Clinical pharmacokinetics and pharmacodynamics: concepts and applications

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Malcolm Rowland, Thomas N Tozer, Clinical pharmacokinetics and pharmacodynamics: concepts and applications. Fourth Edition. Lippincott and Wilkins: 2011.

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Pharmacokinetics and pharmacodynamics are cornerstones in the industrial design, selection, and development of new drugs.

Understanding why individuals vary in their response to drugs is central to personalizing drug therapy.

Basic considerations

Therapeutic Relevance

Those patients who suffer from chronic ailments such as diabetes or epilepsy may have to take drugs every day for the rest of their lives. At the other extreme are those who take a single dose of a drug to relieve an occasional headache. The duration of drug therapy is usually between these extremes. The manner in which a drug is take is called a dosage regimen.

What determines the therapeutic dose of a drug and its manner and frequency of administration, as well as events experienced over time by patients on taking the recommended dosage regimens, constitutes the body of the textbook.

Input-response phases   

Progress has only been forthcoming by realizing that concentrations at active sites, rather than dose admistered, drive responses, and thta to achieve and maintain a response, it is necessary to ensure the generation of the appropriate exposure-time profile of drug within the body, which in turn requires an understanding of the factors controlling this exposure profile.

The issue of time delays between drug administration and response is not confined to pharmacokinetics but extends to pharmacodynamics too. Part of this delay is a result of the time required for the drug to distribute to the target site, which is often in a cell within  in a organ or tissue, such as the brain. Part is also a result of delays within the affected system within the body.

  

Side-effects. A common and clinically significant toxicity of many anticancer drugs is leukopenia, an abnormal fall in the number of leukocytes in blood.

The lesson is clear: understanding the specific concentration-response time relationships help in the management and optimal used of drugs.

   

Variability in drug response

If we were all alike, there would only be one dose strength and regimen of a drug needed for the entire patient population.

 Fundamental concepts and terminology

This chapter introduces input-exposure (pharmacokinetics) and exposure-response (pharmacodynamics)  relationship and defines the terms commonly used in these areas.

Applications of pharmacokinetics and pharmacodynamics in drug therapy:

ü      To relate temporal patterns of response to drug administration following acute and chronic dosing;

ü      To help provide a rational basis for drug design, drug selection, and dosage regimen design:

ü      To provide a means for rationally initiating and individualizing drug administration in patients;

A distinction must be made between those drugs that act locally and those that act systematically. Locally acting drugs are administered at the local site where they are needed such as eye drops, nasal sprays, intravaginal creams, and topical preparations for treating skin diseases. It is given emphasis to those drugs that act within the blood or that must delivered to the site of action by the circulatory system, we say such drugs act systemically.

Kinetics following and intravenous bolus dose 

Administering a drug intravenously ensures that the entire dose enters the systematic circulation. By rapid injection, elevated concentrations of drug can be promptly achieved; by continuous infusion at a controlled rate, a constant concentration, and often response, can be maintained. With no other route of administration can plasma concentration be as promptly and efficiently controlled. Of the two intravascular routes, the i.v one is the most frequently employed. Intra-arterial administration, which has greater inherent manipulative dangers, is reserved for situations in which drug localization in a specific organ or tissue is desired. It is achieved by inputting drug into the artery directly supplying the target tissue.

Appreciation of kinetics concepts  

Why do we get a linear decline when plotting the data on a semilogarithmic scale, and what determines the large difference seen in the profiles for the various drugs?

Volume of distribution and clearance 

Schematic diagram of a perfused organ system. Drug placed into a well-stirred reservoir,

volume V, from which fluid perfuses an extractor at flow rate Q.

The rate of extraction can be expressed as a fraction E of the of presentation, Q.C.

The rate that escaping drug returns to the reservoir is Q.C_out. For modeling purposes,

the amount of drug in the extractor is negligible compared

to the amount of drug 

contained in the reservoir. 

Clearance is the volume of the fluid to the eliminating organ, extractor, that is efficiently, completely cleared of drug per unit of time.

Membranes and distribution

So far emphasis was placed on general input-exposure relationships after a single intravenous (i.v) bolus. Now we focus on the role and function of membranes primarily in the context of determinants of drug distribution, the principles apply as well to drug elimination and absorption. Drugs must also pass through membranes to reach the site of action. This chapter also explores the process of distribution itself and its role in clinical pharmacokinetics from a physiologic point of view.

Membranes

Movement through membranes is known as drug transport.

Elimination

This chapter is concerned with the elimination processes and particularly with the concept of clearance. In the chapter kinetics following an intravenous bolus dose, the method of quantifying clearance following a single dose iv bolus was presented. Herein its physiologic meaning is given.