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DRUG INTERACTIONS in Pharmacotherapy 2010

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 INTERACTIONS in Pharmacotherapy 2010

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  1. DRUG INTERACTIONSin Pharmacotherapy2010 Prof Lukman Hakim PhD Department of Pharmacology and Clinical Pharmacy Faculty of Pharmacy, Gadjah Mada University

  2. 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

  3. 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)

  4. 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

  5. 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

  6. 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

  7. Drug may interact with • Another drug(s) : • Synthetic drugs • Herbal or traditional medicines • Food and drinks • Pollutants : insecticides, herbicides, smoke of tobacco, exhaust, industries

  8. 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

  9. 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. 10 faktor yang berkaitandenganinteraksiobat

  11. 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

  12. Pharmacokinetic Drug Interactions : Absorption

  13. 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

  14. Drugs Affecting Absorption

  15. Cytochrome P450 Isoforms • CYP1A2 • CYP3A • CYP2C9 • CYP2C19 • CYP2D6 Enzyme CYP 2C9, 2C19 dan 2D6 dapat mengalami polymorphisme pada subyek (pasien) – terjadi pengurangan aktivitas metabolisme

  16. 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

  17. 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

  18. 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

  19. 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

  20. CYP3A Inducers • Carbamazepine • Phenytoin • Phenobarbital • Morphine • Rifampin • Rifabutin • St. John’s wort

  21. 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

  22. Proportionality of drug metabolizing enzymes

  23. 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.

  24. 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.

  25. 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

  26. 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

  27. 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,

  28. 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

  29. 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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