This chapter is directly related to Section D(ii) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "define tachyphylaxis, tolerance" and several other terms (dependence, etc).
Of the past paper SAQs, it has only ever appeared once - in Question 15 from the second paper of 2014, where the candidates were expected to define the terms and discuss their mechanisms. This was answered extremely poorly: only 15% of the candidates passed. It is difficult to blame them for this, because the official college textbooks have very little in the way of explanation for mechanisms of drug tolerance, and there actually is no official definition for tachyphylaxis anywhere in the literature.
- Tolerance: larger doses required to produce the same effect.
- Pharmacokinetic clearance: increased drug clearance induced by repeat doses
- Pharmacodynamic tolerance: changes in receptor number or function due to exposure to the drug
- Physiological tolerance: homeostatic adaptation of unrelated systems to compensate for drug effect
- Behavioural tolerance: learned compensation for the effect of the drug which diminishes its effects.
- Tachyphylaxis: a rapid decrease in response to repeated doses over a short time period
- Not dose-dependent (i.e. giving a larger dose of the drug may not restore the maximum effect)
- Rate-sensitive (i.e. requires frequent dosing)
- After a relatively short period of withholding the drug, its effect is restored (i.e tachyphylaxis resolves rapidly)
Where to find information on this topic? Basic and Clinical Pharmacology (14th ed) is almost completely useless for this purpose. On page 38 there is the briefest mention of tolerance and tachyphylaxis with no discussion of different mechanisms; then much later on page 576 Christian Lüscher's chapter on drugs of abuse abandons theoretical pharmacology in favour of discussing tolerance in terms of opioid addiction. Clearly, the CICM examiners must have intended their trainees to read something other than the recommended text. Among published peer-reviewed literature, the best article for this purpose is Vashishta & Berringer's 2014 chapter (Ch.43) for Anesthesiology Core Review. It is not free, but ANZCA keep in in their online library, and resourceful exam candidates will cultivate friends among ANZCA trainees to get access to such materials. For a detailed immersion in the topic, one can rely on Psychoactive drugs: Tolerance and sensitization by Goudie et al, from 1989. It shows its age a bit, but nothing subsequently published has approached this level of detail. The final chapter by Harold Kalant is particularly good.
When most authors write "tolerance", they usually mean "acquired tolerance": the development of drug tolerance in response to pharmacological or physiological challenge. There is also innate tolerance: a reduced in response to the drug even before exposure. In other words, this is tolerance which is not "drug-induced". An example of this might be the total and completely genetically determined resistance of Leuconstoc sp. to vancomycin (Orberg & Sandine, 1984), or the relative tolerance of amphotericin by Homo sapiens.
To borrow a definition from the college answer,
Tolerance is the requirement of higher doses of a drug to produce a given response.
This wording is good enough for government work. Goodman and Gilman (13th ed., Ch. 24 by Charles P. O’Brien) define it as "the reduction in response to the drug after repeated administrations". Another option comes from the Encyclopedia of Psychopharmacology, where Negus et al (2014) describe tolerance as "a drug-induced reduction in subsequent drug effect".
Definitions of tolerance generally include repeat administration, increasing dose requirements, dose-dependence (higher doses lead to more rapid development of tolerance) and chronicity. To be distinct from tachyphylaxis, tolerance apparently needs to happen over some prolonged time period. Having said this, O’Brien also included acute tolerance in his list of definitions, as a sub-variety where repeated doses over a short period are associated with a rapidly increasing resistance to the drug's effects. It is not clear how this definition differs from tachyphylaxis.
The college complained that "Few candidates knew a comprehensive list or had a classification system for the different types of tolerance." This implies that somewhere there is a comprehesive list, or a classification system. In fact there does not seem to be any such agreed-upon system. The following list/classification were scraped together from a combination of textbooks. on drug addiction because they were the most comprehensive.
There are a few other sub-varieties for acquired tolerance which defeat efforts at classification; one might describe these as tolerance-related phenomena.
In their comments for Question 15 from the second paper of 2014 the college examiners complained that "no candidate had a good definition of tachyphylaxis". Their own definition is as follows:
Tolerance is the requirement of higher doses of a drug to produce a given response. When this develops rapidly (with only a few administrations of the drug) this is termed tachyphylaxis.
This is almost a verbatim quote from the 14th edition of Katzung:
"When responsiveness diminishes rapidly after administration of a drug, the response is said to be subject to tachyphylaxis."
It also vaguely resembles the definition from Peck and Hill (p. 38 of the old 3rd edition).
Tachyphylaxis is defined as a rapid decrease in response to repeated doses over a short time period.
Notably, the authors firmly establish that speed is of the essence by reinforcing how tachyphylaxis develops rapidly and over a short time period. Goodman and Gilman (13th ed) also mention rapidity, and describe it as:
"a state... such that the effect of continued or repeated exposure to the same concentration of drug is diminished"
So, it would seem the published literature has a fair variety of definitions, which suggests perhaps that nobody has agreed on any official definition. In general it appears that the distinction between tolerance and tachyphylaxis has some time-related component for most authors. But not for all. For example, this article from 2011 discusses "tachyphylaxis" in antidepressants, occurring over weeks.
There is probably also some sort of difference in mechanisms, though this is not acknowledged by many of the authors. Specifically, it seems Vashishta and Berrigan are the only ones who mention this. The mechanisms of tachyphylaxis seem to require a decrease or increase of some substance or another, producing the rapid change in effect (for example, the depletion of the intracellular stores of some sort of effector).
The cardinal features of tachyphylaxis seem to be:
The mechanisms involved in tachyphylaxis resemble those of tolerance, with the exception of the fact that it is usually impossible to withdraw and reabsorb (or synthesise and express) receptors with that sort of speed.
Examples of tachyphylaxis include: