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

74 DRUG INTERACTIONS
harm (Figure 13.2), and where special caution is required with
concurrent therapy. These include:
• warfarin and other anticoagulants;
• anticonvulsants;
• cytotoxic drugs;
• drugs for HIV/AIDS;
• immunosuppressants;
• digoxin and other anti-dysrhythmic drugs;
• oral hypoglycaemic agents;
• xanthine alkaloids (e.g. theophylline);
• monoamine oxidase inhibitors.
The frequency and consequences of an adverse interaction
when two drugs are used together are seldom known precisely.
Every individual has a peculiar set of characteristics
that determine their response to therapy.
RISK OF ADVERSE DRUG INTERACTIONS
In the Boston Collaborative Drug Surveillance Program, 234 of
3600 (about 7%) adverse drug reactions in acute-care hospitals
were identified as being due to drug interactions. In a smaller
study in a chronic-care setting, the prevalence of adverse
interactions was much higher (22%), probably because of
the more frequent use of multiple drugs in elderly patients
with multiple pathologies. The same problems exist for the
detection of adverse drug interactions as for adverse drug
reactions (Chapter 12). The frequency of such interactions will
be underestimated by attribution of poor therapeutic outcome
to an underlying disease. For example, graft rejection following
renal transplantation is not uncommon. Historically, it
took several years for nephrologists to appreciate that epileptic
patients suffered much greater rejection rates than did nonepileptic
subjects. These adverse events proved to be due to an
interaction between anticonvulsant medication and immunosuppressant
cortico-steroid therapy, which was rendered ineffective
because of increased drug metabolism. In future, a
better understanding of the potential mechanisms of such
interactions should lead to their prediction and prevention by
study in early-phase drug evaluation.
SEVERITY OF ADVERSE DRUG INTERACTIONS
Adverse drug interactions are diverse, including unwanted
pregnancy (from failure of the contraceptive pill due to concomitant
medication), hypertensive stroke (from hypertensive
crisis in patients on monoamine oxidase inhibitors), gastrointestinal
or cerebral haemorrhage (in patients receiving warfarin),
cardiac arrhythmias (e.g. secondary to interactions
leading to electrolyte disturbance or prolongation of the QTc)
and blood dyscrasias (e.g. from interactions between allopurinol
and azathioprine). Adverse interactions can be severe. In
one study, nine of 27 fatal drug reactions were caused by drug
interactions.
Key points
• Drug interactions may be clinically useful, trivial or
adverse.
• Useful interactions include those that enable efficacy to
be maximized, such as the addition of an angiotensin
converting enzyme inhibitor to a thiazide diuretic in a
patient with hypertension inadequately controlled on
diuretic alone (see Chapter 28). They may also enable
toxic effects to be minimized, as in the use of
pyridoxine to prevent neuropathy in malnourished
patients treated with isoniazid for tuberculosis, and
may prevent the emergence of resistant organisms
(e.g. multi-drug regimens for treating tuberculosis, see
Chapter 44).
• Many interactions that occur in vitro (e.g. competition
for albumin) are unimportant in vivo because
displacement of drug from binding sites leads to
increased elimination by metabolism or excretion and
hence to a new steady state where the total
concentration of displaced drug in plasma is reduced,
but the concentration of active, free (unbound) drug is
the same as before the interacting drug was
introduced. Interactions involving drugs with a wide
safety margin (e.g. penicillin) are also seldom clinically
important.
• Adverse drug interactions are not uncommon, and can
have profound consequences, including death from
hyperkalaemia and other causes of cardiac dysrhythmia,
unwanted pregnancy, transplanted organ rejection, etc.
ADVERSE INTERACTIONS GROUPED BY
MECHANISM
PHARMACEUTICAL INTERACTIONS
Inactivation can occur when drugs (e.g. heparin with gentamicin)
are mixed. Examples are listed in Table 13.1. Drugs may
also interact in the lumen of the gut (e.g. tetracycline with
iron, and colestyramine with digoxin).
PHARMACODYNAMIC INTERACTIONS
These are common. Most have a simple mechanism consisting
of summation or opposition of the effects of drugs with,
respectively, similar or opposing actions. Since this type of
interaction depends broadly on the effect of a drug, rather
than on its specific chemical structure, such interactions are
non-specific. Drowsiness caused by an H 1 -blocking antihistamine
and by alcohol provides an example. It occurs to a
greater or lesser degree with all H 1 -blockers irrespective of the
chemical structure of the particular drug used. Patients must
be warned of the dangers of consuming alcohol concurrently
when such antihistamines are prescribed, especially if they
drive or operate machinery. Non-steroidal anti-inflammatory
agents and antihypertensive drugs provide another clinically
important example. Antihypertensive drugs are rendered less
effective by concurrent use of non-steroidal anti-inflammatory
drugs, irrespective of the chemical group to which they
belong, because of inhibition of biosynthesis of vasodilator
prostaglandins in the kidney (Chapter 26).