Classification of Drug Actions

Created on Tue, 12/26/2017 - 20:03
Last updated on Wed, 12/27/2017 - 16:59

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This chapter answers parts from Sections C(ii) and C(iii) of the 2017 CICM Primary Syllabus, which encourages the exam candidate to "explain the concept of drug action, with respect to ...  receptor theory ...enzyme interactions ...physico-chemical interactions".  Unlike the more interesting chapters in this section, this relatively boring topic has actually received some attention from CICM Part I examiners. Question 1 from the first paper of 2013 asked the trainees to "list the different mechanisms of drug actions with examples", for which a good answer would have required them to "think broadly" and "have a system". In essence, this means the more successful candidates would have brought with them some sort of prefabricated classification which they then regurgitated on to the exam paper. The objective of this chapter is therefore to fashion a classification system which can be easily stored in the candidate's cheek pouches, stored away for use in case this question is ever repeated.

There is little of use in the official textbook, or in the college answer to Question 1. The examiners wanted some sort of classification system, but would not commit to anything specific. They vaguely offered receptor vs non-receptor actions as one suggestion, and mentioned that "many candidates used categories such as physiochemical, receptor and enzymes" without commenting whether this was an acceptable approach. Categories like "drugs which act via voltage-gated ion channels" or "gene transcription regulation" were given as classes which should have been mentioned by the candidates but weren't. In the absence of clear marking guidelines and with an overwhelming excess of confusing literature, the following classification was constructed de novo by the author himself. Repeating this in an exam would be a precarious approach, the perils of which cannot be gainsaid. 

In summary:

Assumptions:

  • Drugs exert an effect on the body
  • This effect is exerted by either interacting with macromolecular structures in the body, or by changing the physical or chemical properties of the body
  • The former can be described as a "receptor-effector coupling" mechanisms, and the latter as a "non-receptor" mechanisms.

Non-receptor mechanisms of drug action:

  • Change in the physical or chemical properties of the medium or solution (sodium bicarbonate, helium)
  • Change in the physical or chemical properties of another exogenous substance (eg. sugammadex, desferoxamine, activated charcoal)
  • Action by physical properties of the drug itself (eg. the reflective properties of zinc oxide)

Receptor mechanisms of drug action:

  • Direct effect by binding with a receptor (most drugs; eg. opioid analgesics)
  • Indirect effect by binding with an acceptor, eg. by preventing  the binding of another substance or or displacing it from its usual binding site (eg. action of phenytoin on warfarin)
  • Modulation of receptor function, i.e. changing its function or affinity for its ligand without binding to any active site (benzodiazepines)
  • Acting as a substrate for a receptor (eg. vitamins, oxygen) 

Types of molecular receptor targets and signalling pathways

  • Interaction with the cell membrane (amphotericin)
  • Regulation of transmembrane protein activity
    • Ligand-gated or voltage-gated ion channel permeability (lignocaine, suxamethonium)
    • Tranmembrane transport protein activity (SSRIs)
    • Regulation of transmembrane enzymes with intracellular signalling pathways, eg. tyrosine kinases (insulin)
    • G-protein coupled receptor activity (β-blockers)
  • Acting as a substrate for enzyme activity (oxygen, glucose)
  • Regulation of enzyme activity
    • Intracellular enzymes  eg. phosphodiesterase  (milrinone)
    • Extracellular enzymes eg. acetylcholinesterase (neostigmine)
  • Interaction with intracellular nuclear macromolecules
    • Regulation of gene transcription (corticosteroids)
    • Interaction with genetic material (chlorambucil, cisplatin)

This classification system for different mechanisms of drug actions is based on the system devised by Imming et al, who published an article in 2004 (Die Pharmazie) which covers this topic splendidly, as if anticipating the CICM SAQ. They called their system "TCAT", for Target - Chemistry - Anatomy - Therapy. Their list of Targets was the most attractive to developing a classification of drug action, because one is generally able to say that any given drug act on some sort of target (even when the target is the pH of the body water, or the permeability of the lipid bilayer). Working from this base, one can begin to classify drugs according to how they interact with that target. As far as possible, a literature search was performed to look for a better or more "official" peer-reviewed system. None was found.

Systems of drug classification

An "integrated conceptual framework" is required for humans to make sense of things, and this is particularly important to a system like pharmacology, which has multiple complex overlapping categories. That makes it difficult. For instance, a drug may be a member of a class because

  • It shares an indication with other drugs in the class (antibiotics)
  • It shares a chemical structure with other drugs (β-lactams)
  • It shares a molecular mechanism with other drugs (β-blockers)
  • It shares a mode of action with other drugs (anticholinergic)
  • It shares a legal restriction on its use (Schedule IV)
  • It has the same level of risk to the developing foetus (Pregnancy Category A)

A drug may be a member of multiple classes; structurally diverse drugs may have the same indication, and may be used for multiple indications, or may have different indications depending on their route of administration or pharmaceutical preparation. Trying to frame these concepts in a way which simplifies the system and still makes everybody happy is impossible. This fact is reflected in the current systems, the most popular of which (ATC) sacrifices simplicity in order to remain comprehensive.

