Pharmacokinetics

from Wikipedia, the free encyclopedia
Plasma level curves
Plasma level over 96 hours after oral administration every 24 hours. If there is a linear PK, AUC τ = AUC ∞ applies in steady state .

The pharmacokinetics describes all the processes to which a drug is subject in the body. This includes the uptake of the drug ( resorption ), its distribution in the body (distribution), the biochemical conversion and degradation ( metabolism ) as well as its excretion (excretion). If the release (liberation) of the drug from the drug form is also important prior to absorption , the abbreviation LADME is also used for all of these processes.

As founder of the pharmacokinetics of the pediatrician applies Friedrich Hartmut Dost , who in 1953 with the first textbook on the pharmacokinetics The blood levels by making them available in clinical practice and research. His considerations were based on the knowledge that recommended doses for medicinal products should not simply be “scaled down” from adults to children. From these basic considerations, a separate branch of science developed, which today is an important part of drug development.

Along with pharmacodynamics, pharmacokinetics is one of the two major sub-areas of pharmacology . Pharmacokinetics is largely about the question: What does the organism do with the active substance? Pharmacodynamics is about the question: What does the active ingredient do to the organism?

Overview

Pharmacokinetic processes

In addition to the release (Liberation) from the dosage form and the inclusion of the drug in the body ( absorption , English: absorption ) are also its metabolism in the organism ( metabolism ) and its excretion decisive for the concentration at the site of action. The acronym LADME , derived from English , summarizes these processes:

release

If the drug is not already in dissolved form in the drug form, its release from it is the first and often rate-determining step in the LADME process. Depending on the therapeutic objective, different release profiles are sought for the active ingredient.

Plasma level curves according to various formulations
Plasma level after extravascular administration of various formulations
1 Rapid release
2 Delayed release
3 Slowed release, retarded
4 Transdermal system
  • Indications that allow or even require a rapid onset of action in the context of treatment with solid medicinal forms (e.g. acute pain) are treated with quick-release tablets or effervescent tablets . The rapid release results from the rapid physical disintegration of the dosage form. Suppositories release the drug a little more slowly, as they first have to melt in the rectum , but they have advantages in application when nausea and vomiting accompany the therapy.
  • Some indications require a modified release of the drug from the dosage form, which is not infrequently a challenge for its technological formulation ( galenics ). By choosing appropriate acid / base-buffering auxiliaries , which themselves have no pharmacological therapeutic effect, and the manufacturing technology, the kinetics of the release can be controlled and thus the effect profile (active substance concentration and duration of action) of the drug can be influenced.
    • A delayed release of an oral dosage form is for. B. necessary if the active ingredient is unstable to gastric acid . An acid-proof coating then ensures that the tablet or capsule does not release the active ingredient until it has passed through the stomach in the neutral or slightly alkaline environment of the small intestine.
    • A slowed release ( retardation ) allows the dosage interval to be extended and makes the therapy user-friendly (for example, instead of 3 × 1 tablet, only 1 × 1 prolonged-release tablet per day is required). In addition, the plasma levels fluctuate less and are instead kept at a constant level.
    • Therapeutic systems release the drug particularly slowly and in a controlled manner over a long period of time . They are used, for example, in the form of transdermal patches or implants or inserts containing active substances .

The connection between a certain dosage form and the effect of the contained medicinal substance is the subject of biopharmacy .

admission

Under absorption refers to the uptake of the drug from the site of application in the bloodstream. Depending on the dosage form and application, this happens mainly through the mucous membranes of the gastrointestinal tract (tablets, juices, capsules) including the rectum ( suppositories ) or through the skin (ointments, creams, active substance plasters ). The Resorptionweg on the alveoli is under anesthesia by inhalation narcotics used. So far, only a few drugs can be administered through the nasal mucosa (such as desmopressin , oxytocin ).

The resorption process is based on the following mechanisms:

The absorption is influenced by numerous factors. In addition to the chemical-physical properties of the drug, these physiological factors are particularly important:

  • Size and condition of the resorption area,
  • Blood circulation at the absorption surface,
  • Contact time with the resorption surface.

