Effects of herbal drugs on clinical laboratories testing

This presentation is based on the different effects of herbal medicines

1. EFFECTS OF HERBAL DRUGS ON CLINICAL LABORATORIES TESTING & DISPENSING AND REGULATION OF HERBAL DRUGS PRESENTED BY SWATI WADHAWAN M.PHARMA 1 st YEAR

2. HERBAL DRUGS Herbal drugs are the preparations obtained from natural sources included the parts of plant and tree (stem, roots, flowers, leaves, bark, fruits, seeds etc ) Herbal medicines (phytomedicines) are closest to the conventional therapy approach than any other traditional or alternative medicine approaches Herbal medicines have several chemical constituents (phytoconstituents) which are known for their pharmacological effects on the body and are used since many centuries

3. Clinical Research on Herbal Drugs NEED Herbal products have become an important and indispensable part of public healthcare around the world Various surveys on traditional and alternative medicine have highlighted their widespread use CHALLENGES These include issues such as those related to the financial, ethical, product standardization (quality control ) The design of the study and the regulatory requirements before filing an investigational new drug

4. CLINICAL TRIALS ON HERBAL DRUGS The general principles of the clinical trials of herbal medicines are similar to those applied to synthetic drugs if clinical trial is regarded to be necessary. PHASES OF A CLINICAL TRIAL PHASE I PHASE II PHASE III PHASE IV

5. EFFECTS OF HERBAL DRUGS ON CLINICAL LABORATORIES TESTING It is a popular belief that the herbal remedies are safe and effective Many herbal supplements have known toxicity and unexpected laboratory test results may be the early indications of such toxicity herbal products such as St. John’s wort can interact with many Western drugs causing increased clearance of such drugs and hence treatment failure Falsely elevated or falsely lowered digoxin levels may be encountered in a patient taking digoxin and the Chinese medicine Chan Su or Dan Shen

6. Abnormal laboratory test results due to the use of herbal medicines 1. Direct interference of a component of the herbal medicine. 2. Drug-herb interactions 3. Toxic effects of the herbal product

7. Interference of Chinese Medicines With Digoxin Immunoassays Chan Su is prepared from the dried white secretion of the auricular glands and the skin glands of Chinese toads The cardiotonic effect of Chan Su is due to its major bufadienolides, such as bufalin, cinobufagin, and resibufogenin . At high dosages, Chan Su causes cardiac arrhythmia, breathlessness, seizure, and coma

8. An apparent digoxin concentration of 4.9 ng/mL (6.3 nmol/L) was reported in 1 woman who died of ingestion of Chinese herbal tea containing Chan Su Chan Su are bound very strongly to serum proteins, while digoxin is only 25% protein bound Table1: Intended Uses of Common Herbal Medicines HERBAL MEDICINE INTENDED USE GINSENG USED AS COMPLETE HEALTH TONIC ALSO USED IN STRESS CONDITION VALERIAN TREATMENT OF INSOMNIA SENNA LAXATIVE ALOE TO HEAL WOUNDS, BURNS, SKIN ULCERS; ALSO USED AS A LAXATIVE

9. Table 2: Interferences of herbal products in therapeutic drug monitoring of digoxin . Herbal Product Interference Level Comments Chan Su High Chan Su has active components such as bufalin, which cross-react with digoxin assays; only Bayer assay has no interference; monitoring free digoxin also eliminates interference Dan Shen Moderate Falsely elevated (FPIA) or falsely low (MEIA) digoxin level; no interference with EMIT, Bayer, Randox, Roche, or Beckman assays; monitoring free digoxin eliminates interference Additive effect with digoxin; also interferes with digoxin assay Asian ginseng Moderate Falsely elevated (FPIA) or falsely low (MEIA) digoxin level; no interference with EMIT, Bayer, Randox, Roche, or Beckman assays; monitoring free does not eliminate interference

10. Abnormal Drug Concentrations Due to Use of Herbal Medicines Shankhapushpi, an ayurvedic medicine use for epilepsy, has adversely affected the effectiveness of phenytoin Dandekar observed 2 patients experience loss of seizure control after self-medication with shankhapushpi The serum phenytoin concentration dropped from 9.6 μg/mL to 5.1 μg/mL after ingestion of this herbal product Warfarin Warfarin is an anticoagulant with a narrow therapeutic range. Several herbs interact with warfarin. The herbs that may increase the risk of bleeding include angelica root, arnica flower, ansine, bogbean, borage seed oil, capsicum, feverfew, garlic, ginger, ginkgo, horse chestnut, licorice root, and willow bark. The herbs with documented interaction with warfarin include Dan Shen, ginseng, Siberian ginseng, Devil’s claw, and dong quai, among others .

