Interaktionen in der Psychopharmakotherapie. Klinik für Kinder- und Jugendpsychiatrie, -psychosomatik und- psychotherapie, Berlin

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1 Interaktionen in der Psychopharmakotherapie Manuela Seiferheld n Klinik für Kinder- und Jugendpsychiatrie, -psychosomatik und- psychotherapie, Berlin

2 Überblick Definition Medikamenteninteraktion Faktoren für Wechselwirkungen Pharmakokinetik Pharmakodynamik Zusammenfassung Literaturverweise -2-

3 Medikamenteninteraktion qualitative und quantitative Wirkungsveränderung eines Medikamentes durch eine 2. Substanz pharmakologische Effekte Summe der individuellen Wirkungen -3-

4 Interaktionspaare i = n 2 n 2-4-

5 Faktoren für Wechselwirkungen metabolische Enzyme Substrateigenschaften an metabolisierenden Enzymen pharmakologische Eigenschaften der Metabolite individuelle Gegebenheiten des Patienten -5-

6 Definitionen Pharmakokinetik beinhaltet den Weg von Medikamenten durch den Körper. Pharmakokinetische Interaktionen beinhalten den Einfluss eines Medikamentes auf den Weg eines anderen durch den Körper. Pharmakodynamik beinhaltet biochemische und physiologische Effekte von Medikamenten und deren Wirkmechanismus. Pharmakodynamische Interaktionen beinhalten den Einfluss eines Medikamentes auf die Wirkung eines anderen an der Zielstruktur. -6-

7 Weg eines Arzneimittels Pharmakokinetik (LADME) Faeces Galle Exkretion Magen- u. Darmlumen Enterozyt Blut Hepato- zyt Blut Blut-Hirn- Schranke Zielstruktur Pharmakodynamik Liberation Absorption Distribution First-pass Biotransformation hepatische Elimination -7- Transport 3 Barrieren: physikalisch metabolisch Transporter

8 Gastrointestinale Absorption Liberation ph Wert-Veränderung z. B. durch Antazida Komplexbildungen z. B. Konsum von Schwarztee > TZA, TNL + Gerbstoffe Funktionsveränderungen des Gastrointestinaltraktes schnellere Passage z. B. durch Prokinetika Metabolismus V. a. CYP P450 3A4 (70% der Gesamtaktivität der CYP im Darm) P-Glycoproteine (P-gp) -8-

9 Inhibition der CYP 3A4 durch Grapefruitsaft relevante intestinale Inhibition durch ¼ I Grapefuitsaft nach 3 Tagen Erreichen der Basalaktivität von CYP3A42,3 Felodipin mit Wasser oder mit Grapefruitsaft1 1Wilkinson, 2005 et al., Hanley et al., Greenblatt -9-

10 P-Glycoprotein glykosyliertes Membranprotein Effluxtransporter (P-gp) Funktion Inhibition J. Drewe,

11 P-gp Nonsubstrat Substrat Inhibitor Induktor Citalopram Fluoxetin Amitriptylin Amitriptylin Despramin Johanniskraut Venlafaxin(?) Haloperidol Clozapin Quetiapin Midazolam Morphin Haloperidol (Chlorprothixen) Midazolam GFJ Grüner Tee OJ Pantoprazol -11-

12 Hepatischer Metabolismus Phase I Oxidation Hydroxylierung, N-Oxidation, S-Oxidation, N-Dealkylierung, O-Dealkylierung Desaminierung, Desulfurierung, Oxidative Dehalogenierung Dehydrierung der Hydroxylgruppe Dehydrierung von Aminen N-Oxidation, S-Oxidation Cytochrom P450 Monooxygenasen Alkohol Dehydrogenase Monoaminoxydasen Flavin-Monooxygenasen Reduktion Dehalogenierung von Nitrogruppen Cytochrom P450 Monooxygenasen Hydrolyse Hydrolyse von Epoxiden Epoxid-Hydrolasen Sonstige Oxidation von Radikalen Peroxidation Superoxid-Dismutasen Glutathion-Peroxidasen Phase II Konjugation Glucuronidierung Sulfatierung Acetylierung Methylierung Glutathion- Konjugation UDP-Glucuronosyltransferasen Sulfotransferasen O-, N-Acetyltransferasen O-, N-, S-Methyltransferasen Glutathion-S-Transferasen -12-