Diarrheal diseases and the associated accelerated transport of the drug through the gastrointestinal tract can lead to a reduction in absorption and effectiveness due to the short contact time (for example, oral contraceptives, “ birth control pills ”).

distribution

Distribution of thiopental

As soon as the drug is circulating in the bloodstream, its distribution begins. In pharmacokinetics, it means the transport of substances between different body fluids and tissues . The driving force behind the transport process is the concentration gradient between the various distribution areas. The transport process is reversible, ie it takes place “there” and “back” again.

The distribution depends on:

  • Physiological conditions such as the organ or tissue blood flow, the pH value in the tissue or in the body fluid and the permeability of the membranes to be penetrated . A membrane that is difficult to penetrate, for example, surrounds the brain capillaries and the liquor space ( blood-brain barrier , blood-liquor barrier ) and in this way prevents or reduces central side effects.

The enterohepatic circulation represents a special form of distribution : the medicinal substance dissolved in the blood or its metabolic products are distributed as they pass through the liver into the bile, which is secreted into the intestine. From there the substances are reabsorbed back into the bloodstream. They may circulate several times and for a long time.

metabolism

A medicinal substance is subject to biochemical conversion and degradation processes in various places in the body, the entirety of which is known as metabolism or biotransformation . The aim of these processes is to improve excretion from the body. A distinction is made between phase I reactions (functionalization) and phase II reactions (hydrophilization). The reaction products of these reactions are known as the metabolites of a drug.

The reactions of phase I include, for example, oxidation reactions, reduction reactions and hydrolysis. These reactions generally make a drug less effective. In certain cases, however, an enhancement of the effect or the conversion to metabolites with other effects is possible, which can lead to side effects. In addition, as already mentioned, there are also medicinal substances known as prodrugs which only obtain their intended effect through metabolism from an ineffective form. The phase II reactions mainly include glucuronic acid conjugation, amino acid conjugation, sulfation and acetylation. As a result of these reactions, a drug becomes more hydrophilic and therefore more soluble in water, which accelerates excretion.

The liver is the main source of metabolism. In addition, metabolic reactions also take place in the various mucous membranes, in the intestine, in the lungs and in the blood plasma. During metabolism, there may be interactions between different drugs that are applied at the same time. This is possible, for example, if one of the medicinal substances involved exhausts the metabolism capacity of the body so that the metabolism of a second medicinal substance is delayed. This leads to an increase in the effect for this medicinal substance. Such interactions are also possible between drugs and certain ingredients of food. For example, ingredients in grapefruit juice block certain enzymes in the cytochrome P450 complex in the liver. This delays the breakdown of many drugs, so that when grapefruit juice and corresponding drugs are taken at the same time, their concentration increases, which can lead to side effects.

The decrease in effectiveness of a drug when it is taken for a long time is also due to its metabolism. In this case, repeated ingestion leads to so-called enzyme induction, an increased formation of the enzymes involved in the metabolism. As a result, the drug in question is then broken down more quickly, reducing its duration and intensity of action, in extreme cases to the point of ineffectiveness. Diseases of the organs involved in the metabolism, especially the liver, can lead to an increase in activity and thus to side effects due to the reduced metabolism. Genetic differences are also known for many metabolic processes. For certain reactions, for example, these can lead to a distinction between fast and slow metabolisers.

excretion

The excretion (excretion) of a drug or its metabolites from the bloodstream takes place for the most part via the kidneys and the urine ( renal excretion). A small part is excreted via the bile into the small intestine and then with the stool . If the active substance is then reabsorbed from the intestine (reabsorption), one speaks of the enterohepatic circulation .

Excretion via the skin (sweat) or mucous membrane (intestinal mucosa, intestinal excretion) and via the lungs ( pulmonary excretion) is of minor importance .

