2.

Pharmacodynamic interactions

Pharmacodynamic interactions are those where the effects of one drug are changed by the presence
of another drug at its site of action. Sometimes the drugs directly compete for particular receptors
(e.g. beta2 agonists, such as salbutamol, and beta blockers, such as propranolol) but often the
reaction is more indirect and involves interference with physiological mechanisms. These
interactions are much less easy to classify neatly than those of a pharmacokinetic type.

2.1. Additive or synergistic interactions

If two drugs that have the same pharmacological effect are given together the effects can be
additive. For example, alcohol depresses the CNS and, if taken in moderate amounts with normal
therapeutic doses of any of a large number of drugs (e.g. anxiolytics, hypnotics, etc.), may cause
excessive drowsiness. Strictly speaking (as pointed out earlier) these are not interactions within
the definition given in What is a drug interaction?, (p.1). Nevertheless, it is convenient to
consider them within the broad context of the clinical outcome of giving two drugs together.

Additive effects can occur with both the main effects of the drugs as well as their adverse effects,
thus an additive interaction can occur with antimuscarinic antiparkinson drugs (main effect) or
butyrophenones (adverse effect) that can result in serious antimuscarinic toxicity (see
Antipsychotics + Antimuscarinics, p.708).

Sometimes the additive effects are solely toxic (e.g. additive ototoxicity, nephrotoxicity, bone
marrow depression, QT interval prolongation). Examples of these reactions are listed in Table
1.7, (see below). It is common to use the terms additive, summation, synergy or
potentiation to describe what happens if two or more drugs behave like this. These words have
precise pharmacological definitions but they are often used rather loosely as synonyms because in
practice it is often very difficult to know the extent of the increased activity, that is to say whether
the effects are greater or smaller than the sum of the individual effects.

The serotonin syndrome

In the 1950s a serious and life-threatening toxic reaction was reported in patients taking iproniazid
(an MAOI) when they were given pethidine (meperidine), (p.1140). The reasons were then not
understood and even now we do not have the full picture. What happened is thought to have been
due to over-stimulation of the 5-HT1A and 5-HT2A receptors and possibly other serotonin
receptors in the central nervous system (in the brain stem and spinal cord in particular) due to the
combined effects of these two drugs. It can occur exceptionally after taking only one drug, which
causes over-stimulation of these 5-HT receptors, but much more usually it develops when two or
more drugs (so-called serotonergic or serotomimetic drugs) act in concert. The characteristic
symptoms (now known as the serotonin syndrome) fall into three main areas, namely altered
mental status (agitation, confusion, mania), autonomic dysfunction (diaphoresis, diarrhoea, fever,
shivering) and neuromuscular abnormalities (hyperreflexia, incoordination, myoclonus, tremor).
These are the Sternbach diagnostic criteria named after Dr Harvey Sternbach who drew up this
list of clinical features and who suggested that at least three of them need to be seen before
classifying this toxic reaction as the serotonin syndrome rather than the neuroleptic malignant
syndrome.1

The syndrome can develop shortly after one serotonergic drug is added to another, or even if one
is replaced by another without allowing a long enough washout period in between, and the problem
usually resolves within about 24 hours if both drugs are withdrawn and supportive measures given.
Non-specific serotonin antagonists (cyproheptadine, chlorpromazine, methysergide) have also
been used for treatment. Most patients recover uneventfully, but there have been a few fatalities.

Table 1.7 Additive, synergistic or summation interactions

Following the first report of this syndrome, many other cases have been described involving
tryptophan and MAOIs, (p.1151), the tricyclic antidepressants and MAOIs, (p.1149), and, more
recently, the SSRIs, (p.1142) but other serotonergic drugs have also been involved and the list
continues to grow.

It is still not at all clear why many patients can take two, or sometimes several serotonergic drugs
together without problems, while a very small number develop this serious toxic reaction, but it
certainly suggests that there are as yet other factors involved that have yet to be identified. The full
story is likely to be much more complex than just the simple additive effects of two drugs.

2.2. Antagonistic or opposing interactions

In contrast to additive interactions, there are some pairs of drugs with activities that are opposed
to one another. For example the coumarins can prolong the blood clotting time by competitively
inhibiting the effects of dietary vitamin K. If the intake of vitamin K is increased, the effects of the
oral anticoagulant are opposed and the prothrombin time can return to normal, thereby cancelling
out the therapeutic benefits of anticoagulant treatment (see Coumarins and related drugs +
Vitamin K substances, p.458). Other examples of this type of interaction are listed in Table 1.8,
(see below).

Table 1.8 Opposing or antagonistic interactions

2.3. Drug or neurotransmitter uptake interactions

A number of drugs with actions that occur at adrenergic neurones can be prevented from reaching
those sites of action by the presence of other drugs. The tricyclic antidepressants prevent the re-
uptake of noradrenaline (norepinephrine) into peripheral adrenergic neurones. Thus patients taking
tricyclics and given parenteral noradrenaline have a markedly increased response (hypertension,
tachycardia); see Tricyclic antidepressants + Inotropes and Vasopressors, p.1237. Similarly, the
uptake of guanethidine (and related drugs guanoclor, betanidine, debrisoquine, etc.) is blocked by
chlorpromazine, haloperidol, tiotixene, (p.887), a number of amfetamine-like drugs, (p.886)
and the tricyclic antidepressants, (p.888) so that the antihypertensive effect is prevented. The
antihypertensive effects of clonidine are also prevented by the tricyclic antidepressants, one
possible reason being that the uptake of clonidine within the CNS is blocked (see Clonidine +
Tricyclic and related antidepressants, p.884). Some of these interactions at adrenergic neurones
are illustrated in Figure 1.5, (see below).

