Aznan LeloDep. Farmakologi & Terapeutik,

Fakultas KedokteranUNIBA

7 September 2011, UNIBA, Batam

Background• Polypharmacy is common among supplement

users• Many assume herbs and supplements are safe• Many pharmacological actions but dangerous

side effects and interactions exist• Be sure to ask your patients (non-judgmental)• Knowledge is our best weapon and protection

A Good Medication History: AVOID Mistakes

• Allergies?• Vitamins and herbs?• Old drugs and OTC? (as well as

current)• Interactions? • Dependence? Do you need a contract?• Mendel: Family Hx of benefits or

problems with any drugs?

Problems Associated with Use of Herbal Medicines

• Lack of QC & standardisation• Adulteration with other plants,

pharmaceutical drugs or heavy metals• Inappropriate use / misleading claims• Type A & B ADRs• Potential for drug interactions• Lack of knowledge re: interactions, ADRs

• steroids: prednisolone, hydrocortisone, triamcinolone, methyltestosterone

• benzodiazepines: diazepam, estazolam, chlordiazepoxide• heavy metals: mercury, lead, arsenic, antimony, cadmium• analgesics and NSIADs: acetaminophen, aspirin,

indomethacin, mefanamic acid• other drugs and chemicals: hydrochlorothiazide,

digitalis, caffeine, scopolamine, atropine, strychnine, carbamazepine, phenytoin, valproic acid, dipyrone, diacetyldiphenolisatin

Common Adulterants and Contaminants

Foraging and harvesting Issues, problems, etc….

• Misidentification• Potencies vary from batch to batch…. season

to season….• Chemical composition varies between

cultivars, geography, environmental conditions

• Changing nomenclature– Botanical and medical

Herbals and Supplements:Potential interactions with Rx Drugs• SAMe may increase homocysteine levels• St. John’s wort and Oral contraceptives• Ginkgo may increase anticoagulant effects

of ASA, warfarin, NSAIAs, ticlopidine, and may interact with MAOIs

• Bottom line: Try to know what your patient is taking, and ask in a nonjudgmental way

Definitions and Terms• Side Effects: unintended, usually detrimental,

consequences• Adverse: untoward, unintended, possibly causing harm• AE: Adverse Event, Effect or Experience• ADE (AE associated with a Drug): an AE which

happens in a patient taking a drug• ADR (Adverse Drug Reaction): an ADE in which a

causal association is suspected between the drug and the event

Unfortunately, these terms are frequently used interchangeably

INCIDENCE of ADRs• ADRs are always under reported• ADRs are the 4th-6th largest cause for mortality in

the USA1

• ADRs account for approximately 10% of hospital admissions

– Norway 11.5%, France 13.0% UK 16.0%2

• ADRs increase the length of hospital stay and medical costs

• 15-20% of hospital budget may be spent dealing with drug complications3

1. Lazarou et al.JAMA 1998, 279(15) 1000-52. Safety of Medicines. WHO/EDM/QSM/2002.23. White et al. Pharmacoeconomics,1999,15(5) 445-458

Drug Related Adverse Reactions

• identify the suspected drug• identify factors that contributed to the

occurrence of the adverse reaction such as • multiple drug therapy, • drug-drug interactions• drug-herbal interactions • Drug – food interactions • Excipients, colouring agents

Garlic• Efficacy: ? benefit for use in hyperlipidemia.

Possible other cardiovascular benefits.• Safety: good• Drug interactions: warfarin; possibly aspirin

and other antiplatelet adhesion drugs (pharmacodynamic interaction); not with HIV drugs (other 3A4 substrates?) but depends on product (pharmacokinetic interaction) (maybe raw garlic induces 3A4 but not extracts??)

