As a Singaporean Chinese, I grew up taking a mix of both Traditional Chinese Medicine (TCM) and Western medicine when I fell sick. In particular, one of my favourite medicines a TCM cough medicine, Pipagao. Pipagao is a honey-based, herbal cough syrup flavored using loquat (or Pipa in Mandarin, giving it its name), that is highly soothing for sore throats. Due to the fact that Pipagao tastes good compared to a lot of cough medicines and does not have the unwanted side effect of drowsiness that comes with many Western cough syrups I often recommend Pipagao as a good symptomatic relief for dry cough and itchy throat. (#notsponsored)

There is one particular exception, however, where I will not recommend Pipagao. For patients on warfarin, taking Pipagao can be highly dangerous. Warfarin is an oral anticoagulant used to treat and prevent blood clots. Warfarin is also a drug with a narrow therapeutic index and thus needs to be titrated carefully with frequent follow up by healthcare providers when first prescribed, in order to maintain good efficacy without putting the patient at too high a risk of uncontrolled bleeding. Aside from the dose given, warfarin efficacy can be influenced by a myriad of factors, with one of the significant ones being diet, including supplements and herbal remedies. Pipagao is unfortunately one of the herbal medications known to significantly decrease the efficacy of warfarin, and can thus lead to unwanted outcomes such as further blood clotting and even stroke.

Why, and how exactly does this happen?

As Pipagao is a mix of herbal ingredients, a number of answers are possible and the answer is unfortunately not very clear cut. As a pharmacologist, I have broken this interactions down into 2 possible theories.

Theory 1. Pipagao contains a large amount of vitamin K (Pharmacodynamic herb-drug interaction)

In this theory, we hypothesize the warfarin-pipagao interaction is a pharmacodynamic herb-drug interaction, meaning that Pipagao contains ingredients that act along the same pathway that warfarin acts on. Warfarin prevents blood clotting by reducing the amount of vitamin K available to make clotting factors. As many herbs and leafy vegetables are known to be good sources of vitamin K, we can thus hypothesize that Pipagao as a herbal blend, contains a large amount of vitamin K. The large amount of vitamin K thus negates warfarin’s action, making warfarin less efficient in preventing clotting. During my research on this topic however, I was not able to find much information on the vitamin K content of the various ingredients in Pipagao, as vitamin K is generally not an essential nutrient and is thus not as widely quantified and reported in many consumer products. This makes theory 1 highly plausible in terms of known mechanism. But without actual evidence of the vitamin K content of Pipagao, it is hard to make a definite conclusion.

Theory 2. Pipagao contains ingredients, such as licorice, that induce warfarin breakdown (Pharmacokinetic herb-drug interaction)

In this theory, we hypothesize that Pipagao contains ingredients that hasten the breakdown of warfarin, causing warfarin to be present at levels lower than expected within the body instead. This is could be due to 甘草 （licorice), which has studies showing its capability of inducing liver enzymes that metabolize warfarin, such as CYP3A4 (PMID: 25640094). An increased amount of drug metabolizing enzymes can thus lower warfarin levels, rendering it less efficacious than expected.

While the mechanism of interaction is still up for debate, caution should be taken when a person on warfarin wants to consider taking a herbal medication, as it could greatly alter the efficacy of warfarin.

Both theories, pharmacodynamic (warfarin’s reduced vitamin K antagonism) and pharmacokinetic (warfarin’s reduced drug levels) are plausible as a mechanism of interaction. Which one do you think it is? Let me know in the comments!