Prof Lukman Hakim PhD

Department of Pharmacology and Clinical Pharmacy

Faculty of Pharmacy, Gadjah Mada University

References for further reading

1.

2.

3.

4.
5.

Koda-Kimble MA & Young LY (1998) Hansten and

Horns Managing Clinically Important Drug
Interactions, Applied Therapeutics, Inc, Vancouver
Koda-Kimble et al (2007) Handbook of Applied
Therapeutics, 8th ed, Lippincott Williams & Wilkins,
Philadelphia
Mozayani A & Raymon LP (2004) Handbook of Drug
Interactions- A Clinical and Forensic Guide, Humana
Press, New Jersey
Rodrigues AD (2002) Drug-Drug Interactions, Taylor &
Francis, New York
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 Vitro
In Vivo (in patients) :
Clinically expected or unexpected
Clinically observed or undetected
Clinical effect can be severe or light

In Vitro drug
interactions
Drugs

Interactant

Result

Ceftriaxone sodium

Lactated Ringer's
solution

Ca-Ceftriaxone precipitate

Daptomycin

Dextrose solution

Daptomycin precipitate

Daptomycin

0.9% saline solution

Lactated Ringer's
solution

Compatible

Piperacillintazobactam

Acyclovir

Particle formation

Amphotericin B

Flocculent

Mitomycin

Blue colour

Theophylline

Cefepime
Cefepime
David
W. Newton (2009) Am J Health-System
Pharm.degrades
66(4):348-357up
Thilo Bertsche et al (2008) Am J Health-Syst
25%Pharm. 65(19):1834-1840

to

Sumber variabilitas respon pasien

terhadap obat

Obat

input

Obat, OT, OBA

Makanan
Minuman
Asap tembakau
Polutan
Diurnal/Nocturn
al

Pasie
n

TDM

ADME

Usia, BB
Gender
Kehamilan
Genetik, Ras
Ritme
Sirkadian
Obesitas
Penyakit ADME

Drug assay
Active
compound
Ka, Vd, AUC, CL, T

Dose
adjustment

Contribution of Drug
Interactions to the Overall
Burden of ADRs
Drug interactions represent 35 % of in-

hospital ADRs
Drug interactions are an important
contributor to number of ER visits and
hospital admissions

Leape LL et al. JAMA 1995;274(1):3543

Raschetti R et al. Eur J Clin Pharmacol 1999;54(12):959963

Drug may interact with

1. Another drug(s) :
a. Synthetic drugs
b. Herbal or traditional medicines

2. Food and drinks

3. Pollutants : insecticides,

herbicides, smoke of tobacco,

exhaust, industries

Pasien yang berisiko mengalami efek

buruk interaksi obat
1.
2.
3.
4.
5.
6.
7.
8.

Aplastic anemia
Asthma
Cardiac arrhythmia
Critical care/intensive care patients
Diabetes
Epilepsy
Hepatic disease
Hypothyroid

Obat-obat yang potensial berinteraksi

1.
2.
3.
4.
5.
6.
7.

Autoimmune disorders
Cardiovascular disease
Gastrointestinal disease
Infection
Psychiatric disorders
Respiratory disorders
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

Pharmacokinetic Drug Interactions : Absorption

Alteration
Drug binding in GI tract
GI motility
GI pH

Action
Iron may chelate ciprofloxacin, resulting in
decreased absorption
Increased GI motility caused by metoclopramide
may decrease cefprozil absorption
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
Sucralfate, some
Tract
milk products,
antacids, and oral
iron preparations

Omeprazole,

lansoprazole,
H2-antagonists

Didanosine (given

as a buffered tablet)

Cholestyramine

Block absorption
of quinolones,
tetracycline, and
azithromycin
Reduce absorption
of ketoconazole,
delavirdine
Reduces ketoconazole
absorption
Binds raloxifene,
thyroid hormone, and
digoxin

FOODS HIGH IN TYRAMINE

Ale, 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

Binding agent

Acetaminophen,
diclofenac, digoxin,
glipizide,
furosemide,
iron,lorazepam,
methotrexate,
metronidazole,
piroxicam

Decreased
absorption

Colestipol

Binding agent

Carbamazapine,
diclofenac,
furosemide,
tetracycline,
thiazides

Decreased
absorption

Desipramine

Decreased GI
motility

Phenylbutazone

Decreased
absorption

Cytochrome P450
Isoforms
CYP1A2
CYP3A
CYP2C9
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,
simetidin)

flukonazol,

menyebabkan aritmia jantung

Terfenadine, cisapride dan astemizol masih dijual di Indonesia
Terfenadin dan Astemizol telah dilarang di US market (1998/99)
karena kasus interaksi obat

Astemizole vs
Erythromycin
Erythromycin and astemizole can cause QT interval
prolongation and cardiac arrhythmia due to
astemizole
Risk factors : Not specific
Related drugs: Troleandomycin, clarithromycin and
terfenadine
may also inhibit astemizole metabolism
Management:
Avoid combination
Use loratadine or cetirizine instead of astemizole
Certirizine, fexofenadine, loratadine = non-sedating antihistamines
Hansten & Horn (1998) p. 47

Astemizole vs
Fluvoxamine
Fluvoxamine inhibits astemizole metabolic enzyme
and increases Cp of astemizole leading to cardiac
arrhythmia
Risk factors : Not specific
Related drugs : Terfenadine, fluvoxamine and astemizole
are
metabolized by CYP3A4
Management:
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
Carbamazepine
Phenytoin
Phenobarbital
Morphine
Rifampin
Rifabutin
St. Johns wort

Various herbs 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
(4 capsules/day, 14 days). Each GT capsule contained 211
+/- 25 mg of catechins and <1 mg of caffeine
against 30 mg dextromethorphan (CYP 2D6 activity) and 2
mg alprazolam (CYP 3A4 activity) did not affect
elimination of the two drugs in 11 human volunteers

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 Omethyltransferase; GST, glutathione S-transferase; HMT,
histamine methyltransferase; NAT, N-acetyltransferase;
STs, sulfotransferases; TPMT, thiopurine methyltransferase;
UGTs, uridine 5'-triphosphate glucuronosyltransferases.

