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

[Link] (drug interactions) [Link]

(P450-mediated drug interactions) [Link] (drug-induced arrhythmia) [Link] (antibiotics) [Link]/research/fields/[Link] (cardiovascular therapeutics) [Link]/healthoutcomes/certs/[Link] (therapeutics in pediatrics) [Link] (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
Ceftriaxone sodium Daptomycin Daptomycin Piperacillin-tazobactam

Interactant
Lactated Ringer's solution Dextrose solution 0.9% saline solution Lactated Ringer's solution Acyclovir Amphotericin B Mitomycin

Result
Ca-Ceftriaxone precipitate Daptomycin precipitate Compatible Particle formation Flocculent Blue colour Cefepime degrades up to 25%

Theophylline

Cefepime

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 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. 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
Kepatuhan pasien Dosis/kadar obat Jalur pemberian Durasi penggunaan Bioavailabilitas rendah

Kisar Terapi Sempit

Saat dan urutan penggunaan obat

Masalah non-linearitas
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 Decreased GI bacterial flora caused by an antibiotic admin could decrease bacterial production of vitamin K augmenting anticoagulant effect of warfarin MAO in the wall of GI tract may be inhibited by MAO inhibitors resulting in increased blood pressure to phenylephrine

GI flora

Drug metabolism in wall of intestine

In the GI Tract
Sucralfate, some milk

products, antacids, and oral iron preparations

Omeprazole,

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

lansoprazole, H2-antagonists
Didanosine (given

as a buffered tablet)
Cholestyramine

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
Cholestyramine Binding agent

Object Drug
Acetaminophen, diclofenac, digoxin, glipizide, furosemide, iron,lorazepam, methotrexate, metronidazole, piroxicam Carbamazapine, diclofenac, furosemide, tetracycline, thiazides

Result
Decreased absorption

Colestipol

Binding agent

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. 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

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% CYP1A2 7.1% CYP3A4/5 14.3% CYP2C9 4.3% CYP2C19 14.3%

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.

Pharmacogenetics and Drug Metabolism

Same dose but different plasma concentrations

Patient A GCCCGCCTC
Wild type
Concentration

CYP450

Wild type

Time

CYP450

GCCCACCTC
Mutation

Concentration

Patient B

Mutation

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 Fluoxetine, Paroxetine (strong inhibitors) Haloperidol Quinidine

Inhibited by:

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
IM 140 120 100 80 60 40 20 0 Dose (mg)

Doses need for equivalent exposure

EM

PM

PM
Nortriptyline Plasma Levels

IM Phenotype

EM

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 Fluconazole

Inhibited by :

Cytochrome P450 2C19

Absent in 2030 % of Asians

35 % Caucasians Primary metabolism of :

Diazepam Phenytoin Omeprazole Tricyclic antidepressants Clopidogrel (prodrug) Omeprazole Isoniazid Ketoconazole

Inhibited by :

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. Proton-pump inhibitors : Omeprazole = Esomeprazole > Lansoprazole > Pantoprazole > Rabeprazole

Inhibited by

Cytochrome P450 1A2

Induced by smoking tobacco Catalyzes primary metabolism of :

Theophylline Imipramine Propranolol Clozapine Many fluoroquinolone antibiotics Fluvoxamine Cimetidine

Inhibited by :

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) S Control GFJ 77.5 163.6 R 79.5 163.0 AUC ([Link]/mL) S 19.3 29.9 R 22.2 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 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 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
Carbamazepine Valproic acid Aspirin, clopidogrel, dipyridamole, heparin, ticlopidine, warfarin.

Effect
High dose GB decreases anticonvulsant effect

Anticoagulation increases

Cylosporine

GB protects cell membranes from damage (beneficial effect)

GB enhances antidepressant effect of MAO (serotonin reuptake) inhibitors

Phenelzine , tranylcypromine

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
Chlorpropamide
Fluindione (co-meds : enalapril, furosemide, pravastatin) Warfarin Dextromethorphan Debrisoquine Alprazolam, Midazolam Docetaxel Ritonavir 400-600 mg bid

Indications
Diabetes mellitus Chronic atrial fibrilation
Not reported Healthy subjects; CYP2D6 Healthy subjects; CYP3A4 HIV infection

Clinical results
Hypoglycemia Decreased anticoagulation
Increased anticoagulation No effect on elimination No effect on elimination 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
[Link]*