Garlic

• Heat and acid inactivate allicin, enteric coated products show best results

• May increase effects of anticoagulants, may inhibit thyroid preparations

• Precautions and interactions: Inhibited platelet aggregation (interaction with anticoagulants), may reduce blood sugar so use with caution with various hypoglycemic agents

Echinacea• Efficacy: evidence for treatment not

prevention• Safety: good; rare allergy• Drug interactions:

• don’t give to patients taking immunosuppressive drugs• Antagonises immunosuppressants• Increased bleeding time• Pharmacokinetic:

• may inhibit 1A2; may inhibit intestinal 3A4 but induce hepatic so clinical significance unclear; effect on 2C9 is considered minor

Ginkgo biloba– Efficacy: good for dementia and poor

peripheral circulatory problems– Safety: good; rare bleeding episodes– Drug interactions: no effect on 3A4,2C9 or

2D6 but may induce 2C19; may inhibit platelet adhesion; possible (not necessarily probable!) interaction with “blood thinners” and warfarin so avoid or close monitoring needed.

Ginkgo and coagulation and pharmacodynamic interactions with

antiplatelet adhesion inhibitorsCoagulation in healthy adults (in absence of other drugs) Kohler et al. Blood Coagul Fibrinolysis. 2004;15:303-9. (company study). No effect on coagulation parameters in healthy adults after 7d of EGb761 120mg/d. n=50.

Ginkgo biloba • + Diclofenac or + Tolbutamide Human Studies

Conclusions• No difference was observed in the metabolic

ratio between the two arms of the study (tolbutamide alone and tolbutamide + Ginkgo)

• No difference was seen between the clearances of the two arms of the study (diclofenac alone and diclofenac + Ginkgo)

• Ginkgo extract does not appear to interact with CYP2C9 substrates in humans

Ginkgo biloba• Precautions and interactions:

– Ginkolide is a selective antagonist of platelet aggregation. Case reports of subdural hematoma and spontaneous bleeding with ASA use. Reports of GI disturbances and CNS symptom

– Ginkgo and caffeine may increase risk of subdural hematomas

– Ginkgo helped SSRI induced sexual dysfunction 91% in women, 76% in men (Cohen and Bartlik 1998)

• Use with extreme caution with stimulants

Soy– Efficacy: increased soy ingestion may

decrease hot flashes and other postmenopausal symptoms; cardiovascular benefits as well.

– Safety: good but use in breast cancer may be risky

– Drug interactions: not with with tamoxifen but effect on CYP3A4 is unlikely

Ginseng• Efficacy: some evidence for applications in

geriatric patients (improved “quality of life”) and in diabetes

• Safety: good; • Drug interactions: no apparent induction of

CYP 3A4 but induction of 2C9 (warfarin) with Am ginseng (Panax quinquifolius) but maybe not Panax ginseng. May precipitate hypoglycemia with insulin or oral hypoglycermics.

Ginseng• Precautions and interactions: May increase BP.

Overuse can cause headaches, insomnia, palpitations. Estrogen affects may cause vaginal bleeding, fibrocystic breasts

Interacts with Lasix, decreases diuretic action• One study demonstrates enhanced alcohol

clearance in healthy men (Lee et al, 1987)• May induce mania when used concurrently with

antidepressants (Gonzalez-Seiji et al, 1995)• May potentiate MAO inhibitors (Shader et al, 1988)• May inhibit metabolism of barbituates• May potentiate stimulants (caffeine most studied)• May cause Haloperidol catalepsy

Saint John’s Wort• Contraindications: Severe depression with

akinetic mutism, suicidal tendencies, severe agitation, hypersensitivity and pregnancy (estrogen effects)

• Precautions: photosensitivity• Interactions: May precipitate hypertensive crisis

with MAO inhibitors (Mueller & Shaefer,1996)• May induce “serotonin syndrome” with SSRI’s

and with Triptans• Interferes with cyclosporine, may cause

transplant rejection• May cause hypertension with tyramine

containing foods• Safe with benzodiazapines

St. John’s Wort– Efficacy: good evidence for mild to

moderate depression– Safety: don’t combine with other

medications unless under close monitoring; possible photosensitivity

– Drug interactions: a problem! Is a broad spectrum P450 inducer and a p-glycoprotein inducer.

