Prof Lukman Hakim PhDDepartment of Pharmacology and Clinical Pharmacy

Faculty of Pharmacy, Gadjah Mada University

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

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)

Occurence of drug interactions

In VitroIn Vivo (in patients) :

Clinically expected or unexpected Clinically observed or undetected Clinical effect can be severe or light

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

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

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

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

Obat-obat yang potensial berinteraksi

1. Autoimmune disorders2. Cardiovascular disease3. Gastrointestinal disease4. Infection5. Psychiatric disorders6. Respiratory disorders7. Seizure disorders

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

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

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

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

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

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

Cytochrome P450 Isoforms

CYP1A2

CYP3ACYP2C9

CYP2C19 CYP2D6

Enzyme CYP 2C9, 2C19 dan 2D6 dapat mengalami polymorphisme pada subyek (pasien) – terjadi pengurangan

aktivitas metabolisme

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

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

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

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

CYP3A Inducers

CarbamazepineCarbamazepinePhenytoinPhenytoinPhenobarbitalPhenobarbitalMorphineMorphineRifampinRifampinRifabutinRifabutinSt. John’s wortSt. John’s wort

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

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.

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.

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

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

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,

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

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

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

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

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

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)

* Foods and Products High in Vitamin K

Alfalfa tabletsBroccoliBrussels sproutsCabbageCauliflower (raw)Green leafy vegetables (spinach, collard

greens)Green teaLiverSoybeanVegetable oils (canola, soybean)Watercress

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.

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.

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

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

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

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

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

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)

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

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

Drug-Herbal Interactions

St John’s WortGinkgo bilobaKavaGarlic

Izzo and Ernst (2009) Adis data information BV

After St. John’s Wort

Mean plasma concentration time course of indinavir.

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

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

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

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

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

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*