Verlängerung der QT-Zeit
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Eklärungen für Patienten zu den Wirkstoffen
Monitorisierung von Risperidon und Lorazepam empfohlen.
Verstärkte SedierungMechanismus: Additive zentralnervöse Wirkungen. Keine Hinweise auf pharmakokinetische Interaktionen.
Effekt: Unerwünschte Wirkungen wie Müdigkeit, Sedierung und (orthostatische) Hypotension können sich gegenseitig verstärken. Es kann zu einem erhöhten Risiko für Stürze, insbesondere bei älteren Patienten, kommen. Risperidon wurde zudem mit einer Absenkung der Krampfschwelle in Verbindung gebracht. Dies ist insbesondere bei Patienten, bei denen Benzodiazepine zur Epilepsiebehandlung eingesetzt werden, zu beachten.
Massnahmen: Patient auf verstärkte Sedierung monitorisieren, Blutdruck kontrollieren.
|Risperidon||1 [0.42,4.42] 1||1|
Die genannten Expositionsveränderungen beziehen sich jeweils auf Veränderungen der Plasmakonzentrations-Zeit-Kurve [ AUC ]. Für Lorazepam erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Risperidon (100%) erfolgt. Für Risperidon erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Lorazepam (100%) erfolgt. Die AUC liegt dabei je nach CYP2D6
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Lorazepam hat eine hohe orale Bioverfügbarkeit [ F ] von 85%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell wenig verändern. Die terminale Halbwertszeit [ t12 ] beträgt 14.3 Stunden und konstante Plasmaspiegel [ Css ] werden ungefähr nach 57.2 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 91.9% mässig stark und das Verteilungsvolumen [ Vd ] ist mit 111 Liter sehr gross. Die Metabolisierung erfolgt nicht über die gängigen Cytochrome und der aktive Transport erfolgt insbesondere über UGT2B7.
Risperidon hat eine mittlere orale Bioverfügbarkeit [ F ] von 70%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell verändern. Die terminale Halbwertszeit [ t12 ] ist mit 4.9 Stunden eher kurz und konstante Plasmaspiegel [ Css ] werden schnell erreicht. Die Proteinbindung [ Pb ] ist mit 82.5% mässig stark und das Verteilungsvolumen [ Vd ] ist mit 74 Liter gross, da die Substanz eine tiefe hepatische Extraktionsrate von 0.04 besitzt, kann eine Verdrängung aus der Proteinbindung [Pb] im Rahmen einer Interaktion die Exposition erhöhen. Die Metabolisierung findet unter anderem über CYP2D6 und CYP3A4 statt und der aktive Transport erfolgt insbesondere über PGP.
|Serotonerge Effekte a||0||Ø||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöhen weder Lorazepam noch Risperidon die serotonerge Aktivität.
|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: Risperidon 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. Der anticholinerge Effekt von Lorazepam ist nicht relevant.
Verlängerung der QT-Zeit
Empfehlung: Bitte achten Sie darauf, dass beeinflussbare Risikofaktoren minimiert werden. Elektrolytstörungen, wie tiefe Werte von Calcium, Kalium und Magnesium sollten ausgeglichen werden. Die niedrigst wirksame Dosis von Risperidon sollte eingesetzt werden.
Bewertung: Risperidon kann potentiell die QT-Zeit verlängern und bei Vorliegen von Risikofaktoren können Arrhythmien vom Typ Torsades de pointes begünstigt werden. Für Lorazepam ist uns kein QT-Zeit verlängerndes Potential bekannt.