Drug CYP Effect Management HIV protease inhibitors (nelfinavir,ritonavor,saquinavir)

Induce 3A4 Stop and measure viral load

HIV non-nucleoside RTI (efavirenz,nevirapine)

Induce 3A4 Stop and measure viral load

warfarin Induce 2C9 Stop and adjust warfarin dose

cyclosporin Induce P-glycoprotein

Stop and adjust cyclosporine dose

oral contraceptives Induce 3A4 Stop and use alternate birth control

anticonvulsants Induce 3A4 Stop and adjust anticonvulsant dose

digoxin Induce P-glycoprotein

Stop and adjust digoxin dose

theophylline Induce 1A2 Stop and adjust theophylline dose

Triptans (sumatriptan)

Increase serotonin

Stop

SSRI (fluoxetine,sertraline, etc)

Increase serotonin

Stop

Summary of SJW Interactions(adapted from Henderson et al. Br J Clin Pharmacol 2002;54:349-346)

St. John’s Wort• With SSRIs, triptans - symptoms

characteristic of serotonin syndrome• Theophylline (CYP1A2), cyclosporin

(CYP3A4) and warfarin (CYP2C9) - reports of a reduction in the serum concs

• With COC - reports of breakthrough bleeding - reduced efficacy?

• Advice published by the IMB and CSM

Saw Palmetto• Uses: For male genitourinary problems (BPH),

prostate cancer, antisepsis• Likely safe in usual doses for up to one year• Likely effective for BPH symptoms• Possibly effective for adjunctive therapy for

prostate cancer• Precautions and interactions: Due to anti-

testosterone action do not use in pregnancy or children, can cause stomach upset, no psychotropic interactions

Testosterone Synthesis

Cholesterol Pregnenolone

DHEA

Androstenedione

Testosterone

Evening Primrose• Uses: Lower cholesterol, treat atopic dermatitis, arthritis, PMS, mastalgia• High in gamma-linolenic acid (GLA) and linolenic

acid, prostaglandin precursors, essential fatty acids• Safe in usual doses, increases delivery

complications• Precautions and interactions: May aggravate

temporal lobe epilepsy, interacts with some anti-seizure medications, case reports of seizures in schizophrenics on phenothiazines

Valerian• Valeriana officinalis root extract used to

promote sleep• Increases levels of GABA in CNS• Possibly safe in short term (14 days),

possibly unsafe for long term use (withdrawal)

• Possibly effective for subjective sleep quality

• May potentiate CNS depressants especially benzodiazapines

Feverfew• Uses: Migraine headaches (vasoconstrictive),

used for menstrual problems and fever• Possibly safe in usual doses• Possibly effective in preventing and decreasing

severity of migraines• Precautions and interactions: Leaves can cause

mouth ulcerations, may cause menstrual or lactation problems, occasional GI side effects, may increase effects of anticoagulants, reported hypertensive crisis with triptans

Ephedra ProblemsSynergistic effect with caffeine, decongestants, and stimulantsPro-arrhythmic effects with cardiac glycosides and halothaneMAO inhibitors potentiate stimulation effectsCan increase agitation associated with SSRI’sOverdose syndrome can be fatalMay be detected in urine screening as a banded substance

Kava Kava• Uses: Nervous tension (anxiety), stress and

agitation, insomnia– Likely effective: Head to Head comparison to

benzodiazapines showed equal efficacy for anxiety (Woelk, 1993)

• Kava pyrones have central muscle-relaxing, anticonvulsive, hypnotic/sedative effects by interaction with ion channels and GABA sites

• liver failures even with short term use

Kava Kava Interactions• Synergy with Alcohol. EtOH potentiates

Kava toxicity• Reports of coma with Kava and Xanax• Potentiates all CNS depressants• Antagonizes dopamine, do not use in

Parkinson’s patients• Interaction with cimetidine causes

confusion and disorientation

Interaksi obat-temulawak

• Anti-platelet : dapat menyebabkan resiko perdarahan

• Warfarin : peningkatan efek antikoagulansehingga terjadi perdarahan

• Camptohecin : penghambatan kerja camptothecin dalam menginduksi apoptosis sel kanker payudara

• Ibuprofen : peningkatan resiko perdarahan

• Meclorethamin : Penghambatan kerja meclorethamin dalam menginduksi apoptosis sel kanker payudara

• Bromelain : peningkatan efek anti-agregasi

• Ginkgo biloba: peningkatan efek ginkgo biloba menyebabkan resiko perdarahan

• Bawang putih : Terjadi penurunan gula darah

Seem to have low pharmacokinetic drug interaction

potential• Ginger• Valerian• Milk thistle• Saw palmetto• Black cohosh• CoQ10• glucosamine

What can we do?• dialog with NDs and other prescribers• recommend the best products• ask patients about herbals they may be taking• herbals should not usually be recommended for

acute or serious illnesses• avoid herbal use with drugs with narrow

therapeutic window, esp. warfarin, cyclosporin, digoxin, HIV protease inhibitors, theophylline, carbamazepine

• stay informed

Steps for Detecting and Advising on Herbal/Drug Interactions

– Is the patient taking any herbal supplements?

