REVIEW Fachbereich Pharmazie, Philipps-Universita¨t, Marburg, Germany A classification of drug substances according to their mechanism of action P. Imming, T. Buss, L. A. Dailey, A. Meyer, H. Morck, M. Ramadan, T. Rogosch Received March 1, 2004, accepted March 24, 2004 Prof. Dr. P. Imming, Fachbereich Pharmazie, Martin-Luther-Universita¨t, 06120 Halle, Germany [email protected] Pharmazie 59: 579–589 (2004) Different classification systems for therapeutic agents exist. The most commonly used one is the ATC Code (ATC: Anatomy, Therapeutic properties, Chemical, pharmacological properties). Here, an alter- native classification system (TCAT: Target –– Chemistry –– Anatomy –– Therapy) is proposed which refers to the molecular mechanism of action or rather, target. The main subgroups of targets are: enzymes; substrates, metabolies, proteins; receptors; ion channels; transporter molecules and systems; nucleic acids, ribosomes; physicochemical mechanisms; antigen-antibody reactions; unknown targets. This target-oriented approach may be particularly useful in teaching advanced medicinal chemistry. 1. The organization of pharmaceuticals new targets (e.g. an enzyme or receptor) of clinical inter- est (Schneider 2002; Goodnow et al. 2003), and more “Over 50,000 different medications exist –– and your phar- importantly, to understand the systematics of molecular macist knows them all.” This slogan has recently been recognition (ligand-receptor) (Hendlich et al. 2003; Gohlke used by ABDA (Federal Union of German Associations and Klebe 2002). of Pharmacists) to promote the public image of pharma- Another older criterion for classifying drug substances is cists in Germany. As it may be, the knowledge of such a the division of natural and synthetic substances into differ- vast number of products can only be mastered with the ent groups. The modern-day version of this practice is ex- help of an excellent system of classification –– a virtual emplified in the differentiation between “antibiotics” and filing cabinet similar to the physical ones familiar to us “chemotherapeutics”, still used in the German “Rote from the local pharmacy. Liste”, a compilation of medications. In other cases, che- From a pharmaceutical standpoint there are many different mical properties are purposely used as an exclusion criter- criteria which can be used to classify a certain type of ion for a class of substances, such as in the example of medication: Alphabetical order, type of formulation, the the “non-steroidal anti-inflammatory drugs” (NSAID). frequency with which it is prescribed or recommended, Sometimes it is simply easier to classify something for price, refundibility, prescription or non-prescription medi- what it is not rather than for what it is. cation, etc. If a classification of the active pharmaceutical ingredients is undertaken, numerous possibilities are revealed, as well. 2. The ATC system At the end of the 19th century, Ernst Schmidt (1845–1921), director of the Department of Pharmaceutical Chemisty at Currently, the most commonly used classification system the Philipps-University in Marburg, authored “A Detailed for drug substances is the ATC system (Schwabe 1995). It Textbook of Pharmaceutical Chemistry” in which he pro- was introduced in 1976 by the Nordic Council on Medi- posed that the study of pharmaceutical chemistry and, cines as a method to carry out drug utilization studies thus, drug substances belonged to the science of “pure” throughout Scandinavia. In 1981, the World Health Organi- chemistry. Consequently, the first volume of his work was zation recommended the use of the ATC classification for entitled “Inorganic Chemistry” and was followed by a all global drug utilization studies and in 1982 founded the further volume, “Organic Chemistry”. According to WHO Collaborating Centre for Drugs Statistics Methodol- Schmidt, drug substances were to be classified the same ogy in Oslo to establish and develop the method. The ATC as other chemical entities; by nature of their primary system categorizes drug substances at five different levels elements, functional moieties or organic substance class. according to ) the organ or system on which they act Recently, the idea of classifying drug substances strictly (anatomy) ) therapeutic properties ) and chemical, phar- according to their chemical constitution or structure has macological properties. The first level is comprised of the been revived. Numerous databases now attempt to gather main anatomical groups, while the second level contains the and organize information on existing or potential drug pharmacologically relevant therapeutic subgroup. The third substances according to their chemical structure and diver- level consists of the pharmacological subgroup and the