11. Licorice It is used as an anti-inflammatory herb and also as a remedy for gastric and peptic ulcers Licorice may offset the ability of spironolactones to reduce blood pressure Lower Drug Concentration Due to Use of St John’s Wort The flower to be most abundant and brightest around June 24, the day traditionally believed to be the birthday of John the Baptist. Therefore , the name St John’s wort became popular for this herbal Product Johne reported that 10 days’ use of St John’s wort resulted in a decrease of serum digoxin concentrations by 33% and peak digoxin concentration by 26 %

12. Continue ……. T he lower digoxin concentration is conformed in healthy volunteers who concurrently took St John’s wort St John’s wort also reduced the area under the curve of the HIV-1 protease inhibitor indinavir A case report describes an interaction between St John’s wort and theophylline

13. Table3: The most common interactions between herbs and drugs Herbal Product Interacting Drug Comments Ginseng Warfarin Ginseng may decrease effectiveness of warfarin St John’s wort Paroxetine hydrochloride Digoxin Lethargy, incoherence, nausea Decreased AUC; peak and trough concentration of digoxin; may reduce Ginkgo biloba Aspirin Bleeding; ginkgo can inhibit PAF Garlic Warfarin Increased effectiveness of warfarin; bleeding Shankhapushpi Phenytoin Lower phenytoin level and loss of seizure control

14. Abnormal Laboratory Test Results Due to Toxic Effects of Herbal Medicines The following drugs shows the abnormal laboratory test results due to toxic effects of herbal drugs: Kava-Kava and Abnormal Liver Function Test Results Chaparral and Abnormal Liver Function Test Results Mistletoe and Liver Damage Comfrey and Liver Damage Kelp and Abnormal Thyroid Profile Licorice and Hypokalemia Lead Poisoning Due to Herbs: Abnormal Laboratory Test Results

15. Herbal Medicine and Surgery The American Society of Anesthesiologists suggested that patients should discontinue their herbal medicines at least 2 weeks before surgery garlic and ginseng should be discontinued at least 7 days before surgery because they cause aggravate bleeding Ginkgo biloba should be discontinued 3 days before surgery because it inhibits platelet aggregation, causing bleeding

16. Toxic Effects of Herbal Medicines Table 4: HERB TOXICITY INTENDED USE Comfrey Hepatotoxic Repairing of bone and muscle; prevention of kidney stones Ephedra Cardiovascular Herbal weight loss Chan Su Cardiovascular Tonic for heart Borage oil Hepatotoxic; hepatocarcinogenic Source of essential fatty acids; rheumatoid arthritis; hypertension Licorice Pseudoaldosteronism weight loss product Treatment of peptic ulcer; flavoring agent

17. 1) GINSENG Vaginal bleeding has been reported in cases related to ginseng Use. 2) GINKGO BILOBA The most common adverse effects of ginkgo are gastric disturbances , headache, dizziness and bleeding. 3) GARLIC Chopped garlic and oil mixes left at room temperature can result in fatal botulism food poisoning according to the FDA. 4) EPHEDRA Hypertension was the single most frequent adverse reaction of Ephedra followed by palpitations, tachycardia, stroke, and seizure.

