A Textbook of Clinical Pharmacology and Therapeutics

(see Chapter 17) and ‘lifestyle’ drugs taken for social reasons.
The greater the number of drugs taken, the more likely things
are to go wrong (Figure 13.1).
Drug interactions can be useful, of no consequence, or
harmful.

USEFUL INTERACTIONS

INCREASED EFFECT

Drugs can be used in combination to enhance their effective-
ness. Disease is often caused by complex processes, and drugs
that influence different components of the disease mechanism
may have additive effects (e.g. an antiplatelet drug with a fibri-
nolytic in treating myocardial infarction, Chapter 29). Other
examples include the use of a β 2 agonist with a glucocorticoid in
the treatment of asthma (to cause bronchodilation and suppress
inflammation, respectively; Chapter 33).
Combinations of antimicrobial drugs are used to prevent
the selection of drug-resistant organisms. Tuberculosis is the
best example of a disease whose successful treatment requires
this approach (Chapter 44). Drug resistance via synthesis of a
microbial enzyme that degrades antibiotic (e.g. penicillinase-
producing staphylococci) can be countered by using a combi-
nation of the antibiotic with an inhibitor of the enzyme:
co-amoxiclavis a combination of clavulanic acid, an inhibitor
of penicillinase, with amoxicillin.
Increased efficacy can result from pharmacokinetic
interaction.Imipenem(Chapter 43) is partly inactivated by a
dipeptidase in the kidney. This is overcome by administering
imipenem in combination with cilastin, a specific renal
dipeptidase inhibitor. Another example is the use of the com-
bination of ritonavirandsaquinavirin antiretroviral therapy
(Chapter 46). Saquinavirincreases the systemic bioavailabil-
ity of ritonavir by inhibiting its degradation by gastro-
intestinal CYP3A and inhibits its faecal elimination by block-
ing the P-glycoprotein that pumps it back into the intestinal
lumen.
Some combinations of drugs have a more than
additive effect (‘synergy’). Several antibacterial combinations
are synergistic, including sulfamethoxazolewithtrimetho-
prim(co-trimoxazole), used in the treatment of Pneumocystis
carinii(Chapter 46). Several drugs used in cancer chemother-
apy are also synergistic, e.g. cisplatin plus paclitaxel
(Chapter 48).
Therapeutic effects of drugs are often limited by the acti-
vation of a physiological control loop, particularly in the case of
cardiovascular drugs. The use of a low dose of a second drug
that interrupts this negative feedback may therefore enhance
effectiveness substantially. Examples include the combination
of an angiotensin converting enzyme inhibitor (to block the
renin-angiotensin system) with a diuretic (the effect of which
is limited by activation of the renin-angiotensin system) in
treating hypertension (Chapter 28).

MINIMIZE SIDE EFFECTS

There are many situations (e.g. hypertension) where low

doses of two drugs may be better tolerated, as well as more

effective, than larger doses of a single agent. Sometimes drugs

with similar therapeutic effects have opposing undesirable

metabolic effects, which can to some extent cancel out when

the drugs are used together. The combination of a loop

diuretic (e.g. furosemide) with a potassium-sparing diuretic

(e.g.spironolactone) provides an example.

Predictable adverse effects can sometimes be averted by

the use of drug combinations. Isoniazidneuropathy is caused

by pyridoxine deficiency, and is prevented by the prophylac-

tic use of this vitamin. The combination of a peripheral dopa

decarboxylase inhibitor (e.g. carbidopa) with levodopa

permits an equivalent therapeutic effect to be achieved with a

lower dose of levodopa than is needed when it is used as a sin-

gle agent, while reducing dose-related peripheral side effects

of nausea and vomiting (Chapter 21).

BLOCK ACUTELY AN UNWANTED (TOXIC) EFFECT

Drugs can be used to block an undesired or toxic effect, as for

example when an anaesthetist uses a cholinesterase inhibitor

to reverse neuromuscular blockade, or when antidotes such

asnaloxoneare used to treat opioid overdose (Chapter 54).

Uses of vitamin K or of fresh plasma to reverse the effect of

warfarin(Chapter 30) are other important examples.

TRIVIAL INTERACTIONS

Many interactions are based on in vitro experiments, the

results of which cannot be extrapolated uncritically to the clin-

ical situation. Many such potential interactions are of no prac-

tical consequence. This is especially true of drugs with

shallow dose–response curves and of interactions that depend

on competition for tissue binding to sites that are not directly

involved in drug action but which influence drug distribution

(e.g. to albumin in blood).

SHALLOW DOSE–RESPONSE CURVES

Interactions are only likely to be clinically important when

there is a steep dose–response curve and a narrow therapeutic

window between minimum effective dose and minimum

toxic dose of one or both interacting drugs (Figure 13.2). This

is often not the case. For example, penicillin, when used in

most clinical situations, is so non-toxic that the usual dose is

more than adequate for therapeutic efficacy, yet far below that

which would cause dose-related toxicity. Consequently, a second

drug that interacts with penicillinis unlikely to cause either

toxicity or loss of efficacy.

72 DRUG INTERACTIONS