13 Hepatische Cytochrom P450 Monooxygenasen Verteilung Medikamentenabbau Bezeichnung Familie, Unterfamilie, Enzym dieser Unterfamilie Metabolismus von Xenobiotika vor allem CYP 1, CYP 2 und CYP 3 Isoenzyme 75% aller metabolischen Reaktionen von Arzneimittel H. Wang & L.M. Tompkins,

14 -14- Amitriptylin Clomipramin Imipramin Fluvoxamin Mirtazapin Duloxetin Agomelatin Haloperidol Olanzapin Clozapin Asenapin Melatonin Coffein Bupropion Methadon Amitriptylin Clomipramin Fluoxetin Citalopram Sertralin Diazepam Diclofenac Ibuprofen TZA/ TZAP SSRI/SNRI Haloperidol Atomoxetin Amphetamin Risperidon Aripiprazol Promethazin Opioide Benzos SSRIs TZA Buspiron Haloperidol Risperidon Aripiprazol Quetiapin Ziprasidon Kocain Codein Ethanol Anästhetika Inhibitor Fluvoxamin Fluorochinolone (...floxacin) Fluvoxamin Nor-/Fluoxetin OXC,TPM PPIs Bupropion Nor-/Fluoxetin Paroxetin AP Methadon SSRIs Haloperidol Antimykotica Citrussäfte Disulfiram Isoniazid Induktor Coffein Rauchen Gegrilltes CBZ CBZ Prednison Rifampicin Phenobarbital Rifampicin Johanniskraut CBZ/OXC Dexamethason Rifampicin Ethanol Starvation Rauchen Übergewicht Substrate der Cytochrom P450 Monooxygenasen David A. Flockhart, 2012

15 Antidepressiva Name Substrat von CYP/ P-gp Inhibition Induktion Fluoxetin Fluvoxamin Imipramin Amitriptylin Citalopram Duloxetin Bupropion Sertralin 1A2 2B6 2C9/ 19 2D6 3A4 P-gp 2D6, P-gp 1A2, 2C9/19, 3A4 1A2, 2C19 2C9, 2D6, 3A4, P-gp 2C19, P-gp 2D6, 2C19, P-gp 2D6, 2D6 2D6, P-gp 2D6 P-pg 1A2, 2D6 majorer Metabolismus/ potent -15- minorer Metabolismus/ moderat-schwach

16 Neuroleptika Name Substrat von CYP/ P-gp Inhibition Induktion Haloperidol Risperidon Aripiprazol Olanzapin Quetiapin Clozapin Chlorprothixen 1A2 2B6 2C9/ 19 2D6 3A4 P-gp 2D6, P-pg 2D6 nicht bekannt nicht bekannt P-pg 1A2, 2C9/19, 2D6, 3A4 2D6 P-gp Pipamperon? nicht bekannt Melperon? 2D6 majorer Metabolismus/ potent minorer Metabolismus/ moderat-schwach

17 Diverse Name Substrat von CYP/ P-gp Inhibition Induktion 1A2 2B6 2C9/ 19 2D6 3A4 P-gp Atomoxetin Amphetamin Methylphenidat? Methadon P-gp, 2D6 3A4 Buprenorphin Diazepam majorer Metabolismus/ potent minorer Metabolismus/ moderat-schwach

18 Hepatischer Metabolismus von Clomipramin aktiver Metabolit Handbuch der Psychopharmakologie, 1. Auflage

19 CYP-Polymorphismus Extensiv metabolizer (EM): 2 funktionelle Allele vom Wildtyp Intermediate metabolizer (IM): 1 funktionelles Allel vom Wildtyps und ein funktionsloses Allel Poor metabolizer (PM): 2 funktionslose Allele Ultrarapid metabolizer (UM): Genduplizierung oder Mutation eines funktionellen Allels Unterschiede in: Maximale Plasmakonzentration Halbwertzeit Clearance -19-

20 CYP-Polymorphismen 5-14% Kaukasier 0-5% Afro-Amerikaner 0-1% Asiaten 1-10% Kaukasier 10-29% Nordafrikaner/ Orientalen 1-5% Kaukasier/ Afro-Amerikaner 10-25% Asiaten 20% Kaukasier CYP2D6 PM CYP2D6 UM CYP2C19 PM CYP2C19 UM 15% Kaukasier CYP2C9 EM CYP1A2: Varianten Auswirkungen auf Induzierbarkeit CYP3A4: Interindividuelle Variabilität Zhou et al.,

