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DRUG INTERACTIONS in Pharmacotherapy 2010. Prof Lukman Hakim PhD Department of Pharmacology and Clinical Pharmacy Faculty of Pharmacy, Gadjah Mada University. References for further reading.
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DRUG INTERACTIONSin Pharmacotherapy2010 Prof Lukman Hakim PhD Department of Pharmacology and Clinical Pharmacy Faculty of Pharmacy, Gadjah Mada University
References for further reading • 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 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 • Another drug(s) : • Synthetic drugs • Herbal or traditional medicines • Food and drinks • 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 disorders 2. Cardiovascular disease 3. Gastrointestinal disease 4. Infection 5. Psychiatric disorders 6. Respiratory disorders 7. Seizure disorders
Drugs with Narrow Therapeutic Window Examples : Aminoglycoside antibiotics : gentamicin, tobramycinAnticoagulants : warfarin, heparins, high protein bound Aspirin (salicylate derivatives), high PB Carbamazepine : 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
In the GI Tract • Block absorptionof quinolones, tetracycline, and azithromycin • Reduce absorptionof ketoconazole, delavirdine • Reduces ketoconazole absorption • Binds raloxifene,thyroid hormone, and digoxin • Sucralfate, some milk products, antacids, and oral iron preparations • Omeprazole, lansoprazole,H2-antagonists • Didanosine (givenas a buffered tablet) • Cholestyramine
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 extractsversusCYP 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 O-methyltransferase; 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% CYP 2D6 PhaseII 72.9% 11.4% CYP1A2 7.1% CYP3A4/5 14.3% CYP2C9 CYP2C19 4.3% 14.3% Breakdown of Genotyping and Phenotyping in FDA Survey • 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.
GCCCGCCTC GCCCACCTC Pharmacogenetics and Drug Metabolism Same dose but different plasma concentrations Patient A Wild type CYP450 Concentration Wild type Time Patient B Mutation CYP450 Concentration Mutation 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,
Nortriptyline: 25-300 mg 140 120 100 80 Dose (mg) 60 40 20 0 PM IM EM Phenotype Inherited Activity of CYP 2D6 and Nortriptyline Dosing IM Doses need forequivalent exposure EM PM Nortriptyline Plasma Levels 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 andAfrican-Americans • Primary metabolism of: • Most NSAIDs (incl COX-2 inhibitors : Celecoxib, Rofecoxib) • S-warfarin (active form) • Phenytoin • Inhibited by: • Fluconazole