Rul Afiyah Syarif Pharmacology and Therapy Depart.

School of Medicine UGM

1.
2.

3.

Know the side effect of herbal medicine/ phytopharmaca Understand the risk of interaction between modern drug and herbal medicine/ phytopharmaca Know mechanism pharmacokinetic and pharmacodinamic interaction between modern drug and herbal medicine/ phytopharmaca

 Used

by 65-80% of the world population as their primary form of health care, especially in developing countries perceived that natural products are safe but the evidence suggests the HM is not without risk:

82% patient RA had tried more than 1 form of alternative medicine (n=90), 31% of them had experienced at least one adverse effect

mixtures of more than one active ingredient

Herbs and drugs may interact either pharmacokinetically or pharmacodynamically .

the likelihood of herb drug interactions is theoretically higher than that of drugdrug interactions

 Skin:

hypersensitivity reaction Liver: hepatotoxic effect, elevation of hepatic enzyme GI tract: nausea, vomiting, diarrhea Neurologic: dizzines, headache, insomnia Cardiovascular: syncope, hypotension Renal: failure, K-Na retention, urinary retention Pulmo: bronkhiolitis etc
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The risk and severity, depend on: Patients age Genetic constitution: G6PD defisiensi (anemi hemolitik) Nutritional state Concomitant diseases Concurrent medication Consumption of large amounts Consumption of wide variety

1.
a. b.

Intrinsic
Type A reactions: dose-dependent, predictable toxicity, over dosage, interaction with pharmaceuticals Type B reactions: unpredictable, idiosyncratic reactions (e.g. allergy, anaphylaxis), no dose-dependent

2.

Extrinsic
Failure of Good Manufacturing Practice a. Misidentification f. Incorrect preparation b. Lack of standardization and/or dosage c. Contamination g. Inappropriate labeling and/or advertising d. Substitution e. Adulteration

(Source: Drew and Myers, 1997)

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Yohimbine (an alkaloid found in Pausynistalia yohimbe bark) Has 2-adrenoreceptor antagonist activity, for male impotence Type A reaction: hypertension, anxiety Type B reaction; bronchospasm, increased mucus production when taken in normal doses by a patient with severe allergic dermatitis

1.

Misidentification
Use binomial Latin names for genus and species for plants occur when other names are used

2.

Lack of standardisation
examination in 50 commercial brands of ginseng sold in 11 countries,1 in 44 of these products, the concentration of ginsenoside ranged from 1.9% to 9% w/w; six products contained no ginsenoside

3.

Contamination
contaminated by pesticide residues, microorganisms, aflatoxins, radioactive substances and heavy metals; lead, cadmium, mercury, arsenic
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4.

Substitution
A Belgian slimming treatment, Stephania tetrandra was replaced with Aristolochia fangchi, containing the nephrotoxic component aristolochic acid, caused severe kidney damage

5.

Adulteration
Herbal products contain steroids (e.g. prednisolone, dexamethasone), pain killer (aminopyrine, acetaminophen), skeletal muscle relaxant (e.g. chlorzoxazone), minor tranquilizer (e.g. diazepam) and glybenclamide.
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6.

Incorrect preparation/dosage

7.

Inappropriate labelling/advertising

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16% of prescription users consume herbal suplements (Izzo, 2005)

potential interaction of alternative medicine products with prescription medications.

especially important to drugs with narrow therapeutic indices, such as warfarin.

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Follow modern pharmacological principle 1. Pharmacokinetic interaction

a.

Induction/inhibition of hepatic and intestinal drug metabolizing enzymes (cytochrome P450)

1) 2)

St Johns wort, echinacea, kava, garlic Flavonoids, coumarins, furanocoumarins, anthraquinon, caffeine, terpene

b.

induction/inhibition of drug transporters, such as P-glycoprotein :

Curcumin, ginsenosides, piperines, sylimarin, catechins

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2.
a.

Pharmacodynamic interaction
Additive/synergistic:
HM potentiates the action of synthetic drugs : anticoagulant warfarin interacts with antiplatelet herbs
b.

