herb - drug interactions

HERB – DRUG INTERACTIONS : 

HERB – DRUG INTERACTIONS Dr. RODDA HARISH CHANDRA M.Pharm., Ph.D. ASSOCIATE PROFESSOR Vaagdevi College of Pharmacy Hanamkonda , Warangal drrodda@yahoo.com

Slide 2: 

Global Increase demand for herbs/herbal formulations 25,000 Plant based formulations – Available 1.5 Million Practioners of Traditional Medicinal system 25% of all modern medicines – directly /indirectly derived from plants 60% of antitumour and antimircobial medicines are derived from plants 5 billion /yr industry More than 700 therapeutic herbs and phytomedicines sold in German Pharmacies Approximately 70% Physicians prescribe registered herbal remedies 7800 Medicinal drug manufacturing Units - India

Purpose for use of Herbal Medicine?: 

Purpose for use of Herbal Medicine? Health Benefit Total Shoppers (1000) Female (711) Male (289) Ensure overall good health 88% 91% 82% Reduce fat intake 81% 84% 72% Doctor’s advice 73% 75% 69% Weight Reduction/Control 73% 76% 67% Reduce cholesterol levels 72% 74% 66% Reduce the risk of a specific condition or illness 66% 69% 59% Improve stamina or energy level 64% 65% 60% Desire to manage or treat specific health condition on their own 63% 65% 56% Cope with food intolerance 48% 50% 43% Manage Stress 46% 46% 44% Manage allergies 41% 45% 33% Slow down the aging process 39% 41% 35%

Slide 5: 

A MILLION DOLLAR QUESTION SAFETY OF HERBAL MEDICINES ? Answer: Equivocal

Facts about drug interactions/herbal medicine/ herb-drug interactions: 

Drug interactions - 4 th – 6 th Cause of death At least 100 preoperative fatalities due to herb -drug/surgery interactions >70 – 80 Herbs - Increase risk of bleeding >30 – 40 Herbs possibility of causing hepatic failure Ephedra – 54 deaths , 1600 Adverse events Aloe vera injection – 4 Deaths Pennyroyal tea – 2 infants Multiorgan Dysfunction Aristolochic Acid – Death of 100 Belgian Women Facts about drug interactions/herbal medicine/ herb-drug interactions

Interactions between Immunomodulatory herbs and drugs: 

Herb Drug/ Class of drugs Mechanism of Herb – Drug Interaction Astragalus (ASTRAGALUS MEMBRANACEUS) Azathioprine Cyclosporine Methotrexate Antagonism Borage (BORAGO OFFICINALIS) Hypnotics Potentiation Echinacea (ECHINACEA PURPUREA) Acetaminophen Potentiation of Hepatotoxicity Corticosteroids Cyclosporine Antagonism Fexofenadine Itraconazole Lovastatin Inhibition of CYP3A4 leading to increase in drug concentration Interactions between Immunomodulatory herbs and drugs

Slide 8: 

Ginseng (PANAX GINSENG) Amlodipine Induction of CYP3A4 Digoxin Increased drug concentrations Hexobarbital Induction of CYP2C9 Opioid analgesics Decreased activity of opioids – clear mechanism is unknown Phenelzine and MAO inhibitors Increased CNS side effects due to additive effect Warfarin Alteration of INR value Shankpushpi (CONVOLVULUS PLURICAULIS) Phenytoin Decreased therapeutic effect

Interactions between herbs used for cardiovascular disorders and drugs: 

Interactions between herbs used for cardiovascular disorders and drugs GARLIC Antihyperglycemic effect when it was co – administered with chlorpropamide Decreases – bioavailabilty of saquinavir – induction of P- glycoprotein (P – gP) GUM GUGGULU ( COMMIPHORA MUKUL) It may produce an additive effect with anticoagulants It is believed to act as a thyroid stimulating agent – avoid the co – administration with thyroid drugs Guggul - predicted to decrease the absorption of beta blockers and calcium-channel blockers

Interactions between herbs used for central nervous system disorders and drugs : 

Interactions between herbs used for central nervous system disorders and drugs Herb Drug/Class of drugs Mechanism of Herb Drug Interaction Areca (ARECA CATECHU) Procyclidine Antagonistic effect on drug – leading to extra pyramidal syndrome Capsicum (CAPSICUM FRUTESCENCE, CAPSICUM ANNUM) ACE inhibitors Increased risk of developing cough Theophylline Enhanced bioavailability can lead to theophylline toxicity Chasteberry (VITEX AGNUS – CASTUS) Dopamine receptor antagonists Interferes with the activity of drugs Feverfew (TANACETUM PARTHENIUM) Antimigraine Drugs Potentiation of drug effect Warfarin Additive antiplatelet effect due to inhibition of platelet aggregation

Slide 11: 