21 CYP2D6 Poor Metabolizer Steigerung der Halbwertszeiten Haloperidol Risperidon Aripiprazol 4x (18 72h) 6x (3 20h ) u. 9-OH Risperidon 1,5x (20 30h) 3x (47 146h) Cave: EPMS-Risiko!!! Goodman & Gilman s The Pharmacological Basis of Therapeutics, 12th Edition,

22 Induktion von CYP P450 Beginn und Dauer abhängig von: PK des Medikaments t 1/2 der CYP (1-6d) verstärkte Genexpression Neusynthese Induktionspeak nach 4-14 Tagen Basallevel der CYP 1-3 Wochen nach Absetzen Kalra,

23 Induktion Rauchen Neuropsychobiology. 2002;45(1):32-5. Interaction between fluvoxamine and cotinine or caffeine. Yoshimura R, Ueda N, Nakamura J, Eto S, Matsushita M. Abstract: We examined the relationships between plasma fluvoxamine concentrations and plasma levels of cotinine and caffeine, respectively, under steady-state conditions in 30 patients who met DSM-IV criteria for a major depressive disorder and who were being treated with fluvoxamine. The daily dosages of fluvoxamine ranged from 50 to 200 mg (mean +/- SD 108 +/- 42 mg). Eleven patients were smokers and the remaining 19 were nonsmokers. The plasma fluvoxamine concentrations were significantly higher in nonsmokers (0.92 +/ ng/ml/mg) than in smokers (0.56 +/ ng/ml/mg); in addition, a trend towards negative correlations was observed between the plasma fluvoxamine concentrations and the plasma cotinine levels, although it was not significant. Significant positive correlations were found between the plasma fluvoxamine concentrations and the plasma caffeine levels. These findings are compatible with those in earlier reports that cytochrome P450 1A2 plays a major role in fluvoxamine metabolism. -23-

24 De-Induktion Rauchen Int Clin Psychopharmacol May;17(3): Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Zullino, D.F.; Delessert, D.; Eap, C.B.; Preisig, M.; Baumann, P. Abstract: Plasma levels of clozapine and olanzapine are lower in smokers than in nonsmokers, which is mainly due to induction of cytochrome P4501A2 (CYP1A2) by some smoke constituents. Smoking cessation in patients treated with antipsychotic drugs that are CYP1A2 substrates may result in increased plasma levels of the drug and, consequently, in adverse drug effects. Two cases of patients who smoked tobacco and cannabis are reported. The first patient, who was receiving clozapine treatment, developed confusion after tobacco and cannabis smoking cessation, which was related to increased clozapine plasma levels. The second patient, who was receiving olanzapine treatment, showed important extrapyramidal motor symptoms after reducing his tobacco consumption. The clinical implication of these observations is that smoking patients treated with CYP1A2 substrate antipsychotics should regularly be monitored with regard to their smoking consumption in order to adjust doses in cases of a reduction or increase in smoking. Klinik für Kinder- und Jugendpsychiatrie, Psychotherapie und PsychosomatikTitel der Präsentation -24-

25 Johanniskraut - Hypericum perforatum wirksame Inhaltsstoffe - Hypericin, Hyperforin Hyperforin Interaktionspotential Induktionseffekt nach ca. 10 Tagen Einnahme (mind. 0,87mg/d) Recovery der CYP 3A4 nach Absetzen zwischen 7-14d (HWZ 31,2 43,2h) De-Induktion der P-gp ca. 14Tage H. Imai et al., 2008 Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition Bauer et al.,

26 Inhibition von CYP P450 meist reversibel - kompetetiv schnell einsetzend teilweise irreversibel von CYP generiertem Metabolit -26-

