prof lukman hakim phd department of pharmacology and clinical pharmacy faculty of pharmacy, gadjah...
TRANSCRIPT
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Prof Lukman Hakim PhDDepartment of Pharmacology and Clinical Pharmacy
Faculty of Pharmacy, Gadjah Mada University
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References for further reading
1. Koda-Kimble MA & Young LY (1998) Hansten and Horn’s Managing Clinically Important Drug Interactions, Applied Therapeutics, Inc, Vancouver
2. Koda-Kimble et al (2007) Handbook of Applied Therapeutics, 8th ed, Lippincott Williams & Wilkins, Philadelphia
3. Mozayani A & Raymon LP (2004) Handbook of Drug Interactions- A Clinical and Forensic Guide, Humana Press, New Jersey
4. Rodrigues AD (2002) Drug-Drug Interactions, Taylor & Francis, New York
5. Stockley IH (1994) Drug Interactions, 3rd ed, Blackwell Science, London
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Web sites for more learning tools
www.arizonacert.org (drug interactions)www.drug-interactions.com
(P450-mediated drug interactions)www.torsades.org (drug-induced arrhythmia)www.penncert.org (antibiotics)www.dcri.duke.edu/research/fields/certs.html
(cardiovascular therapeutics)www.sph.unc.edu/healthoutcomes/certs/
index.htm(therapeutics in pediatrics)
www.uab.edu (therapeutics of musculoskeletal disorders)
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Occurence of drug interactions
In VitroIn Vivo (in patients) :
Clinically expected or unexpected Clinically observed or undetected Clinical effect can be severe or light
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In Vitro drug interactions
Drugs Interactant ResultCeftriaxone sodium Lactated Ringer's
solutionCa-Ceftriaxone precipitate
Daptomycin Dextrose solution Daptomycin precipitate
Daptomycin 0.9% saline solutionLactated Ringer's solution
Compatible
Piperacillin-tazobactam
Acyclovir Particle formation
Amphotericin B Flocculent
Mitomycin Blue colour
Theophylline Cefepime Cefepime degrades up to 25%
David W. Newton (2009) Am J Health-System Pharm. 66(4):348-357Thilo Bertsche et al (2008) Am J Health-Syst Pharm. 65(19):1834-1840
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Leape LL et al. JAMA 1995;274(1):35–43Raschetti R et al. Eur J Clin Pharmacol 1999;54(12):959–963
Contribution of Drug Interactions to the Overall Burden of ADRs
Drug interactions represent 3–5 % of in-hospital ADRs
Drug interactions are an important contributor to number of ER visits and hospital admissions
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Drug may interact with
1. Another drug(s) :a. Synthetic drugsb. Herbal or traditional medicines
2. Food and drinks3. Pollutants : insecticides,
herbicides, smoke of tobacco, exhaust, industries
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Pasien yang berisiko mengalami efek buruk interaksi obat
1. Aplastic anemia2. Asthma3. Cardiac arrhythmia4. Critical care/intensive care patients5. Diabetes 6. Epilepsy7. Hepatic disease8. Hypothyroid
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Obat-obat yang potensial berinteraksi
1. Autoimmune disorders2. Cardiovascular disease3. Gastrointestinal disease4. Infection5. Psychiatric disorders6. Respiratory disorders7. Seizure disorders
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10 faktor yang berkaitan dengan interaksi obat
Jumlah dan jenis obat yang digunakan
Jalur pemberian
Kepatuhan pasien Durasi penggunaan
Dosis/kadar obat Bioavailabilitas rendah
Kisar Terapi Sempit Masalah non-linearitas
Saat dan urutan penggunaan obat
Fraksi termetabolisme
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Drugs with Narrow Therapeutic WindowExamples :