Ginkgo (GINKGO BILOBA) Aspirin Clopidogrel Ticlopidine Increased risk of bleeding Digoxin Increased bioavailability of digoxin Diltiazem Increased bioavailability of drug Ibuprofen Intracerebral mass bleeding due to inhibition of platelet aggregation Nicardipine Induction of CYP 3A4 leading to decreased activity of drug Omeprazole Induction of CYP2C9 Thiazide diuretics Increase in blood pressure Trazodone Induction of CYP3A4 Warfarin Increased risk of bleeding

Slide 12: 

Green tea (CAMELIA SINENSIS) Warfarin Increased risk of bleeding Guarana(PAULLINIA CUPANA) Caffeine/ Respiratory stimulants Potentiation of activity Kava (PIPER METHYSTICUM) Alprazolam Potentiation of sedation Anesthetics Prolongation of anesthesia Levodopa Antagonism Lemon balm (MELISSA OFFICINALIS) CNS depressants Additive CNS effects Thyroid hormones Inhibits binding of thyroid hormones to TSH receptors Sage (SALVIA MITILIORRHIZA) Warfarin Increased risk of bleeding Diazepam Induction of enzymes

Slide 13: 

St.John’s wort (HYPERICUM PERFORATUM) Amitryptyline Induction of CYP3A4 Cyclosporine Induction of CYP3A4 and P - gP leading to decrease in drug concentration and rejection of transplanted organ Digoxin Induction of P – gP Fexofenadine Inhibition of P - gP Indinavir, Saquinavir Induction of CYP 3A4 Loperamide Acute delirium – mechanism unknown

Slide 14: 

St.John’s wort (HYPERICUM PERFORATUM) Methadone Induction of CYP 3A4, 2C8 and CYP 2D6 leading to decrease in drug concentration Oral Contraceptives Failure of contraception due to induction of CYP3A4 Piroxicam Photosensitizing drugs Increased risk of phototoxicity Quazepam Induction of CYP 3A4 Sertraline Inhibits vesicular uptake of monoamines leading to serotonergic syndrome Simvastatin Induction of CYP3A4 Tacrolimus Immuno graft rejection due to induction of CYP enzymes

Slide 15: 

St.John’s wort (HYPERICUM PERFORATUM) Theophylline Induction of CYP1A2 leading to decreased concentration of drug Thyroid stimulating hormone Elevation of TSH levels Venlaxafine Serotonin syndrome – Inhibition of serotonin reuptake and MAO Inhibition Verapamil Induction of CYP3A4, leading to decreased bioavailabilty Warfarin Induction of CYP3A4 and CYP2C9 Valerian (VALERIANA OFFICINALIS) Barbiturates Additive sedation Yohimbine ( PAUSINYSTALIA YOHIMBE ) Clomipramine Increased blood pressure

Slide 16: 

Herb CYP Enzyme In – vitro model ANGELICA DAHURICA Inhibits CYP3A4 Inhibtis multidrug-resistant and methicillin-resistant strains of Staphylococcus aureus Liver microsomes Devil’s Claw (HARPOGOPHYTUM PROCUMBENS) CYP2C8,CYP2C19, CYP3A4,CYP1A2, CYP2D6 Human kidney (HK-2) proximal tubule cell line Echinacea (ECHINACEA PURPUREA) Inhibits CYP2C19, CYP2D6 Baculovirus expressed CYP enzymes Herb – drug interactions due to alteration of cytochrome P450 enzymes in in - vitro models

Slide 17: 

Herb CYP Enzyme In – vitro model Garlic ( ALLIUM SATIVUM) Inhibits CYP2C9, CYP2C19, Inhibits CYP3A4 Inhibits CYP2E1 Human liver microsomes CYP 3A4 Substrates (7-Benzyloxyresorufin and 7-ethoxy-3 cyanocoumarin Rat iver microsomal cytochrome P450 fractions Ginseng (PANAX GINSENG) Inhibits CYP1A2, CYP2B1, CYP2C9,CYP3A4 c-DNA-expressed cytochrome P450 enzyme catalytic activity Goldenseal (HYDRASTIS CANADENSIS) CYP2D6, CYP3A4, CYP3A5 Caco – 2 cell lines Kava (PIPER METHYSTICUM) Inhibits CYP3A4, CYP1A2, CYP2C9, CYP2C19,CYP2D6 Human liver microsomes

Slide 18: 

Herb CYP Enzyme In – vitro model Liquorice (GLYCYRRHIZA GLABRA) CYP3A4, CYP2C9 Human recombinant enzymes Schizandra (SCHIZANDRA CHINENSIS ) Inhibits CYP3A4 Liver microsomes Silymarin (SILYBUM MARIANUM) Inhibits CYP3A4 CYP2C9 Human hepatocytes/ Human recombinant enzymes Valerian (VALERIANA OFFICINALIS) Inhibits CYP3A4, CYP2C9 and CYP2C19 Cytochrome P450 CYP3A4 supersomes Vinca (CATHARANTHUS ROSEUS) Inhibits CYP2D6 Human Liver Microsomes

Interactions between other herbs and drugs: 

