Deranged Physiology » CICM Primary Exam

» Required Reading » Variability in drug response

Mechanisms of tolerance and tachyphylaxis

!is 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 "estion
15 from the second paper of 2014, where the candidates were expected to
define the terms and discuss their mechanisms. !is 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 li%le
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:

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)
A'er 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. !e 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. !ere 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.

!is 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.

!e college complained that "Few candidates knew a comprehensive list

or had a classification system for the different types of tolerance." !is
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.
!e 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.
!ere 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 - Li%leton, 2001)
Receptor refractory period
period, which is a transient
period of tolerance a'er 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. !e 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.

!ere 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 intermi%ent doses. !is is seen with
amphetamines (Scholl et al, 2009)
Cross-tolerance is the development of tolerance to multiple
drugs belonging to the same class, a'er exposure to only one of
them. An example of this is seen in the administration of nitrates.

Tachyphylaxis

In their comments for "estion 15 from the second paper of 2014 the
college examiners complained that "no candidate had a good definition of
tachyphylaxis". !eir 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.

!is 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.

!ere 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. !e
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).

!e 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)

!e 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. !erea'er, 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
neurotransmi%ers 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. !is develops a'er 1 dose and takes
a week to resolve (Haney et al, 2005).!e mechanism is
apparently some sort of uncoupling of the receptor from its
intracellular effector mechanism.
Nicotine: tachyphylxis develops a'er 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)
:
 Previous chapter: Mechanisms
of pharmacodynamic drug-
drug interactions

Next chapter: Addiction,

dependence and withdrawal

References

Webb, Nadia. "Tachyphylaxis." Encyclopedia of Clinical Neuropsychology.

Springer New York, 2011. 2463-2463.

Figueras, Albert, et al. "!erapeutic Ineffectiveness." Drug safety 25.7

(2002): 485-487.

Meyboom, Ronald HB, et al. "!e value of reporting therapeutic

ineffectiveness as an adverse drug reaction." Drug Safety 23.2 (2000): 95-
99.

Freeman, Brian, and Jeffrey Berger. Anesthesiology Core

Review. McGraw-Hill Education, 2014.

Katz, Gregory. "Tachyphylaxis/tolerance to antidepressive medications: a

review." !e Israel journal of psychiatry and related sciences 48.2 (2011):
129.

De Moraes, S., and Varela De Carvalho. "On the mechanism of action of

tachyphylaxis by ephedrine." Pharmacology 1.1 (1968): 53-59.

Cowan, F. F., T. Koppanyi, and G. D. Maengwyn‐Davies. "Tachyphylaxis

III. Ephedrine." Journal of pharmaceutical sciences 52.9 (1963): 878-883.

Swanson, James M. "Long-acting stimulants: development and

dosing." !e Canadian Child and Adolescent Psychiatry Review 14.Suppl
1 (2005): 4.

Agvald, Per, et al. "Nitric oxide generation, tachyphylaxis and cross-

tachyphylaxis from nitrovasodilators in vivo." European journal of
:
 pharmacology 385.2-3 (1999): 137-145.

Sage, Peter R., et al. "Nitroglycerin tolerance in human vessels: evidence

for impaired nitroglycerin bioconversion." Circulation 102.23 (2000): 2810-
2815.

Haney, Sarah, and Robert J. Hancox. "Rapid onset of tolerance to beta-

agonist bronchodilation." Respiratory medicine 99.5 (2005): 566-571.

Barnes, Peter J. "Beta-adrenergic receptors and their

regulation." American journal of respiratory and critical care
medicine 152.3 (1995): 838-860.

Zuo, Yantao, et al. "Acute nicotine-induced tachyphylaxis is differentially

manifest in the limbic system." Neuropsychopharmacology 36.12 (2011):
2498.

Packer, Milton, et al. "Hemodynamic and clinical tachyphylaxis to

prazosin-mediated a'erload reduction in severe chronic congestive heart
failure." Circulation 59.3 (1979): 531-539.

Li%leton, John. "Receptor regulation as a unitary mechanism for drug

tolerance and physical dependence‐not quite as simple as it
seemed!." Addiction 96.1 (2001): 87-101.

Orberg, PAULO K., and WILLIAM E. Sandine. "Common occurrence of

plasmid DNA and vancomycin resistance in Leuconostoc spp." Applied
and environmental microbiology48.6 (1984): 1129-1133.

Ehrman, Ronald, et al. "Conditioned tolerance in human opiate

addicts." Psychopharmacology 108.1-2 (1992): 218-224.

Scholl, Jamie L., et al. "Individual differences in amphetamine

sensitization, behavior and central monoamines." Physiology &
behavior 96.3 (2009): 493-504.

Lê, A. D., and Jatinder M. Khanna. "Dispositional mechanisms in drug

tolerance and sensitization." Psychoactive Drugs. Humana Press, Totowa,
NJ, 1989. 281-351.
:
 Goudie, Andrew J., and Michael W. Emme%-Oglesby. Psychoactive drugs:
Tolerance and sensitization. Springer Science & Business Media, 1989.

Pandey, Subhash C. "Neuronal signaling systems and ethanol

dependence." Molecular neurobiology 17.1-3 (1998): 1-15.

Huganir, Richard L., and Paul Greengard. "Regulation of receptor function

by protein phosphorylation." Trends in Pharmacological Sciences 8.12
(1987): 472-477.
:
 [Submit a comment or correction]
:
 © Alex Yartsev
2013-2021
: