Drug Interactions

DRUG INTERACTIONS

SUMMARY

+ A drug interaction occurs when the effect of one drug is altered by the presence
of another drug, food, drink or environmental agent.

+ Risk factors for drug interaction occurrence include drugs with a narrow
therapeutic index, patient age and genetic characteristics.

+ Information sources on drug interactions include the BNF, Stockley’s Drug
Interactions and the NMIC.

INTRODUCTION
A drug interaction is a pharmacological response which cannot be explained by the
action of a single drug but may be due to two or more drugs acting simultaneously but
The effects of a drug may also be changed by the presence of food, drink or by some
environmental chemical agent. The outcome of a drug interaction may be harmful if
the interaction results in increased efficacy or toxicity of one or more drugs.
However, reduction in efficacy due to a drug interaction can sometimes be just as
harmful.
1,2
The clinical relevance of drug interactions is evident when one considers
that up to 8% of hospital admissions are due to adverse drug reactions and over 20%
of these are due to drug interactions.
3
The incidence of drug interactions is difficult to
quantify as this may depend on the “clinical significance” of the interaction.
1

However the greater the number of drugs taken inevitably increases the risk of a drug
interaction occurring.
1


RISK FACTORS FOR DRUG INTERACTIONS
Several factors may increase the likelihood of a clinically significant drug interaction
and include:

a) Drugs with a narrow therapeutic index i.e where a small margin exists between
therapeutic and toxic drug levels. (Table 1) For other drugs with a wide
therapeutic index e.g penicillins and many benzodiazepines, a 20-50% change in
concentration may not have clinical sequelae.

Table 1: Commonly Prescribed Drugs With a Narrow Therapeutic Index
4


Drug

Initial Signs of Toxicity
Digoxin

Nausea, vomiting, loss of appetite
Lithium Drowsiness, slurred speech, tremor,
loss of appetite, nausea and vomiting,
diarrhoea
Phenytoin Unsteadiness, blurred vision,
dizziness, drowsiness, stuttering,
slurred speech
Theophylline Nausea, loss of appetite, tremor - less
severe effects don’t always precede
more serious effects e.g. tachycardia,
seizures, ventricular arrhythmias
Warfarin Bruising, bleeding

Tricyclic antidepressants

Fast, slow or irregular heartbeat

b) High risk patients. The patient characteristic which has the most bearing on drug
interactions is age. Certain patient groups e.g. the elderly may have an increased
risk of suffering a clinically significant drug interaction due to polypharmacy. It is
estimated that for patients taking 2-5 drugs daily the incidence of a potential drug
interaction is 19%. This rises to over 80% for those taking 6 or more drugs.
5

Renal or in particular, hepatic impairment, either age-related or otherwise may
affect the ability to metabolise drugs.
4,6,7
Patients with severe underlying disease
may be less tolerant of changes in plasma concentration of their therapy.
4
The
disease being treated and any concomitant diseases may also influence drug
interactions as can the patients pre-existing clinical status.
2


c) Genetic characteristics relating to approximately 10% of the population, may
affect some drug interactions e.g. grapefruit juice and terfenadine resulting in an
increased risk of cardiotoxicity. This appears only to be important in the small
number of patients who are poor metabolisers of terfenadine.
2
This risk factor may
also explain the propensity of warfarin and tricyclic antidepressants to cause
problems.

CLASSIFICATION AND MECHANISM OF DRUG INTERACTIONS
Drug interactions may be classified by their mechanism and usually involve one of
two processes namely pharmacodynamic or pharmacokinetic.
4


Pharmacodynamic Interactions
Pharmacodynamic interactions occur when two drugs have either equal (additive)
pharmacological effects e.g. alcohol and tricyclic antidepressants or opposing
(antagonistic) pharmacological effects e.g beta-blockers and beta-2-agonists. These
interactions may also occur if electrolyte levels are altered e.g. diuretics and
digoxin.
2,4,6,8,9
Pharmacodynamic interactions may manifest without alterations in the
serum concentration or pharmacokinetics of the interacting drugs. These interactions
can often be predicted and monitored successfully by the clinician provided that they
have knowledge of the drugs mechanism of action and pharmacological effects.