27 Inhibition Aripiprazol und SSRI EM vs. IM Paroxetin Abfall Cl: 58% EM 23% IM Fluvoxamin Abfall Cl: 39-40% EM=IM -27-

28 Inhibition Risperidon und Fluoxetin J Clin Psychopharmacol Aug;22(4): Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinical relevant pharmacokinetic drug interaction. Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, Perucca E. Abstract: The effect of fluoxetine on the steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was evaluated in 10 patients with schizophrenia or schizoaffective disorder. Patients stabilized on risperidone (4-6 mg/day) received additional fluoxetine (20 mg/day) to treat concomitant depression. One patient dropped out after 1 week due to the occurrence of akathisia associated with markedly increased plasma risperidone concentrations. In the other subjects, mean plasma concentrations of risperidone increased during fluoxetine administration from 12 +/- 9 ng/ml at baseline to 56 +/- 31 at week 4 (p < 0.001), while the levels of 9-OH-risperidone were not significantly affected. After 4 weeks of combined treatment, the levels of the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) increased by 75% (range, 9-204%, p < 0.01) compared with baseline. The mean plasma risperidone/9-oh-risperidone ratio also increased significantly. During the second week of adjunctive therapy, two patients developed Parkinsonian symptoms, which were controlled with anticholinergic medication. These findings indicate that fluoxetine, a potent inhibitor of the cytochrome P450 enzyme CYP2D6 and a less potent inhibitor of CYP3A4, reduces the clearance of risperidone by inhibiting its 9-hydroxylation or alternative metabolic pathways. This interaction may lead to toxic plasma risperidone concentrations. In addition to careful clinical observation, monitoring plasma risperidone levels may be of value in patients given adjunctive therapy with fluoxetine. -28-

29 Inhibition Olanzapin und Imipramin J Clin Pharmacol Oct;37(10): Olanzapine: interaction study with imipramine. Callaghan JT, Cerimele BJ, Kassahun KJ, Nyhart EH Jr, Hoyes-Beehler PJ, Kondraske GV. Abstract: Olanzapine is an "atypical" antipsychotic agent with a high affinity for serotonin 5HT2A/C, 5HT3, 5HT6, and dopamine D1, D2, D3, D4 receptors. Depressed patients with psychotic disorders frequently require treatment with concomitant antipsychotic and antidepressant medications. Imipramine pharmacokinetics serve as a marker for hepatic CYP2D6, CYP1A2, CYP3A activity. An open-label, three-way randomized crossover study was done to determine the safety, pharmacokinetics, and potential for a drug interaction between olanzapine (5 mg) and imipramine (75 mg). Each drug was administered alone and in combination. Nine healthy men, ages 32 to 54 years, enrolled in the study. Psychomotor performance capacities, plasma olanzapine, imipramine, desipramine concentrations, and clinical laboratory tests were measured. Pharmacokinetic variables, vital signs, subjective tests for liveliness, and psychomotor outcomes were analyzed using a two-way ANOVA. Olanzapine was safe. Sedation, postural hypotension, and minor vital sign alterations occurred during all treatments. On the liveliness questionnaire, patients generally reported poorer (less lively) scores with olanzapine alone or coadministered with imipramine versus baseline scores. These effects disappeared within 24 hours after administration. Olanzapine alone and in combination decreased motor-speed tasks (finger tapping and visual-arm random reach) compared with baseline or imipramine treatment. Peak 6-hour changes were statistically significant but clinical importance was only marginal. Olanzapine concentrations were < 19% greater with imipramine. But olanzapine did not affect the kinetics of imipramine or desipramine and, therefore, did not show a metabolic drug interaction involving CYP2D

30 Antidepressiva - Antipsychotika Fluvoxamin Fluoxetin + Haloperidol 5-10x + Risperidon 2,5x + Clozapin 5-10x + Olanzapin 1,3x + Olanzapin 1,5-2x + Clozapin 2x Cave: t 1/2 von Norfluoxetin 6,4±2,5d!!! Goodman & Gilman s The Pharmacological Basis of Therapeutics, 12th Edition, 2011 Drug Interaction Principles For Medical Practice, Second Edition,

31 Manchmal ist mehr drin als man glaubt -31-

32 Pille - Metabolismus Zhang, Hongjian; Cui, Donghui; Wang, Bonnie; Han, Yong- Hae; Balimane, Praveen; Yang, Zheng; Sinz, Michael; Rodrigues, A Pharmacokinetic Drug Interactions Involving 17[alpha]-Ethinylestradiol: A New Look at an Old Drug. Clinical PharmacokineCcs. 46(2): , Relative contribution of different cytochrome P450 (CYP) isoforms toward 17[alpha]-ethinylestradiol (EE) 2-hydroxylation (adapted from Wang et al.[37]). -32-

33 Pille - Inhibitionspotential -33-

34 Pille - P-gp-Inhibition Fig. 8. Effect of 17[alpha]- ethinylestradiol (EE) on digoxin transport in Caco-2 cells. Bi-directional permeability of 5 [mu]mol/l [3H]digoxin (classical P-gp substrate) was evaluated using Caco-2 cells (24-well format) in the presence of various concentrations of EE. A potent P-gp inhibitor, elacridar (GF ) 4 [mu]mol/l, was used as a positive control. Incubations were performed at 37[degrees]C and were allowed to proceed for 2 hours in Hank's balanced salt solution (ph 7.4). Each column represents the mean +/- SD of three data points. -34-

