ABSTRACT
Importance of pharmacovigilance in herbal medicine and herb-drug interactions is apparent for the identification and assessment of associated risks.Clinical studies and case reports have identified a number of herb-drug interactions. Drugs like warfarin,digoxin,cyclosporine, tacrolimus, amitriptyline etc.usually have a narrow margin of safety and a high potential to interact with herbal medicines. Some very commonly used herbal drugs such as garlic (Allium sativum), ginger (Zingiber officinallis),ginkgo(Ginkgo biloba),and ginseng (Panax ginseng) etc. are reported to interact with conventional drugs. The clinical consequence of herb-drug interactions may vary fom moderate to serious adverse reactions. The multitude of pharmacologically active compounds in herbal drugs bviously increases the possibility of interactions to take place.Hence,the likelihood of herb–drug interactions is supposedly higher than drug– drug interactions.Pharmacovigilance whose purpose is to detect, assess, and understand, and to prevent the adverse effects or any other possible drug-related problems may prove very much helpful in this regard.The purpose of this paper is to impart significance of pharmacovigilance in herb-drug interactions in the light of the published studies.

Keywords: Herbal medicine; Drug interaction; Pharmacovigilance; Drug safety.

INTRODUCTION

With the aim to move away from ‘synthetic’ to ‘organic’, patients are more and more seeking herbal remedies (Staines, 2011; Heck, 2000). All medicinal agents including herbs are potentially toxic and have likelihood of interactions. Moreover, most patients receive information about herbs and herbal supplements from sources other than their healthcare providers (Staines, 2011; AS, 2014). Clinicians are also often unaware about their patients’ use of these medicines. Most patients who take herbal drugs wrongly believe that natural products are always safe; others fear that their physician may have negative attitudes towards their use of such products, and therefore they do not report about using such remedies. In addition, healthcare professionals never mind to ask patients about their self medication (Butterweck, 2004; Williamson, 2003; Zeping, 2005; WAbebe, 2002), as they are well aware about the mind set of their patients. This lack of communication could results in adverse effects or drug-herb interactions, which both patient and physician are often uninformed about. Patients may also substitute herbal remedies for more conventional therapies without informing their doctor. In clinical practice, recognizing adverse effects of herbal medicine is not a routine and their reporting is even less common. Several studies have concluded that drug-herb interactions are based on the same pharmacokinetic and pharmacodynamic principles as drug-drug interactions (Williamson, 2003; Heck, 2000). The rationale is not to avoid herbal medicines , rather only fundamental issue is that whenever a drug is prescribed with a herb, the potential interactions should always be considered (Williamson, 2003).
No drug is absolutely safe (Ray, 2004; Ac, 1998; Dubey et al., 2004; Jagtenberg and Evans, 2003; Ramawat and Goyal, 2008). All drugs are capable of producing adverse effect. An adverse effect is any response to a drug that is noxious and untended and that occurs at doses used in man for the prophylaxis, diagnosis or therapy of the disease or for modification of physiological functions. It excludes poisoning, over dose and prolongs use (Staines, 2011; Paoletti et al., 2011; Shi and Klotz, 2012).

Experts suggest that natural does not mean it is completely safe. Everything you put in your mouth has the potential to interact with something else (Zeping, 2005; Fugh-Berman 2000; Fugh-Berman, 2001). The medication that is taken by mouth travels through the digestive system in much the same way as food and herbs taken orally do. So, when a drug is mixed with food or another herb, each can alter the way the body metabolizes the other. Some drugs interfere with the body’s ability to absorb nutrients. Similarly, some herbs and foods can decrease or increase the impact of a drug (Izzo, 2004; Mahady, 2001). The general sense that herbs reduce the side effects of drugs and help them to perform their function better; in turn, drugs will make an herb formula work more strongly and quickly. Together, herbs and drugs may produce a more desirable result than either taken alone; but is not correct always. Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug related problems. It collects data on adverse reaction of drugs. This may be done by experimental and observational studies (Izzo AA, 2001).

Herb–Drug interaction
A drug interaction is a condition in which two or more drugs are administered together. One drug affects the activity of another drug. This action can be synergistic (when the effect of drugs is increased) or antagonistic (when the effect of drugs is decreased) or a new effect can be produced that neither produces on its own (Kane, 2000). Practically all interactions are not important. Only those interactions which appear clinically as adverse reactions are important.
Generally the nature of herb-drug interactions is not a chemical interaction which produces toxic substances. Instead, it may involve an herb component which either increases or decreases the amount of drug in the blood stream. A decrease in the amount of drug may occur by herb components preventing the drug from getting into the blood stream from the gastrointestinal tract, or by stimulating the activity of enzymes that degrade the drug. An increase in the drug dosage could occur when an herb component increases absorption of the drug, or inhibits the enzymes that break down the drug. A decrease in drug dosage by virtue of an interaction could make the drug ineffective; an increase in drug dosage could make it reach levels that produce side effects (Smolinske, 1999, Scott 2002).