– Does the herbal have efficacy for the intended use?

– Is the product reliable? (i.e.,what are they REALLY taking?)

– Is the Rx drug one with a narrow therapeutic margin?

Evaluation of Herbal/Drug Interactions• Speculative or Theoretical

– e.g. St. John’s Wort and tyramine containing foods due to MAOI effects or evening primrose oil and risk for bleeds with warfarin

• In vitro effects– e.g. ginkgo and microsomal studies showing inhibition

of CYP2C9• In vivo - animal studies

– e.g. kava and alcohol• In vivo - human case reports

– e.g. ginkgo and warfarin bleeds• In vivo - healthy human volunteer studies

– e.g. indinivir and St. John’s Wort• In vivo - clinical studies in patients

Herbal Medicines

................. Not all that is natural is harmless

Herb Drug Interactions• Dong Quai: taken for menopausal symptom control. Do not mix Dong

Quai with warfarin (anticoagulants), St John's Wort and some antibiotics such as sulfonamides, quinolones.

• Echinacea: mostly taken as an immune boost to prevent cold and flu. Do not mix Echinacea with some heart medications, antifungal medications, HIV medications and anti-anxiety medications.

• Ephedra: A powerful decongestant. Contains ephedrine, which can open up bronchial passages. It's controversial because it's a powerful stimulant that can raise blood pressure, cause insomnia and high blood pressure. Do not mix with heart medications or if you are being treated for high blood pressure, glaucoma or thyroid problems.

• Feverfew: taken to reduce the severity of migraines. Do not take with other migraine medications, as, it may raise heart rate and blood pressure. Feverfew has the potential to react with warfarin anti-coagulants, increasing the thinning of blood.

Herb Drug Interactions• Ginkgo: increases blood flow and circulation throughout the body, can also help

improve memory. May interact with anti-coagulant medications such as Aspirin, Coumadin, heparin and warfarin, causing the blood to thin too much, and provoking a serious bleeding disorder. A recent report in the New England Journal of Medicine describes a case of a man who'd been taking Aspirin to prevent a heart attack and had spontaneous bleeding into the eye from the iris within a week of taking a daily dose of ginkgo.

• Garlic: is thought to help lower cholesterol and prevent the formation of blood clots that could lead to heart attacks. Garlic capsules may increase blood thinning if you are already on anti-coagulants. Do not take with diabetes medication because it may cause a decrease in blood sugars.

• Ginseng: used to help reduce stress, boost energy and improve stamina, and may also help lower cholesterol. Can cause nervousness and excitation, and overuse can lead to headaches, insomnia and heart palpitations. Can increase blood pressure. Should not be used if you are taking prescriptions for high blood pressure or Coumadin.

• Hawthorn: claimed to be effective in helping reduce angina attacks by lowering blood pressure and cholesterol levels. Should not be taken digoxin, a heart medication. The mix may lower heart rate too much.

Herb Drug Interactions• Kava: is used to treat anxiety. It's also used to relieve insomnia and

nervousness. Do not take Kava if you have a history of liver problems. Also do not mix with antidepressants, sedatives, and do not mix Kava with alcohol.

• Licorice: used to treat coughs, colds and peptic ulcers. High doses can lead to increased blood pressure, water retention and potassium loss. Do not use with diuretics or digoxin because it could lead to further loss of potassium, essential for heart function.

• St. John's wort: a natural anti-depressant for mild to moderate depression. Do not take with other anti-depressants, HIV medications, oral contraceptives, some heart/blood thinning medications and Tamoxifen (a cancer drug).

• Valerian: a mild sedative with hypnotic effects, used to promote sleep, Should not be taken with alcohol or Valium.