Antagonistic: HM reduces the efficacy of synthetic drugs:

Kava (Piper methysticum) possesses dopaminergic antagonist propertise, reduce the pharmacological activity of levodopa

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1.

Herba Hypericum perforatum (St. John's wort) Rhizoma Hydrastis canadensis (Golden seal)

2.

keduanya berinteraksi dengan obat-obat konvensional menyebabkan efek berlawanan atau menghilangkan efek dari obat kimia itu sendiri
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3.

Piper methysticum (kava-kava) : menyebabkan kerusakan hati

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4.

5.

6.

Atropa belladonna: atropine, hyoscyamine, scopolamine mengandung senyawa berkhasiat amat toksik, dikembangkan menjadi obat dan digolongkan Digitalis sp.: digitoxin sebagai obat keras (tidak dijual bebas), penggunaannya harus Ephedra sp.: efedrine & diawasi dokter pseudoefedrine Rauwolfia serpentina: yohimbine, reserpine, serpentinine

7.

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BPOM, 2011
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 The

possible interaction between conventional drugs and popular herbal medicine : 1. Ginkgo (Ginkgo biloba) 2. St Johns wort (Hyperiicum perforatum) 3. Ginseng (Panax sp) 4. Garlic (Allium Sativum L.) 5. Echinacea, 6. Saw palmetto (Serenoa repens) 7. Kava (Piper methysticum)

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to improve cognitive function Alzheimers disease and dementia to improve blood flow

peripheral vascular disease, tinnitus, or memory impairment

Main constituents: ginkolides, flavonoid Ginkgolide B inhibits platelet-activating factor by displacing it from its receptor-binding site, resulting in reduced platelet aggregation. Several cases of bleeding thought to be secondary to ginkgo ingestion Ginkgo force, Ginkan, Ginokan, etc

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Drugs Aspirin

results Spontaneous hyphema

Mechanism additive effect on platelet agregation (ginkgolides are potent inhibitors of PAF or have antiplatelet activity)

Comments hyphema is a clinical rare problem

NSAID Paracetamol and ergotamine/ca ffeine

bleeding Bilateral subdural hematoma

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Drugs Warfarin

results

Mechanism

Comments Intracerebral hemorrhage This effect may be an unusual adverse reaction to the drug or herb;

overadditive effect on anticoagulation coagulation mechanism Hypertension

Thiazide diuretic

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Main compounds: hypericine, hyperforin, flavonoids management of depression. as a MAO inhibitor Result of research :

1.

acts as a selective serotonin reuptake inhibitor (SSRI) Concurrent use of SSRIs with St Johns wort is contraindicated. may act in the cytochrome P-450 system of the liver. Another research :unlikely to inhibit the CYP2D or CYP3A4 liver enzyme systems. More research is needed.

2. 3.

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Drugs Digoxin (cardiac inotropic) warfarin

results decreased plasma digoxin concentration decreased anticoagulant effect decreased plasma simvastatin concentration

mechanism St Johns Wort induces Pglycoprotein involved in digoxin absorption/ excretion

Comments Digoxin has a narrow therapeutic index

Warfarin is metabolised potential by CYP enzyme which are thrombotic induced by St Johns complications Wort Simvastatin is a substrate P-glycoprotein and is metabolized by CYP enzymes Both P-glycoprotein and CYP enzymes are induced by St Johns Wort
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Simvastatin

Drugs Verapamil

results Decreased bioavailability of verapamil Reduction theophylline concentration in plasma

mechanism Induction of intestinal CYP3A4 by St Johns Wort St Johns Wort induce hepatic enzyme

Comments

Theophylline

Cyclosporin Decreased (immunnosupres Cyclosporin sant) concentrations in serum Combined oral contraceptive (ethinyloestradi ol and desogestrel) Breakthrough bleeding

St Johns Wort decrease intestinal absorption and increase metabolism of Cyclosporin Induction of intestinal CYP3A4 by St Johns Wort
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Decreae plasma level of ethinyloestradi ol and desogestrel

 Three
1. 2. 3.

ginseng species: American ginseng (Panax quinquefolius) : polysacharides (Panax ginseng Oriental ginseng (Panax ginseng): ginsenosides Siberian ginseng (Eleutherococcus senticosus) : eleutherosides have been promoted as energy enhancers, stress reducers, and mood improvers.
(Panax quinquefolius)
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 marketed

for a wide range of indications:

erectile dysfunction, cancer prevention, enhanced physical function and improved cognitive functions.