Alternatively, an herb might produce an effect that is opposite to the effect desired for the drug, resulting in reduced drug effect; or, an herb might produce the same kind of effect as the drug. It is common for herbs to be combined with drugs. The combination is sometimes incidental, but is often intentional and based on a prevalent favorable theory about using herbs and drugs. Little attention has been paid to adverse herb-drug interactions (Tilburt and Kaptchuk, 2008; WAbebe, 2002).

In view of the above, few studies that have been done in which herb-drug interaction has shown some changes in the pharmacokinetics as well as pharmacodynamics of the drugs are given below:

1. Ephedra may interact with certain antidepressant medications or certain high blood pressure medications to cause dangerous elevation in blood pressure or heart rate. It could cause death in certain individuals.
2. Garlic and Ginger + Warfarin increase bleeding (anti coagulant)
3. Carica papaya (extract) + Warfarin increase international normalised ratio (INR)
4. Yohimbine + Tricyclic anti depressant causes Hypertension
5. Liquorice + prednisolone increased plasma concentration of prednisolone
6. Liquorice + Digoxin increase effect of cardiac glycoside
7. Liquorice + oral contra captive increased hypersensitivity
8. Chili pepper + ACEI causes cough
9. Tamarind + aspirin increased bioavailability of aspirin
10. Mukul + beta blockers decreased bioavailability of beta blockers
11. Jujube + indomethacin increased bioavailability of indomethacin
12. Psoralia seed + tetra cyclin causes photo allergy
13. Piper nigrum and Piper longum + antibiotics increased bioavailability of antibiotics
14. Orange juice + antacids containing aluminum. ‘The juice increases the absorption of the aluminum.
15. Orange Juice and milk + antibiotics. Decreased the effectiveness of antibiotics
16. Echinacea + methotrexate and amiodarone causes hepatotoxisc
17. Ginseng + anti-clotting medications decrease effectiveness of certain anti- clotting medications.
18. Valerian + anti-seizure medications increase the effects of certain anti-seizure medications
19. Shankhapushpi + phenytoin decrease concentration of phenytoin (Ebadi, 2007; Fugh-Berman, 2000; Fugh-Berman, 2001; Zeping, 2005; Heck, 2000; Izzo, 2004; Izzo, 2001; Johne, 1999; Smolinske, 1999; Staines, 2011; WAbebe, 2002).

A standard procedure is to test the herb extract alone and to test it with drugs that cause the same effect. If the drug effect is increased or prolonged by the herb, it is implied that the herb has a similar effect, even though it may have a different mechanism (Ac, 1998; Dubey et al., 2004; Jagtenberg and Evans, 2003; Mahady 2001; Ramawat and Goyal, 2008; Yadav and Dixit, 2008). Thus, a study intended to demonstrate that a traditional claim for an herb is true turns out to be a source of worry about herb-drug interactions.

Some dietary components increase the risk of side effects, e.g. Theophylline, a medication administered to treat asthma, contains xanthenes. It is also found in tea, coffee, and chocolate and consuming large amounts of these substances while taking theophylline increases the risk of drug toxicity (Ebadi, 2007). Certain vitamins and minerals impact on medications too. Large amounts of broccoli, spinach, and other green leafy vegetables high in vitamin K, which promotes the formation of blood clots, can counteract the effects of heparin, warfarin, and other drugs given to prevent clotting (Piscitelli, 2002; Johne, 1999; Kane, 2000; Smolinske, 1999; Scott, 2002; Ebadi, 2007).

How pharmacovigilance can help?
Since more than 70% of patients who use herbal medicine do not inform their health-care providers about these products. So pharmacists and other health-care professionals should question all patients about their use of alternative therapies. Health-care professionals should remain vigilant for potential interactions between alternative therapies and prescription medications, especially medications with a narrow therapeutic index, and should report suspected interactions to the pharmacovigilance committee who have to assess and to prevent the adverse effects. Health-care professionals can produce public awareness about adverse effect. Thus pharmacovigilance may helpful to prevent and decrease herb drug interaction problems.
High-risk patients, such as the elderly, patients taking three or more medications for chronic conditions, patients suffering from diabetes, hypertension, depression, high cholesterol or congestive heart failure, should be especially on the lookout for such side reactions.

CONCLUSIONS

The above mentioned studies showed that herbal medicines too have adverse effects and may give rise to potential drug-herb interactions. However, it does not imply that use of herbal medicine should be discouraged. Herbal medicines have their own benefits and found to be effective, and are sometimes a suitable alternative to conventional drugs. The only issue is that their adverse effects and potential drug interactions should be considered when prescribed with conventional drugs. It should be known to all health care professionals.

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