Others
22.9%
Receptors
7%
Pgp
4.3%

CYP2D
CYP
2D6
6
72.9%

PhaseII
11.4%

72.9 %

CYP1A2
7.1%
CYP3A4/5
14.3%
CYP2C9
4.3%

CYP2C19
14.3%

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.

Same dose but different plasma concentrations

Patient A
GCCCGCCTC
Wild type

Concentration

CYP450

Wild type

Time

GCCCACCTC
Mutation

CYP450

Mutation

Concentration

Patient B

Time

Cytochrome P450 2D6

Absent in 7 % of Caucasians

12 % 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

Aklillu E et al. J Pharmacol Exp Ther 1996;278(1):441 446

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,

Nortriptyline: 25-300 mg

EM

PM

Nortriptyline Plasma Levels

Dose (mg)

IM

140
120
100
80
60
40
20
0

Doses need for

equivalent exposure

PM

IM

EM

Phenotype

Consequences: discontinue medication (ADR, lack of efficacy), delay to

relief of symptoms (suicide), premature switch to other medications

Cytochrome P450 2C9

Absent in 1 % Caucasians and

African-Americans
Primary metabolism of :
Most NSAIDs (incl COX-2 inhibitors : Celecoxib,
Rofecoxib)
S-warfarin (active form)
Phenytoin

Inhibited by :

Fluconazole

Cytochrome P450
2C19
Absent in 2030 % of Asians

35 %

Caucasians
Primary metabolism of :
Diazepam
Phenytoin
Omeprazole
Tricyclic antidepressants
Clopidogrel (prodrug)

Inhibited by :
Omeprazole
Isoniazid
Ketoconazole

Cytochrome P450
2C19
Absent in 2030 % of Asians

35 % Caucasians
Primary metabolism of Clopidogrel (antiplatelet)
Clopidogrel metabolized by CYP2C19 to active
metabolite (ADP receptor ; P2Y12).
Clopidogrel may cause severe GI bleeding.
Guideline : Clopidogrel is combined with PP Inhibitors to
minimize bleeding.

Inhibited by

Proton-pump inhibitors : Omeprazole = Esomeprazole >

Lansoprazole > Pantoprazole > Rabeprazole

Cytochrome P450 1A2

Induced by smoking tobacco
Catalyzes primary metabolism of :
Theophylline
Imipramine
Propranolol
Clozapine

Inhibited by :
Many fluoroquinolone antibiotics
Fluvoxamine
Cimetidine

Drug-Food
Interactions
Tetracyclines and milk products
Warfarin and vitamin K-containing foods*
Grapefruit juice
Fam Brassicaceae (Cruciferous)

* Foods and Products High in Vitamin K

Alfalfa tablets
Broccoli
Brussels sprouts
Cabbage
Cauliflower (raw)
Green leafy vegetables (spinach, collard
greens)
Green tea
Liver
Soybean
Vegetable 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
17-estradiol
Statins : simvastatin, lorvastatin, atorvastatin
Antidepressants : sertraline, buspirone, clomipramine
Antiepileptics : carbamazepine
Antiretroviral agents : saquinavir, indinavir
Antiarrhythmics : amiodarone
Misce : methadone, sildenafil
GFJ increases bioavailability for felodipine by 200%, nifedipine 57% and verapamil
by 36%. Inhibition of P-glycoprotein increases bioavailability of drugs.
GFJ : enzyme and P-glycoprotein inhibitor

South Med J. 2009;102(3):308-309.

Hours after Dose

Hours after Dose

Effects of grapefruit juice on felodipine

pharmacokinetics and pharmacodynamics.
Dresser GK et al Clin Pharmacol Ther 2000;68(1):2834

Effect of grape fruit juice on talinolol

in rats
Cmax
(ng/mL)

AUC
(ug.min/mL)

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 ethanol
Management : 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 risk
Smoking > 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 Johns Wort
Ginkgo biloba
Kava
Garlic

Izzo and Ernst (2009) Adis data information BV

After St. Johns 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 anticonvulsant 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 : 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
Drugs

Indications

Clinical results

Chlorpropamide

Diabetes mellitus

Hypoglycemia

Fluindione
(co-meds : enalapril,
furosemide,
pravastatin)

Chronic atrial
fibrilation

Decreased
anticoagulation

Warfarin

Not reported

Increased
anticoagulation

Dextromethorphan
Debrisoquine

Healthy subjects;
CYP2D6

No effect on
elimination

Alprazolam,
Midazolam
Docetaxel

Healthy subjects;
CYP3A4

No effect on
elimination

HIV infection

Severe GI toxicity

Ritonavir 400-600 mg
bid

Izzo and Ernst (2009) Adis Data

Drug-Drug Interactions:
A Stepwise Approach
1. Take a medication history
2. Remember high risk patients
Any patient taking 2 medications
Anticonvulsants, antibiotics, digoxin,

warfarin, amiodarone, etc

3. Check pocket reference

4. Consult pharmacists/drug info
specialists
5. Check up-to-date website
www.epocrates.com*