Download DRUG INTERACTIONS

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 Horn’s
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
Piperacillin-tazobactam
Acyclovir
Particle formation
Amphotericin B
Flocculent
Mitomycin
Blue colour
Cefepime
Cefepime degrades up to 25%
Theophylline
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
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
Leape LL et al. JAMA 1995;274(1):35–43
Raschetti R et al. Eur J Clin Pharmacol 1999;54(12):959–963
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. Aplastic anemia
2. Asthma
3. Cardiac arrhythmia
4. Critical care/intensive care patients
5. Diabetes
6. Epilepsy
7. Hepatic disease
8. Hypothyroid
Obat-obat yang potensial berinteraksi
1. Autoimmune disorders
2. Cardiovascular disease
3. Gastrointestinal disease
4. Infection
5. Psychiatric disorders
6. Respiratory disorders
7. 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 Window
Examples :
Aminoglycoside antibiotics : gentamicin, tobramycin
Anticoagulants : warfarin, heparins, high protein bound
Aspirin (salicylate derivatives), high PB
Carbamazepine : enzyme inducer
Conjugated estrogens : OC pills, enzyme inducers
Cyclosporine : immunosupressant
Digoxin : cardiac stimulant/tonic
Esterified estrogens : OC pills, enzyme inducers
Hypoglycemic agents : shock hypoglycemic ?
Levothyroxine
Lithium
Phenytoin : nonlinear pharmacokinetics
Procainamide : heart arrhythmia
Quinidine : heart arrhythmia
Theophylline (aminophylline)
Tricyclic antidepressants
Valproic acid
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 Tract
 Sucralfate, some 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, flukonazol, simetidin)
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. 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 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
Proportionality of drug metabolizing enzymes
 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 Stransferase; HMT, histamine methyltransferase; NAT, Nacetyltransferase; STs, sulfotransferases; TPMT, thiopurine
methyltransferase; UGTs, uridine 5'-triphosphate
glucuronosyltransferases.
Breakdown of Genotyping and
Phenotyping in FDA Survey
Others
22.9%
Receptors
7%
Pgp
4.3%
CYP 2D6
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.
Pharmacogenetics and Drug Metabolism
Same dose but different plasma concentrations
Patient A
GCCCGCCTC
Wild type
Wild type
Concentration
CYP450
Time
GCCCACCTC
Mutation
CYP450
Mutation
Concentration
Patient B
Time
Cytochrome P450 2D6
 Absent in 7 % of Caucasians
1–2 % 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,
Inherited Activity of CYP 2D6 and
Nortriptyline Dosing
Nortriptyline: 25-300 mg
EM
PM
Dose (mg)
IM
140
120
100
80
60
40
20
0
Doses need for
equivalent exposure
PM
Nortriptyline Plasma Levels
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 20–30 % of Asians
3–5 % Caucasians
 Primary metabolism of :





Diazepam
Phenytoin
Omeprazole
Tricyclic antidepressants
Clopidogrel (prodrug)
 Inhibited by :



Omeprazole
Isoniazid
Ketoconazole
Cytochrome P450 2C19
 Absent in 20–30 % of Asians
3–5 % 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
17β-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):28–34
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 “antabuselike 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 John’s Wort
 Ginkgo biloba
 Kava
 Garlic
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 Pglycoprotein  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
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 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*