Verlängerung der QT-Zeit
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Eklärungen für Patienten zu den Wirkstoffen
Für die Kombination von Lorcaserin und Morphin liegen uns keine zusätzlichen Warnhinweise vor. Bitte konsultieren Sie zusätzlich die jeweiligen Fachinformationen.
Die genannten Expositionsveränderungen beziehen sich jeweils auf Veränderungen der Plasmakonzentrations-Zeit-Kurve [ AUC ]. Für Lorcaserin erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Morphin (100%) erfolgt. Für Morphin erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Lorcaserin (100%) erfolgt.
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Für Lorcaserin ist die Bioverfügbarkeit nicht bekannt. Die terminale Halbwertszeit [ t12 ] beträgt 11 Stunden und konstante Plasmaspiegel [ Css ] werden ungefähr nach 44 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 70% eher schwach. Die Metabolisierung findet unter anderem über CYP1A2, CYP2B6, CYP2C19, CYP2D6 und CYP3A4 statt.
Morphin hat eine tiefe orale Bioverfügbarkeit [ F ] von 30%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell stark verändern. Die terminale Halbwertszeit [ t12 ] ist mit 2.5 Stunden eher kurz und konstante Plasmaspiegel [ Css ] werden schnell erreicht. Die Proteinbindung [ Pb ] ist mit 35% eher schwach. Die Metabolisierung über Cytochrome wird aktuell noch bearbeitet und der aktive Transport erfolgt zum Teil über MRP2 und PGP.
|Serotonerge Effekte a||3||++||+|
Das Risiko für ein serotonerges Syndrom ist erhöht, aber ohne exakte
Bewertung: Morphin beeinflusst das serotonerge System mild. Lorcaserin moduliert das serotonerge System in moderatem Ausmass.
|Kiesel & Durán b||1||Ø||+|
Empfehlung: Insbesondere nach einer Dosiserhöhung und bei Dosierungen im oberen therapeutischen Bereich sollte vorsichtshalber auf anticholinerge Symptome geachtet werden.
Bewertung: Morphin beeinflusst das anticholinerge System nur mild. Das Risiko für ein anticholinerge Syndrom ist bei dieser Medikation eher als gering einzustufen, wenn die Dosierung sich im üblichen Bereich befindet. Gemäss unseren Erkenntnisse erhöht Lorcaserin nicht die anticholinerge Aktivität.
Verlängerung der QT-Zeit
Für Lorcaserin und Morphin ist uns kein QT-Zeit verlängerndes Potential bekannt.
Koma (4.9%): Morphin
Krampfanfall (4.9%): Morphin
Schläfrigkeit (3%): Morphin
Erhöhter Hirndruck: Morphin
Kardiogener Schock: Morphin
Orthostatische Hypotonie: Morphin
Basierend auf Ihren
Abstract: Plasma concentrations of morphine were followed for 24 hours in eight patients after intravenous and rectal administration of 10 mg morphine chloride. The plasma levels of morphine were determined by a sensitive and specific radioimmunoassay based upon an extraction procedure which separates morphine from its major polar metabolites. The bioavailability of morphine after rectal administration was found to be 53.3 +/- 17.8% (mean +/- S.D.). Peak concentrations of 16.3 +/- 8.7 ng ml-1 were reached after 59 +/- 16 min. The study indicates that first pass elimination of morphine may be partially avoided by rectal administration.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: OBJECTIVES: To examine the longitudinal relationship between cumulative exposure to anticholinergic medications and memory and executive function in older men. DESIGN: Prospective cohort study. SETTING: A Department of Veterans Affairs primary care clinic. PARTICIPANTS: Five hundred forty-four community-dwelling men aged 65 and older with diagnosed hypertension. MEASUREMENTS: The outcomes were measured using the Hopkins Verbal Recall Test (HVRT) for short-term memory and the instrumental activity of daily living (IADL) scale for executive function at baseline and during follow-up. Anticholinergic medication use was ascertained using participants' primary care visit records and quantified as total anticholinergic burden using a clinician-rated anticholinergic score. RESULTS: Cumulative exposure to anticholinergic medications over the preceding 12 months was associated with poorer performance on the HVRT and IADLs. On average, a 1-unit increase in the total anticholinergic burden per 3 months was associated with a 0.32-point (95% confidence interval (CI)= 0.05-0.58) and 0.10-point (95% CI=0.04-0.17) decrease in the HVRT and IADLs, respectively, independent of other potential risk factors for cognitive impairment, including age, education, cognitive and physical function, comorbidities, and severity of hypertension. The association was attenuated but remained statistically significant with memory (0.29, 95% CI=0.01-0.56) and executive function (0.08, 95% CI=0.02-0.15) after further adjustment for concomitant non-anticholinergic medications. CONCLUSION: Cumulative anticholinergic exposure across multiple medications over 1 year may negatively affect verbal memory and executive function in older men. Prescription of drugs with anticholinergic effects in older persons deserves continued attention to avoid deleterious adverse effects.
