gradually transfers the excess protamine zinc into
the soluble insulin, thus converting it intolente
insulin. Other examples include almost any drug
in blood or elemental foodstuffs. Also, heparin is
the most acidic drug in common usage, and it
chelates almost everything; for some reason peni-
cillins are reported as the most chelated combina-
tion in the infusion bag.
Site of absorption
There are common examples of both wanted and
unwanted drug interactions at the site of absorption.
Examples include activated charcoal/any overdose
(wanted), metoclopramide–naproxen (the absorp-
tion of the latter being hastened by the former for
improved efficacy when treating migraine acutely),
lipid or olefin fecal emulsifiers and fat-soluble vita-
mins (the latter being unabsorbed, an unwanted
interaction) and tetracyclines – calcium-containing
drugs (e.g. milk, an unwanted interaction because of
the calcium-chelating properties of tetracyclines).
Note that the epinephrine–lidocaine (adrenaline–
lignocaine) interaction can be both wanted or
unwanted; in most injection sites localized vasocon-
striction reduces the rate of systemic absorption,
prolongs local anesthesia and reduces the potential
for central nervous system adverse effects (i.e. a
wanted interaction). However, in tissues that form
a salient (fingers, toes, nose, ear pinna, penis) the
vasoconstrictor can cause necrosis because of the
absence of collateral circulation.
Drug distribution
Most of these drug interactions involve displace-
ment of drug from plasma proteins, thus increasing
the free/bound ratio for drug concentration. When
the free moieties are those that are pharmacologi-
cally active, then unexpectedly exaggerated
responses result from standard doses. Most (but
not all) such interactions are unwanted. Almost
any nonsteroidal anti-inflammatory drug (NSAID)
displaces warfarin, thus enhancingitsanticoagulant
effect and rendering the patient liable to unexpected
ecchymosis or more serious hemorrhagic adverse
events. Similarly unwanted are the interactions
between phenytoin and thyroxine (sedation and
thyrotoxicosis), and salicylates with tolbutamide
(hypoglycemia). Oral contraceptives compete for
albumin-binding sites, and phenytoin doses may
need to be adjusted when the former are introduced.
A rare example of a beneficial drug interaction at
this locus are the use of NSAIDs with some gluco-
corticoids, where enhanced anti-inflammatory
effects of the latter can result, even though a rela-
tively low dose has been administered.
Drug interactions at the site of actionare many-
fold and familiar. All receptor antagonists, when
used in the face of an agonist challenge, are clini-
cally desirable. Obvious examples include nalox-
one for opioid overdose and physostigmine for
reversal of tubocurarine in anesthesia. Note that
succinylcholine paralysis during anesthesia is only
made worse with anticholinesterase administration
(an adverse drug interaction at the receptor,
beloved by multiple-choice question setting exam-
iners!).
Sequential biochemistry interactions also fall
within this category. Sulfamethoxazole and tri-
methoprim inhibit different stages of the folate
metabolism pathway. Concomitant administration
reduces the probability that a bacterial strain can
mutate in any single step to evade the antibiotic
effects of both drugs.
Physiological interactions are a subset of site of
action interactions. Adding spironoloactone to fur-
osemide (frusemide) provides noextra diuresis, but
does antagonize the potassium loss that occurs
when the latter drug is used alone. Both progesta-
gens and estragens (progesterones and estragens)
such as ethinyl(o)estradiol and levonorgestrol inhi-
bit ovulation and uterine deciduation, thus being
positive or wanted interactions, albeit acting at
different receptors.
Unwanted interactions at the site of action clas-
sically include the highly undesirable concomitant
use of tetracyclines and penicillins. The latter are
bacteriocidal when the organism is dividing
because they obstruct cell wall manufacture, and
thus expose the new bacterial membrane to osmo-
tic destruction. Bacteriostatic compounds, such as
tetracyclines, reduce the rate of bacterial division
and thus reduce the effectiveness of penicillins.258 CH20 DRUG INTERACTIONS