Aminoglycoside antibiotics : gentamicin, tobramycinAnticoagulants : warfarin, heparins, high protein boundAspirin (salicylate derivatives), high PBCarbamazepine : enzyme inducerConjugated estrogens : OC pills, enzyme inducersCyclosporine : immunosupressantDigoxin : cardiac stimulant/tonicEsterified estrogens : OC pills, enzyme inducers Hypoglycemic agents : shock hypoglycemic ?LevothyroxineLithiumPhenytoin : nonlinear pharmacokineticsProcainamide : heart arrhythmiaQuinidine : heart arrhythmia Theophylline (aminophylline)Tricyclic antidepressantsValproic acid
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Pharmacokinetic Drug Interactions : Absorption
Alteration Action
Drug binding in GI tract Iron may chelate ciprofloxacin, resulting in decreased absorption
GI motility Increased GI motility caused by metoclopramide may decrease cefprozil absorption
GI pH GI alkalinization by omeprazole may decrease absorption of ketoconazole
GI flora
Decreased GI bacterial flora caused by an antibiotic admin could decrease bacterial production of vitamin K augmenting anticoagulant effect of warfarin
Drug metabolism in wall of intestine
MAO in the wall of GI tract may be inhibited by MAO inhibitors resulting in increased blood pressure to phenylephrine
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In the GI TractSucralfate, some
milk products, antacids, and oral iron preparations
Omeprazole, lansoprazole,H2-antagonists
Didanosine (givenas a buffered tablet)
Cholestyramine
• Block absorptionof quinolones, tetracycline, and azithromycin
• Reduce absorptionof ketoconazole, delavirdine
• Reduces ketoconazole absorption
• Binds raloxifene,thyroid hormone, and digoxin
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FOODS HIGH IN TYRAMINEAle, Avocados (especially if over-ripe)
Bananas
Bean pods, lima beans, butter bean
Canned Figs, Caviar
Cheese (especially aged)
Chicken livers
Chocolate, Coffee, Cola beverages
Fermented meats (salami, pepperoni, summer sausage)
Herring (pickled or dry)
Raspberries
Soy sauce, Sour cream, Tofu
Wines (especially red)
Yeast preparations, Yogurt
May, R.J. (1993). Adverse drug reactions. In J.T. DiPiro et al (Eds.), Pharmacotherapy: A Pathopysiologic approach (2nd ed., p. 71). Norwalk , CT, Appleton & Lange
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Drugs Affecting Absorption
Mechanism of Action
Object Drug Result
Cholestyramine
Colestipol
Desipramine
Binding agent
Binding agent
Decreased GI motility
Acetaminophen, diclofenac, digoxin, glipizide, furosemide, iron,lorazepam, methotrexate, metronidazole, piroxicam
Carbamazapine, diclofenac, furosemide, tetracycline, thiazides
Phenylbutazone
Decreased absorption
Decreased absorption
Decreased absorption
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Cytochrome P450 Isoforms
CYP1A2
CYP3ACYP2C9
CYP2C19 CYP2D6
Enzyme CYP 2C9, 2C19 dan 2D6 dapat mengalami polymorphisme pada subyek (pasien) – terjadi pengurangan
aktivitas metabolisme
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Terfenadin dan Astemizol berinteraksi dengan:
- Antifungal imidazol (eg. ketokonazol, flukonazol)
- Inhibitor CP-450 (eg ketokonazol, flukonazol, simetidin)
menyebabkan aritmia jantung
Terfenadin dan Astemizol telah dilarang di US market (1998/99) karena kasus interaksi obat
Terfenadine, cisapride dan astemizol masih dijual di Indonesia
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Astemizole vs Erythromycin
Erythromycin and astemizole can cause QT interval prolongation and cardiac arrhythmia due to astemizole
Risk factors : Not specificRelated drugs: Troleandomycin, clarithromycin and
