MeReC Bulletin Volume 10, Number 4, 1999 13
Contents: Drug interactions in general practice
NUMBER 4, 1999VOLUME 10
Drug interactions in general practice
An interaction occurs when the
effects of one drug are changed
by another drug, food, drink or
exposure to an environmental
However, not all
drug interactions are clinically
significant. This Bulletin
discusses drug interactions
and explores how they can be
managed in general practice.
What are drug interactions?
A drug interaction occurs when
two or more drugs interact in
such a way that the effectiveness
or toxicity of one or more of the
drugs is altered.2
can be harmful, either by in-
creasing the toxicity of a drug or
by reducing its efficacy. However,
some drug interactions can also
be beneficial; for example, an
additive effect is seen when
diuretics and beta-blockers are
combined to treat hypertension.
Are interactions a significant
problem in general practice?
It is not known exactly how
common drug interactions are.
Several studies in over 370,000
primary and secondary care
patients found that between
2.2% and 70.3% may be affected
by potential drug interactions.2
Up to 11.1% of patients actually
experienced symptoms that may
have been attributable to the
effects of an interaction.2
Drug interactions may cause
hospital admission, although
this may be relatively infrequent.
In one ten week study of 691
admissions, 68 (9.8%) were
drug related and three (0.4%)
were due to drug interactions.3
NATIONAL PRESCRIBING CENTRE
* Drug interactions occur when two or more drugs
interact in such a way that the effectiveness or toxicity
of one or more of the drugs is altered.
* Although not all drug interactions are clinically
significant, it is important to be alert for those that
are. A knowledge of the main types of drugs that are
more likely to be involved will act as a useful alert.
* Drugs most likely to be involved in interactions are
those with a narrow margin between the therapeutic
and toxic dose, those requiring careful dosage control
and those which either induce or inhibit liver enzymes.
Over-the-counter or herbal products may also interact
with prescribed medicines.
* The effect and severity of drug interactions may vary
considerably from one patient to another. Elderly
patients and those taking multiple medications are
particularly susceptible to drug interactions.
* Interactions are most likely when an interacting drug
is being introduced or stopped. However, the time
course of interactions can vary, depending, for
example, on the half-lives of the drugs involved.
* If the potential hazards of starting an interacting drug
outweigh the benefits, an alternative drug should be
chosen if possible. Other courses of action include
adjusting the dose of one or both drugs when an
interacting drug is stopped or started. Monitoring the
patient may be necessary, where practical.
* It is important to report any suspected drug
interactions involving newly introduced products (J),
to the Committee on Safety of Medicines (CSM).
The MeReC Bulletin is produced
by the NHS for the NHS
14 MeReC Bulletin Volume 10, Number 4, 1999
Absorption Protein binding Metabolic Renal
Rate Extent Free Bound Enzyme Enzyme Excretion Excretion
drug drug induction inhibition increased decreased
Displacement Decreased Increased Decreased Increased
interactions levels levels levels levels
What mechanisms are involved?
Drug interactions often occur by
more than one mechanism at the
same time. They are not always
easy to predict.
are those where the effects of one
drug are changed by another at
the site of action.1
occur when two drugs with the
same pharmacological effects
are given together. For example,
the concurrent use of alcohol
with benzodiazepines may cause
an enhanced sedative effect.
Conversely, antagonism occurs
when interacting drugs have
affect the processes by which
drugs are absorbed, distributed,
metabolised or excreted.1
There are several types of
(see below and figure 1).
Antacids and binding agents
such as cholestyramine may
impair absorption of other drugs
from the gastrointestinal tract by
forming complexes with them.
For example, antacids reduce
the absorption of quinolones
such as ciprofloxacin. Other
drugs, such as metoclopramide
or opiates, may affect gut transit
time. This generally influences
the rate, rather than the extent,
of drug absorption. Most absorp-
tion interactions are not clinically
significant and can be managed
by separating the administration
of the drugs.
Drug displacement interactions
occur when two drugs compete
for the same protein binding
site and one or both is displaced.
This results in an increase in
the concentration of free (active)
drug, but is usually compensated
for by an increase in excretion.
These interactions usually involve
highly protein bound drugs such
as phenytoin, warfarin and
tolbutamide. However, the effects
of displacement interactions are
usually minor and transient.
Many drugs are metabolised
in the liver, mainly by the
cytochrome P450 enzyme
system. Induction of enzymes by
one drug can increase the rate of
metabolism of another, resulting
in a reduced effect. Conversely,
enzyme inhibitors may result in
accumulation and increased
toxicity of other drugs (table 1).
Finally, drugs that alter renal
excretion can affect plasma levels
of other drugs. For example,
methotrexate and non-steroidal
anti-inflammatory drugs compete
for renal excretion. Concomitant
use of these agents may result in
raised methotrexate levels and
an increased risk of toxicity,
although this combination may
be used successfully under
specialist supervision. The
importance of this type of inter-
action depends on the extent
to which a drug and/or its
metabolites are renally excreted.