Pharmacokinetic Interactions
Pharmacokinetic drug interactions are the drug interactions most often reported in the
literature. These drug interactions are more complicated and may not be as easily
predicted. Many of them affect only a small proportion of patients taking a
combination of drugs.
4,9
Pharmacokinetic drug interactions occur when one drug
alters the absorption, distribution, metabolism or excretion of another drug, this can
either decrease or increase plasma concentration of the interacting drug(s). As a
result therapeutic failure or enhancement or emergence of toxic effects may occur.
2,6,7,8,9

Pharmacokinetic drug interactions which occur with one drug cannot be assumed to
occur with drugs in the same class unless their pharmacokinetic properties are
similar.
9
Pharmacokinetic interactions may be of the following types:

• Absorption interactions e.g. binding interactions may result in a reduction in the
rate and/or the extent of absorption e.g formation of a complex between quinolone
antibiotics and antacids or between tetracycline and sodium bicarbonate antacids.
1,2,6

Delayed absorption is rarely of clinical significance unless high peak plasma
concentrations are required e.g. in analgesia.
9
Most of these interactions can be
managed by separating the administration of the interacting drugs.

• Distribution interactions involve competition between two drugs for binding sites
on plasma proteins or tissues. One or both may be displaced resulting in an
increase in the concentration of free (active) drug. These interactions are
uncommon and are likely to produce only a detectable increase in effect if the drug
is extensively protein bound (more than 90%) e.g warfarin and aspirin.
2,8,9


• Pharmacokinetic interactions through metabolic processes occur primarily in the
liver. Many drugs are metabolised in the liver mainly by the Cytochrome (CY)
P450 enzyme system. It is now appreciated that the CYP450 system comprises a
family of isoenzymes with at least fifteen human liver isoenzymes involved with
CYP1A2, CYP3A, CYP2D6, CYP2C9 and CYP2C19 responsible for the
metabolism of the majority of drugs
10
(Table 2). Some drugs activate this enzyme
system (induction) e.g carbamazepine, phenytoin, rifampicin thus increasing the
metabolism of other drugs e.g oestrogens, cyclosporin. This may result in a
reduced effect. The converse may occur with drugs which are enzyme inhibitors
e.g. cimetidine, ciprofloxacin, erythromycin, ketoconazole.
1,2,8,9
If two drugs
metabolised by the same isoenzyme are co-administered then the concentration of
one or both drugs may be increased e.g. patients receiving theophylline or
carbamazepine may experience drug toxicity when co-prescribed cimetidine.

Table 2: Some Drugs that are Metabolised by, Inhibit or Induce Cytochrome
P450 isoenzymes
1,11,12,13



Cytochrome P450
Isoenzyme
Drugs
Metabolised
Inhibitors Inducers
CYP1A2

Theophylline
Imipramine
Cimetidine
Ciprofloxacin
Fluvoxamine
Grapefruit juice
Phenytoin
CYP2D6 Fluoxetine
Codeine
Venlafaxine
Haloperidol
Paroxetine
Thioridazine
Phenobarbitone
CYP2C9

Diclofenac
Phenytoin
Warfarin
Fluconazole
Fluvoxamine
Fluoxetine
Ritonavir
Barbiturates
Rifampicin
CYP2C19 Diazepam
Omeprazole
Fluoxetine
Fluvoxamine
Omeprazole
Phenytoin
CYP3A4 Carbamazepine
Cyclosporin
Cisapride
Erythromycin
Terfenadine
Cimetidine
Erythromycin
Itraconazole
Fluvoxamine
Ritonavir
Carbamazepine
Phenytoin
Rifampicin
Barbiturates
Miconazole

• Pharmacokinetic drug interactions by renal excretion mostly involve reduced
excretion of one drug leading to increased plasma levels and possible toxicity e.g.
methotrexate and NSAIDs, lithium and diuretics.
2
The precise mechanism is often
unknown but may involve competition between those drugs that share active
transport mechanisms in the proximal tubule.
8,9


