Introduction

Pharmacokinetics is concerned with the bioavailability, distribution and excretion of drugs. For many classes of drugs there is a direct relationship between the pharmacological and toxicological effects of a drug and its concentration in the body. For most lipophilic drugs, which would include psychotropic agents, there is a positive relationship between the concentration of the drugs in the blood and its concentration at the site of action. Pharmacokinetics also enables the relationship between the efficacy of the drug and the dose administered to the patient to be determined.

The bioavailability of a drug is defined as the fraction of the unchanged drug that reaches the systemic circulation following administration by any route. For an intravenously administered drug this equals unity, whereas for an orally administered drug this will be less than unity. This is due to factors such as incomplete absorption, metabolism by the liver and incomplete reabsorption of the drug following enterohepatic cycling.

When assessing the bioavailability of a drug it is also possible to determine the rate at which a given dose reaches the general circulation. Thus by plotting a graph of the blood concentration against the time following administration, the rate at which the peak drug concentration is reached may be calculated from the graph and the bioavailability can be calculated from the area under the curve. The duration of the pharmacological effect is a function of the length of time that the blood concentration is above the minimum effective concentration, while the intensity of the pharmacological effect is directly related to the degree to which the drug concentration exceeds the minimum effective concentration.

There are two further terms which are important in pharmacokinetics -the clearance and the volume of distribution. The volume of distribution (Vd) relates the quantity of drug in the body to that in the blood or plasma. This

Fundamentals of Psychopharmacology. Third Edition. By Brian E. Leonard © 2003 John Wiley & Sons, Ltd. ISBN 0 471 52178 7

factor reflects the space available in the general circulation or within the tissues. Depending on the dissociation constant (pKa) of the drug in the various body fluids, the lipophilicity, the degree of protein binding to serum and tissue proteins, the Vd of drugs may vary widely. For example, the antimalarial drug quinacrine (mepacrine) has an apparent Vd of 50 000 litres, while drugs that are extensively plasma protein bound have Vd values of as little as 7 litres. The tricyclic antidepressants have a high Vd value despite their strong protein binding; this may be related to their lipophilicity and to the fact that their binding to brain proteins is greater than to plasma proteins.

The clearance of a drug is usually defined as the rate of elimination of a compound in the urine relative to its concentration in the blood. In practice, the clearance value of a drug is usually determined for the kidney, liver, blood or any other tissue, and the total systemic clearance calculated from the sum of the clearance values for the individual tissues. For most drugs clearance is constant over the therapeutic range, so that the rate of drug elimination is directly proportional to the blood concentration. Some drugs, for example phenytoin, exhibit saturable or dose-dependent elimination so that the clearance will not be directly related to the plasma concentration in all cases.

The rate of elimination of a drug from a specific organ can be calculated from the blood flow to and from the organ and the blood concentration. If a drug is largely metabolized in the liver, the clearance of the drug will be largely dependent on the hepatic blood flow; many classes of psychotropic drug are almost completely metabolized by the liver. Small changes in the hepatic circulation or in the rate of liver metabolism will therefore have a dramatic effect on the drug clearance.

Once the clearance rate for a drug is known, the frequency of dosing may be calculated. It is usually desirable to maintain drug concentrations at a steady-state level within a known therapeutic range. This will be achieved when the rate of drug administration equals the total rate of clearance.

Another term which is important in pharmacokinetics is the half-life (i1/2) of a drug. This value is related to the Vd and the total clearance. If it is assumed that the body is a single compartment in which the size of the compartment equals the Vd, the t1/2 may be calculated from the equation:

Cl where Cl is the total clearance. The t1/2 is defined as the time required for the drug to obtain 50% of the steady-state level, or to decay 50% from the steady-state concentration after the drug administration has ceased. It must be emphasized that disease states can profoundly affect both the Vd and the clearance, so the i1/2 value of a drug is not a reliable indicator of drug disposition unless the functional state of the liver, kidneys, etc. is normal.

This short introduction to the terms used in pharmacokinetics is intended to provide a general overview of the subject. Those wishing to obtain a proper grounding in this important subject are recommended to consult a standard textbook of pharmacology.

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