DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

652 paucity of other options for pleasure, diversion, or
income. These factors are particularly important in communities
where educational levels are low and job
opportunities scarce.
SECTION II
NEUROPHARMACOLOGY
Pharmacological Phenomena
Tolerance. While abuse and addiction are complex conditions
combining the many variables outlined earlier,
there are a number of relevant pharmacological phenomena
that occur independent of social and psychological
dimensions. First are the changes in the way the
body responds to a drug with repeated use. Tolerance,
the most common response to repetitive use of the same
drug, can be defined as the reduction in response to the
drug after repeated administrations. Figure 24–1 shows
an idealized dose-response curve for an administered
drug. As the dose of the drug increases, the observed
effect of the drug increases. With repeated use of the
drug, however, the curve shifts to the right (tolerance).
Thus, a higher dose is required to produce the same
effect that was once obtained at a lower dose. Diazepam,
e.g., typically produces sedation at doses of 5-10 mg
in a first-time user, but those who repeatedly use it to
produce a kind of “high” may become tolerant to doses
of several hundreds of milligrams; some abusers have
had documented tolerance to >1000 mg/day. As outlined
in Table 24–3, there are many forms of tolerance likely
arising through multiple mechanisms.
Tolerance to some drug effects develops much more rapidly
than to other effects of the same drug. For example, tolerance develops
rapidly to the euphoria produced by opioids such as heroin, and
Relative effect
Sensitization
Dose
Tolerance
Figure 24–1. Shifts in a dose-response curve with tolerance and
sensitization. With tolerance, there is a shift of the curve to the
right such that doses higher than initial doses are required to
achieve the same effects. With sensitization, there is a leftward
shift of the curve such that for a given dose, there is a greater
effect than seen after the initial dose.
Table 24–3
Types of Tolerance
Innate (pre-existing sensitivity or insensitivity)
Acquired
Pharmacokinetic (dispositional or metabolic)
Pharmacodynamic
Learned tolerance
Behavioral
Conditioned
Acute tolerance
Reverse tolerance (sensitization)
Cross-tolerance
addicts tend to increase their dose in order to re-experience that
elusive “high.” In contrast, tolerance to the gastrointestinal effects
of opioids develops more slowly. The discrepancy between tolerance
to euphorigenic effects (rapid) and tolerance to effects on vital functions
(slow), such as respiration and blood pressure, can lead to
potentially fatal overdoses in sedative abusers trying to re-experience
the euphoria they recall from earlier use.
Innate tolerance refers to genetically determined lack of sensitivity
to a drug that is observed the first time that the drug is administered.
Innate tolerance was discussed earlier as a host variable that
influences the development of addiction. See Chapter 23 for discussion
of the inheritance of level of response to ethanol.
Acquired tolerance can be divided into three major types:
pharmacokinetic, pharmacodynamic, and learned tolerance, and
includes acute, reverse, and cross-tolerance (Table 24–3).
Pharmacokinetic or dispositional tolerance refers to changes in
the distribution or metabolism of a drug after repeated administrations
such that a given dose produces a lower blood concentration than the
same dose did on initial exposure. The most common mechanism is an
increase in the rate of metabolism of the drug. For example, barbiturates
stimulate the production of higher levels of hepatic CYPs, causing
more rapid removal and breakdown of barbiturates from the
circulation. Since the same enzymes metabolize many other drugs,
they too are metabolized more quickly. This results in a decrease in
their plasma levels as well and a reduction in their therapeutic effects.
Pharmacodynamic tolerance refers to adaptive changes that
have taken place within systems affected by the drug so that response
to a given concentration of the drug is reduced. Examples include
drug-induced changes in receptor density or efficiency of receptor
coupling to signal-transduction pathways (Chapters 3 and 14).
Learned tolerance refers to a reduction in the effects of a drug
owing to compensatory mechanisms that are acquired by past experiences.
One type of learned tolerance is called behavioral tolerance.
This simply describes the skills that can be developed through
repeated experiences with attempting to function despite a state of
mild to moderate intoxication. A common example is learning to
walk a straight line despite the motor impairment produced by alcohol
intoxication. This probably involves both acquisition of motor
skills and the learned awareness of one’s deficit, causing the person
to walk more carefully. At higher levels of intoxication, behavioral
tolerance is overcome, and the deficits are obvious.