brankac hendric glorea
Latarsha Dorrance
After a basic introduction to pharmacokinetics and its related fields, the book provides a clear introduction to quantitative pharmacokinetic relations and the interplay between pharmacokinetic parameters after different routes of drug administration. Emphasizing the application and importance of pharmacokinetic concepts in clinical practice throughout, the book features:
Accompanying the book is a website with self-instructional tutorials and pharmacokinetic simulations, allowing visualization of concepts for enhanced comprehension. This learning tool received an award from the American Association of Colleges of Pharmacy for innovation in teaching, making it a valuable supplement to this textbook.
1.Introduction to Pharmacokinetics. 2.Drug Pharmacokinetics Following Single Intravenous Bolus Administration: Drug Distribution. 3.Drug Pharmacokinetics Following a Single IV Bolus Administration: Drug Clearance. 4.Drug Pharmacokinetics Following Single IV Bolus Administration: The Rate of Drug Elimination. 5.Drug Absorption Following Extravascular Administration: Biological, Physicochemical, and Formulation Considerations. 6.Drug Pharmacokinetics Following Single Oral Drug Administration: The Rate of Drug Absorption. 7.Drug Pharmacokinetics Following Single Oral Drug Administration: The Extent of Drug Absorption. 8.Bioequivalence. 9.Drug Pharmacokinetics during Constant Rate IV Infusion, the Steady State concept. 10.Steady State during Multiple Drug Administration. 11.Renal Drug Excretion. 12.Metabolite Pharmacokinetics. 13.Nonlinear Pharmacokinetics. 14.Multicompartment Pharmacokinetic Models. 15.Drug Pharmacokinetics Following Administration by Intermittent Intravenous Infusions. 16.Physiological Approach to Hepatic Clearance. 17.Pharmacokinetics in Patients with Eliminating Organ Dysfunction. 18.Noncompartmental Approach in Pharmacokinetic Data Analysis. 19.Pharmacokinetic-Pharmacodynamic Modeling. 20.Pharmacogenetics: The Genetic Basis of Pharmacokinetic and Pharmacodynamic Variability. 21.Therapeutic Drug Monitoring. 22.Pharmacometic Applications in Drug Development and Individualization of Drug Therapy. 23.Answer to Practice Problems.
Mohsen A. Hedaya, PharmD, PhD, is a professor at the Faculty of Pharmacy, Tanta University, Egypt, and is currently on leave to work at the Faculty of Pharmacy, Kuwait University, Kuwait. He received his Bachelor of Science in Pharmacy degree Tanta University, and his Doctor of Pharmacy and Doctor of Philosophy degrees from the University of Minnesota, USA. He joined the College of Pharmacy, Washington State University, USA, in 1993 as an Assistant Professor of Pharmaceutical Sciences. After returning to Egypt in 1999, he was promoted to the rank of associate and then full professor. He served as the Chair of the Clinical Pharmacy Department and Vice Dean for Academic Affairs at the Faculty of Pharmacy, Tanta University.
Possessing an understanding of these processes allows practitioners the flexibility to prescribe and administer medications that will provide the greatest benefit at the lowest risk and allow them to make adjustments as necessary, given the varied physiology and lifestyles of patients.
Absorption is the process that brings a drug from the administration, eg, tablet or capsule, into the systemic circulation. Absorption affects the speed and concentration at which a drug may arrive at its desired location of effect, eg, plasma. There are many possible methods of drug administration, including but not limited to oral, intravenous, intramuscular, intrathecal, subcutaneous, buccal, rectal, vaginal, ocular, otic, inhaled, nebulized, and transdermal. Each administration method has its own absorption characteristics, advantages, and disadvantages.
The absorption process also often includes liberation or the process by which the drug is released from its pharmaceutical dosage form. This is especially important in the case of oral medications. For instance, an oral medication may be delayed in the throat or esophagus for hours after being taken, delaying the onset of effects or even causing mucosal damage. Once in the stomach, the low pH may begin to chemically react with these drugs before they even arrive in the systemic circulation.[1]
Bioavailability is the fraction of the originally administered drug that arrives in systemic circulation and depends on the properties of the substance and the mode of administration. Bioavailability can be a direct reflection of medication absorption. For example, when administering medication intravenously, 100% of the drug arrives in circulation virtually instantly, giving this method a bioavailability of 100%.[2] This makes intravenous administration the gold standard regarding bioavailability. This concept is especially important in orally administered medications.
Once swallowed, oral medications must navigate the stomach acidity and be taken up by the digestive tract. The digestive enzymes begin the process of metabolism for oral drugs, already diminishing the amount of drug arriving in circulation before being taken up. Once absorbed by gut transporters, the medications often undergo "first-pass metabolism." When oral medication is administered, it is often processed in large quantities by the liver, gut wall, or digestive enzymes, subsequently lowering the amount of drug that arrives in circulation and, therefore, having a lower bioavailability.[2]
These processes will be discussed in greater detail under metabolism. Other modes of administration may delay certain quantities of drugs from arriving in circulation at the same time (intramuscular, oral, transdermal), giving rise to the use of the area under the plasma concentration curve (AUC). The AUC is a method of calculating the drug bioavailability of substances with different dissemination characteristics, and this observes the plasma concentration over a given time. By calculating the integral of that curve, bioavailability can be expressed as a percentage of the 100% bioavailability of intravenous administration.
Distribution describes how a substance is spread throughout the body. This varies based on the biochemical properties of the drug as well as the physiology of the individual taking that medication. In the simplest sense, the distribution may be influenced by two main factors: diffusion and convection.[3]
These factors may be influenced by the polarity, size, or binding abilities of the drug, the fluid status of the patient (hydration and protein concentrations), or the body habitus of the individual.[4] The goal of the distribution is to achieve what is known as the effective drug concentration. This is the concentration of the drug at its designed receptor site. To be effective, a medication must reach its designated compartmental destination, described by the volume of distribution, and not be protein-bound to be active.
This metric is a common method of describing the dissemination of a drug. The volume of distribution is defined as the amount of drug in the body divided by the plasma drug concentration.[4] One must remember that the body is made up of several theoretical fluid compartments (extracellular, intracellular, plasma, etc.), and Vd attempts to describe the fictitious homogenous volume in a theoretical compartment.
When a molecule is very large, charged, or primarily protein-bound in circulation, such as the GnRH antagonist cetrorelix (Vd = 0.39 L/kg), it stays intravascular, unable to diffuse, reflected by a low Vd. A different molecule that is smaller and hydrophilic would have a larger Vd reflected by its distribution into all extracellular fluid. Finally, a small lipophilic molecule, such as chloroquine (Vd = 140 L/kg), would have a very large Vd as it can distribute throughout cells and into adipose tissues.[5] There may be multiple volumes of distribution depending on the rate of distribution within the subject.[4]
Knowledge of the volume of distribution is an important factor for a practitioner to understand dosing schemes. For example, an individual with advanced infection may require a loading dose of vancomycin to achieve desired trough concentrations. A loading dose allows the drug concentrations to rapidly achieve their ideal concentration instead of needing to accumulate before becoming effective. Loading doses are directly related to the volume of distribution and are calculated by Vd times the desired plasma concentration divided by bioavailability.[6]
In the body, a drug may be protein-bound or free. Only free drug can act at its pharmacologically active sites, eg, receptors, cross into other fluid compartments, or be eliminated. In the clinical setting, the free concentration of a drug at receptor sites in plasma more closely correlates with effect than the total concentration in plasma.[4] The protein binding of the substance largely determines this. Any reduction in plasma protein binding increases the amount of drug available to act on receptors, possibly leading to a greater effect or an increased possibility of toxicity. The principal proteins responsible for binding medications of interest are albumin and alpha-acid glycoprotein.[7]
These proteins may fluctuate depending on the age and development of the patient, any underlying liver or kidney disease, or nutrition status. One example in which this is relevant is renal failure. In renal failure, uremia decreases the ability of acidic drugs, such as diazepam, to bind to serum proteins. Even though the same amount of drug is initially given, there is far more drug in the "active" space, unbound by serum protein. This will increase the effect of the medication and increase the possibility of toxicity, eg, respiratory depression.[4]
Metabolism is the processing of the drug by the body into subsequent compounds. This is often used to convert the drug into more water-soluble substances that will progress to renal clearance or, in the case of prodrug administration, such as codeine, metabolism may be required to convert the drug into active metabolites.[8]
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