The

active components : ginsenosides The pharmacological activity of each ginsenoside appears to vary depending on where the plant grew and the extraction techniques used. Also, data suggest that the ginsenoside composition varies widely among commercially available ginseng products (1,9-9%). This variability makes it difficult to evaluate the safety and efficacy of ginseng products.
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 Pharmacological

effect of ginsenosides:

may increase adrenal hormone synthesis, decrease blood glucose concentrations, and promote immunomodulation.

Oriental

ginseng (Ginsana)

may antagonize the anticoagulant effects of warfarin.

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Drugs Warfarin

results decreased anticoagulant effect Increased alcohol clearance

Mechanism not known

Comments potential thrombotic complications

Alcohol

Ginseng increases the activity of alcohol dehydrogenase and aldehyde dehydrogenase

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 Main

constituents: polisacharides, phenol, alkamides Echinacea boosts the immune system and helps fight colds and flu, aids wound healing Used for prevention and treatment of upper respiratory tract infection Prepared from the roots and or other part of the plants: E. purpurea, E. angustifolia, E. pallida Drug interaction: cause inflammation of the liver if used with anabolic steroids, methotrexate
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Drugs Caffeine

results Reduction of caffeine oral clearance Increased (oral midazolam) or decreased (systemic midazolam) clearance

mechanism Caffeine is a sustrate of CYP1A2 which is inhibited by echinacea Midazolam is a sustrate of CYP3A4 Echinacea inhibits intestinal CYP3A4, whie it induces hepatic CYP3A4

Comments This inteaction is not clinically relevant Therapeutic manifestation is not determined

Midazolam

Remedy:

Imboost
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 Main

constituents: aliins have several beneficial cardiovascular effects:

lowering blood pressure and serum lipid, hypercholestrolemia, prevention atherosclerosis and antithrombotic activity.

Garlic

oil has been reported to interrupt thromboxane synthesis, thereby inhibiting platelet function.
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Drugs
Warfarin

results
overanticoagulation A fall in glucose level Changes in paracetamol pharmacokinetics variable Severe GI toxicity

Mechanism
additive effect on coagulation mechanism Additive effect Not known

Comments
Risk of bleeding.

Chlorpropamide Paracetamol

Ritonavir

Ritonavir inhibit metabolism of the active ingredients of garlic

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 The

ripe, dried fruit For urination problem in BPH stage I and II The lipophilic extract of the herb inhibits binding of dihydrotestosterone (DHT) to the cytosolic androgenic receptor and alpha 1adrenoceptor in the prostate, thus preventing accumulation of the steroid, which may lead to prostate hyperplasia No clinical evidence for serious toxicity No evidence for herb-drug interaction Remedy : Bioprost, Lanaprost
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 Roots

and rhizome Main compounds:Kavapyrones Anxiolitics Side effect :hepatotoxic

Drugs Alprazolam results Semicomatose state mechanism Additive efect on GABA receptors Comments Patient was lethargic and disoriented for several hours

Levodopa

Reduced efficacy of levodopa

Kava possesses dopaminergic antagonistic properties

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36

=curcuma Compounds: Curcuminoids (0.8 to 2%), including curcumin, demethoxycurcumin Indications and usage Liver and gallbladder complaints Loss of appetite Precautions and adverse reactions Stomach complaints: in the case of overdose. Stimulate the biliary tract, it should not be administered if there is a bile duct blockage. Colic can occur when the patient suffers from gallstones.

