drug interaction profesi new
TRANSCRIPT
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Prof Lukman Hakim PhD
Department 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 HornsManaging Clinically Important Drug Interactions, AppliedTherapeutics, Inc, Vancouver
2. Koda-Kimble et al (2007) Handbook of Applied Therapeutics,
8th
ed, Lippincott Williams & Wilkins, Philadelphia3. 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 Vitro
In 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 solution Ca-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):348-357
Thilo 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):3543
Raschetti R et al. Eur J Clin Pharmacol1999;54(12):959963
Contribution of Drug Interactions to the
Overall Burden of ADRs
Drug interactions represent 35 % of in-hospital
ADRs
Drug interactions are an important contributorto 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 drinks
3. Pollutants : insecticides, herbicides, smoke oftobacco, exhaust, industries
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Pasien yang berisiko mengalami efek burukinteraksi obat
1. Aplastic anemia2. Asthma
3. Cardiac arrhythmia4. Critical care/intensive care patients5. Diabetes6. Epilepsy7. Hepatic disease
8. Hypothyroid
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Obat-obat yang potensial berinteraksi
1. Autoimmune disorders
2. Cardiovascular disease3. Gastrointestinal disease
4. Infection
5. Psychiatric disorders
6. Respiratory disorders
7. Seizure disorders
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10 faktor yang berkaitan dengan interaksiobat
Jumlah dan jenis obatyang 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 : immunosupressant
Digoxin : cardiac stimulant/tonicEsterified estrogens : OC pills, enzyme inducersHypoglycemic agents : shock hypoglycemic ?LevothyroxineLithiumPhenytoin : nonlinear pharmacokinetics
Procainamide : heart arrhythmiaQuinidine : heart arrhythmiaTheophylline (aminophylline)Tricyclic antidepressantsValproic acid
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Pharmacokinetic Drug Interactions : Absorption
Alteration ActionDrug binding in GI tract
Iron may chelate ciprofloxacin, resulting indecreased absorption
GI motilityIncreased GI motility caused by metoclopramide
may decrease cefprozil absorption
GI pHGI alkalinization by omeprazole may decreaseabsorption of ketoconazole
GI flora
Decreased GI bacterial flora caused by an antibioticadmin could decrease bacterial production of
vitamin K augmenting anticoagulant effect ofwarfarin
Drug metabolism in wallof intestine
MAO in the wall of GI tract may be inhibited by MAOinhibitors resulting in increased blood pressure to
phenylephrine
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In the GI Tract Sucralfate, some milk
products, antacids,and oral ironpreparations
Omeprazole,lansoprazole,H2-antagonists
Didanosine (given
as a buffered tablet)
Cholestyramine
Block absorptionof quinolones,tetracycline, andazithromycin
Reduce absorptionof ketoconazole,delavirdine
Reduces ketoconazole
absorption
Binds raloxifene,thyroid hormone, anddigoxin
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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 liversChocolate, 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
CYP3A CYP2C9
CYP2C19
CYP2D6
Enzyme CYP 2C9, 2C19 dan 2D6 dapat mengalamipolymorphisme pada subyek (pasien) terjadi pengurangan
aktivitas metabolisme
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Terfenadin danAstemizol
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 intervalprolongation and cardiac arrhythmia due to astemizole
Risk factors : Not specific
Related drugs: Troleandomycin, clarithromycin and terfenadinemay 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 andincreases Cp of astemizole leading to cardiac arrhythmia
Risk factors : Not specificRelated drugs : Terfenadine, f luvoxamine and astemizole are
metabolized by CYP3A4
Management:
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 astemizoleleading to QT interval prolongation andcardiac arrhythmia due to astemizole
Risk factors : Not specificRelated drugs : Miconazole, itraconazole, and fluconazolemay also inhibit astemizole metabolism. Terfenadineconcentrations 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
Carbamazepine
Phenytoin
Phenobarbital
Morphine
Rifampin
Rifabutin St. Johnswort
Various herbs extracts versus
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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 days
A decaffeinated green tea (GT; Camellia sinensis) extract (4capsules/day, 14 days). Each GT capsule contained 211 +/- 25 mg of
catechins and
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Proportionality of drug metabolizing enzymes
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Most drug-metabolizing enzymes exhibit clinically relevantgenetic polymorphisms. Essentially all of the major humanenzymes responsible for modification of functional groups [phaseI reactions] or conjugation with endogenous substituents [phase IIreactions] exhibit common polymorphisms at the genomic level.