Atrioventrikulärer Block: Risperidon
Gesteigerter Appetit: Risperidon
Diabetische Ketoazidose: Risperidon
Muskuloskelettale Schmerzen: Risperidon
Krampfanfall: Lorazepam, Risperidon
Malignes neuroleptisches Syndrom: Risperidon
Verschwommenes Sehen: Risperidon
Thrombotische thrombozytopenische Purpura: Risperidon
Erektile Dysfunktion: Risperidon
Venöse Thromboembolie: Risperidon
Basierend auf Ihren
Abstract: No Abstract available
Abstract: This histological and immunohistochemical study of 6 food handlers affected by immediate contact dermatitis due to foods shows that apparently normal skin of patients with this condition presents several histological and immunohistochemical abnormalities. Skin biopsies of normal hand skin showed focal parakeratosis and moderately dense dermal infiltrates. Immunohistochemistry showed an increased number of Langerhans cells in the epidermis and in the superficial dermis and a mononuclear dermal infiltrate consisting of peripheral T lymphocytes with a CD4/CD8 ratio of 5-6/1. Biopsies of the immediate vesicular reactions induced by foods showed spongiotic vesicles within the epidermis and a moderate to dense mononuclear dermal perivascular infiltrate. The immunohistochemical features were similar to those described in apparently normal skin. The mechanism of this immediate vesicular reaction requires further research. The rapid appearance of the lesions (after 20-30 min) probably excludes an immunological cell-mediated pathogenesis. A non-immunological mechanism due to direct liberation of mediators by foods is more readily conceivable than an immediate immunological type of contact reaction.
Abstract: Healthy volunteers received single doses of three benzodiazepines (diazepam, 10 mg i.v.; alprazolam, 1.0 mg orally; lorazepam, 2 mg i.v.) on two occasions in random sequence. One trial was a control; for the other, subjects ingested propoxyphene, 65 mg every 6 h, for the duration of the benzodiazepine study. The kinetics of each benzodiazepine were determined from multiple plasma concentrations measured following each dose. For diazepam, propoxyphene produced a small and statistically insignificant prolongation of elimination half-life (43 vs 38 h) and reduction of total clearance (0.41 vs 0.47 ml min-1 kg-1). Propoxyphene significantly prolonged alprazolam half-life (18 vs 12 h, P less than 0.005) and reduced total clearance (0.8 vs 1.3 ml min-1 kg-1, P less than 0.005). Propoxyphene had no apparent influence on lorazepam half-life (13.4 vs 13.5 h) or clearance (1.5 vs 1.4 ml min-1 kg-1). Thus propoxyphene significantly impairs the clearance of alprazolam, biotransformed mainly by the oxidative reaction of aliphatic hydroxylation. Propoxyphene has far less effect on the oxidation of diazepam by N-demethylation, and has no apparent influence on lorazepam conjugation.
Abstract: Eleven subjects received acetaminophen (650 mg i.v.) on two occasions in random sequence, with and without concurrent administration of probenecid (500 mg) every 6 hr. Nine subjects similarly received lorazepam (2 mg. i.v.) with and without concurrent probenecid. Acetaminophen half-life was prolonged during probenecid treatment (mean +/- S.E., 4.30 +/- 0.23 vs. 2.51 +/- 0.16 hr; P less than .001) due to markedly decreased clearance (178 +/- 13 vs. 329 +/- 24 ml/min; P less than .001) with no change in volume of distribution (65 +/- 4 vs. 69 +/- 3 l; NS). Urinary excretion of acetaminophen glucuronide during 24 hr was decreased (84 +/- 9 vs. 260 +/- 21 mg of acetaminophen as glucuronide; P less than .001) and acetaminophen sulfate excretion was increased (323 +/- 25 vs. 217 +/- 17 mg of acetaminophen as sulfate; P less than .005) during concurrent probenecid treatment. However, the sum of the two conjugated metabolites was not significantly different (407 +/- 28 vs. 476 +/- 20 mg of acetaminophen as glucuronide plus sulfate excreted per 24 hr; NS). Lorazepam half-life was also prolonged during probenecid treatment (33.0 +/- 3.9 vs. 14.3 +/- 1.08 hr; P less than .001) due to decreased clearance (44.7 +/- 5.4 vs. 80.3 +/- 13.2 ml/min; P less than .001) with no change in volume of distribution (111 +/- 5 vs. 111 +/- 7 l; NS). Formation of the ether glucuronides of acetaminophen and lorazepam is impaired markedly by therapeutic doses of probenecid. Sulfate conjugation is not affected.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: No Abstract available