Abstract: Lorcaserin, a selective serotonin 5-hydroxytryptamine 2C receptor agonist, is being developed for weight management. The oxidative metabolism of lorcaserin, mediated by recombinant human cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) enzymes, was examined in vitro to identify the enzymes involved in the generation of its primary oxidative metabolites, N-hydroxylorcaserin, 7-hydroxylorcaserin, 5-hydroxylorcaserin, and 1-hydroxylorcaserin. Human CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4, and FMO1 are major enzymes involved in N-hydroxylorcaserin; CYP2D6 and CYP3A4 are enzymes involved in 7-hydroxylorcaserin; CYP1A1, CYP1A2, CYP2D6, and CYP3A4 are enzymes involved in 5-hydroxylorcaserin; and CYP3A4 is an enzyme involved in 1-hydroxylorcaserin formation. In 16 individual human liver microsomal preparations (HLM), formation of N-hydroxylorcaserin was correlated with CYP2B6, 7-hydroxylorcaserin was correlated with CYP2D6, 5-hydroxylorcaserin was correlated with CYP1A2 and CYP3A4, and 1-hydroxylorcaserin was correlated with CYP3A4 activity at 10.0 μM lorcaserin. No correlation was observed for N-hydroxylorcaserin with any P450 marker substrate activity at 1.0 μM lorcaserin. N-Hydroxylorcaserin formation was not inhibited by CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, and CYP3A4 inhibitors at the highest concentration tested. Furafylline, quinidine, and ketoconazole, selective inhibitors of CYP1A2, CYP2D6, and CYP3A4, respectively, inhibited 5-hydroxylorcaserin (IC(50) = 1.914 μM), 7-hydroxylorcaserin (IC(50) = 0.213 μM), and 1-hydroxylorcaserin formation (IC(50) = 0.281 μM), respectively. N-Hydroxylorcaserin showed low and high K(m) components in HLM and 7-hydroxylorcaserin showed lower K(m) than 5-hydroxylorcaserin and 1-hydroxylorcaserin in HLM. The highest intrinsic clearance was observed for N-hydroxylorcaserin, followed by 7-hydroxylorcaserin, 5-hydroxylorcaserin, and 1-hydroxylorcaserin in HLM. Multiple human P450 and FMO enzymes catalyze the formation of four primary oxidative metabolites of lorcaserin, suggesting that lorcaserin has a low probability of drug-drug interactions by concomitant medications.
Abstract: Serotonin syndrome is a potentially life-threatening condition caused by excessive central and peripheral stimulation of serotonin brainstem receptors, usually triggered by inadvertent interactions between agents with serotonergic activity. Evidence supporting an association between nonserotonergic opiates, such as oxycodone or morphine, and serotonin syndrome is very limited and even contradictory. In this case report, we describe a patient who developed serotonergic-adverse effects likely precipitated by an interaction between morphine and phenelzine. A 57-year-old woman presented to the emergency department with complaints of increasing visual hallucinations, restlessness, photophobia, dizziness, neck stiffness, occipital headache, confusion, sweating, tachycardia, and nausea over the previous week. On admission, her blood pressure was 185/65 mm Hg, and clonus was noted in the lower extremities. The patient was hospitalized 10 days earlier for cellulitis of the left breast secondary to a left mastectomy 5 months earlier, and a short course of oral morphine was prescribed for pain control. Her routine medications consisted of aspirin, atorvastatin, bisoprolol, clopidogrel, gabapentin, omeprazole, phenelzine, and ramipril. Supportive measures were initiated on admission. Phenelzine and morphine were discontinued immediately, leading to a progressive resolution of symptoms over the next 48 hours. Phenelzine was restarted on discharge without further complications. Use of the Drug Interaction Probability Scale indicated a probable relationship (score of 6) between the patient's development of serotonin syndrome and the combination of morphine and phenelzine. The mechanism underlying this interaction, however, remains unclear and warrants further investigation. Clinicians should carefully weigh the risk and benefits of initiating morphine in patients taking monoamine oxidase inhibitors or any other serotonin-enhancing drugs.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.