Verlängerung der QT-Zeit
|Verlust von Appetit|
Varianten ✨Für die rechenintensive Bewertung der Varianten bitte das kostenpflichtige Standard Abonnement wählen.
Eklärungen für Patienten zu den Wirkstoffen
Für die Kombination von Dibenzepin und Digitoxin 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 Dibenzepin erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Digitoxin (100%) erfolgt. Für Digitoxin erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Dibenzepin (100%) erfolgt.
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Dibenzepin hat eine tiefe orale Bioverfügbarkeit [ F ] von 25%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell stark verändern. Die terminale Halbwertszeit [ t12 ] ist mit 5 Stunden eher kurz und konstante Plasmaspiegel [ Css ] werden schnell erreicht. Die Proteinbindung [ Pb ] ist mit 80% mässig stark. Die Metabolisierung erfolgt nicht über die gängigen Cytochrome.
Für Digitoxin ist die Bioverfügbarkeit nicht bekannt. Das therapeutische Fenster ist eng und die Sicherheitsmarge daher klein. Schon kleine Expositionsänderungen können das Toxizitätsrisiko erhöhen. Die Proteinbindung [ Pb ] ist nicht bekannt. Die Metabolisierung findet vor allem über CYP3A4 statt.
|Serotonerge Effekte a||0||Ø||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöhen weder Dibenzepin noch Digitoxin die serotonerge Aktivität.
|Kiesel & Durán b||2||+||+|
Empfehlung: Insbesondere nach einer Dosiserhöhung und bei Dosierungen im oberen therapeutischen Bereich sollte vorsichtshalber auf anticholinerge Symptome geachtet werden.
Bewertung: Dibenzepin und Digitoxin beeinflussen 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.
Verlängerung der QT-Zeit
Für Dibenzepin und Digitoxin ist uns kein QT-Zeit verlängerndes Potential bekannt.
|Atrioventrikulärer Block||10.0 %||n.a.||10.0|
|Verlust von Appetit||1.0 %||n.a.||+|
|Gestörtes Farbsehen||0.0 %||n.a.||0.1|
Basierend auf Ihren
Abstract: The antimuscarinic potency of dibenzepin (Noveril) was estimated by measuring (a) central in vivo effects in mice (antihypothermia and antitremor, both induced by oxotremorine), (b) peripheral in vivo activity (mydriasis caused by systemic administration of the drug), (c) the effects of dibenzepin on isolated smooth muscle from guinea pig ileum, and (d) in vitro determination of the affinity constant of dibezepine toward the muscarinic binding sites in whole mouse-brain homogenate. The data allowed the construction of a normalized antimuscarinic potency scale for some of the common tricyclic antidepressants. With a value of 1 for scopolamine, the following relative anticholinergic potencies were calculated: dibenzepin--1/600, nortriptylne--1/300, imipramine - 1/200, and amitriptyline - 1/75. These values suggest an explanation for the absence of clinically detectable anticholinergic side effects during treatment of depression with high doses of dibenzepin. Structural and spatial interrelations among various tricyclic antidepressants and scopolamine are discussed.
Abstract: In rats, cytochrome P450 (P450) IIIA enzymes are an important determinant of digitoxin toxicity. Induction of these liver microsomal enzymes decreases the toxicity of digitoxin by increasing its oxidative cleavage to digitoxigenin bis- and monodigitoxoside (dt2 and dt1). The present study shows that the susceptibility of different mammalian species to digitoxin toxicity is inversely related to liver microsomal P450 IIIA activity (measured as testosterone 6 beta-hydroxylase activity). Based on this correlation, we correctly predicted that hamsters, which have the highest P450 IIIA activity, are extremely resistant to digitoxin toxicity. To further examine the relationship between digitoxin toxicity and P450 IIIA activity, the pathways of digitoxin metabolism catalyzed by liver microsomes from nine mammalian species were examined by high performance liquid chromatography. The overall rate of digitoxin metabolism varied approximately 90-fold and followed the rank order: hamster greater than rat greater than guinea pig greater than dog greater than mouse approximately monkey greater than rabbit approximately cat greater than human. The qualitative differences in digitoxin metabolism were as striking as the quantitative differences. Formation of 16- and/or 17-hydroxydigitoxin was the major pathway of digitoxin oxidation catalyzed by liver microsomes from hamster, guinea pig, rabbit, cat, dog, and cynomolgus monkey. Guinea pig and, to a lesser extent, hamster liver microsomes also converted digitoxin to an unknown metabolite, the formation of which was catalyzed by P450. None of the species examined catalyzed the 12-hydroxylation of digitoxin to digoxin at a high rate. Similarly, none of the species examined catalyzed a high rate of conversion of digitoxin to dt2, with the notable exception of the rat. However, dt2 formation was the major pathway of digitoxin metabolism catalyzed by human liver microsomes, although humans were much less active (approximately 2%) than rats in this regard. The rate of dt2 formation varied approximately 41-fold among 22 samples of human liver microsomes, which was highly correlated (r = 0.841) with the rate of testosterone 6 beta-hydroxylation. Antibody against rat P450 IIIA1 inhibited the high rate of dt2 formation by rat liver microsomes and the low rate catalyzed by mouse, guinea pig, dog, monkey, and human liver microsomes. In contrast, anti-P450 IIIA1 did not inhibit the 12-, 16-, or 17-hydroxylation of digitoxin (or the formation of the unknown metabolite), despite the fact that anti-P450 IIIA1 strongly inhibited (greater than 70%) the 6 beta-hydroxylation of testosterone by liver microsomes from each of the species examined (except rabbit liver microsomes, which were inhibited only approximately 30%).(ABSTRACT TRUNCATED AT 400 WORDS)
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: The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug-free serum was added to medication and atropine standard-curve samples. For medications that showed detectable AA, average steady-state peak plasma and serum concentrations (C(max)) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L-hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above-average C(max) values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.
Abstract: BACKGROUND: Cognitive decline is common in Parkinson's disease (PD). Although some of the aetiological factors are known, it is not yet known whether drugs with anticholinergic activity (AA) contribute to this cognitive decline. Such knowledge would provide opportunities to prevent acceleration of cognitive decline in PD. OBJECTIVE: To study whether the use of agents with anticholinergic properties is an independent risk factor for cognitive decline in patients with PD. METHODS: A community-based cohort of patients with PD (n=235) were included and assessed at baseline. They were reassessed 4 and 8 years later. Cognition was assessed using the Mini-Mental State Examination (MMSE). A detailed assessment of the AA of all drugs prescribed was made, and AA was classified according to a standardised scale. Relationships between cognitive decline and AA load and duration of treatment were assessed using bivariate and multivariate statistical analyses. RESULTS: More than 40% used drugs with AA at baseline. During the 8-year follow-up, the cognitive decline was higher in those who had been taking AA drugs (median decline on MMSE 6.5 points) compared with those who had not taken such drugs (median decline 1 point; p=0.025). In linear regression analyses adjusting for age, baseline cognition and depression, significant associations with decline on MMSE were found for total AA load (standardised beta=0.229, p=0.04) as well as the duration of using AA drugs (standardised beta 0.231, p=0.032). CONCLUSION: Our findings suggest that there is an association between anticholinergic drug use and cognitive decline in PD. This may provide an important opportunity for clinicians to avoid increasing progression of cognitive decline by avoiding drugs with AA. Increased awareness by clinicians is required about the classes of drugs that have anticholinergic properties.
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.