A Textbook of Clinical Pharmacology and Therapeutics

PLASMA AND TISSUE BINDING SITE

INTERACTIONS

One large group of potential drug interactions that are seldom
clinically important consists of drugs that displace one
another from binding sites on plasma albumin or α-1 acid glyco-
protein (AAG) or within tissues. This is a common occurrence
and can readily be demonstrated in plasma or solutions of
albumin/AAG in vitro. However, the simple expectation that
the displacing drug will increase the effects of the displaced
drug by increasing its free (unbound) concentration is seldom
evident in clinical practice. This is because drug clearance
(renal or metabolic) also depends directly on the concentra-
tion of free drug. Consider a patient receiving a regular main-
tenance dose of a drug. When a second displacing drug is
commenced, the free concentration of the first drug rises only
transiently before increased renal or hepatic elimination
reduces total (bound plus free) drug, and restores the free con-
centration to that which prevailed before the second drug was
started. Consequently, any increased effect of the displaced
drug is transient, and is seldom important in practice. It must,
however, be taken into account if therapy is being guided by
measurements of plasma drug concentrations, as most such
determinations are of total (bound plus free) rather than just
free concentration (Chapter 8).
An exception, where a transient increase in free concentra-
tion of a circulating substance (albeit not a drug) can have dev-
astating consequences, is provided by bilirubin in premature
babies whose ability to metabolize bile pigments is limited.
Unconjugated bilirubin is bound by plasma albumin, and inju-
dicious treatment with drugs, such as sulphonamides, that
displace it from these binding sites permits diffusion of free

bilirubin across the immature blood–brain barrier, consequent

staining of and damage to basal ganglia (‘kernicterus’) and

subsequent choreoathetosis in the child.

Instances where clinically important consequences do

occur on introducing a drug that displaces another from

tissue binding sites are in fact often due to additional actions

of the second drug on elimination of the first. For instance,

quinidinedisplacesdigoxinfrom tissue binding sites, and

can cause digoxintoxicity, but only because it simultaneously

reduces the renal clearance of digoxinby a separate mech-

anism.Phenylbutazone(an NSAID currently reserved for

ankylosing spondylitis unresponsive to other drugs, Chapter

26) displaces warfarinfrom binding sites on albumin, and

causes excessive anticoagulation, but only because it also

inhibits the metabolism of the active isomer of warfarin

(S-warfarin), causing this to accumulate at the expense of the

inactive isomer. Indometacin(another NSAID) also displaces

warfarinfrom binding sites on albumin, but does not inhibit

its metabolism and does not further prolong prothrombin

time in patients treated with warfarin, although it can cause

bleeding by causing peptic ulceration and interfering with

platelet function.

HARMFUL INTERACTIONS

It is impossible to memorize reliably the many clinically

important drug interactions, and prescribers should use suit-

able references (e.g. the British National Formulary) to check

for potentially harmful interactions. There are certain drugs

with steep dose–response curves and serious dose-related tox-

icities for which drug interactions are especially liable to cause

HARMFULINTERACTIONS 73

Response

Dose

Therapeutic range Toxic range

Steep dose–response curve

Narrow therapeutic index

Adverse effect likely Adverse effect unlikely

Shallow dose–response curve

Wide therapeutic index

Therapeutic range Toxic range

Dose

Response

Figure 13.2:Drug dose–response curves illustrating likelihood of adverse effect if an interaction increases its blood level.