Enzyme polymorphisms that have already been associated with
changes in drug effects are separated from the corresponding piecharts.
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, thiopurinemethyltransferase; UGTs, uridine 5'-triphosphateglucuronosyltransferases.
B kd f G t i d
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Breakdown of Genotyping and
Phenotyping in FDA Survey
CYP2C19
14.3%
CYP2C94.3%
CYP3A4/5
14.3%
CYP1A2
7.1%
PhaseII
11.4%
Pgp
4.3%
Receptors
7%
Others
22.9%
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 -phosphatedehydrogenase, ApoE etc.
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GCCCACCTC
GCCCGCCTC
Patient A
Patient B
Wild type
Mutation
Wild type
Concentratio
n
Mutation
Concentration
Time
Time
CYP450
CYP450
Same dose but different plasma concentrations
Pharmacogenetics and Drug Metabolism
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Aklillu E et al. J Pharmacol Exp Ther1996;278(1):441 446
Cytochrome P450 2D6
Absent in 7 % of Caucasians12 % non-Caucasians
Hyperactive in up to 30 % of East Africans (Ethiopia)Catalyzes primary metabolism of:
Codeine (prodrug), Dextro-methorphan Many-blockers Many tricyclic antidepressants
Inhibited by: Fluoxetine, Paroxetine (strong inhibitors) Haloperidol Quinidine
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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 byCYP 2D6
mainly drugs acting on CNS and cardiovascular systems, includingnortriptyline
Phillips et al, JAMA, 286 (18), 2001,
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0
20
40
60
80
100120
140
Dose(mg)
PM IM EM
Phenotype
Nortriptyline: 25-300 mg
Inherited Activity of CYP 2D6 and
Nortriptyline Dosing
Nortriptyline Plasma Levels
PMEM
IM
Consequences: discontinue medication (ADR, lack of efficacy), delay torelief of symptoms (suicide), premature switch to other medications
Doses need forequivalent exposure
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Cytochrome P450 2C9
Absent in 1 % Caucasians andAfrican-Americans
Primary metabolism of : Most NSAIDs (incl COX-2 inhibitors : Celecoxib, Rofecoxib)
S-warfarin (active form)
Phenytoin
Inhibited by : Fluconazole
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h
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Cytochrome P450 2C19
Absent in 2030 % of Asians35 % Caucasians
Primary metabolism of : Diazepam
Phenytoin
Omeprazole
Tricyclic antidepressants
Clopidogrel (prodrug)
Inhibited by : Omeprazole
Isoniazid
Ketoconazole
h
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Cytochrome P450 2C19
Absent in 2030 % of Asians35 % Caucasians
Primary metabolism of Clopidogrel (antiplatelet)
Clopidogrel metabolized by CYP2C19 to active metabolite (ADPreceptor ; P2Y12).
Clopidogrel may cause severe GI bleeding.
Guideline : Clopidogrel is combined with PP Inhibitors tominimize bleeding.