18. REGULATIONS

19. HERBAL DRUG REGULATION Each country or area should adopt a regulatory system to manage the appropriate use of herbal medicines. Adopting a regulatory mechanism will help ensure that herbal medicines have acceptable quality, safety and efficacy. The regulatory process is a mechanism for evaluating the safety, efficacy and quality of medicinal products. The levels of evaluation may vary depending on the product. Various assessment procedures can be established with consideration of the categories of herbal medicine and country’s situations. (a) Notification procedure (listing ) ( b) Registration procedure (licensing )

20. Continue…… All manufacturing procedures should be in accordance with Good Manufacturing Practices (GMP ) Different regulatory procedures may be applied to raw plant materials, processed plant materials and medicinal herbal products the regulatory authority may issue a list of controlled toxic plant materials to guide manufacturers, wholesalers or importers and the public For countries where a mechanism for the regulation of herbal medicines has not yet been established, the regulation procedure could be initiated step by step.

21. Regulatory Status of Herbal Drugs Research About 80% - 90 % of the population depend on herbal drugs but it is also a fact that in these populations, the herbal drugs are not regulated by the state. For drug registration application, the data to be submitted include general product data, pharmaceutical data, pharmacological/toxicological data, and clinical data. From 1995, it became mandatory for manufacturers and marketers to be certified by the local drug regulatory authorities It is important that the manufacturers firmly adhere to good agricultural and collection practices (GACP), GMP and good laboratory practice standards

22. Continue…. The national drug regulatory authority must ensure issue of license for importers, wholesalers, manufacturers and assemblers of herbal medicinal. The registration of herbal products require detailed information of the herbal medicinal products like: licence or certificate from the drug regulatory authority, brand name, dosage form, indications , dosage, mode of administration, adverse effects, contraindications, warnings, precautions, and major drug interactions etc. Pharmacovigilance centers for herbal products are required to assess and collect information about the safety and efficacy of herbal products through monitoring adverse drug reactions.

23. Regulatory aspects and approval of herbal drugs The legal process of regulation and legislation of herbal medicines changes from country to country The reason for this involves mainly cultural aspects and also the fact that herbal medicines are rarely studied scientifically WHO has published guidelines in order to define basic criteria for evaluating the quality, safety, and efficacy of herbal medicines the WHO has prepared pharmacopeic monographs on herbal medicines and the basis of guidelines for the assessment of herbal drugs Several regulatory models for herbal medicines currently exist

24. A summary of the regulatory processes related to herbal drugs in some selected countries are as: 1) Australia The Australian Parliament established the Working Party on Natural and Nutritional Supplements to review the quality, safety , efficacy and labeling of herbal and related products. 1) Brazil The legal requirements for registration of herbal medicines in Brazil demand complete documentation of efficacy, safety and well-defined quality control.

25. 3) France Approximately 200 herbs are approved as OTC in France with varying claims. Licensing approval for phytomedicines is subject to regulations generally required for all drugs. 4) United States of America Since 1994, herbal medicines have been regulated under the " Dietary Supplement Health and Education Act of 1994". On the basis of this law, herbal medicines are not evaluated by the Food and Drug Administration and, most important, these products are not intended to diagnose, treat, cure, or prevent diseases .

26. Regulatory Requirements for Herbal Medicines in India: Herbal medicines are being used in India since Vedic age and it has been documented in Rig-Veda. It has been mentioned in Charak Samhita In In­dia herbal medicines are being used in Ayurveda , Siddha , Unani and Homoeopathic system of med­icines India has around 45,000 species of plants, out of which 15,000-20,000 plants have proven medicinal value The traditional sys­tem utilizes around 7,000-7,500 species in its for­mulations Ayurveda uses 2000, Unani 1000, Sid­dha 1300, Tibetan 500 and 200 varieties in the modern medicine

27. Standards of Drugs as per Existing Leg­islature of India: Standards of medicines are prescribed in the Drugs and Cosmetic Act 1940 and individual mono­graphs has been prescribed in the respective Phar­macopoeias Recently the Govt. of India has published 4 volumes of Ayurvedic Pharmacopoeia which is grossly inadequate in comparison to the number of herbs used in the Ayurvedic system of medicines Unfortunately neither the herbal products nor the herbal Pharmacopoeias have any statutory standing in India In India there are some gray areas in case of status of herbal drugs ( Table 5) and there exists no definite policies about food supplements.

