Mechanisms responsible for variability in drug response

This chapter is related to Section D from the 2017 CICM Primary Syllabus, which broadly describes the expectations of the College of Intensive Care medicine with respect to their trainee's understanding of Variability in Drug Response.  Though there is no particular subsection of the syllabus which could describe this matter, the broad classification of mechanisms which underpin different reactions to drugs among different people would probably need to be discussed before one takes a dive into specifics like"mechanisms and significance of pharmacogenetic disorders (e.g. malignant hyperthermia, porphyria, atypical cholinesterase and disturbance of cytochrome function)". 

In terms of exam relevance, this has never really been examined, though perhaps it popped up in some of the pharmacodynamics vivas.  Question 11(p.2) from the second paper of 2008 and the identical Question 2 from the second paper of 2012 asked the candidates to "describe the factors contributing to inter-individual variability in drug response", but this was in relation to an induction dose of an intravenous anaesthetic drug rather than anything more broad and theoretical. 

So, what is the point of this theoretical gibberish? In essence, this template of factors which produce variability in drug response can be used by the ICU trainee in every circumstance where they might be asked "how does Drug X change its behaviour in Population Y?". The objective of this chapter is to produce such a template. In essence, all factors were stripped out which might be attributed to properties of the drug, leaving only factors which are dependent on the ever-variable human organism. 

In summary, variation in drug response is due to:

Excellent works by Chris Andersen (2012) and the Part I team cover this topic with an enviable level of precision and coherence, and the time-poor exam candidate is advised to limit their revision to these authors. In terms of published peer-reviewed resources, nothing can beat the brevity and relevance of Katzung, which also happens to be the college-recommended text. There, in Mark von Zastrow's Chapter (Chapter 2 in the 14th edition) there is a page-long section titled "Variation in Drug Responsiveness" which covers this territory to a level which presumably represents the CICM standard. The 1983 article by G.D. Sweeney (a supplement from an issue of Thrombosis Research) is also excellent in terms of the alternative classification system it describes, but is quite dated and in any case paywalled by Elsevier. A free alternative (thanks, Wiley Periodicals) is Turner et al, 2015.  If an exam candidate is for whatever reason unwilling to get hold of the official exam textbook, but somehow willing to buy another textbook, a suitable one might be Variability in human drug response by Smith and Rawlins (2013).  Given the near-total lack of SAQs on this topic in the past papers, reading this 180-page text would probably be a poor decision. 

Pharmacokinetic factors

The pharmacokinetic factors which influence the availability of the drug to its receptor are discussed at great length elsewhere. In short, these would mainly be: 

• Factors affecting absorption:
  • Food (recent meal, fasting status, etc)
  • Variations in gastric pH (eg. due to PPIs)
  • Gut microbiome
  • Cardiac output and blood flow to the site of injection (for IM or subcutaneous)
• Factors affecting distribution:
  • Protein metabolism
  • Fluid balance
• Factors affecting metabolism:
  • Metabolising organ function
  • Metabolising organ blood flow
  • Factors affecting chemical reaction rate (eg. body temperature)
• Factors affecting clearance:
  • Clearance organ function
  • Clearance organ blood flow

This topic in its broadest application has never appeared in the scientific literature, it would seem. It just happens to be something that everybody considers to be so banal as to never merit a review article. The only thing one can find is an article from 1987  by du Souich et al, published in something called "Interactions between drugs and chemicals in industrial societies" using a monospaced font resembling that of a typewriter. There is also Marchant (1981), from the Scandinavian Journal of Rheumatology. 

Competition with endogenous ligands

This is mainly relevant to competitive antagonists.

Consider: where there is a significant concentration of an endogenous ligand, there is a substantial amount of receptor binding going on, i.e. many of the receptors have an agonist ligand bound upon them, and therefore there is a substantial clinically apparent agonist effect. The addition of a competitive antagonist displaces some of these agonist molecules from the receptor, and the clinically apparent effect decreases.

The opposite happens when there is a paucity of the endogenous ligand. Then, there is some small population of agonist-bound receptors producing some small clinical effect, and there is a vast population of unbound receptors sitting around doing nothing. The addition of an antagonist to this situation will have the antagonist molecules shared equally between all the receptors.  Therefore most of these molecules will end up binding a receptor which was not previously activated by an agonist, and which will continue to sit there pointlessly. There will be some minuscule number of previously agonist-occupied receptors from whence the agonist molecules will be displaced, and this might produce some sort of subtle barely-detectable clinical effect.

In summary, where there is a lot of endogenous ligand molecules available, antagonist effects will be exaggerated, and where endogenous ligands are scarce the antagonist will have a decreased clinical effect. Katzung (14th ed) use propanolol as an example: in phaeochromocytoma, its effect is significant, whereas in marathon runners the effect is negligible.

Alteration in the number or function of receptors

Obviously, drug receptors are pretty central to drug responses, and the alteration to anything about them (function, number, availability) will change the way an individual responds to any given substance. The regulation of receptor number and activity is discussed in greater detail elsewhere. The mechanisms which govern receptor number and function give rise to several phenomena which all require a chapter dedicated to them individually:

• Tolerance
• Dependence
• Addiction
• Withdrawal and "overshoot" phenomena
• Tachyphylaxis

These effects will not only vary in a population of drug users, but will also vary over the course of drug therapy in an individual subject. Good examples to quote in the vivas would include the change in number of acetylcholine-associated sodium channels at the neuromuscular junction (Martyn et al 1995) and the change in the function of opioid receptors in the course of sustained opioid use (Harrison et al, 1998). Alternatively, this variability may be pharmacogenomic, i.e there may be a genetic basis for the variation among a population, which may have a basis in the polymorphism of enzymes or receptor molecules among the members of a species.

Alteration in post-receptor response

The post-receptor responses account for the largest proportion of the population variability in drug response. These might include:

• Difference in the physiology of secondary messenger systems
• Compensatory or complimentary physiological responses to drug effect
• Behavioural responses to the drug
• Pharmacodynamic interactions between drugs
• Severity of the disease (obviously very individual)
• Environmental factors (eg. ambient temperature, pressure, partial pressure of oxygen)