Drug Interaction Profesi New

8/3/2019 Drug Interaction Profesi New

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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



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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



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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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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.


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


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*

Documents

Drug Interaction Profesi New