terfenadine may also inhibit astemizole metabolism
Management: Avoid combination Use loratadine or cetirizine instead of astemizole
Hansten & Horn (1998) p. 47
Certirizine, fexofenadine, loratadine = non-sedating antihistamines
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Astemizole vs Fluvoxamine
Fluvoxamine inhibits astemizole metabolic enzyme and increases Cp of astemizole leading to cardiac arrhythmia
Risk factors : Not specificRelated drugs : Terfenadine, fluvoxamine and astemizole
are metabolized by CYP3A4Management: Avoid combination Use loratadine or cetirizine instead of astemizole
Hansten & Horn (1998) p. 48
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Astemizole vs Ketoconazole
Ketoconazole can increase Cp astemizole leading to QT interval prolongation and cardiac arrhythmia due to astemizole
Risk factors : Not specific
Related drugs : Miconazole, itraconazole, and fluconazole may also inhibit astemizole
metabolism. Terfenadine concentrations are increased with the antifungal agents
Management : Avoid combination Use loratadine or cetirizine instead of astemizole
Hansten & Horn (1998) p. 48
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CYP3A Inducers
CarbamazepineCarbamazepinePhenytoinPhenytoinPhenobarbitalPhenobarbitalMorphineMorphineRifampinRifampinRifabutinRifabutinSt. John’s wortSt. John’s wort
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Various herb’s extracts versus CYP 2D6 and 3A4 activities
Ginkgo biloba extract (120 mg, 2x a day, PO; 14 days).Siberian Ginseng extract (485 mg, 2x a day, 14 days)Saw Palmetto extract (320 mg/day, 14 days)The valerian supplement contained a total valerenic acid
content of 5.51 mg/tablet (every night, 14 days)Garlic extract (3 x 600 mg twice daily) for 14 daysA decaffeinated green tea (GT; Camellia sinensis) extract
(4 capsules/day, 14 days). Each GT capsule contained 211 +/- 25 mg of catechins and <1 mg of caffeine
aagainst 30 mg dextromethorphan gainst 30 mg dextromethorphan (CYP 2D6 activity)(CYP 2D6 activity) and and 2 mg alprazolam 2 mg alprazolam (CYP 3A4 activity)(CYP 3A4 activity) did not affect did not affect elimination of the two drugs in 11 human elimination of the two drugs in 11 human volunteersvolunteers
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Most drug-metabolizing enzymes exhibit clinically relevant genetic polymorphisms. Essentially all of the major human enzymes responsible for modification of functional groups [phase I reactions] or conjugation with endogenous substituents [phase II reactions] exhibit common polymorphisms at the genomic level.
Enzyme polymorphisms that have already been associated with changes in drug effects are separated from the corresponding pie charts.
ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; CYP, cytochrome P450; DPD, dihydropyrimidine dehydrogenase; NQO1, NADPH:quinone oxidoreductase or DT diaphorase; COMT, catechol O-methyltransferase; GST, glutathione S-transferase; HMT, histamine methyltransferase; NAT, N-acetyltransferase; STs, sulfotransferases; TPMT, thiopurine methyltransferase; UGTs, uridine 5'-triphosphate glucuronosyltransferases.
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CYP2C19
14.3%
CYP2C9
4.3%
CYP3A4/514.3%
CYP1A2
7.1%
PhaseII11.4%
Pgp4.3%
Receptors7%
Others22.9%
CYP 2D6
72.9%
• Genotyping and phenotyping performed in some submissions• Phase II enzymes measured: NAT-2, UGT, GSTM1, etc• Receptors: Dopamine, 5-HT, beta-adrenergic, alpha-1 adrenergic, potassium channels, etc • Others: HMC, CETP, ACE, alpha-reductase, AAG, CYP2B6, glyceraldehyde 3 -phosphate dehydrogenase, ApoE etc.
