Mechanisms of tolerance and tachyphylaxis

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. 

In summary:

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. 

Tolerance

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.

• Pharmacokinetic tolerance: the persistent exposure makes the drug clearance mechanisms more active; classically by induction of metabolic enzymes. An example is the effect of ethanol on CYP450 enzymes.
• Pharmacodynamic tolerance: persistent exposure to the drug produces an adaptive homeostatic response whereby the drug receptors are down-regulated or the second messenger systems are dampened, such that the pharmacological effect is decreased. There are multiple possible examples, mentioned in the college answer around the statement that "various mechanisms exist". Judging by the content of what the examiners wrote, they wanted pharmacodynamic tolerance to be further subdivided. 
  • Receptor downregulation  where receptors are inactivated or endocytosed and degraded in response to sustained stimulation.
  • Receptor deactivation; where the receptor protein is phosphorylated in response to excess stimulus (eg. the nicotonic receptor and nicotine - Huganir et al, 1987)
  • Receptor subunit modification, where a modified receptor complex is selectively expressed, with diminished sensitivity for the drug but maintained sensitivity for the endogenous ligand (eg. the GABA-A receptor and benzodiazepines - Littleton, 2001)
  • Receptor refractory period, which is a transient period of tolerance after the last drug-receptor interaction (by stretching the imagination, one can make this look like a form of drug tolerance)
  • Second messenger changes where the post-receptor second messenger system is deactivated, as with β-2 agonists (Haney et al, 2005).
  • Drug target depletion where some key molecule is used up in the course of drug action; subsequent drug doses will therefore have diminished activity until the key molecule is regenerated. A classical example is presynaptic noradrenaline depletion due to ephedrine therapy.
• Physiological tolerance is tolerance to the effects of the drug rather than to the drug itself (at a receptor level). Receptor responses may remain the same but physiological adaptive mechanisms restore homeostasis, such that the effect of the drug appear to be reduced. A good example of this is the physiological adaptation to the use of vasodilator antihypertensives, by the increased heart rate and cardiac output which maintains blood pressure.
• Learned tolerance, or behavioural tolerance is the development of learned behavioral adjustments that compensate for the drug's effects. The result is an apparently diminished drug effect. A good example of this is the alcoholic who might remain safely functional within their own home in spite of scandalous intoxication. A sub-variety of this is conditioned tolerance, the development of behavioural tolerance which is strongly dependent on some specific environmental or behavioural trigger. For instance, conditioned tolerance to the effects of opiates was observed by Ehrman et al (1992) who found that pre-injection "rituals" (spoon, cooking, etc) were associated with a decrease in drug effect, whereas unexpected injections were not.

There are a few other sub-varieties for acquired tolerance which defeat efforts at classification; one might describe these as tolerance-related phenomena.

• Sensitisation  is the development of "reverse tolerance", or "intolerance" if one extends the metaphor. It is the increase in drug effect associated with intermittent doses. This is seen with amphetamines (Scholl et al, 2009)
• Cross-tolerance is the development of tolerance to multiple drugs belonging to the same class, after exposure to only one of them. An example of this is seen in the administration of nitrates.

Tachyphylaxis

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:

• Repeat administration
• Same dose
• Diminished physiological effect
• Develops over a short period of time
• 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)

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:

• Indirect sympathomimetics: ephedrine and metaraminol both displace noradrenaline from storage vesicles; tachyphylaxis results from repeated administration because noradrenaline is depleted from said vesicles. Thereafter, giving ever-increasing doses will not be able to restore the effectiveness of the first bolus. With ephedrine, three doses is all it may take (Cowan et al, 1963). 
• Amphetamines: the response to slow release (intentionally zero order kinetics) methylphenydate was not the expected sustained effect in ADHD-affected children; rather, tachyphylaxis was observed over 3-4 hours (Swanson, 2005) - again depletion of neurotransmitters is blamed.
• Nitroglycerin: tachyphylaxis develops over hours of infusion due to mechanisms which nobody seems to be able to agree upon but which are thought to be multiple. Some combination of "pseudotolerance" with vascular remodelling and physiological tolerance due to counteractive endogenous vasopressors is blamed, but some aspect must also be due to "true" tachyphylaxis because there is cross-tachyphylaxis among different nitrates (Agvald et al, 1999; Sage et al, 2000).
• β-2 agonists: "rapid onset of tolerance"is described, particularly to the bronchodilator effects. This develops after 1 dose and takes a week to resolve (Haney et al, 2005).The mechanism is apparently some sort of uncoupling of the receptor from its intracellular effector mechanism.
• Nicotine: tachyphylxis develops after a single dose, and this occurs by mechanisms which are incompletely understood. Weirdly, the degree of tachyphylaxis has some sort of regional variability in the brain (Zuo et al, 2011). 
• Non-nitrate vasodilators, eg. prazocin are subject to tachyphylaxis effects not because of some sort of receptor effect but mainly because of the development of a vigorous and counterproductive sympathetic regulatory response to vasodilation (Packer et al, 1979)