Which patients are likely to be
The effect and severity of
drug interactions may vary
considerably from one patient to
another. Various factors can
affect patient susceptibility to
Elderly patients may be
at increased risk of drug
interactions, as they are more
likely to be taking multiple
drugs and may have impaired
renal and hepatic function.
Genetic characteristics may
also affect some interactions;
for example, grapefruit juice
may inhibit the metabolism of
terfenadine, possibly increasing
the risk of cardiotoxicity.4
However, this only appears
to be important in the small
number of patients who are
poor metabolisers of terfenadine.
Both the disease being treated,
and any concomitant disease can
influence drug interactions. For
example, although diuretics may
reduce lithium excretion, patients
can be successfully stabilised on
the combination. However, any
subsequent illness affecting fluid
and electrolyte balance may alter
lithium levels, causing either loss
of effect or toxicity.
The importance of a drug
interaction may also depend
upon the patient's pre-existing
clinical status. For example,
plasma concentrations of digoxin
may be increased by diltiazem
and verapamil. If digoxin levels
are low before one of these drugs
is started, the interaction could
produce beneficial effects.
However, if levels are within
or above the therapeutic
range when the interacting
drug is introduced, digoxin
toxicity may result.
MeReC Bulletin Volume 10, Number 4, 1999 15
When are interactions most likely
Drug interactions are most
likely when an interacting drug
is being introduced, or when
it is stopped. The time course
of an interaction can vary
depending on the dosage, route
of administration, importance
of active metabolites and the
half-lives of the drugs involved
(particularly the drug that has
been recently started). For
example, amiodarone and
monoamine oxidase inhibitors
have very long half-lives and the
effects of interactions involving
these drugs can persist for
weeks after therapy has been
introduced or discontinued.
The mechanism of an interaction
can also have an effect on its
stimulate the production of new
metabolising enzymes and it
often takes between one and
three weeks before their effects
are at a maximum. In contrast,
enzyme inhibitors usually have
an effect on hepatic metabolism
within 24 hours.
The time course of interactions
may also be affected when drugs
are given ‘as required’, since
patients will take different
quantities at different times,
depending on their requirements.
Which interactions are
Not all drug interactions are
clinically significant. Some are
theoretical, while others require
either avoidance of a combination
of drugs or careful monitoring.
Many potentially harmful drug
interactions occur only in a small
proportion of patients. For
example, the risk of terfenadine
and astemizole prolonging the
QT interval and causing cardiac
arrhythmias may be increased
when they interact with other
drugs. Only a few patients are
affected at therapeutic doses, but
the interactions are potentially
in those with QT prolongation
or electrolyte imbalances.
There are various classes of
drugs that are likely to be
involved in clinically significant
drug interactions (see table 1).
Drugs which have a narrow
margin between the therapeutic
and toxic dose, those that require
careful dosage control and those
which either induce or inhibit
liver enzymes are often involved.
Many substances involved in
interactions may not be thought
of as drugs by the public. It is
important to remember that
patients may be taking over-
the-counter or herbal products
which could have the potential to
interact with prescribed drugs.
What action should be taken?
The first step in managing drug
interactions is to be aware of
patients taking potentially inter-
acting drugs. It is then necessary
to assess the clinical significance
of the interaction and find the
patients actually at risk. Various
steps can then be taken to
minimise any potential adverse
effects (see table 2).
Avoid the combination
If the potential hazards of adding
an interacting drug outweigh
the benefits, an alternative drug
should be chosen. However,
if there is no alternative to the
new drug, then the existing
therapy may occasionally
need to be changed.
The choice of an alternative agent
may depend on whether or
not an interaction is a class
effect. For example, cimetidine is
more likely to cause interactions
than other H2
because it is an enzyme inducer.
Conversely, most interactions
involving loop and thiazide
diuretics are due to their diuretic
and hypotensive effects. Although
these drugs may have different
mechanisms of action and
potencies, they all have the
potential to exert these effects
to some extent.
Adjust the dose
If the net effect of an interaction
is to increase or reduce the effect
of a drug, then modification of
the dose of one or both drugs
may compensate for this. Dose
modification may be necessary
when an interacting drug is
started or stopped.
If an interaction is relatively
minor and there are no
predisposing patient factors,
dose adjustment may not be
necessary. In addition, if the
interaction is rare or theoretical,
it may not be appropriate to
adjust the dosage in most
patients taking the drugs.
If an interacting combination of
drugs is used, then monitoring
may be required, if practical.