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GCCCACCTC
GCCCGCCTC
Patient A
Patient B
Wild type
Mutation
Wild type
Co
nce
ntr
atio
n
Mutation
Co
nce
ntr
atio
n
Time
Time
CYP450
CYP450
Same dose but different plasma concentrations
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Aklillu E et al. J Pharmacol Exp Ther 1996;278(1):441– 446
Cytochrome P450 2D6Cytochrome P450 2D6Absent in 7Absent in 7 % of Caucasians% of Caucasians
1 1––22 % non-Caucasians% non-CaucasiansHyperactive in up to 30Hyperactive in up to 30 % of East Africans% of East Africans
(Ethiopia)(Ethiopia)Catalyzes primary metabolism of:Catalyzes primary metabolism of:
CodeineCodeine (prodrug) (prodrug), Dextro-methorphan, Dextro-methorphan Many Many -blockers-blockers Many tricyclic antidepressantsMany tricyclic antidepressants
Inhibited by:Inhibited by: FluoxetineFluoxetine, , ParoxetineParoxetine (strong inhibitors) (strong inhibitors) HaloperidolHaloperidol QuinidineQuinidine
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Scientific Basis for Using Pharmacogenetics
Top 27 drugs frequently cited in ADR reports
59% (16/27) metabolized by at least one enzyme having poor metabolizer (PM) genotype
38% (11/27) metabolized by CYP 2D6 mainly drugs acting on CNS and cardiovascular systems,
including nortriptyline
Phillips et al, JAMA, 286 (18), 2001,
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020406080
100120140
Dos
e (m
g)PM IM EM
Phenotype
Nortriptyline: 25-300 mg
Nortriptyline Plasma Levels
PMEM
IM
Consequences: discontinue medication (ADR, lack of efficacy), delay to relief of symptoms (suicide), premature switch to other medications
Doses need forequivalent exposure
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Cytochrome P450 2C9Cytochrome P450 2C9
Absent in 1 % Caucasians andAfrican-Americans
Primary metabolism of : Most NSAIDs (incl COX-2Most NSAIDs (incl COX-2 inhibitors : Celecoxib, inhibitors : Celecoxib,
RofecoxibRofecoxib)) S-warfarin (active form)S-warfarin (active form) PhenytoinPhenytoin
Inhibited by : FluconazoleFluconazole
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Cytochrome P450 2C19Cytochrome P450 2C19
Absent in 20Absent in 20––3030 % of Asians % of Asians 3–53–5 % % CaucasiansCaucasians
Primary metabolism ofPrimary metabolism of :: DiazepamDiazepam PhenytoinPhenytoin OmeprazoleOmeprazole Tricyclic antidepressantsTricyclic antidepressants Clopidogrel (prodrug)Clopidogrel (prodrug)
Inhibited byInhibited by :: OmeprazoleOmeprazole IsoniazidIsoniazid KetoconazoleKetoconazole
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Cytochrome P450 2C19Cytochrome P450 2C19
Absent in 20–30 % of Asians 3–5 % Caucasians
Primary metabolism of Clopidogrel (antiplatelet)
Clopidogrel metabolized by CYP2C19 to active Clopidogrel metabolized by CYP2C19 to active metabolite (ADP receptor ; P2Y12).metabolite (ADP receptor ; P2Y12).
Clopidogrel may cause severe GI bleeding.Clopidogrel may cause severe GI bleeding. Guideline Guideline : Clopidogrel is combined with PP Inhibitors : Clopidogrel is combined with PP Inhibitors
to minimize bleeding.to minimize bleeding.
