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Herb-drug interactions seem to be common – herbal remedies were taken by 24 per cent of acute medical emergency admissions to a Liverpool hospital.¹

Eighty-three per cent of the patients had taken a herb with at least one prescription medication and 46 per cent had used a preparation with known sideeffects or interactions, yet just one patient record mentioned the herb.

A more recent study from the US reported that 28 per cent of people using St John’s wort took a drug that could cause a potentially dangerous interaction, such as a SSRI, benzodiazepine, warfarin, statin, verapamil, digoxin or oral contraceptive.²

For instance, combining St John’s wort and other serotonergic agents – such as SSRIs – may trigger the potentially fatal serotonin syndrome, while St John’s wort can also interact with oral contraceptives, possibly leading to unplanned pregnancies and breakthrough bleeding.³

Even aspirin – along with other NSAIDs – potentially interacts with herbs that also inhibit platelet aggregation (e.g. ginkgo, garlic, ginger, ginseng, bilberry, chamomile, turmeric, willow and meadowsweet). NSAIDs may interact with coumarin-containing herbs (e.g. chamomile, fenugreek, red clover). In both cases, these interactions may increase the risk of bleeding.⁴

The grapefruit effect

Pharmacists also need to be wary of food-drug interactions. Grapefruit, for instance, increases the peak plasma concentrations of at least 85 concomitant drugs. Depending on the drug, this may increase the risk of, for example, torsades de pointes, rhabdomyolysis, bone marrow toxicity, respiratory depression, gastrointestinal bleeding and renal toxicity.

In general, drugs that interact with grapefruit undergo extensive metabolism by CYP3A4 in the intestine, which results in a low oral bioavailability (<50 per cent).⁴

Grapefruit, Seville orange, lime and pomelo contain chemicals called furanocoumarins that strongly and irreversibly bind to CYP3A4. Overcoming this block means producing new CYP3A4 in the gut. Totally renewing intestinal CYP3A4 takes about three days.⁴

Unfortunately, characterising interactions between drugs and natural products is difficult. Bees, for instance, use propolis to build, repair and protect hives. Many patients take a propolis supplement for its anti-cancer, antioxidant, immune-modulatory, antibacterial, antiviral, and anti-inflammatory actions.

In one study, propolis potently inhibited CYP1A2, CYP2C19 and CYP2E1 but did not markedly inhibit CYP2C9, CYP2D6 and CYP3A4. Previous studies, however, found that propolis inhibited these isozymes. The chemical composition of propolis depends on which plants the bees visited and the species of bees, which may explain the discordant cytochrome inhibition.⁵

Chemically complex

Natural products are chemically complex, which complicates investigations into the interactions. For instance, Nigerian bee propolis seems to contain 60 different important phytochemicals⁶, while herbal supplements can contain between three and 20 plants.⁷ And each plant may contain several active chemicals: St John’s wort contains at least nine groups of pharmacologically active compounds.³

In addition, genetically determined differences in metabolic enzymes can influence the risk of interaction. For instance, levels of CYP3A4 in the intestine vary 10 to 20-fold between humans. The higher the amount of intestinal CYP3A4, the greater the risk of interaction.⁴

Pharmacists should therefore ask patients whether they are taking herbal or other supplements since relatively few patients volunteer this information. People buying herbal remedies should be asked whether they are taking conventional medicines. And pharmacists and patients should complete Yellow Cards, which can help identify drug, herb and diet interactions.

Based on Yellow Card reports, for example, the MHRA was able to warn that patients taking warfarin should limit or avoid drinking cranberry juice and that St John’s wort could reduce the efficacy of hormonal contraceptives.⁸ Given that these interactions are so common but so difficult to characterise, pharmacists need to remain vigilant for and report suspected interactions.

_REFERENCES

1. British Journal of Clinical Pharmacology 2007; 63:247-248 
2. Journal of Alternative and Complementary Medicine 2014; 20: 578-579
3. British Journal of Clinical Pharmacology 2002; 54:349-356
4. Pharmacological Research 2016; DOI: 10.1016/j.phrs.2016.09.038
5. Toxicological Research 2016; 32:207-213
6. Journal of Intercultural Ethnopharmacology 2016; 5:308-311
7. Hepatology 2016; DOI:10.1002/hep.28813
8. Prescriber 2016; 27:22-27