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CONCEPTS IN CLINICAL PHARMACOKINETICS 4TH EDITION PDF

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Concepts in Clinical Pharmacokinetics - 4th Ed. - Ebook download as PDF File .pdf), Text File .txt) or read book online. This programmed manual presents basic pharmacokinetic concepts and Although the fourth edition of Concepts in Clinical Pharmacokinetics. CONCEPTS IN CLINICAL PHARMACOKINETICS - 4th Ed. Pages · · OXFORD HANDBOOK OF CLINICAL DENTISTRY - 4th Ed. ().


Concepts In Clinical Pharmacokinetics 4th Edition Pdf

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When preparing tables, if you are using a table grid, use only one grid for each individual table and not a grid for each row. If no grid is used, use tabs, not spaces, to align columns.

Concepts in Clinical Pharmacokinetics - 4th Ed. 2005

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List here those individuals who provided help during the research e. Phenytoin is primarily metabolized to its inactive form by the enzyme CYP2C9.

Variations within the CYP2C9 gene that result in decreased enzymatic activity have been associated with increased phenytoin concentrations, as well as reports of drug toxicities due to these increased concentrations. Phenytoin induces metabolizing enzymes in the liver. This leads to increased metabolism of vitamin D , thus decreased vitamin D levels.

Vitamin D deficiency , as well as low calcium and phosphate in the blood cause decreased bone mineral density. Antacids administered in a peptic ulcer regimen may decrease the AUC of a single dose of phenytoin. Patients should be cautioned against concomitant use of antacids and phenytoin. Consider using other options if possible.

Sodium channels are: 1 Closed 2 Open 3 Inactive phenytoin effect Phenytoin is believed to protect against seizures by causing voltage-dependent block of voltage gated sodium channels. However, we can measure drug concentration in the blood or plasma, urine, saliva, and other easily sampled fluids Figure Kinetic homogeneity describes the predictable relationship between plasma drug concentration and concentration at the receptor site Figure Changes in the plasma drug concentration reflect changes in drug concentrations in other tissues.

As the concentration of drug in plasma increases, the concentration of drug in most tissues will increase proportionally. Similarly, if the plasma concentration of a drug is decreasing, the concentration in tissues will also decrease.

Figure is a simplified plot of the drug concentration versus time profile after an intravenous drug dose and illustrates the property of kinetic homogeneity. The property of kinetic homogeneity is important for the assumptions made in clinical pharmacokinetics.

It is the foundation on which all therapeutic and toxic plasma drug concentrations are established.

That is, when studying concentrations of a drug in plasma, we assume that these plasma concentrations directly relate to concentrations in tissues where the disease process is to be modified by the drug e. This assumption, however, may not be true for all drugs. Clinical Correlate Drugs concentrate in some tissues because of physical or chemical properties. Examples include digoxin, which concentrates in the myocardium, and lipid-soluble drugs, such as benzodiazepines, which concentrate in fat.

Figure Blood is the fluid most often sampled for drug concentration determination. Relationship of plasma to tissue drug concentrations. Drug concentration versus time. The effect of a drug present at the site of action is determined by that drug's binding with a receptor.

Receptors may be present on neurons in the central nervous system to depress pain sensation, on cardiac muscle to affect the intensity of contraction, or even within bacteria to disrupt maintenance of the bacterial cell wall. For most drugs, the concentration at the site of the receptor determines the intensity of a drug's effect Figure However, other factors affect drug response as well. The drug's effect may ultimately be determined by the density of receptors on the cell surface, the mechanism by which a signal is transmitted into the cell by second messengers substances within the cell , or regulatory factors that control gene translation and protein production.

This multilevel regulation of drug effect results in variation of sensitivity to drug effect from one individual to another and also determines enhancement of or tolerance to drug effects. In the simplest examples of drug effect, there is a relationship between the concentration of drug at the receptor site and the pharmacologic effect.

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If enough concentrations are tested, a maximum effect Emax can be determined Figure When the logarithm of concentration is plotted versus effect Figure , one can see that there is a concentration below which no effect is observed and a concentration above which no greater effect is achieved.

When two drugs are tested in the same individual, the drug with a lower EC50 would be considered more potent.

This means that a lesser amount of a more potent drug is needed to achieve the same effect as a less potent drug. The EC50 does not, however, indicate other important determinants of drug response, such as the duration of effect. Duration of effect is determined by a complex set of factors, including the time that a drug is engaged on the receptor as well as intracellular signaling and gene regulation.

For some drugs, the effectiveness can decrease with continued use.

This is referred to as tolerance. Tolerance may be caused by pharmacokinetic factors, such as increased drug metabolism, that decrease the concentrations achieved with a dose. There can also be pharmacodynamic tolerance, which occurs when the same concentration at the receptor site results in a reduced effect with repeated exposure.

Tolerance can be described in terms of the dose-response curve, as shown in Figure To assess the effect that a drug regimen is likely to have, the clinician should consider pharmacokinetic and pharmacodynamic factors.