Inhibited by Proton-pump inhibitors : Proton-pump inhibitors : OmeprazoleOmeprazole = Esomeprazole > = Esomeprazole >
Lansoprazole > Pantoprazole > RabeprazoleLansoprazole > Pantoprazole > Rabeprazole
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Cytochrome P450 1A2Cytochrome P450 1A2
Induced by smoking tobaccoInduced by smoking tobaccoCatalyzes primary metabolism ofCatalyzes primary metabolism of ::
TheophyllineTheophylline ImipramineImipramine PropranololPropranolol ClozapineClozapine
Inhibited byInhibited by :: Many fluoroquinolone antibioticsMany fluoroquinolone antibiotics FluvoxamineFluvoxamine CimetidineCimetidine
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Drug-Food Drug-Food InteractionsInteractions
Tetracyclines and milk productsTetracyclines and milk productsWarfarin and vitamin K-containing Warfarin and vitamin K-containing
foodsfoods**Grapefruit juiceGrapefruit juiceFam Brassicaceae (Cruciferous)Fam Brassicaceae (Cruciferous)
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* Foods and Products High in Vitamin K
Alfalfa tabletsBroccoliBrussels sproutsCabbageCauliflower (raw)Green leafy vegetables (spinach, collard
greens)Green teaLiverSoybeanVegetable oils (canola, soybean)Watercress
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DRUGS THAT INTERACT WITH GRAPE FRUIT JUICE
Benzodiazepines : midazolam, diazepam, triazolam
Cytotoxic drugs : cyclosporine, tacrolimus, sirolimus
Dyhydropyridine Calcium-channel blockers :
amlodipine, felodipine, nifedipine, nisoldipine, nitrendipine, verapamil
Theopylline
17β-estradiol
Statins : simvastatin, lorvastatin, atorvastatin
Antidepressants : sertraline, buspirone, clomipramine
Antiepileptics : carbamazepine
Antiretroviral agents : saquinavir, indinavir
Antiarrhythmics : amiodarone
Misce : methadone, sildenafil
GFJ : enzyme and P-glycoprotein inhibitor South Med J. 2009;102(3):308-309.
GFJ increases bioavailability for felodipine by 200%, nifedipine 57% and verapamil by 36%. Inhibition of P-glycoprotein increases bioavailability of drugs.
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Dresser GK et al Clin Pharmacol Ther 2000;68(1):28–34
Hours after Dose Hours after Dose
Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics.
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Effect of grape fruit juice on talinolol in rats
Cmax
(ng/mL)AUC
(ug.min/mL)
S R S R
Control 77.5 79.5 19.3 22.2
GFJ 163.6 163.0 29.9 30.1
• GFJ administered together with a racemic 10 mg/kg (po) in rats
• GFJ did not change T1/2 elimination of talinolol
Spahn-Langguth & Languth - Eur J Pharm Sci. 2001 Feb;12(4):361-7
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Grape fruit juice reduces talinolol bioavailability
in humans
Pharmacokinetics of talinolol (50 mg, PO) was determined with water, with 1 glass of GFJ (300 mL), and after repeated GFJ (900 mL/d, 6 days) in 24 healthy white volunteers
Results :
A glass or repeated administration of GFJ : - decreases talinolol AUC, Cmax, and Fel (p <
0.001) decreases bioavailability of talinolol.- does not affect CLr, T1/2 elimination, Tmax.
Schwarz et al - Clin Pharmacol Ther. 2005 Apr; 77(4): 291-301
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Grape fruit juice vs oral digoxin
Digoxin: a P-glycoprotein substrate, not metabolized by CYP 3A4.
7 subjects received a single dose of digoxin 1mg with water or GFJ (3x/day, 5 days) before digoxin admn to maximize any effect on P-glycoprotein.
• GFJ reduces digoxin absorption rate constant and increases absorption lag time (p<0.05).
• GFJ does not affect Cmax, AUC, T1/2 elim, or CLr digoxin.• Inhibition of intestinal P-glycoprotein by GFJ does not play an
important role in drug interactions.
Parker et al - Pharmacotherapy. 2003 Aug;23(8):979-87
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Daya analgetik parasetamol sebelum dan setelah pemberian brokoli 7-kali pada mencit jantan BALB/C
1. Parasetamol mempunyai daya analgetik 54, 74 %2. Brokoli menaikkan % daya analgetik parasetamol
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Daya analgetik salisilat sebelum dan setelah pemberian brokoli
7-kali mencit jantan BALB/C
1. Salisilat mempunyai daya analgetik 56,84%2. Brokoli menaikkan % daya analgetik salisilat
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Onset dan durasi fenobarbital sebelum dan setelah pemberian jus brokoli 7-kali pada mencit jantan
1. Brokoli memperlama onset fenobarbital tetapi tidak signifikan (P > 0,05)
2. Brokoli mempercepat durasi fenobarbital (P <0,05)
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Chlorpropamide vs Ethanol
Excessive ethanol intake may lead to hypoglycemia. An “antabuse-like reaction” may occur in patients taking sulfonylureas.
