Pharmacodynamics
Tolerance & Sensitization
Repeated drug administration sometimes produces differences in the
magnitude of effect produced by the repeated administrations. When effects
become weaker over repeated drug administration, tolerance is said
to develop to the drug effect. When effects become stronger over repeated
drug administration, sensitization is said to develop to the drug.
Such changes in responsiveness to a drug can be produced by pharmacokinetic
changes, learning effects, and neuroadaptive responses. Of these three
processes the latter two are actually inseparable--learning effects involve
CNS changes and neuroadaptive effects can be considered a type of cellular
learning. The applied label reflects the relative emphasis and not mediation
by independent processes.
Tolerance
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Diminished responsiveness to a drug
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Can be shown by either of two methods
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constant-dose method
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requires fewest subjects
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a fixed drug dose is given over repeated trials and diminished responding
noted
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constant-effect method
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most comprehensive
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full dose-response analysis is sometimes conducted before and after the
tolerance-inducing manipulation
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alternatively, a limited dose range is examined to determine the minimum
dose necessary to maintain a constant effect
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Types of tolerance
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dispositional (pharmacokinetic; includes but not limited to metabolic tolerance)
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cellular (pharmacodynamic, neuronal)
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physiological (includes but not limited to behavioral tolerance)
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A large number of pharmacological actions show tolerance
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most opiate-induced effects
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amphetamine-induced anorexia
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Special cases of tolerance
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cross tolerance
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compounds in the same pharmacological class often show cross tolerance
(e.g., opiates)
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sometimes compounds producing similar effects show cross tolerance (e.g.,
barbiturates and ethanol)
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tachyphylaxis
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denotes the rapid induction of tolerance, usually following a single exposure
to drug
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can occur within the first drug exposure interval (e.g., cocaine's cardiovascular
effects)
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for most purposes, the term tachyphylaxis can be used interchangeably
with the term desensitization
Sensitization (reverse tolerance)
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Increased responsiveness to a drug
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Can be shown by the same methods as used to demonstrate tolerance
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Fewer compounds and effects show sensitization than show tolerance
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several psychomotor stimulant effects
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stimulatory actions of opiates
Physical Dependence & Withdrawal Reactions
Withdrawal reactions (and physical dependence) are traditionally associated
with tolerance, although more recent data suggest than can also be associated
with sensitization.
Copyright 1999 Michael A. Bozarth
This page was last updated 04 November 1999 11:11 EDT
Report technical problems to: bozarth@buffalo.edu