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6/3/13

pharmacokinetics


The route of administration is determined primarily by the properties of the drug (for example, water or lipid solubility, ionization, etc.) and by the therapeutic objectives (for example, the desirability of a rapid onset of action or the need for long-term administration or restriction to a local site). There are two major routes of drug administration, enteral and parenteral.

A. Enteral
B. Parenteral
C. Other



Absorption is the transfer of a drug from its site of administration to the bloodstream. The rate and efficiency of absorption depend on the route of administration. For IV delivery, absorption is complete; that is, the total dose of drug reaches the systemic circulation. Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability. For example, the oral route requires that a drug dissolve in the GI fluid and then penetrate the epithelial cells of the intestinal mucosa, yet disease states or the presence of food may affect this process.

A. Transport of a drug from the GI tract
B. Effect of pH on drug absorption
C. Physical factors influencing absorption



Bioavailability is the fraction of administered drug that reaches the systemic circulation. Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form. For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or seventy percent. 

A. Determination of bioavailability 
B. Factors that influence bioavailability

    1. First-pass hepatic metabolism: 
    2. Solubility of the drug
    3. Chemical instability
    4. Nature of the drug formulation

C. Bioequivalence 



Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. The delivery of a drug from the plasma to the interstitium primarily depends on blood flow, capillary permeability, the degree of binding of the drug to plasma and tissue proteins, and the relative hydrophobicity 

A. Blood flow 
B. Capillary permeability

    1. Capillary structure
    2. Drug structure

C. Binding of drugs to plasma proteins 



The volume of distribution is a hypothetical volume of fluid into which a drug is dispersed. Although the volume of distribution has no physiologic or physical basis, it is sometimes useful to compare the distribution of a drug with the volumes of the water compartments in the body 


A. Water compartments in the body

1. Plasma compartment
2. Extracellular fluid
3. Total body water
4. Other sites

B. Apparent volume of distribution

1. Determination of Vd)

    a. Distribution of drug in the absence of elimination
    b. Distribution of drug when elimination is present
    c. Calculation of drug concentration if  distribution is instantaneous:
    d. Uneven drug distribution between compartments


2. Effect of a large Vd on the half-life of a drug





Drug molecules may bind to plasma proteins (usually albumin). Bound drugs are pharmacologically inactive; only the free,unbound drug can act on target sites in the tissues, elicit a biologic response, and be available to the processes of elimination. [Note: Hypoalbuminemia may alter the level of free drug.]

A. Binding capacity of albumin
B. Competition for binding between drugs
C. Relationship of drug displacement to Vd



Drugs are most often eliminated by biotransformation and/or excretion into the urine or bile. The process of metabolism transforms lipophilic drugs into more polar readily excretable products. The liver is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues, such as the kidney and the intestines. [Note: Some agents are initially administered as inactive compounds (pro-drugs) and must be metabolized to their active forms.]

A. Kinetics of metabolism
B. Reactions of drug metabolism



Removal of a drug from the body occurs via a number of routes, the most important being through the kidney into the urine. Other routes include the bile, intestine, lung, or milk in nursing mothers. A patient in renal failure may undergo extracorporeal dialysis, which removes small molecules such as drugs.

A. Renal elimination of a drug
B. Quantitative aspects of renal drug elimination
C. Total body clearance
D. Clinical situations resulting in changes in drug half-life


The preceding discussion describes the pharmacokinetic processes that determine the rates of absorption, distribution, and elimination of a drug.
Pharmacokinetics also describes the quantitative, time-dependent changes of both the plasma drug concentration and the total amount of drug in the body, following the drug's administration by various routes, with the two most common being IV infusion and oral fixed-dose/fixed-time interval regimens (for example, one tablet every 4 hours). The interactions of the processes previously described determine the pharmacokinetics profile of a drug. The significance of identifying the pharmacokinetics of a drug lies not only in defining the factors that influence its levels and persistence in the body, but also in tailoring the therapeutic use of drugs that have a high toxic potential.
 [Note: The following discussion assumes that the administered drug distributes into a single body compartment. In actuality, most drugs equilibrate between two or three
compartments and, thus, display complex kinetic behavior. However, the simpler model suffices to demonstrate the concepts.]

A. Kinetics of IV infusion
B. Kinetics of fixed-dose/fixed-time-interval regimens

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