Viva C(ii)

This viva is relevant to the objectives of 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".  

What are the mechanisms by which drugs exert their effect on the human body?
  • The effect of a drug 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.
What is a "receptor"?

"A cellular macromolecule, or an assembly of macromolecules, that is concerned directly and specifically in chemical signaling between and within cells"

(from this  2003 review of pharmacological nomenclature)

What is "receptor theory"?
  • Drugs interact with receptors in a reversible manner to produce a change in the state of the receptor
  • This interaction can be modeled mathematically and follows the Law of Mass Action
  • The binding of drug and receptor determines the quantitative relationship between dose and effect.
  • Mutual affinity of drugs and receptors determines the selectivity of drug effects
  • Competition of mutually exclusive molecules for the same receptors explains agonist, partial agonist and antagonist drug activity
With regards to receptor theory, what is meant by occupancy theory?

"Receptor occupancy theory describes the quantitative relationships between drug concentrations and the responses that result from the interaction of those drugs with receptors".

(Kenakin, 2008)

In short, Occupancy theory rests  on the concept that the proportion of occupied receptors is related to the effect of the drug (eg. for full agonists and a linear relationship, 100% occupancy = 100% effect).

This assumes that only occupied receptors produce a response.

What are the possible receptor mechanisms of drug effect? Give an example of each.
  • 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) 
What non-receptor mechanisms of drug effect can you think of? Give examples.
  • 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)
How are drugs classified? What are "classes" of drugs?

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.

What drug classification systems do you know of?
  • The Anatomical Therapeutic Chemical Classification System (ATC) by the WHO is a comprehensive system
  • Schedule system of legal restriction classifications
  • Pregnancy Category classification
  • Classification into therapeutic categories:
    • 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

Rang, H. P. "The receptor concept: pharmacology's big idea." British journal of pharmacology 147.S1 (2006).

Kenakin, Terry. "Principles: receptor theory in pharmacology.Trends in pharmacological sciences 25.4 (2004): 186-192.

Kenakin, Terry. "Receptor theory." Current protocols in pharmacology (2008): 1-2.

Clark, Alfred Joseph. Mode of action of drugs on cells. Edward Arnold: London, 1933.

Clark, Alfred Joseph. "The reaction between acetyl choline and muscle cells." The Journal of physiology 64.2 (1927): 123-143.

Schild, H. O. "pA, a new scale for the measurement of drug antagonism." British journal of pharmacology 2.3 (1947): 189-206.

Ariens, E. J. "Affinity and intrinsic activity in the theory of competitive inhibition. 1. Problems and theory." Archives internationales de pharmacodynamie et de thérapie 99 (1954): 32-49.

Stephenson, R. P. "A modification of receptor theory." British journal of pharmacology 11.4 (1956): 379-393.

Black, J. W., and P. Leff. "Operational models of pharmacological agonism." Proceedings of the Royal Society of London. Series B, Biological Sciences (1983): 141-162.

Katz, B., and S. Thesleff. "A study of the ‘desensitization’produced by acetylcholine at the motor end‐plate." The Journal of physiology 138.1 (1957): 63-80.

De Lean, Andre, JMand Stadel, and R. J. Lefkowitz. "A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor." Journal of Biological Chemistry 255.15 (1980): 7108-7117.

Neubig, Richard R., et al. "International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology." Pharmacological Reviews 55.4 (2003): 597-606.