Abstract: The absorption, metabolism, and excretion of the novel antipsychotic risperidone was studied in three healthy male subjects. One week after a single oral dose of 1 mg [14C]risperidone, 70% of the administered radioactivity was recovered in the urine and 14% in the feces. Unchanged risperidone was mainly excreted in the urine and accounted for 30, 11, and 4% of the administered dose in the poor, intermediate, and extensive metabolizer of debrisoquine, respectively. Alicyclic hydroxylation at the 9-position of the tetrahydro-4H-pyrido[1,2-a]-pyrimidin-4-one moiety was the main metabolic pathway. The active metabolite 9-hydroxy-risperidone accounted for 8, 22, and 32% of the administered dose in the urine of the poor, intermediate, and extensive metabolizer, respectively. Oxidative N-dealkylation at the piperidine nitrogen, whether or not in combination with the 9-hydroxylation, accounted for 10-13% of the dose. In methanolic extracts of feces, risperidone, and benzisoxazole-opened risperidone and hydroxylated metabolites were detected. 9-Hydroxy-risperidone was by far the main plasma metabolite. The sum of risperidone and 9-hydroxy-risperidone accounted for the largest part of the plasma radioactivity in the three subjects. Although the debrisoquine-type genetic polymorphism plays a distinct role in the metabolism of risperidone, the pharmacokinetics of the active fraction (i.e. risperidone plus 9-hydroxy-risperidone) remained similar among the three subjects.
Abstract: Risperidone is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses. Formation of 9-hydroxyrisperidone, an active metabolite, is the most important metabolic pathway of risperidone in human. In the present study, in vitro metabolism of risperidone (100 microM) was investigated using the recombinant human cytochrome P450 (CYP) enzymes CYP1A1, CYP1A2, CYP2C8, CYP2C9-arg144, CYP2C9-cys144, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 supplemented with an NADPH-generating system. 9-Hydroxyrisperidone was determined by a new HPLC method with an Hypersil CN column and a UV detector. Of these enzymes, CYPs 2D6, 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9-hydroxyrisperidone, with activities of 7.5, 0.4 and 0.2 pmol pmol(-1) CYP min(-1), respectively. A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with CYP2D6 and 3A activities. Thus, both CYP2D6 and 3A4 are involved in the 9-hydroxylation of risperidone at the concentration of risperidone used in this study. This observation is confirmed by the findings that both quinidine (inhibitor of CYP2D6) and ketoconazole (inhibitor of CYP3A4) can inhibit the formation of 9-hydroxyrisperidone. Furthermore, inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat. The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6beta-hydroxylase activities, suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat.
Abstract: OBJECTIVE: To evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point. METHODS: Nine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 microg/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs. RESULTS: The bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins. CONCLUSION: Despite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.
Abstract: OBJECTIVE: The authors review the mechanisms and establish the risk of torsade de pointes and sudden death with antipsychotic drugs. METHOD: They present a review of original concepts, the distinction between familial and drug-induced cases of torsade de pointes, and the recognition of the role of noncardiac drugs in torsade de pointes and sudden death. They review the evidence linking QTc interval prolongation, potassium channels, and torsade de pointes from both the long QT syndrome and drugs. They examine the risk for torsade de pointes from antipsychotic drugs and estimate the frequency of sudden death on the basis of epidemiological data in normal and schizophrenic populations. RESULTS: All drugs that cause torsade de pointes prolong the QTc interval and bind to the potassium rectifier channel, but the relationships are not precise. Prediction of torsade de pointes and sudden death can be improved by examining dose dependency, the percent of QTc intervals higher than 500 msec, and the risk of drug-drug interactions. Although sudden unexpected death occurs almost twice as often in populations treated with antipsychotics as in normal populations, there are still only 10-15 such events in 10,000 person-years of observation. CONCLUSIONS: Although pimozide, sertindole, droperidol, and haloperidol have been documented to cause torsade de pointes and sudden death, the most marked risk is with thioridazine. There is no association with olanzapine, quetiapine, or risperidone. Ziprasidone does prolong the QT interval, but there is no evidence to suggest that this leads to torsade de pointes or sudden death. Only widespread use will prove if ziprasidone is entirely safe. To date, all antipsychotic drugs have the potential for serious adverse events. Balancing these risks with the positive effects of treatment poses a challenge for psychiatry.
