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The first international symposium on drug interactions was held 50 years ago, triggered in part by the effect cheese was having on MAOIs.

“IT ALL BEGAN WITH CHEESE,” Folke Sjöqvist, professor emeritus, department of clinical pharmacology at Karolinska University, Sweden, recalled during a recent meeting at the Royal Society of Medicine (RSM).

During the late 1950s, researchers assessing iproniazid for tuberculosis reported that patients taking this monoamine oxidase inhibitor (MAOI) showed “striking” psychological changes – in particular greater vitality. Iproniazid was found to engender a party mood and dancing even among people critically ill with tuberculosis and produced similar moodenhancing effects in patients with other chronic illnesses, including rheumatoid arthritis and cancer.

By 1957, psychiatrists had confirmed that iproniazid alleviated clinical depression. Despite being marketed for tuberculosis only, within a year more than 400,000 depressed people had received iproniazid. Other MAOIs, including isocarboxazid, tranylcypromine and phenelzine, soon followed.

Achilles heel

However, early MAOIs had an Achilles heel: the ‘cheese effect’. Cheese and several other foods – including yeast products, liver, snails, pickled herrings, red wines, some beers, tinned figs, broad beans and chocolate – contain high levels of the amino acid tyramine, which monoamine oxidase (MAO) degrades. The high blood levels of tyramine that arose from MAO inhibition in people eating these foods potentially provoked hypertensive crises.

The cheese effect and other interactions with MAOIs was a “complete surprise” and “a major reason for arranging the first international symposium on drug interactions 50 years ago,” Professor Sjöqvist, who attended that first meeting, commented during his introduction to the RSM’s anniversary conference earlier this year.

Body of evidence

Since then, a vast body of evidence has accumulated on drug interactions. Professor Sjöqvist noted that the number of papers examining drug interactions increased from 320 in 1965 to 44,000 in 2010. How many of the interactions identified are clinically relevant is, however, a moot point. Yet despite this wealth of research, some important information is missing.

Currently, Pubmed contains more than 200,000 references on drug interactions, which form the basis of the databases that healthcare professionals use to prescribe safely. However, as Professor Sjöqvist noted, “databases only contain pairs of drugs when, in clinical reality, many patients, particularly the elderly, often use five or more drugs simultaneously”.

Many patients on polypharmacy are at risk of a serious drug-drug interaction (DDI). Munir Pirmohamed, holder of the David Weatherall chair of medicine at the University of Liverpool, highlighted a Slovakian study at the University Medical Centre Ljubljana that enrolled 323 randomly selected patients. Of these, 51 per cent had potential DDIs on admission and 63 per cent on discharge. Thirteen and 18 per cent respectively had major DDIs.

Furthermore, DDIs accounted for 1.2 per cent of admissions. “This is a big figure considering the number of patients admitted to hospital,” Professor Pirmohamed remarked.

Highlighting the increased risk of interactions in patients receiving polypharmacy, Professor Pirmohamed said that doctors are often reluctant to stop drugs once started. “Medication reviews are extremely important in determining when to stop therapy,” he said.

Iproniazid was found to engender a party mood and dancing even among people critically ill with tuberculosis

 

Not just medicines

Over the past 50 years, evidence has also accumulated that drugs can interact with food, drinks (e.g. grapefruit juice) and herbal medicines.

Professor Pirmohamed told the meeting that several herbs – including feverfew, ginseng and garlic – might reduce platelet function, which raises the prospect of interactions with drugs that influence coagulation.

“The herbs most likely to be associated with clinically significant adverse interactions include St John’s wort, ephedra, liquorice, ginkgo, ginseng and schisandra,” commented Philip Routledge, head of pharmacology, Cardiff University school of medicine, with St John’s wort associated with “the greatest number of interactions”.

St John’s wort’s numerous interactions arise from the herb’s ability to induce various cytochrome P450 isozymes – including CYP3A4, CYP2E1 and CYP2C19 – and increase the activity of p-glycoprotein.

A transmembrane transporter vital for drug elimination and absorption, p-glycoprotein, is extensively expressed by the intestinal epithelium, hepatocytes, renal proximal tubular cells, adrenal gland and bloodbrain barrier.

The effect of St John’s wort on cytochrome isozymes and p-glycoprotein account for many of the herb’s interactions, some of which can be serious. For example, St John’s wort is a selective serotonin reuptake inhibitor (SSRI), which helps explain the herb’s benefit in depression and anxiety.

When combined with other serotonergic agents, however, St John’s wort can increase the risk of serotonin syndrome. People with this “potentially life-threatening condition” experience at least three of the following: confusion, agitation, hyperreflexia, diaphoresis, shivering or tremor, nausea, diarrhoea, lack of coordination, fever, coma, flushing or rhabdomyolysis.

Interactions between conventional medicines and St John’s wort might be relatively common. A study from the US reported that 28 per cent of people using St John’s wort also took a drug that could cause a potentially dangerous interaction, such as a SSRI (13.7 per cent), benzodiazepines (9.8 per cent), warfarin (4.2 per cent), statins (3.3 per cent), verapamil (1.0 per cent), digoxin (1.0 per cent) and oral contraceptives (0.6 per cent)4.

HIV and HCV

St John’s wort can also interact with some drugs used to treat HIV, contributing to the high risk of interactions in these patients. David Back, professor of molecular and clinical pharmacology, University of Liverpool, noted that a quarter of people taking drugs for HIV also take another medicine with a “significant risk” of DDIs.

“The actual risk to patients is compounded by an ageing HIV population receiving multiple drugs for co-morbidities, often from different prescribers,” Professor Back remarked.

Meanwhile, recent drugs have transformed management of infections with chronic hepatitis C virus (HCV), with “between 70 and 80” antivirals for HCV probably in the pipeline. “While representing a huge advance, these drugs also present the challenge of understanding and managing complex pharmacology,” Professor Back said. He highlighted, in particular, the risk of DDIs arising from CYP3A4 inhibition.

To help clinicians navigate this tricky area, the University of Liverpool hosts websites covering interactions with HIV (www.hiv-druginteractions.org) and HCV (www.hep-druginteractions.org) medicines.

Investigations over the past 50 years into genetic, pharmacological and environmental causes of interactions have helped prescribers tailor treatment with unprecedented accuracy. Over the next few years, improved understanding of the relationship between genes and environment will further enhance our ability to avoid interactions.