A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

HARMFUL INTERACTIONS 73
Response
Response
Dose
Dose
Therapeutic range
Toxic range
Therapeutic range
Toxic range
Steep dose–response curve
Narrow therapeutic index
Shallow dose–response curve
Wide therapeutic index
Adverse effect likely
Adverse effect unlikely
Figure 13.2: Drug dose–response curves illustrating likelihood of adverse effect if an interaction increases its blood level.
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 glycoprotein
(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 concentration
of free drug. Consider a patient receiving a regular maintenance
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 concentration
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 concentration
of a circulating substance (albeit not a drug) can have devastating
consequences, is provided by bilirubin in premature
babies whose ability to metabolize bile pigments is limited.
Unconjugated bilirubin is bound by plasma albumin, and injudicious
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,
quinidine displaces digoxin from tissue binding sites, and
can cause digoxin toxicity, but only because it simultaneously
reduces the renal clearance of digoxin by a separate mechanism.
Phenylbutazone (an NSAID currently reserved for
ankylosing spondylitis unresponsive to other drugs, Chapter
26) displaces warfarin from 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
warfarin from 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 suitable
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 toxicities
for which drug interactions are especially liable to cause