Abstract: The transmembrane transporter P-glycoprotein (P-gp) is an ATP-dependent efflux pump for a wide range of drugs. P-gp potentially limits access to brain tissue of psychoactive substrates, but little is known about its specificity for antipsychotics. The objective of this study was to assess the affinity of some atypical antipsychotic drugs in vitro for P-gp as indicative of their potential as P-gp substrates in vivo. The activity of P-gp towards four atypical and two conventional antipsychotics and a proven substrate, verapamil, was examined by their P-gp ATPase activity, a putative measure of P-gp affinity. The Michaelis-Menten equation was fitted to the data. The rank order of the ratio V(max) / K(m) was: verapamil (2.6) > quetiapine (1.7) > risperidone (1.4) > olanzapine (0.8) > chlorpromzaine (0.7) > haloperidol (0.3) = clozapine (0.3). The atypical antipsychotics quetiapine and risperidone were relatively good P-gp substrates, although their affinities were not as high as verapamil. Olanzapine showed intermediate affinity and clozapine showed the least affinity of the drugs studied. These results suggest that P-gp is likely to influence the access to the brain of all of the atypical antipsychotics studied to various degrees. In vivo studies are needed to confirm these findings.
Abstract: The present study investigates the kinetic disposition with focus on the racemization, glucuronidation capacity and the transplacental transfer of lorazepam in term parturients during labor. The study was conducted on 10 healthy parturients aged 18-37 years with a gestational age of 36-40.1 weeks, treated with a single oral dose of 2 mg racemic lorazepam 2-9 h before delivery. Maternal venous blood and urine samples were obtained over a 0-48 h interval and the umbilical cord sample was obtained immediately after clamping. Lorazepam enantiomers were determined in plasma and urine samples by LC-MS/MS using a Chiralcel OD-R column. In vitro racemization of lorazepam required the calculation of the pharmacokinetic parameters as isomeric mixtures. The data were fitted to two-compartment model and the pharmacokinetic parameters are reported as means (95% CI): t(1/2a) 3.2h (2.6-3.7 h), K(a) 0.23 h(-1) (0.19-0.28 h(-1)), t(1/2) 10.4h (9.4-11.3h), beta 0.068 h(-1) (0.061-0.075h(-1)), AUC(0-infinity) 175.3(ngh)/ml (145.7-204.8(ngh)/ml), Cl/F 2.6 ml/(minkg) (2.3-2.9 ml/(minkg)), Vd/F178.8l (146.5-211.1l), Fel 0.3% (0.1-0.5%), and Cl(R) 0.010 ml/(minkg) (0.005-0.015 ml/(minkg)). Placental transfer of lorazepam evaluated as the ratio of vein umbilical/maternal vein plasma concentrations, obtained as an isomeric mixture, was 0.73 (0.52-0.94). Pregnancy changes the pharmacokinetics of lorazepam, with an increase in the apparent distribution volume, an increase in apparent oral clearance, and a reduction of elimination half-life. The increase in oral clearance may indicate an increase in glucuronidation capacity, with a possible reduction in the plasma concentrations of drugs depending on glucuronidation capacity as the major metabolic pathway.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
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: Cases of catatonia in patients with renal failure have been rarely reported. In this report, we describe two renal-insufficient patients with catatonia who had a good response to intramuscular lorazepam whereby the catatonic symptoms were relieved. Case 1 involved a patient with end-stage renal disease and severe pneumonia related respiratory failure. He responded well to intramuscular lorazepam (total dose, 4 mg) whereby the catatonia was elieved. Case 2 involved a patient with alcoholic liver cirrhosis and rhabdomyolysis-related acute renal failure. He showed great improvement with intramuscular lorazepam (2 mg) whereby the catatonia was subsequently relieved. This report demonstrates that intramuscular lorazepam is safe, effective and rapid in relieving catatonia associated with renal function impairment. Neither of the patients had a recurrence of catatonia during a period of 6- months follow-up. In conclusion, intramuscular lorazepam may play an important role in the treatment of catatonia associated with renal insufficiency.