With the urinal excretion of ethinylestradiol , a synthetic estrogen that is contained in most contraceptive pills , there are detectable changes in aquatic life, such as a slowdown in the natural reproductive cycle of fish. The excretion of medicinal substances with breast milk can lead to symptoms of poisoning in the breastfed infant.

Special case of toxicokinetics

The toxicokinetics deals with the temporal and quantitative concentration of a toxic substance in various areas of an organism such. B. in certain tissues .

Knowledge of the toxicokinetics of the toxin helps in the treatment of poisoning

  • the risk of poisoning (the expected severity),
  • the necessity and usefulness of a specific therapy , in particular the method to accelerate the elimination
  • and estimate the duration and consequences of the poisoning.

In addition to the factors of the LADME concept, the following factors must also be taken into account:

Parameters

Important descriptive parameters in pharmacokinetics are, for example, volume of distribution , clearance , bioavailability , plasma half-life , loading dose , maintenance dose .

Influencing variables

The pharmacokinetic behavior of a substance is influenced by its physicochemical properties and the biological parameters of the organism.

relevance

Pharmacokinetics in drug approval

Precise knowledge of all the processes mentioned is an essential part of the application documents required for the approval of a new drug. Corresponding data are obtained through studies in the respective phases of the development of a drug. All LADME processes influence the concentration-time course and thus the bioavailability of a drug in the body. This is relevant, for example, for the approval of generics . For these, the manufacturer must demonstrate what is known as bioequivalence, i.e. the comparability within certain permissible limits with the original preparation with regard to bioavailability.

Therapeutic aspects of pharmacokinetics

The analytical determination of the drug concentration in blood, urine, saliva and other body fluids is used in therapy for some drugs in order to determine the exact dosage and to monitor the therapy, especially in the case of repeated and prolonged therapy. This is known as Therapeutic Drug Monitoring .

literature

  • Friedrich H. Dost: The blood level . Kinetics of the concentration processes in the circulating fluid. Georg Thieme, Leipzig 1953, DNB  450986519 (362 p., 96 ill.).
  • Milo Gibaldi, Donald Perrier: Pharmacokinetics . In: Drugs and the Pharmaceutical Sciences . 2nd Edition. Volume 15. Marcel Dekker, Inc., New York, Basel 1982, ISBN 0-8247-1042-8 (English).
  • Malcolm Rowland, Thomas N. Tozer: Clinical Pharmacokinetics . Concepts and Applications. 4th edition. Lippincott Williams & Wilkins, a Wolters Kluwer business, Baltimore, Philadelphia 2010, ISBN 978-0-7817-5009-7 (English).
  • Hartmut Derendorf, Thomas Gramatte, Hans G. Schäfer: Pharmacokinetics . Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 2002, ISBN 3-8047-1907-4 .
  • Ernst Mutschler , Gerd Geisslinger, Heyo K. Kroemer , Peter Ruth, Monika Schäfer-Korting: Mutschler drug effects . Textbook of pharmacology and toxicology. 9th edition. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 2008, ISBN 978-3-8047-1952-1 .
  • Klaus Aktories, Ulrich Förstermann, Franz Hofmann, Wolfgang Forth: General and special pharmacology and toxicology . Urban & Fischer at Elsevier, Munich and Jena 2004, ISBN 3-437-42521-8 .
  • Peter Langguth, Gert Fricker , Heidi Wunderli-Allenspach: Biopharmacy . Wiley-VCH, Weinheim 2004, ISBN 3-527-30455-X .
  • EJ Ariëns : Stereochemistry, a Basis for Sophisticated Nonsense in Pharmacokinetics and Clinical Pharmacology . In: European Journal of Clinical Pharmacology . tape 26 , no. 6 . Springer, 1984, p. 663-668 , doi : 10.1007 / BF00541922 .

Web links

Individual evidence

  1. ^ Karen Kidd : Effects of a Synthetic Estrogen on Aquatic Populations: a Whole Ecosystem Study . Freshwater Institute, Fisheries and Oceans Canada , October 2004, archived from the original on June 19, 2008 ; accessed on September 5, 2011 (English).