WHEN ARE DRUG INTERACTIONS MOST LIKELY TO OCCUR?
The possibility of a drug interaction should be considered when a drug is being
introduced and when it is being withdrawn. The time course of the interaction is
variable depending on factors such as the half life of the drugs involved (especially
the half-life of the drug whose metabolism is inhibited), dosage, route and presence of
active metabolites. The mechanism of an interaction can also have an effect on its
time course.
6
Enzyme inducers e.g. phenobarbitone, warfarin, stimulate the
production of new metabolising enzymes and it frequently takes one to three weeks
before their effects are at a maximum. In contrast enzyme inhibitors may have an
effect on hepatic metabolism within 24 hours.
2
Some interactions therefore occur
almost immediately while others may take days, weeks or even months to develop.
Other interactions tend to dissipate with time even when therapy is continued with the
two interacting drugs e.g long term broad spectrum antibiotics and the oral
contraceptive pill. Thus if the drug interaction is evaluated at the wrong time one
may falsely conclude that an interaction does not exist e.g amiodarone interaction
with warfarin.
1,8
The time course of interactions becomes even more complex when
drugs are given on an “as required” basis since the frequency and timing of doses can
be highly variable between patients.
6


Table 3: Commonly Encountered Drug Interactions
1,9,14,15


Interacting Drug Interacting Drug Mechanism of
Interaction
Outcome/Action
Erythromycin Theophylline Possible inhibition of
theophylline
metabolism
↑theophylline levels.
May take several days
to manifest
Erythromycin/
Clarithromycin
Cisapride Inhibition of cisapride
metabolism via
CYP3A4
Prolongation of QT
interval. Risk of
arrythmias. Concurrent
use should be avoided
Warfarin NSAIDs Unknown but possibly
involves drug
displacement
↑risk of bleeding.
Unpredictable &
occasionally serious
∴monitor concurrent
use
Warfarin Antibacterials Effects on warfarin
metabolism
e.g.erythromycin,
independent effects on
clotting systems or
effects on Vit.K
synthesising bacteria in
gut e.g. broad spectrum
antibiotics

↑ anticoagulant effects
of warfarin ∴
increased risk of
bleeding
Combined Oral
Contraceptive
Broad Spectrum
antibiotics e.g
ampicillin
Impairment of bacterial
flora responsible for
recycling oestrogen
↓ contraceptive
efficacy. Observe “7
day rule”

HOW TO MANAGE DRUG INTERACTIONS?
Four steps are involved in managing a drug interaction.
• Avoid the combination - if the potential hazards of the interaction outweigh the
benefits then choose an alternative drug if available.
• Adjust the dose - if the effects of the interaction are an increase or decrease in the
drug’s effect then a dosage modification may compensate for this. This may be
needed when starting and stopping two interacting drugs.
• Monitor the patient - if interacting drugs are used the patient should be closely
monitored for signs of toxicity, adverse effects, reduction in efficacy or where
possible plasma concentration.
• Continue medication as before - if interacting drugs are the optimal therapy for a
condition or if the interaction is not clinically significant.
2,6,7


SOURCES OF INFORMATION ON DRUG INTERACTIONS
Table 4 provides examples of some of the more commonly encountered drug
interactions. Further information on clinically significant drug interactions can be
obtained from the following sources:

• British National Formulary (BNF)
• Summary of Product Characteristics / Data Sheet Compendium
• Martindale - The Complete Drug Reference
• Drug Interactions, Stockley
• National Medicines Information Centre (NMIC)

REFERENCES
1. Stockley, Drug Interactions, 5
th
Ed,
Pharmaceutical Press, London 1999
8. Koda Kimble, Applied Therapeutics 6
th
Edn
9. BNF 2000 No.39
2. MeReC 1999;10(4):13-16
3. Drug Safety 2000;22(2):161-8
4. Aust P’cist 1994 (J uly):419-425
5. Textbook of Clinical Pharmacology, 1986,
Gillies, Rogers (Eds), Hodder&Staughton:190-99
6. SMRC 1999;54:211-214
7. Aust P’cist 1994 (Aug):489-495
10. Clin P’cokinetic 1997;32(3):210-258
11. Postgrad Med 1999;105(2):193-222
12. P’cotherapy 1995;15:84s-99s
13. Aust P’cist 2000;19(1):38-46
14. SMRC 1999;55:215-218
15. Aust P’cist 2000;19(2):113-118