Abstract: PURPOSE: To evaluate the role of cytochrome 450 2D6 (CYP2D6) and ABCB1 variants on plasma risperidone concentrations and treatment response in 83 drug-naive patients experiencing a first episode of psychosis. METHODS: All patients were treated with risperidone for 8 weeks. The CYP2D6 genotyping was performed by allele-specific PCR-restriction fragment length polymorphism analysis (for alleles *3,*4,*6) and long-distance PCR (for duplications and allele *5), while real-time PCR analysis was used for the ABCB1 G2677T/A and C3435T variants. Plasma concentrations of risperidone and 9-OH risperidone were measured by high-performance liquid chromatography. RESULTS: The number of patients with the CYP2D6 wild type (wt)/wt, wt/mutation (mut) and mut/mut genotype was 43, 32 and 8, respectively. The number of patients with the ABCB1 2677G/G, G/T and T/T variants was 29, 42 and 12, respectively; those with the 3435CC, C/T and T/T variants was 25, 37 and 21, respectively. The CYP2D6 genotype had a strong effect on the steady-state dose-corrected plasma levels (C/D) of risperidone, its 9-OH metabolite and the active moiety, while the ABCB1 2677 T/T and 3435 T/T genotypes has similarly strong effects on the active moiety C/D. The CYP2D6 poor metabolizers had a significantly higher risperidone C/D and active moiety C/D and lower 9-OH risperidone C/D. The ABCB1 3435 T allele and the ABCB1 2667 T-3435 T haplotype carriers were more frequent among subjects without extrapyramidal syndromes. Patients showed significant improvements in positive and general symptoms, but not in negative symptoms. These changes were not related to variations in genetic and drug concentration data. CONCLUSION: Our findings suggest that CYP2D6 and ABCB1 G2677T and C3435T may be useful determinants of risperidone plasma concentrations, but the clinical implications of these associations in relation to treatment response and side-effects remain unclear.
Abstract: WHAT IS KNOWN AND OBJECTIVE: Risperidone is an atypical antipsychotic agent used for the treatment of schizophrenia. It is mainly metabolized by human cytochrome P450 CYP2D6 and partly by CYP3A4 to 9-hydroxyrisperidone. Ketoconazole is used as a CYP3A4 inhibitor probe for studying drug-drug interactions. We aim to investigate the effect of ketoconazole on the pharmacokinetics of risperidone in healthy male volunteers. METHODS: An open-label, randomized, two-phase crossover design with a 2-week washout period was performed in 10 healthy male volunteers. The volunteers received a single oral dose of 2mg of risperidone alone or in combination with 200mg of ketoconazole, once daily for 3days. Serial blood samples were collected at specific periods after ingestion of risperidone for a period of 96h. Plasma concentrations of risperidone and 9-hydroxyrisperidone were determined using a validated HPLC-tandem mass spectrometry method. RESULTS AND DISCUSSION: After pretreatment with ketoconazole, the clearance of risperidone decreased significantly by 34·81±5·10% and the T(1/2) of risperidone increased significantly by 28·03±40·60%. The AUC(0-96) and AUC(0-∞) of risperidone increased significantly by 66·61± 43·03% and 66·54±39·76%, respectively. The Vd/f of risperidone increased significantly by 39·79±53·59%. However, the C(max) and T(max) of risperidone were not significantly changed, indicating that ketoconazole had minimal effect on the absorption of risperidone. The C(max) , T(max) and T(1/2) of 9-hydroxyrisperidone did not decrease significantly. However, the Cl/f of 9-hydroxyrisperidone increased significantly by 135·07± 124·68%, and the Vd/f of 9-hydroxyrisperidone decreased significantly by 29·47±54·64%. These changes led to a corresponding significant decrease in the AUC(0-96) and AUC(0-∞) of 9-hydroxyrisperidone by 47·76±22·39% and 48·49± 20·03%, respectively. Ketoconazole significantly inhibited the metabolism of risperidone through the inhibition of hepatic CYP3A4. our results suggest that besides CYP2D6, CYP3A4 contributes significantly to the metabolism of risperidone. WHAT IS NEW AND CONCLUSION: The pharmacokinetics of risperidone was affected by the concomitant administration of ketoconazole. If a CYP3A4 inhibitor is used concomitantly with risperidone, it is necessary for the clinicians to monitor their patients for signs of adverse drug reactions.
