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Electrochemistry of Drug
Interactions and Incompatibilities

G. M. Eckert, F. Gutmann, and H. Keyzer

ABSTRACT: Molecular associations involving drugs are of considerable pharmacological

importance. Incompatibilities and the binding of "active" drugs to "inert" formulation com-
ponents are characterized by such associations and may result in rendering otherwise carefully
planned therapeutic regimens ineffective. The "large cation-large anion" incompatibility is
considered. Association between two drugs or a drug and tissue component in vivo may
greatly modify the distribution and therefore the therapeutic effect of the drug. In spite of
complications caused by tissue binding and metabolic modification the therapeutic interaction
between some pairs of drugs is suitable for study by physicochemical in vitro techniques.
Further details with respect to the interactions of the anticoagulant heparin are given. The
study of the mechanism of drug action is greatly assisted by the in vitro study of simplified
model systems. The chlorpromazine/iodine system is discussed. Electrochemical techniques,
such as conductimetric titration, voltammetry, and potentiometry, are indicated when there is
a decrease (as in cation-anion association) or increase (as in the dissociation of a charge
transfer complex) in the concentration of charge carriers. Other physicochemical techniques
are complementary with these electrochemical techniques. Biological and clinical studies are
essential before deciding the practical therapeutic significance of an interaction demonstrated
by physicochemical means.

1. Scope and Limitations

In the complicated situation involved in the effect of a drug administered to

the living subject, the action of the drug may be greatly modified by other
drugs.

G. M. Eckert • Clinical Pharmacologist, The St. George Hospital, Kogarah, N.S.W. 2217,
Australia. F. Gutmann • School of Chemistry, Macquarie University, North Ryde,
N.S.W. 2113, Australia. H. Keyzer • Department of Chemistry and Biochemistry,
California State University, 5151 State University Drive, Los Angeles, California 90032.
503

F. Gutmann et al. (eds.), Modern Bioelectrochemistry

© Plenum Press, New York 1986
504 G. M. Eckert, F. Gutmann, and H. Keyzer

A drug-drug interaction (or simply drug interaction) occurs "when the

overall biological response of two or more drugs is markedly different from
the simple sum of the effects of each component given singly."(l)
It is important to note that "drug interaction" by this definition is a
biological effect. A drug interaction may occur without an in vitro
physiochemical interaction between the two drugs, and conversely a
physicochemical interaction does not necessarily imply a biological interac-
tion.
The interaction between drugs and tissue components is also of prac-
tical pharmacological significance and it is convenient to consider some
aspects of this.
The term "drug incompatibility" is applied to unfavorable reactions
which occur between two or more drugs before the administration of the
drugs.
The above definitions notwithstanding, the word "interactions" has of
course, many meanings. No attempt will be made here at further
clarification.

1.1. Significance of Drug Interactions

1.2.1. Therapeutic Importance

Clinically, drug interactions are important because of their significance
in therapeutics.
Incompatibility, such as that between anionic and cationic antiseptics
discussed below, may inactivate the agent(s) involved.
Study of drug interactions which occur after administration of the
drugs to the patient is more difficult.
With the development of potent, more specific drugs during the post-
World War II period, the fashion for mixing drugs in small-scale mixtures,
dispensed individually by the pharmacist, was replaced by industrially
manufactured, quality controlled, single (or sometimes fixed dose com-
bination) drug formulations resulting in a decreasing interest in com-
patibilities. Along with this development was the pious hope, at least
among medical academics, that polypharmacy ("shot-gun therapy") would
disappear in favor of definite diagnoses and specific therapy. This hope,
however, has not been realized. The common use of more than one drug
for most patients in both hospitals and the community has been
documented.(2,3) In a survey carried out by one of the authors (G.E.) the
average number of drugs prescribed concurrently per hospitalized patient
was 6.8. Polypharmacy in practice is not dead. Instead of the drugs being
mixed in the bottle before administration they are now mixed in the
patient. It should be noted that during the same period, there has been an