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 =turmeric
Compound:

Curcuminoids (3-5%), including curcumin, demethoxy curcumin, bidemethoxy curcumin Indication/usage:

Dyspeptic complaints, loss of appetite

Interaction:

turmeric inhibit platelet aggregation, increase risk bleeding Side effect:

stomach complaints can occur in the case of overdose. 38

 jamu

kunyit asam sebagai pelancar haid, sebaiknya dihindari saat masa awal kehamilan, karena ekstrak kunyit memiliki efek stimulan pada kontraksi uterus dan berefek abortivum Asam untuk menstabilkan dan mensuspensikan kunir, memberi rasa

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Main constituents: gingerols, zingerone Used as an antinausea and antispasmodic agent a potent inhibitor of thromboxane synthetase and thus reduce platelet aggregation and prolongs bleeding time. may lead to an increased risk of bleeding when taken with warfarin.

Jahe
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 The

main constituents: triterpene acids Effect:

Anti-inflammatory (a reduction of acute radiation reaction in rats), antineoplastic (involve direct action on DNA synthesis), ulcer-protective (reduced the formation of stressinduced ulcers) wound healing (an increase in peptidic hydroxyproline content, tensile strength, collagen synthesis, angiogenesis and epithelialization)

Precautions

and Adverse Reactions

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Allergic Contact Dermatitis

 Papain

is a mixture of proteolytic enzymes Papain has an antimicrobial, anthelmintic and anti-ulcerative effect, edema-reducing effect. Usage: reduces edema, inflammation, herpes zoster symptoms, diarrhea, and psoriasis symptoms. contraindicated in pregnancy, because of embryotoxic and teratogenic effect
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 The

pharmacological mechanisms by which papain may affect coagulation are not known. Patients receiving warfarin should be advised to avoid papain supplementation
Drugs Warfarin results Increased INR Comments

INR used to determine the clotting tendency of blood Normal INR = 0,8 1,2
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 Compounds:

caffeine, saponin, flavonoid,

prevent various cancers, treat gastrointestinal disorders, enhance cognition.

dried

green tea leaves

contain substantial amounts of vitamin K,

brewed

green tea : not considered a significant source of the vitamin.

large amounts of brewed green tea: potentially antagonize the effects of warfarin.

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 Side

effects:

persons who have sensitive stomachs, chiefly due to the chlorogenic acid and tannin content. Hyperacidity, gastric irritation, reduction of appetite, as well as obstipation or diarrhea, could be the result of intense tea consumption.

These

side effects can be generally avoided by the addition of milk (reduction of the chlorogenic acid and other tannins).
results
decreased anticoagulant effect

Drugs
warfarin

mechanism
green tea contain vit K , antagonize warfarin effect

Comments
potential thrombotic complications
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 increase

breast milk production during nursing period increased the expressions of prolactine and oxytocin genes in lactating BALB/C mice and was predicted to correlate with papaverine content, which is only detected in mature S. androgynus leaves

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 Ibu-ibu

hamil yang minum jamu cabe puyang (RS Sardjiito): kesulitan persalinan alkaloid piperin: berefek menghambat kontraksi otot, sehingga akan menyulitkan persalinan Diminum di awal kehamilan : memperkokoh otot uterus, resiko keguguran kecil Diminum terus sampai akhir kehamilan, otot uterus sulit kontraksi
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 Daun:

antiastma (melonggarkan pernafasan) Dikeringkan, diserbuk untuk rokok, dihisap Daun segar dilumatkan ditempelkan di pipi untuk sakit gigi Jika diseduh dan diiminum : keracunan berupa midriasis Bila disalahgunakan untuk mabuk sangat berbahaya, bisa kematian

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 Mengandung

antrakinon untuk melancarkan

BAB Mengandung skopoletin untuk menurunkan tekanan darah

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 Drew,

A.K. and Myers S.P. 1997. Safety Issues in Herbal Medicine: Implications for Health Professions. The Medical Journal of Australia. 166:538-541 2000. Physician Desk Reference for Herbal Medicine 2011. Info POM, Vol. 12 No. 3. BPOM RI

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