sity. The objective is to create substance “libraries”, which fourth the chemical subgroup. The fifth level represents the contain pertinent information about possible ligands for chemical substance (¼ the actual drug entity). Substances Pharmazie 59 (2004) 8 579 REVIEW with multiple effects and different therapeutic indications effect of the drug cannot be fully described by the interac- can be found more than once within the system. The ATC tions with i.e. one target protein alone. For instance, anti- system is used routinely within the current university phar- bacterial oxazolidinones interact with 23S-rRNA, tRNA, macy curriculum. For example, the well-known German and two polypeptides, ultimately leading to an inhibition textbook “Mutschler –– Drug Actions” (Mutschler et al. of protein synthesis. In this case, a description of the me- 2001) organizes its content according to the system. Each chanism of action which only includes interactions with subject is introduced by the organ upon which an effect is the 23S-rRNA target would be too narrowly defined. shown, followed by the therapeutic effect, the mechanism Especially in situations where the dynamics of the drug of activity and finally the chemical substance class. substance stimulate or inhibit a biological process, it is necessary to move away from the descriptions of single proteins, receptors, etc., and view the entire signal chain 3. Alternative to ATC: TCAT as the target. The progress achieved within the past few decades in The following mechanisms of action exemplify dynamic deciphering the biochemical mechanism of activity of drug (process) mechanisms of drug action: substances and investigating the structure of biological sys- –– (non-)covalent modifications of the active center (e.g. tems has been accompanied by a deeper understanding of acetylation of bacterial transpeptidases by beta-lactam anti- how drug substances act at a molecular level. This greater biotics); knowledge of how drugs interact with the body (mechan- –– allosteric modulations (e.g. benzodiazepines/GABA-re- isms of action, drug-target interactions) has not only nar- ceptors); rowed the gap between the disciplines (i.e. pharmaceutical –– substrate modifications (e.g. vancomycin); chemistry, pharmacology, and molecular biology), but has –– molecules requiring activation (pharmacodynamic pro- also led to the reduction of established drug doses and in- drugs in contrast to pharmacokinetic prodrugs, e.g. parace- spired the development of newer, highly specific drug sub- tamol); stances for a known mechanism of action. A preoccupation –– instances of modifications of a substrate or cofactor with the molecular details has sometimes, however, resulted (e.g. asparaginase that depletes tumor cells of asparagine; in a tendency to focus only on this one aspect of the drug’s isoniazide that is “inadvertently” activated by the Myco- effect. For example, cumulative evidence is now suggesting bacteria leading to an inactive covalently modified NADH; that the proven influence of certain psychopharmaceuticals vancomycin that binds to the building block bacteria use on neurotransmitter metabolism has little to do with the for the construction of the murein saccculus). treatment of schizophrenia or the effectiveness of the drug However, as already mentioned, our current knowledge of for this indication (Hyman and Fenton 2003). the molecular dynamics of the effect of most drug sub- Nonetheless, a categorization of drug substances according stances is still too patchy to lay the foundation for even a to their molecular mechanism of action has advantages. somewhat complete “dynamics” classification system. Similar to the ATC system, such a “taxonomy” also requires A further criterion required for the categorization of drug a hierarchy of levels. However, in this case, the first level substances according to their target is the anatomical loca- is not grouped according to an anatomical parameter (e.g. lization of the target. This is essential for a differentiation sympathetic nerve system, CNS, kidneys, etc.), but rather a between substances with the same biochemical target, yet “micro-anatomical” characteristic; namely, the biochemical a different organ specificity (example: nifedipine and vera- structure with which the substance interacts. In the place pamil are both L type calcium channel inhibitors; the for- of a physiological functional unit would be a type of reac- mer interacts primarily with vascular calcium channels and tion; for example “Ezetimib: Inhibition of cholesterine ab- the latter with cardial calcium channels). sorption”. In view of these observations, we propose an alternative The term “mechanism of action” itself implies an inherent classification system based upon the following