The results received on the following Monday
indicated low concentrations. This was
followed by a second unpleasant phone call
complaining about our poor service and the
lousy assay (the good doctor wasn’t aware we
sent the specimen out). I asked him if he
checked to see if there were other drugs that
might change the clearance rate of chloram-
phenicol or whether he had checked other
possibilities. He replied angrily that he knew
what he was doing. Then I became angry. I
went onto the ward and found the chart. The
nursing notes were very interesting.
It happened that the child had been hospital-
ized for a long time. Her veins were very
poor and keeping IV lines was very difficult.
If the child’s IV line came out near the time of
her dose, the house officer ordered an oral
dose and then put back in the IV line when he
could. But in that hospital changing orders
results in a significant delay in getting the
drug to the floor. By the time the oral dose
came, it was time for the next intravenous
dose so the oral dose was dropped to avoid
giving two doses together. And so for days
the patient received only about half of her
doses. The house officer and the attending
physician were unaware of this persistent
problem. The doses most often missed were
those on the night shift when the delays in
pharmacy service and in replacing the IV lines
were greatest because the pharmacy and the
house staff were on skeleton shifts. Thus,
because the samples for analysis were drawn
in the morning after rounds, the effect of
missing the 2:00 a.m. dose was great, even if
the 8:00 a.m. dose was given. The child’s
drug concentrations were consistently low
because she consistently received less drug
than she should have.
I wrote Dr. L.P. a controlled but angry letter
informing him and we both decided not to
bring the matter up again. We are still
friendly and the child recovered uneventfully.
Molecular heterogeneity
For some drugs, the molecules of drug in the
body differ in their bioactivity, that is, in the magni-
tude of their physiologic effects. This molecular
heterogeneity may arise because of differences in
molecular chirality, because of alterations in molecu-
lar structure due to metabolic processes, and because
of reduced availability for diffusion and cellular
uptake due to plasma protein binding.
Chirality.
Chiral drugs are generally not
produced as pure enantiomer preparations, which are
expensive to manufacture, but are instead marketed
as racemic mixtures. If the enantiomers of a drug
have appreciable differences in their bioactivity,
total drug effect will depend upon the fraction of
drug in each of the enantiomeric forms. Differences
in the pharmacokinetics of enantiomers further
complicate matters because the fraction of drug
present in each of the various enantiomeric forms
will vary over time. It makes sense to employ
enantiomer-specific drug assays in the therapeutic
monitoring of such drugs (Lee and Williams 1990)
but this is currently not done.
Active metabolites.
Drug metabolism usually
leads to drug inactivation, but not always. Metabo-
lism may yield a product that has a reduced but still
clinically significant degree of bioactivity. For
example, the products of the hepatic metabolism of
the tertiary amine cyclic antidepressants, such as
imipramine and amitriptyline, include the cor-
responding secondary amines (desipramine and nor-
triptyline, respectively) which have antidepressant
effects and which are themselves sometimes used as
antidepressant agents. When monitoring therapy in
patients taking tertiary amine cyclic antidepressants,
the plasma concentrations of both the parent drug
and the active metabolite are measured. Because the
potencies of the secondary amine antidepressants
effects are roughly comparable to those of the terti-
ary amines, the concentrations are interpreted by
adding the two concentrations together and compar-
ing the sum to the therapeutic range defined for the
combined concentrations. For a metabolite that has
a potency that is significantly different from the
parent drug, one can scale the concentration of the
metabolite by multiplying it by its potency relative to
the parent drug and then add the concentration of the
parent drug and the scaled concentration of the
metabolite together.
A drug metabolite may also have drug effects
that are different from those of the parent drug.
These effects are often unwanted and may be
seriously toxic. For instance, thiocyanate and cya-
nide are metabolites of nitroprusside. Treatment of
a hypertensive crisis with nitroprusside can lead to
the accumulation of these metabolites to
Drug Therapy
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