Principles and Practice of Pharmaceutical Medicine

type of drug combination can exceed the effect that
is achievable with even maximal doses of either
alone. Combination of antihypertensive therapy or
chemotherapy is a good example.
More complicated isobolograms exist. TheN-
acetyl cysteamine dosage algorithm is an isobolo-
gram with time and acetaminophen (paracetamol)
plasma concentration on the axes in the plane of
the paper and a two-step measure in the third
dimension (probability of toxicity that requires
treatment). Somewhat as famous is Professor
Herxheimer’s depiction of the interaction between
coffee and wine: two glasses of each provide the
maximum possible beneficial effect (the effect
being ‘happiness’). The contours are thus of a hill
on a plane.

20.3 Systematic consideration

of drug interactions

The key to considering the potential for drug inter-
actions lies in considering all the places that drug
molecules may occupy. In this section, we shall

present arepertoireof drug interactions sorted by

locus, which the reader may like to consider, and

those sitting the Diploma in Pharmaceutical Med-

icine might like to be able to deliver to the exam-

iners. The full set of drug loci are the sites of drug

storage, absorption, distribution, action, metabo-

lism and excretion, plus, in some cases, the pre-

sence of the drug in blood and urine samples that

reach the clinical laboratory; clearly there are

exceptions. For example, some drugs act at the

site of absorption, and others are excreted

unchanged.

Prior to administration: drug storage

These interactions are always unwanted. A good

example is the inappropriate mixing of insulins.

Slower release insulins are complexed with prota-

mine zinc in excess, while the conjugation of insu-

lin with such adjuvant takes place slowly,

especially in the relatively low temperature of a

refrigerator. Drawing up thelenteinsulin first, and

then sticking the needle into the soluble insulin,

Dose of drug A

1 3 5 7 9

E9

E6

E3

4A + 4 B has

an effect

> E9

Dose of drug B

9

7

5

3

1

Figure 20.3 Classical isobologram for a synergistic or potentiating drug interaction. The dotted lines show how four
dose units of drug A plus four dose units of drug B result in an effect that exceeds E8. The formulae for the contours are
ayþbx>kEcusing the same notation as in Figure 20.1

20.3 SYSTEMATIC CONSIDERATION OF DRUG INTERACTIONS 257