Risk factors : Not specific (can be to anyone/any case)
Related drugs : Insulin and other oral hypoglycemic agents,
including tolbutamide, cause hypoglycemia.Taking phenformin may develop lactic acidosis when
consuming ethanolManagement : Avoid combination.
Hansten & Horn (1998) p. 99
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Cigarette smoking vs Oral contraceptive
Risk of OC-induced adverse cardiovascular events is increased by smoking
Risk factors:Women aged > 35 years old are at greater riskSmoking > 15 cigs/day places women at greater risk
Management:Avoid combination.Women on OC are adviced not to smoke, or use
another contraception method
Hansten & Horn (1998) p. 107
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Drug-Herbal Interactions
St John’s WortGinkgo bilobaKavaGarlic
Izzo and Ernst (2009) Adis data information BV
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After St. John’s Wort
Mean plasma concentration time course of indinavir.
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Pengaruh SJ Wort terhadap
Digoxin, Fenoxfenadine, Irinotecan : memodulasi P-glycoprotein kadar obat ↓
Cyclosporin, OC pills, Ritonavir, Venlafaxine : induksi CYP3A4 & modulasi Pgp kadar obat ↓
Alprazolam, Amitriptyline, Imatinib, Indinavir, Midazolam, Omeprazol, Simvastatin, Tacrolimus, Verapamil : induksi CYP3A4.
Warfarin : induksi CYP2C9
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Ginkgo biloba (40-60 mg; 2x sehari; 2-3 bulan)
Efek: antioksidan, menghambat agregasi platelet (ginkgolide = inhibitor PAF), menyembuhkan Alzheimer
Efek samping :Perdarahan okular & intraserebral
Interaksi Obat :next slide
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Effect of Ginkgo biloba on various drugs
Drugs Effect
Carbamazepine Valproic acid
High dose GB decreases anti-convulsant effect
Aspirin, clopidogrel, dipyridamole, heparin, ticlopidine, warfarin.
Anticoagulation increases
Cylosporine GB protects cell membranes from damage (beneficial effect)
Phenelzine , tranylcypromine
GB enhances antidepressant effect of MAO (serotonin reuptake) inhibitors
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Kava (Piper methysticum)
Zat aktif : kavapironEfek : penenang, sedatifES : disorientasi, gangguan kendali ototPenggunaan kronis : gangguan kimia darah,
hipertensi paru, nafas pendek, mata merah, berat badan turun
Interaksi obat : CNS depressants, L-dopa, nembutal, barbiturat, Xanax => efek aditif
Izzo and Ernst (2009) Adis Data
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Garlic
Drugs Indications Clinical resultsChlorpropamide Diabetes mellitus Hypoglycemia
Fluindione (co-meds : enalapril, furosemide, pravastatin)
Chronic atrial fibrilation
Decreased anticoagulation
Warfarin Not reported Increased anticoagulation
DextromethorphanDebrisoquine
Healthy subjects; CYP2D6
No effect on elimination
Alprazolam, MidazolamDocetaxel
Healthy subjects; CYP3A4
No effect on elimination
Ritonavir 400-600 mg bid
HIV infection Severe GI toxicity
Izzo and Ernst (2009) Adis Data
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Drug-Drug Interactions: A Stepwise Approach
1. Take a medication history2. Remember high risk patients• Any patient taking 2 medications• Anticonvulsants, antibiotics, digoxin,
warfarin, amiodarone, etc3. Check pocket reference 4. Consult pharmacists/drug info
specialists5. Check up-to-date website• www.epocrates.com*