E. Drug-herb interactions

The market for herbal medicines and supplements in the Western world has markedly increased in
recent years, and, not surprisingly, reports of interactions with conventional drugs have arisen.
The most well known and documented example is the interaction of St Johns wort (Hypericum
perforatum) with a variety of drugs, see below. There have also been isolated reports of other
herbal drug interactions, attributable to various mechanisms, including additive pharmacological
effects.

Based on these reports, there are a growing number of reviews of herbal medicine interactions,
which seek to predict likely interactions based on the, often hypothesised, actions of various herbs.
Many of these predictions seem tenuous at best.

Rather than add to the volume of predicted interactions, at present, Stockleys Drug Interactions
includes only those interactions for which there are published reports.
Fig. 1.5 Interactions at adrenergic neurones. A highly simplified composite diagram of an
adrenergic neurone (molecules of noradrenaline (norepinephrine) indicated as () contained in a
single vesicle at the nerve-ending) to illustrate in outline some of the different sites where drugs
can interact. More details of these interactions are to be found in individual monographs.

To aid collection of data in this area, health professionals should routinely ask patients about their
use of herbal medicines and supplements, and report any unexpected responses to treatment.

An additional problem in interpreting these interactions, is that the interacting constituent of the
herb is usually not known and is therefore not standardised for. It could vary widely between
different products, and batches of the same product.

St Johns wort

An increasing number of reports have implicated St Johns wort (Hypericum perforatum) in drug
interactions. Evidence has shown that the herb can induce the cytochrome P450 isoenzyme
CYP3A4, and can also induce P-glycoprotein, (p.8). Hence St Johns wort decreases the levels
of ciclosporin, (p.1037) and digoxin, (p.927), respectively. Other less certain evidence suggests
that CYP2E1 and CYP1A2 may also be induced. St Johns wort has serotonergic properties, and
this has resulted in a pharmacodynamic interaction with the SSRIs, (p.1224), namely the
development of the serotonin syndrome. St Johns wort contains many possible constituents that
could be responsible for its pharmacological effects. The major active constituents are currently
considered to be hyperforin (a phloroglucinol) and hypericin (a naphthodianthrone). Hypericin is
the only constituent that is standardised for, and then only in some St Johns wort preparations.
F. Drug-food interactions

It is well established that food can cause clinically important changes in drug absorption through
effects on gastrointestinal motility or by drug binding, see Drug absorption interactions, (p.3). In
addition, it is well known that tyramine (present in some foodstuffs) may reach toxic
concentrations in patients taking MAOIs, (p.1153). With the growth in understanding of drug
metabolism mechanisms, it has been increasingly recognised that some foods can alter drug
metabolism. Currently, grapefruit juice causes the most clinically relevant of these interactions,
see (b) below.

(a) Cruciferous vegetables and charcoal-broiled meats

Cruciferous vegetables, such as brussels sprouts, cabbage, and broccoli, contain substances
that are inducers of the cytochrome P450 isoenzyme CYP1A2. Chemicals formed by
burning meats additionally have these properties. These foods do not appear to cause any
clinically important drug interactions in their own right, but their consumption may add
another variable to drug interaction studies, so complicating interpretation. In drug
interaction studies where alteration of CYP1A2 is a predicted mechanism, it may be better
for patients to avoid these foods during the study.
(b) Grapefruit juice
By chance, grapefruit juice was chosen to mask the taste of alcohol in a study of the effect
of alcohol on felodipine, which led to the discovery that grapefruit juice itself markedly
increased felodipine levels, see Calciumchannel blockers + Grapefruit juice, p.869. In
general, grapefruit juice inhibits intestinal CYP3A4, and only slightly affects hepatic
CYP3A4. This is demonstrated by the fact that intravenous preparations of drugs that are
metabolised by CYP3A4 are not much affected, whereas oral preparations of the same
drugs are. These interactions result in increased drug levels. Some drugs that are not
metabolised by CYP3A4 show decreased levels with grapefruit juice, such as
fexofenadine, (p.588). The probable reason for this is that grapefruit juice is an inhibitor
of some drug transporters (see Drug transporter proteins, (p.8)), and possibly affects
organic aniontransporting polypeptides (OATPs), although inhibition of P-glycoprotein
has also been suggested.
 The active constituent of grapefruit juice is uncertain. Grapefruit contains naringin, which
degrades during processing to naringenin, a substance known to inhibit CYP3A4. Because
of this, it has been assumed that whole grapefruit will not interact, but that processed
grapefruit juice will. However, subsequently some reports have implicated the whole fruit.
Other possible active constituents in the whole fruit include bergamottin and
dihydroxybergamottin

G. Conclusions

It is now quite impossible to remember all the known clinically important interactions and how
they occur, which is why this reference publication has been produced, but there are some broad
general principles that need little memorising:

Be on the alert with any drugs that have a narrow therapeutic window or where it is necessary to
keep serum levels at or above a suitable level (e.g. anticoagulants, antidiabetic drugs,
antiepileptics, antihypertensives, anti-infectives, antineoplastic cytotoxics, digitalis glycosides,
immunosuppressants, etc.).

Remember some of those drugs that are key enzyme inducers (e.g. phenytoin, barbiturates,
rifampicin, etc) or enzyme inhibitors (e.g. azole antifungals, HIV-protease inhibitors,
erythromycin, SSRIs).

Think about the basic pharmacology of the drugs under consideration so that obvious problems
(additive CNS depression for example) are not overlooked, and try to think what might happen if
drugs that affect the same receptors are used together. And dont forget that many drugs affect
more than one type of receptor.

Keep in mind that the elderly are at risk because of reduced liver and renal function on which
drug clearance depends.