Other nonreceptor site of action interactions
include MAOIs – pethidine (acute dystonias),
ethanol – benzodiazepines (synergisitic sedation
and respiratory depression), cocaine – ampheta-
mines (hypertensive crisis) and dihydrocodeine –
morphine (the former is a partial agonist and
reduces the efficacy of the full agonist).
As far as drug metabolismis concerned, it is
essential to understand some of the basic biochem-
istry before being able to anticipate the interactions
that can occur at this locus. Mobile omnivore
mammals are constantly exposed to xenobiotics,
many of which can be toxic. An efficient defence
against these toxins resides in the gut and the liver,
with the general aim of metabolizing such toxic
molecules into smaller and less toxic metabolites;
these are generally more water-soluble and thus
more capable of excretion, thus reducing the expo-
sure of the rest of thebody to highconcentrations of
the parent toxin. Drugs fall foul of the same
defence mechanisms.
Cytochromesare a diverse class of enzymes, and
are so named because they are brightly colored
when in solution. This color is because these
enzymes contain heme groups and transition
metal ions (e.g. Feþþ,Cuþþ, etc.). As they are
colored, these enzymes may be classified by the
wavelength of light which they absorb maximally.
Although a comprehensive discussion of cyto-
chrome classification is beyond the scope of this
chapter, suffice it to say that cytochrome class P
enzymes, with a maximal absorption of 450 nm
(CYP450), are the most important for drug meta-
bolism. These CYP450 enzymes themselves exist
as several hundred isoenzymes, denoted by code
letters and digits, for example CYP450 2D6. Each
isoenzyme has a preferential substrate. Different
species (includingH. sapiens) exhibit different
patterns of isoenzymes in their phenotype, and
there may be further variation in the activity of
particular isoenzymes between individuals,
whether or not this is predictable on the basis of
membership of particular ethnic groups.
CYP450 isoenzymes usually reside on the
smooth endoplasmic reticulum, and are classic
examples of mixed-function oxidases (or oxyge-
nases); these enzymes oxidize and reduce two
substrates simultaneously, and atoms from mole-
cular oxygen usually are incorporated into one of
the substrates. Alternatives include the loss of
hydrogen atoms or alkyl groups, with the corre-
sponding formation of water or formate. The loss
of hydrogen atoms (i.e. a substrate that becomes
less reduced) is another form of molecular oxida-
tion within the Lowry-Brønstein formulation.
Thus, drug metabolism by CYP450 can involve
hydroxylation, dealkylation, aromatic oxidation,
sulfation, ring opening with hydroxylation and so
on. Sometimes, the isoenzyme itself is oxidized,
and in this case it is usually regenerated by reduced
nicotinamide adenine phosphate (NADP-H).
When thinking about interactions at the site of
metabolism, one must therefore think about classi-
cal enzymology, and from the enzyme’s point of
view. Drugs can be substrates, inhibitors or enzyme
activators (i.e. inducers or promoters). Competi-
tion by two drugs for saturated enzyme is mutual
competitive antagonism and elimination times for
both will increase. Drugs that are enzyme inhibi-
tors will prolong the elimination time for another
substrate, but the pharmacokinetics of the inhibitor
itself will not change (unless the drug is itself not
only an inhibitor but also a substrate for the
enzyme). Some drugs (e.g. rifampicin, barbiturates
and cigarette smoke) are enzyme inducers. In
molar terms per gram protein, the concentration
of enzyme increases during exposure to the indu-
cing drug a period of several days and there is
secondarily hastening of the metabolism of some
other drug substrate. Barbiturates (barbitals) are
classic enzyme inducers; by enhancing the elim-
ination of warfarin, anticoagulant effect can be
lost. Some drugs (e.g. opiates) auto-induce their
own isoenzyme, and this is one reason why doses
tend to escalate in palliative care (note that there is
no adaptive reduction in the gut, and oral opiate-
induced constipation under these conditions gets
only worse because this is a local effect at the site of
absorption which is unprotected by hepatic meta-
bolism of absorbed drug).
For a census of commonly prescribed drugs, the
predominant CYP450 isoenzyme for drug metabo-
lism is 3A4 (about 55% of all prescribed drugs).
Next comes 2D6 (25%). About 15% of drugs are
metabolized by isoenzyme 2C9 (although this
number probably includes small contributions by20.3 SYSTEMATIC CONSIDERATION OF DRUG INTERACTIONS 259