Quantification of Drug Action II

To illustrate this point, we consider
an experiment in which the subjects individually
respond in all-or-none fashion,
as in the Straub tail phenomenon
. Mice react to morphine with excitation,
evident in the form of an abnormal
posture of the tail and limbs. The dose
dependence of this phenomenon is observed
in groups of animals (e.g., 10
mice per group) injected with increasing
doses of morphine. At the low dose,
only the most sensitive, at increasing
doses a growing proportion, at the highest
dose all of the animals are affected
. There is a relationship between the
frequency of responding animals and
the dose given. At 2 mg/kg, one out of 10
animals reacts; at 10 mg/kg, 5 out of 10
respond. The dose-frequency relationship
results from the different sensitivity
of individuals, which as a rule exhibits
a log-normal distribution (C, graph at
right, linear scale). If the cumulative frequency
(total number of animals responding
at a given dose) is plotted
against the logarithm of the dose (abscissa),
a sigmoidal curve results .
The inflection point of the curve lies at
the dose at which one-half of the group
has responded. The dose range encompassing
the dose-frequency relationship
reflects the variation in individual sensitivity
to the drug. Although similar in
shape, a dose-frequency relationship
has, thus, a different meaning than does
a dose-effect relationship. The latter can
be evaluated in one individual and results
from an intraindividual dependency
of the effect on drug concentration.
The evaluation of a dose-effect relationship
within a group of human subjects
is compounded by interindividual
differences in sensitivity. To account for
the biological variation, measurements
have to be carried out on a representative
sample and the results averaged.
Thus, recommended therapeutic doses
will be appropriate for the majority of
patients, but not necessarily for each individual.
The variation in sensitivity may be
based on pharmacokinetic differences
(same dose ! different plasma levels)
or on differences in target organ sensitivity
(same plasma level !different effects).