The decision around whether
or not to monitor depends
on various factors such as
concomitant diseases, the
timing of introduction of the
interacting drug and the
expected time course of
• may be needed when starting or
• if interacting drugs are the optimal
therapy for a condition or if the
Table 1. Some drugs likely to be involved
Drugs with a narrow therapeutic
16 MeReC Bulletin Volume 10, Number 4, 1999
The National Prescribing Centre, The Infirmary, 70 Pembroke Place, Liverpool, L69 3GF.
Telephone: 0151-794 8146/8140/8143/8145 Fax: 0151-794-8139/44
Date of preparation: June 1999
1 Stockley IH. Chapter 1, General considerations
and an outline survey of some basic interaction
mechanisms. In: Drug interactions, 4th Ed.
The Pharmaceutical Press, London 1996; 1-15
2 Jankel CA, Speedie SM. Detecting drug
interactions: a review of the literature. Ann
Pharmacother 1990; 24: 982-989
3 Stanton LA, Peterson GM, et al. Drug-related
admissions to an Australian hospital. J Clin
Pharm Ther 1994; 19: 341-347
4 Stockley IH. Chapter 24, Miscellaneous drug
interactions. In: Drug interactions, 4th Ed. The
Pharmaceutical Press, London 1996; 900
5 Anastasio GD, Cornell KO, Menscer D. Drug
interactions: keeping it straight. Clinical
Pharmacology 1997; 56: 883-894
Monitoring may involve:
• Clinical monitoring to detect
any adverse effects, either
by examining the patient
or by warning them about
• Measurement of drug levels,
if appropriate monitoring
facilities are available and if
the potential danger from
the interaction justifies it.
• Measurement of markers
for an interaction, such as
international normalised ratio
(INR) for oral anticoagulants.
Continue medication as before
If an interaction is not clinically
significant, or if interacting
drugs are the optimal therapy
for a condition, the patient's
medication may be continued
unchanged. It may be useful to
document the reasons for this
in the patient's notes.
Report the interaction
There may be few data on drug
interactions of newly licensed
drugs, as only around 1,500
patients will have taken the drug
during clinical trials. Mibefradil
(Posicor; Roche) was voluntarily
withdrawn worldwide in 1998
due to reports of serious
interactions with other drugs.
The extent of the problem only
became apparent post-launch.
It is important to report any
suspected drug interactions
involving new products (J), or
serious interactions involving
established products, to the
Committee on Safety of
Sources of information on drug
The most widely available source
of information on interactions is
appendix 1 of the British National
Formulary (BNF), where the
symbol • denotes those that are
potentially hazardous. However,
few data are available on the
background to the interaction,
which can range from a large
clinical trial to a case-report.
The electronic version of the BNF
is also useful for searching for
information on specific drugs.
Other resources include drug
information centres, which
often hold specialist textbooks
on drug interactions. Community
pharmacists are another valuable
resource, especially on interac-
tions involving over-the-counter
drugs. Most pharmacy and GP
computer systems will also flag
Although not all drug
interactions are clinically
significant, it is important to
be alert for those that are. It is
impossible to remember all the
known important drug interac-
tions. However, a knowledge of
the main types of drugs that are
more likely to be involved will act
as a useful alert when prescrib-
ing. In addition, it is important to
remember that various groups
such as the elderly are more
susceptible to drug interactions.
Application of these principles
should reduce serious drug
interactions when prescribing.
with permission from an
article published in Medicines
Resource, by the Information
and Statistics Division of the
Common Services Agency,
NHS in Scotland.
After successful piloting of the
scheme from 1994, community
nurse prescribing is being
introduced in England. This is
based on the recommendations
of the 1989 Crown Report on
improving nursing care in
Nurses working in community
NHS Trusts or as practice
nurses, and who hold the Health
Visitor or District Nurse qualifica-
tions (or equivalents), and who
have completed an approved
training course are entitled to
prescribe from a limited Nurse
Prescribers’ Formulary (NPF).
Nurse prescribing should be
fully implemented by mid-2001,
when around 26,000 nurses
will be qualified to prescribe.
The NPF consists of a list of
drugs, dressings and appliances
published as an appendix of the
British National Formulary. Most
of the products can be purchased
from pharmacies, although a few
are prescription-only medicines.
Nurse prescribing is intended to
be substitute, not additional,
prescribing as it will mainly
involve those products histori-
cally prescribed by GPs at the
request of nurses. This aims
to legitimise existing practice,
resulting in more effective
patient care and better use of
GP, nurse and patient time. As
a result, part of GPs’ unified
budgets have been allocated
to nurse prescribing.
To aid newly qualified nurse
prescribers in England, the
National Prescribing Centre is
currently publishing a series of
educational support materials.
Seven Prescribing Nurse bulletins
(see panel) will be sent to all
qualified nurse prescribers. All of
these bulletins will be available
by the end of October 1999. They
are also available to browse or
download from the Internet and