35 Pille und Benzodiazepine Clin Pharmacol Ther May;33(5): Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives. Abernethy DR, Greenblatt DJ, Ochs HR, Weyers D, Divoll M, Harmatz JS, Shader RI. Abstract:... metabolic clearance by glucuronidation of lorazepam and oxazepam is not significantly affected by OCs, in contrast with the highly significant reduction in clearance of the oxidized benzodiazepine diazepam. -35-

36 Phamakodynamik - Interaktionen Kompetetiver Synergismus Wirkung an gemeinsamen Rezeptor Funktioneller Synergismus Effekt an unterschiedlichen Angriffspunkten Wirkungsverstärkung Kompetetiver Antagonismus reversible oder irreversible Verdrängung am gleichen Rezeptor Funktioneller Antagonismus unterschiedliche Angriffspunkt Wirkungsabschwächung -36-

37 Pharmakodynamik der Antidepressiva Handbuch der Psychopharmakologie, 1. Auflage,

38 Pharmakodynamik der Antidepressiva Goodman & Gilman s The Pharmacological Basis of Therapeutics, 12th Edition,

39 Pharmakodynamik von Aripiprazol Aripiprazole activity at D 2 receptors in the presence or absence of dopamine. Aripiprazole is a partial D 2 agonist; thus it inhibits effects of DA and reduces stimulation at the D 2 receptor only to the extent of its own capacity as an agonist. Haloperidol, an antagonist without agonist activity, completely antagonizes D 2 receptor activation Goodman & Gilman s The Pharmacological Basis of Therapeutics, 12th Edition, 2011

40 Serotoninsyndrom (I) Autonom vegetative Symptome: Tachykardie, Schwitzen, Durchfall, Übelkeit, Tachypnoe, RR-Erhöhung, Kopfschmerz, Pupillenerweiterung Zentralnervösen Symptome: Koordinationsstörung, Unruhe, Halluzinationen, Akathisie, Hypomanie Neuromuskuläre Symptome: Tremor, Myoklonien, gesteigerte Reflexe, Anfälle Nach Sternbach, 1991: mind.3 Symptome -40-

41 Ursachen des Serotoninsyndroms Serotoningebundener Mechanismus Wirkstoffe Steigerung der Synthese Steigerung der Freisetzung Wiederaufnahmehemmung Tryptophan Amphetamine, Ecstasy, Cocain SSRI, SNRI, TZA Johaniskrautextrakt, Opiate, Trazodon, Dextromethorphan Abbauhemmung Stimulierung von Rezeptoren Verstärkung der Wirkung Hemmung des Abbaus der genannten Substanzen MAO-Hemmer, Buspiron, Triptane Lithium z.b. durch 2D6- oder 3A4-Inhibitoren Sternbach,

42 SSRI und NSAID Aufnahmehemmung von Serotonin in Thrombozyten verminderte Aggregationsfähigkeit gestörte Hämostase 1321 Fällen und Kontrollen OR von 1,6 gastrointestinaler Blutungen unter SSRI und SSNRI Kombination mit nichtsteroidalen Antiphlogistika (OR bei alleiniger Gabe: 2,8) additive Risikosteigerung OR von 4,8-42-

43 Pharmakodynamische Interaktionen von Neuroleptika Verstärkung der dämpfenden Wirkung von: Sedativa/Hypnotika Narkotika Opioid-Analgetika Alkohol Verstärkung der anticholinergen Wirkung von: Atropin Scopolamin Biperiden Propiverin H1-Blocker (Dimenhydrinat, Diphenhydramin, Loratadin) trizyklische Antidepressiva Verstärkung der Wirkung von α- und β-adrenozeptorenblockade -43-

44 Zusammenfassung (I) Monotherapie falls Effekt nicht ausreicht: Beachtung von Lebensgewohnheiten Medikamentenanamnese (orale Kontrazeption) Erfahrungen mit Medikamenten Therapeutisches Drug Monitoring Compliance? Therapeutischer Bereich? -44-

45 Zusammenfassung (II) wenn Polypharmazie notwendig: CAVE: Interaktionen Pharmakokinetische Wechselwirkungen L A D M E Pharmakodynamische Wechselwirkungen synergistisch/antagonistisch denn: i = n 2 n 2-45-

46 Literatur-/ Internetverweise (Flockhart)

47 Vielen Dank für Ihre Aufmerksamkeit. -47-