Interactions between other herbs and drugs Artemesinin Artemisinin, - decreases – omeprazole bioavailability - induction of CYP2C19 activity ( Svensson et al., 1998 ). Foeniculum vulgare Decrease the rate of absorption of ciprofloxacin - chelation of the drug ( Zhu et al., 1999 ). Liquorice Antihypertensive drugs - synergistic effect ( Cumming et al., 2003 ) Hydrocortisone - pseudoaldosteronism ( Beate et al., 1999 ) Oral contraceptives - hypertension, edema and hyperkalemia ( Gerty et al., 1997). Silymarin potentiate the effects of antiarrhythmic drugs ( Gyonos et al., 2001 ) Increases - pharmacological activity of cisplatin ( Scambia et al., 1996 ), Decreases the blood concentrations of indinavir ( Piscitelli et al., 2002 ) losartan ( Han et al., 2009 ) and metronidazole ( Chon et al., 2005 )

Interactions between herbs and drugs acting on blood : 

ALTERATION OF INR Herbs containing coumarins: Arnica, celery, chlorella, danshen, dong quai, chamomile, fenugreek, goldenseal, guar gum, horse chestnut seeds, papain, passionflower, red clover, sweet clover, boldo Herbs containing vitamin K: Eg: Acerola, agrimony, stinging nettle, plantain INHIBITION OF PLATELET AGGREGATION Bilberry, cayenne, bromelain, capsicum, European mistletoe, feverfew, garlic INHIBITION OF PLATELET ACTIVATING FACTOR (PAF) Garlic, Ginkgo and saw palmetto B L O O D C L O T T I N G Interactions between herbs and drugs acting on blood

PREDICTED - HDI: 

PREDICTED - HDI Bearberry ( ARCTOSTAPHYLOUS UVA URSI ) Estrogens/Oral contraceptives - May ↓ response to estrogen Lipid lowering drugs – Possibility of additive effect Black Cohosh ( CIMIFUGA RACEMOSA ) Lipid lowering drugs - Possibility of additive effect Bladderwrack ( FUCUS VESICULOSUS ) Hypoglycemic drugs - Possibility of additive effect Blue Cohosh ( CAULOPHYLLUM THALICTROIDES ) - Nitrates and Calcium channel blockers - May antagonize the hypertensive effect

Slide 22: 

Chamomile (MATRICARIA RECUTITA) - Iron - May inhibit iron absorption Chaste tree berry (VITEX AGNUS – CASTUS) - Dopamine receptor antagonists (Phenothiazines) - May antagonize drug effect Devil’s claw (HARPAGOPHYTUM PROCUMBENS) - Antiarrhythmic drugs - May interfere with drug activity Echinacea ( ECHINACEA PURPUREA) –Corticosteroids/ Cyclosporine – May nullify the effect of drug

Slide 23: 

Guarana ( PAULLINIA CUPANA) Adenosine - May lower response Benzodiazepine - Drugs may be less effective Hawthorn ( CRATAEGUS LAEVIGATA , C. MONOGYNA, C. PINNATIFIDA, C.OXYCANTHA ) Anesthetics - May enhance hypotension

Herbs to be avoided prior to surgery: 

Herbs to be avoided prior to surgery Ephedrine – 24 hrs Garlic/Garlic products – 7 days Ginkgo – 36 hrs Ginseng – 7 days Kava – 24 hrs St.Johns Wort – 5 days Valerian – weeks before surgery by tapering

THE OTHER SIDE OF HERB – DRUG INTERACTIONS: 

THE OTHER SIDE OF HERB – DRUG INTERACTIONS Aromatic herbs such as ginger can be used to prevent drug-induced nausea Milk thistle can be used to prevent the liver toxicity associated with drugs Capsaicin reduces gastric mucosal damage induced by aspirin Combination of aqueous extract of Chinese medicinal plant Tripterygium wilfordi and cyclosporine significantly increases the heart and kidney allograft survival compared to cyclosporine alone Garlic prevents the formation of toxic metabolites of paracetamol

Slide 26: 

Co – administration of ginkgo with antipsychotics (haloperidol) in chronic schizophrenic patients reduces extra pyramidal side effects associated with haloperidol Centella asiatica can also be used as an adjunctive medication for patients with epilepsy due to its additive anticonvulsant activity Momordica charantia is reported to augment the hypoglycemic effect of rosiglitazone which can be used to reduce the dose of rosiglitazone to achieve enhance therapeutic effect with minimum side effects

Slide 27: 

Piperine can be used as bioavailability enhancer for several drugs and studies bolster that piperine enhances the bioavailability of propranolol which can be used as a means to achieve better therapeutic control and improved patience compliance Ginseng is considered to be potent adjuvant for delivery of vaccines which have been proven to induce higher or similar antibody titres than vaccines adjuvanted with aluminium hydroxide Rosemary ( Rosmarinus officinalis ) has chemopreventive effect as it increases efflux and intracellular accumulation of doxorubicin and vinblastine Silybinin enhances the antitumour activity of cisplatin

CONCLUSION: 

We need to bring into lime light about the herb – drug interactions CONCLUSION