–(iii) are based on the assumption that the system volume remains unchanged. They can be rewritten every bit corporeality-based formulae. For example, Eq. (3) can be expressed as follows because C = X ∙ (book)^{− ane} :

(four) $\frac{dX}{dt} = - one thousand ∙ 10$

where X is the corporeality of drug in the organisation at time t, and k is chosen an elimination charge per unit constant, indicating its defining role for the rate of drug elimination dX/dt. Although an emptying rate constant k in Eq. (four) and a concentration disuse charge per unit λ in Eq. (3) are symbolized differently, they are equivalent.

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ADME-Tox Approaches

J.V. Turner , S. Agatonovic-Kustrin , in Comprehensive Medicinal Chemistry II, 2007

5.29.2.five Impact of Interindividual Variability

Drug concentration is amidst the about important determinants of clinical response to a drug. Variability in pharmacokinetic profiles makes drug concentrations unpredictable: the greater the variability, the greater the magnitude of this problem.

Bioavailability of a drug may vary within the same person over fourth dimension also as between different people in a population. The cause of large interpatient pharmacokinetic variability is multifactorial and includes differences in drug absorption, metabolism, or distribution, and complex drug–drug or drug–food interactions. ⁵³ Population subgroups such as infants, pregnant women, and other groups with underlying traits or disease states are also likely to exhibit variable bioavailability and absorption, distribution, metabolism, and excretion (ADME) characteristics. ⁵⁴ Population variability in clinical data is a reality and should be incorporated into the modeling process.

Although predictive models may be constructed with good accuracy based on a given information set, the quality of such models ultimately reflects the quality of the data: poor-quality bioavailability information with wide uncertainty will result in poor models regardless of apparent accuracy. Care must also be taken when extrapolating outside the limits of model training data.

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Design and Fabrication of Encephalon-Targeted Drug Commitment

Vandana Soni , ... Rakesh M. Tekade , in Basic Fundamentals of Drug Commitment, 2022

14.6.three.one.9 Drug Concentration and Dosing Volume

The drug concentration and dosing book can accept an upshot on the nasal delivery of drug to the encephalon. The drug concentration has a direct effect on the nasal drug absorption, that is, increase in the concentration of drug causes better assimilation at the site of administration. This is more of import for the drugs primarily having a passive diffusion mechanism of assimilation of the drug. But, higher concentrations of the drug when administered in large volume tin have opposite consequence on the assimilation of the drug; which may be every bit a result of local adverse furnishings. In some cases, it may cause nasal mucosa damage. The delivery of the dosing book and their drug concentration is restricted by the size and shape of the nasal cavity. A volume of 25–200 µL/nostril and an upper limit of 25 mg/dose are recommended (Kushwaha et al., 2022).

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Influence of transporters in treating cancers in the CNS

Gautham Gampa , ... William F. Elmquist , in Drug Efflux Pumps in Cancer Resistance Pathways: From Molecular Recognition and Characterization to Possible Inhibition Strategies in Chemotherapy, 2022

Targeted bioavailability

The drug concentrations in the blood or plasma are routinely measured as surrogates for concentrations at the site of action, due to ease of accessibility. While the drug concentration in systemic circulation may somewhat reflect the concentration at the site of action when the target is in a peripheral, more accessible, tissue, their use as a surrogate for brain drug concentrations tin be misleading. This is important specially in the context of brain compared to other organs due to presence of the BBB that can severely restrict drug distribution to the brain [thirteen, 14]. To differentiate the bioavailability estimated using drug concentrations at the site of activeness, brain in this discussion, from the traditional bioavailability determined using the systemic concentrations, we would like to utilize the term 'targeted bioavailability' [48] (Fig. 2). Diverse factors can influence a chemical compound's targeted bioavailability in the brain such as BBB permeability, drug transport by ship proteins, drug metabolism, poly peptide bounden, protein expression, receptor affinity, factor regulation and dosage regimen [48]. The findings from diverse studies testing dissimilar anti-cancer agents betoken that the concentrations of a drug in the brain tin can be remarkably unlike from systemic concentrations [13, 14, 49]. The relevance of the concentration–outcome relationship should be judiciously assessed when using systemic concentrations, as the variability in pharmacodynamic measurements (i.eastward., drug response, and toxicity) may non be reflected by the variability observed in the pharmacokinetic measurements [48]. Therefore, the measurement of target site concentrations, when possible, is more than advisable to evaluate a pharmacokinetic–pharmacodynamic (PK–PD) relationship.

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