FURTHER READING
There is a very useful website for CYP450 substrates with inhibitors
and inducers: http://medicine.iupui.edu/flockhart/
British Medical Association and Royal Pharmaceutical Society of
Great Britain. British National Formulary54. London: Medical
Association and Royal Pharmaceutical Society of Great Britian,- (Appendix 1 provides an up-to-date and succinct alphabet-
ical list of interacting drugs, highlighting interactions that are
potentially hazardous.)
Brown HS, Ito K, Galetin A et al. Prediction of in vivo drug–drug inter-
actions from in vitro data: impact of incorporating parallel path-
ways of drug elimination and inhibitor absorption rate constant.
British Journal of Clinical Pharmacology2005; 60 : 508–18.
Constable S, Ham A, Pirmohamed M. Herbal medicines and acute
medical emergency admissions to hospital. British Journal of
Clinical Pharmacology2007; 63 : 247–8.
De Bruin ML, Langendijk PNJ, Koopmans RP et al. In-hospital cardiac
arrest is associated with use of non-antiarrhythmic QTc-prolonging
drugs. British Journal of Clinical Pharmacology2007; 63 : 216–23.
Fugh-Berman A, Ernst E. Herb–drug interactions: Review and assess-
ment of report reliability. British Journal of Clinical Pharmacology
2001; 52 : 587–95.
Hurle AD, Navarro AS, Sanchez MJG. Therapeutic drug monitoring
of itraconazole and the relevance of pharmacokinetic interactions.
Clinical Microbiology and Infection2006; 12 (Suppl. 7): 97–106.
Jackson SHD, Mangoni AA, Batty GM. Optimization of drug prescrib-
ing.British Journal of Clinical Pharmacology2004; 57 : 231–6.
Karalleidde L, Henry J. Handbook of drug interactions. London: Edward
Arnold, 1998.
Mertens-Talcott SU, Zadezensky I, De Castro WV et al.
Grapefruit–drug interactions: Can interactions with drugs be
avoided?Journal of Clinical Pharmacology2006; 46 : 1390–1416.
HARMFULINTERACTIONS 77Table 13.5:Competitive interactions for renal tubular transport
Primary drug Competing drug Effect of
interactionPenicillin Probenecid Increased penicillin
blood levelMethotrexate Salicylates Bone marrow
suppression
SulphonamidesSalicylate Probenecid Salicylate toxicity
Indometacin Probenecid Indometacin toxicity
Digoxin Spironolactone Increased plasma
Amiodarone digoxin
VerapamilKey points- There are three main types of adverse interaction:
- pharmaceutical;
- pharmacodynamic;
- pharmacokinetic.
- Pharmaceutical interactions are due to in vitro
incompatibilities, and they occur outside the body (e.g.
when drugs are mixed in a bag of intravenous solution,
or in the port of an intravenous cannula). - Pharmacodynamic interactions between drugs with a
similar effect (e.g. drugs that cause drowsiness) are
common. In principle, they should be easy to anticipate,
but they can cause serious problems (e.g. if a driver fails
to account for the interaction between an
antihistamine and ethanol). - Pharmacokinetic interactions are much more difficult to
anticipate. They occur when one drug influences the
way in which another is handled by the body:
(a) absorption(e.g. broad-spectrum antibiotics
interfere with enterohepatic recirculation of
oestrogens and can cause failure of oral
contraception);
(b) distribution– competition for binding sites seldom
causes problems on its own but, if combined with
an effect on elimination (e.g. amiodarone/digoxin
or NSAID/methotrexate), serious toxicity may
ensue;
(c) metabolism– many serious interactions stem from
enzyme induction or inhibition. Important
inducing agents include ethanol, rifampicin,
rifabutin, many of the older anticonvulsants,
St John’s wort, nevirapine and pioglitazone.
Common inhibitors include many antibacterial
drugs (e.g. isoniazid, macrolides, co-trimoxazole
and metronidazole), the azole antifungals,
cimetidine, allopurinol, HIV protease inhibitors;
(d) excretion(e.g. diuretics lead to increased
reabsorption of lithium, reducing its clearance
and predisposing to lithium accumulation and
toxicity).
Case history
A 64-year-old Indian male was admitted to hospital with mil-
iary tuberculosis. In the past he had had a mitral valve
replaced, and he had been on warfarin ever since. Treatment
was commenced with isoniazid, rifampicin and pyrazi-
namide, and the INR was closely monitored in anticipation of
increased warfarin requirements. He was discharged after
several weeks with the INR in the therapeutic range on a
much increased dose of warfarin. Rifampicin was subse-
quently discontinued. Two weeks later the patient was again
admitted, this time drowsy and complaining of headache
after mildly bumping his head on a locker. His pupils were
unequal and the INR was 7.0. Fresh frozen plasma was
administered and neurosurgical advice was obtained.
Comment
This patient’s warfarin requirement increased during treat-
ment with rifampicin because of enzyme induction, and
the dose of warfarin was increased to maintain anticoagu-
lation. When rifampicin was stopped, enzyme induction
gradually receded, but the dose of warfarin was not
readjusted. Consequently, the patient became over-anti-
coagulated and developed a subdural haematoma in
response to mild trauma. Replacment of clotting factors
(present in fresh frozen plasma) is the quickest way to
reverse the effect of warfarin overdose (Chapter 30).from urine (e.g. the excretion of salicylateis increased in an alka-
line urine). Such effects are used in the management of overdose
(Chapter 54).