Question 1

College Answer

A good answer to this question required candidates to think broadly about how drugs act 
and have a system for classifying their actions. One possible classification is action via 
receptors or non-receptor actions. Many candidates used categories such as 
physiochemical, receptor and enzymes. Common problems were failure to mention a whole 
class of drug actions e.g. drugs acting via voltage-gated ion channels or gene transcription 
regulation. Candidates also gave far too much detail in some sections e.g. a description of 
zero order and first order kinetics is not required. Candidates often did not give examples of 
the drug action they described.

Discussion

This is actually a very difficult question to answer, as there are no formal or widely accepted systems for classifying mechanisms of drug action. Attempts to make a system into something simple and general leads to reductive madness like Bjornsson's therapeutic categories (eg. "preventative", "directed at specific aetiology", etc) or to a hyperproliferation of malignant code categories (like the WHO's monstrous five-tiered ATC classification). Neither is a particularly attractive option for the exam candidate who just wants to produce an answer which suggests that they "think broadly about how drugs act and have a system".

The following suggested system was generated using an article by Imming et al (2004), who were forced to generate a classification in order to compile a pharmacology teaching curriculum. Their system (TCAT) focused on drug targets as the top-level tier. The author of Φ then took creative liberties to explore these targets and list the mechanisms via which drugs interact with them in some sort of systematic order. The exam candidate should not develop the impression that this system is an acceptable answer for this SAQ (though in all honesty it is impossible to guess what an acceptable answer might have been from the official CICM commentary).

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)

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