Concepts in Clinical Pharmacokinetics - 4th Ed - Joseph T. Dipiro

Both are important in determining a drug's effect. Clinical Correlate Tolerance can occur with many commonly used drugs. One example is the hemodynamic tolerance that occurs with continued use of organic nitrates, such as nitroglycerin. For this drug, tolerance can be reversed by interspersing drug-free intervals with chronic drug use. For some patients with diabetes mellitus there is a reduction in the number of insulin receptors on the surface of cells using glucose.

These patients then become relatively insensitive to insulin and require higher doses. Therefore, the pharmacologic response for one person can be quite different from another, even with the same insulin concentrations at the receptor site. Clinical Correlate One way to compare potency of two drugs that are in the same pharmacologic class is to compare EC The drug with a lower EC50 is considered more potent.

Relationship of drug concentration to drug effect at the receptor site. Relationship of drug concentration at the receptor site to effect as a percentage of maximal effect. Demonstration of tolerance to drug effect with repeated dosing. Within this therapeutic range, the desired effects of the drug are seen. Below it, there is greater probability that the therapeutic benefits are not realized; above it, toxic effects may occur.

No absolute boundaries divide subtherapeutic, therapeutic, and toxic drug concentrations. A gray area usually exists for most drugs in which these concentrations overlap due to variability in individual patient response. Both pharmacodynamic and pharmacokinetic factors contribute to this variability in patient response. Although this course focuses on pharmacokinetics, it is important to remember the fundamental relationship between drug pharmacokinetics and pharmacologic response.

The pharmacokinetics of a drug determine the blood concentration achieved from a prescribed dosing regimen. It is generally assumed that after continued drug dosing, the blood concentration will mirror the drug concentration at the receptor site; and it is the receptor site concentration that should principally determine the intensity of a drug's effect. Consequently, both the pharmacokinetics and pharmacologic response characteristics of a drug and the relationship between them must be understood before predicting a patient's response to a drug regimen.

Theophylline is an excellent example of a drug whose pharmacokinetics and pharmacodynamics are fairly well understood. When theophylline is administered at a fixed dosage to numerous patients, the blood concentrations achieved vary greatly. That is, wide interpatient variability exists in the pharmacokinetics of theophylline.

Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents

This is important for theophylline because subtle changes in the blood concentration may result in significant changes in drug response. Figure shows the relationship between theophylline concentration x-axis, on a logarithmic scale and its pharmacologic effect, changes in pulmonary function [y-axis]. Figure illustrates that as the concentration of theophylline increases, so does the intensity of the response for some patients. Wide interpatient variability is also shown.

Drugs like theophylline possess a narrow therapeutic index because the concentrations that may produce toxic effects are close to those required for therapeutic effects. The importance of considering both pharmacokinetics and pharmacodynamics is clear. Examples of therapeutic ranges for commonly used drugs are shown in Table As can be seen in this table, most drug concentrations are expressed as a unit of mass per volume e.

Many pharmacokinetic factors cause variability in the plasma drug concentration and, consequently, the pharmacologic response of a drug. For most drugs, the intersubject variability is likely to result in differing plasma drug concentrations Figure This variability is primarily attributed to factors influencing drug absorption, distribution, metabolism, or excretion. Disease states e.

Therapeutic drug monitoring is defined as the use of assay procedures for determination of drug concentrations in plasma, and the interpretation and application of the resulting concentration data to develop safe and effective drug regimens. If performed properly, this process allows for the achievement of therapeutic concentrations of a drug more rapidly and safely than can be attained with empiric dose changes. Together with observations of the drug's clinical effects, it should provide the safest approach to optimal drug therapy.

The major potential advantages of therapeutic drug monitoring include maximization of therapeutic drug benefits as well as minimization of toxic drug effects. Therapeutic drug monitoring may be used in designing safe and effective drug therapy regimens. Recall the definition of pharmacodynamics as the relationship between drug concentration at the site of action and pharmacologic response.

As demonstrated in Figure , pharmacodynamics and pharmacokinetics are closely interrelated Figure Some drugs lend themselves to clinical pharmacokinetic monitoring because their concentrations in plasma correlate well with pharmacologic response; for other drugs, this approach is not valuable. For example, it is advantageous to know the plasma theophylline concentration in a patient receiving this drug for the management of asthma.

Because plasma theophylline concentration is related to pharmacologic effect, knowing that the plasma concentration is below the therapeutic range could justify increasing the dose. However, it is of little value to determine the plasma concentration of an antihypertensive agent, as it may not correlate well with pharmacologic effects and the end-point of treatment, blood pressure, is much easier to measure than the plasma concentration.

Plasma levels are often monitored for the drugs listed in Table Blood is the fluid most often sampled for drug concentration determination.

After that point. The property of kinetic homogeneity is important for the assumptions made in clinical pharmacokinetics. If 3 g of a drug are added and distributed throughout a tank and the resulting concentration is 0. Please use 'Highlights' in the file name and include 3 to 5 bullet points maximum 85 characters, including spaces, per bullet point.

Therefore, these tissues may be in different compartments. Incorrect answers

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