28. Table 5: Standards of Herbal Drugs as per Indian legislation System of medicine standard Modern drugs The second schedule of D & C Act. Homeopathic drugs The second schedule of D & C Act. Ayurvedic, siddha and unani drugs Rule 168 of D & C Act. Herbal drugs ? Standards of Ayurvedic Drugs: O nly four volumes of Ayurvedic Pharmacopoeia having monographs of about 326 herbs have been published, which is quite inadequate with respect to the huge number of herbs used in the Ayurvedic system of medicines. There is ample scope of misuse of this provision, as 55 books out of 57 are not properly defined in the legislature.

29. Standards of Siddha Drugs Amongst the 30 books, 29 are old texts and Siddha Formulary of India (Part I) is the only book published by the Govt . of India recently . Standards of Unani Tibetan System of Drugs Amongst the 13 books, 12 are old texts and the only modern book is National Formulary of Unani Medicine (Part I) published by Govt. of India. Schedule T for Good Manufacturing Practice: To manufacture good quality Ayurvedic , Siddha and Unani medicines Good Manufacturing prac­tices have been made mandatory by incorporation of revised Schedule T in the year of 2003.

30. Standards of Homoeopathic Medicines: Standard of Homoeopathic medicines has been prescribed in Second schedule of the Drugs and Cos­metics Act, 1940 .

31. dispensing

32. DISPENSING OF HERBAL DRUGS Herbal medicines are defined as herbal preparations or finished herbal products that contain as their active ingredients parts of plants or other plant materials or combinations of plants According to the World Health Organization (WHO), 70–95% of the populations in developing countries rely on traditional medicines for primary care, while 70-90% of the populations in industrialized countries have used traditiona medicines the 1994 Dietary Supplement Health and Education Act allows manufacturers to make claims regarding the benefits from the use of these products. Studies in the USA and Italy found that consumers need information on herbal safety. However pharmacists were more likely to answer correctly about the use of herbs rather than about cautions, adverse effects and interactions

33. DISPENSING Dispensing refers to the process of preparing and giving medicine to a named person on the basis of a prescription It involves the correct interpretation of the wishes of the pre- scriber and the accurate preparation and labeling of medicine for use by the patient Dispensing is one of the vital elements of the rational use of medicines Dispensing environment Dispensing environments must be clean, because most medicinal products are for internal use, making it important that they be hygienic and uncontaminated.

34. The dispensing environment includes—   • Staff • Physical surroundings • Shelving and storage areas • Surfaces used during work • Equipment and packaging materials Dispensing process The term dispensing process covers all activities involved, from receiving the prescription to issuing the prescribed medicine to the patient.

35. The dispensing prosess may be based on the six major areas of activity: 1 . Receive and validate the prescription 2. Understand and interpret the prescription 3. Prepare and label items for issue 4. Make a final check 5. Record the action taken 6. Issue medicine to the patient with clear instructions and advice Medication Counselling Medication counselling should be provided to patients to ensure the proper use of dispensed medicines. And it is also useful to the patient in chronic disease conditions.

36. Promoting efficient management in dispensing Organizing patient flow, such as establishing systems to receive payment and prescriptions and issue medicines, can reduce the potential for dispensing errors One good way to reduce dispensing time and improve safety is to prepackage and label commonly used medicines Techniques to ensure quality in dispensing include— •Requiring that all staff work in accordance with written SOPs • Maintaining records • Scheduling worker shifts to make best use of staff • Involving the pharmacy staff in hospital/facility committees

37. Labelling of Dispensed Medicines All medicines dispensed by a pharmacy or medical practitioner should be labeled with the following essential information: name of patient date of dispensing dosage per unit precaution where applicable method and dosage of administration trade name or common name of the medicine name and address of the pharmacy/medical practitioner

38. PACKAGING Packaging can be defined as an economical means of providing presentation , protection, identification information, containment , convenience and compliance for a product during storage , carriage, display and until the product is consumed. Packaging must provide protection against climatic conditions biological , physical and chemical hazards and must be economical . The package must ensure adequate stability of the product throughout the shelf life . Types of packaging Primary packaging Secondary packaging Tertiary packaging

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