Inhibited by Proton-pump inhibitors : Omeprazole = Esomeprazole >
Lansoprazole > Pantoprazole > Rabeprazole
C t h P450 1A2
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Cytochrome P450 1A2
Induced by smoking tobacco
Catalyzes primary metabolism of : Theophylline
Imipramine Propranolol
Clozapine
Inhibited by : Many fluoroquinolone antibiotics Fluvoxamine
Cimetidine
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Drug-Food Interactions
Tetracyclines and milk products
Warfarin and vitamin K-containing foods* Grapefruit juice
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 teaLiver
SoybeanVegetable oils (canola, soybean)Watercress
DRUGS THAT INTERACT WITH
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GRAPE FRUIT JUICEBenzodiazepines : midazolam, diazepam, triazolam
Cytotoxic drugs :cyclosporine, tacrolimus, sirolimusDyhydropyridine Calcium-channel blockers :
amlodipine, felodipine, nifedipine, nisoldipine, nitrendipine, verapamil
Theopylline
17-estradiol
Statins :simvastatin, lorvastatin, atorvastatin
Antidepressants : sertraline, buspirone, clomipramine
Antiepileptics : carbamazepine
Antiretroviral agents : saquinavir, indinavir
Antiarrhythmics : amiodaroneMisce : 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 verapamilby 36%. Inhibition of P-glycoprotein increases bioavailability of drugs.
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Dresser GK et al Clin Pharmacol Ther2000;68(1):2834
Hours after Dose Hours after Dose
Effects of grapefruit juice on felodipine pharmacokinetics and
pharmacodynamics.
Effect of grape fruit juice on talinolol
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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
Grape fruit juice reduces talinolol bioavailability
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Grape fruit juice reduces talinolol bioavailabilityin humans
Pharmacokinetics of talinolol (50 mg, PO) was determined withwater, with 1 glass of GFJ (300 mL), and after repeated GFJ (900mL/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
G f it j i l di i
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Grape fruit juice vs oral digoxin
Digoxin: a P-glycoprotein substrate, notmetabolized by CYP 3A4.
7 subjects received a single dose of digoxin 1mg with
water or GFJ (3x/day, 5 days) before digoxin admn tomaximize any effect on P-glycoprotein.
GFJ reduces digoxin absorption rate constant and increases
absorption lag time (p
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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
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Chlorpropamidevs 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, includingtolbutamide, cause hypoglycemia.
Taking phenformin may develop lactic acidosiswhen
consuming ethanol
Management : Avoid combination.
Hansten & Horn (1998) p. 99
Cigarette smoking vs Oral contraceptive
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Cigarette smoking vs Oral contraceptive
Risk of OC-induced adverse cardiovascular events isincreased by smoking
Risk factors:
Women aged > 35 years old are at greater risk Smoking > 15 cigs/day places women at greater risk
Management:Avoid combination.
Women on OC are adviced not to smoke, or use anothercontraception method
Hansten & Horn (1998) p. 107
Drug Herbal Interactions
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Drug-Herbal Interactions
St Johns Wort
Ginkgo biloba
Kava
Garlic
Izzo and Ernst (2009) Adis data information BV
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After St. Johns 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 : induksiCYP3A4 & modulasi Pgp kadar obat
Alprazolam, Amitriptyline, Imatinib, Indinavir,Midazolam, Omeprazol, Simvastatin, Tacrolimus,
Verapamil : induksi CYP3A4.
Warfarin : induksi CYP2C9
Ginkgo biloba
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g
(40-60 mg; 2x sehari; 2-3 bulan)
Efek: antioksidan, menghambat agregasiplatelet (ginkgolide = inhibitor PAF),menyembuhkan Alzheimer
Efek samping :
Perdarahan okular & intraserebral
Interaksi Obat :
next slide
Effect of Ginkgo biloba on various drugs
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Effect of Ginkgo biloba on various drugs
Drugs EffectCarbamazepine Valproicacid
High dose GB decreases anti-convulsant effect
Aspirin, clopidogrel,dipyridamole, heparin,ticlopidine, warfarin.
Anticoagulation increases
Cylosporine GB protects cell membranes fromdamage (beneficial effect)
Phenelzine ,tranylcypromine
GB enhances antidepressant effect ofMAO (serotonin reuptake) inhibitors
Kava (Pi th ti )
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Kava(Piper methysticum)
Zat aktif: kavapiron
Efek: penenang, sedatif
ES: disorientasi, gangguan kendali otot
Penggunaan 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
Garlic
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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 anticoagulatio
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, etc
3. Check pocket reference
4. Consult pharmacists/drug info specialists5. Check up-to-date website
www.epocrates.com*