Comprehensive classification systems 

The Anatomical Therapeutic Chemical Classification System (ATC) is probably the most widely used and comprehensive system which combines therapeutic indications and phamacological properties. The WHO Guidelines for ATC classification and DDD assignment 2018 describes its codes and structure. In brief, the ATC classification system is divided into five levels. 

  1. Anatomical/pharmacological main group. There are 14 of them
  2. Therapeutic subgroup 
  3. Pharmacological subgroup
  4. Chemical subgroup
  5. Chemical substance

Everything is easier with an example. To borrow the illustration of this system from the WHO's own document, here is the code for metformin:

  1. Anatomical main group A (Alimentary tract and metabolism)
  2. Therapeutic subgroup 10: Drugs used in diabetes
  3. Pharmacological subgroup B Blood glucose lowering drugs, excl. insulins
  4. Chemical subgroup B (Biguanides)
  5. Chemical substance 02 (metformin)

Thus, the ATC code for metformin is A10BA02. This bottom level describes a chemical substance or pharmaceutical combination with a single indication. Many substance may be classified several times, reflecting the fact that they may have many indications which span multiple top-level anatomical groups, and the fact that drugs may be combined for novel effect. The system is massively granular and has a category for everything (eg. A02AF, Antacids with antiflatulents; or P01AR, Arsenic compounds). For reference, the top level anatomical main groups are:

Code Contents
A Alimentary tract and metabolism
B Blood and blood forming organs
C Cardiovascular system
D Dermatologicals
G Genito-urinary system and sex hormones
H Systemic hormonal preparations, excluding sex hormones and insulins
J Antiinfectives for systemic use
L Antineoplastic and immunomodulating agents
M Musculo-skeletal system
N Nervous system
P Antiparasitic products, insecticides and repellents
R Respiratory system
S Sensory organs
V Various

This system has several limitations:

  • It is complex, and difficult to learn
  • It promotes confusion as a single drug may have numerous code entries, as many as it has indications and preparations (theoretically, an infinite number)
  • Its "anatomic main" top level classification is organised according to largely arbitrary boundaries
  • Its pharmacological and therapeutic subgroups are derived from a wide variety of sources including in vitro or in vivo pharmacologic effects,  effects on specific receptors or enzymes and effects on specific organ systems.

Classification of drug action according to therapeutic effect

In answer to the limitations of the classical pharmacological classification system, Thorir Bjornsson's 1996 paper offers an alternative which is more related to the intention of the user. In this fashion, atorvastatin and the chickenpox vaccine are both classified as Category 0 substances, "preventative" in their intent. In summary, this system:

  • Category 0: Preventative drugs, drugs or drug uses that are aimed at preventing the occurrence or development of a disease when none exists (eg. vaccines, anticoagulants such as heparin)
  • Category 1: Drugs directed at the specific disease aetiology; i.e. ones which prevent the disease process from evolving, or aim to reverse it (eg. antibiotics, steroids for Addison's disease)
  • Category 2: Drugs which correct pathophysiological processes; i.e. ones which cannot address the underlying aetiology but which can ameliorate its effects on the patient (eg. antihypertensives for hypertension)
  • Category 3: Drugs which address specific disease manifestations, without either addressing the aetiology or any specific pathophysiological processes (antipsychiotics in schizophrenia)
  • Category 4: Drugs which address non-specific disease-related symptoms, for examples analgesics and antihistamines
  • Category 5: Drugs which do not treat any specific disease, for example general anaesthetics,  muscle relaxants and diagnostic agents like edrophonium.

 

References

Mahoney, A., and J. Evans. "Comparing drug classification systems." AMIA... Annual Symposium proceedings. AMIA Symposium. 2008.

Imming, P., et al. "A classification of drug substances according to their mechanism of action." Die Pharmazie-An International Journal of Pharmaceutical Sciences 59.8 (2004): 579-589.

Bjornsson, Thorir D. "A classification of drug action based on therapeutic effects." The Journal of Clinical Pharmacology36.8 (1996): 669-673.

Swinney, David C. "Biochemical mechanisms of drug action: what does it take for success?." Nature reviews Drug discovery 3.9 (2004): 801-808.

Goldstein, Avram, Lewis Aronow, and Sumner M. Kalman. "Principles of drug action; the basis of pharmacology." Wiley, 1968