Abstract: BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.
Abstract: Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd.
Abstract: OBJECTIVE: To compare the risk of antipsychotic-related seizure (ARS) by identifying seizures first diagnosed within 12 months after starting new antipsychotics, using a 12-year total population health claims database from Taiwan. METHODS: Seizure events were identified through emergency department visits or hospitalization with a diagnosis of convulsion (ICD-9-CM: 780.3) or epilepsy (ICD-9-CM: 345). Subjects had an ICD-9-CM diagnosis of schizophrenia, bipolar disorders, or major depressive disorders. Incidence rates of ARS were calculated by person-years of exposure. The ARS risk, adjusted for patient characteristics and medical conditions, of individual antipsychotics versus risperidone was examined by high-dimensional propensity score stratification analyses, followed by sensitivity analyses. RESULTS: The overall 1-year incidence rate of ARS was 9.6 (95% CI, 8.8-10.4) per 1,000 person-years (550 ARS events among 288,397 new antipsychotic users). First-generation antipsychotics were marginally associated with a higher ARS risk than second-generation antipsychotics (adjusted hazard ratio [aHR] = 1.34; 95% CI, 0.99-1.81; P = .061). Most antipsychotics, first- or second-generation, had comparable ARS risks versus risperidone. Notably, clozapine (aHR = 3.06; 95% CI, 1.40-6.71), thioridazine (aHR = 2.90; 95% CI, 1.65-5.10), chlorprothixene (aHR = 2.60; 95% CI, 1.04-6.49), and haloperidol (aHR = 2.34; 95% CI, 1.48-3.71) had higher ARS risks than risperidone, whereas aripiprazole (aHR = 0.41; 95% CI, 0.17-1.00; P = .050) had a marginally lower ARS risk. Sensitivity analyses largely confirmed such findings. CONCLUSIONS: Higher vigilance for ARS is warranted during use of clozapine, chlorprothixene, thioridazine, and haloperidol. The possible lower ARS risk associated with aripiprazole can be clinically significant but needs to be confirmed by larger-scale systematic studies. The comparative ARS risks of antipsychotics supplement empirical knowledge for making judicious choices in prescribing antipsychotics.
Abstract: Therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding side effects by maintaining long-term exposure to minimally effective blood concentrations. The rationale for using therapeutic drug monitoring in relation to second-generation antipsychotics is still being discussed at least with regard to the real clinical utility, but there is evidence that it can improve efficacy, especially when patients do not respond or develop side effects using therapeutic doses. Furthermore, drug plasma concentration determinations can be of some utility in medico-legal problems. This review concentrates on the clinical pharmacokinetic data related to clozapine, risperidone, paliperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole, sertindole, asenapine, iloperidone, lurasidone, brexpiprazole and cariprazine and briefly considers the main aspects of their pharmacodynamics. Optimal plasma concentration ranges are proposed for clozapine, risperidone, paliperidone and olanzapine because the studies of quetiapine, amisulpride, asenapine, iloperidone and lurasidone provide only limited information and there is no direct evidence concerning ziprasidone, aripiprazole, sertindole, brexpiprazole and cariprazine: the few reported investigations need to be confirmed and extended.
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.
Abstract: BACKGROUND AND OBJECTIVES: The genetic polymorphism of cytochrome P450 (CYP) 2D6 is characterized by an excessive impact on positive and adverse drug reactions to antipsychotics, such as risperidone. Consequently, the pharmacokinetics of the drug and metabolite can be substantially altered and exhibit a high variability between the different phenotypes. The goal of this study was to develop a physiologically based pharmacokinetic (PBPK) model considering the CYP2D6 genetic polymorphism for risperidone and 9-hydroxyrisperidone (9-OH-RIS) taking CYP3A4 into account. Additionally, risperidone dose adjustments, which would compensate for genetically caused differences in the plasma concentrations of the active moiety (sum of risperidone and 9-OH-RIS) were calculated. METHODS: Based on available knowledge about risperidone, 9-OH-RIS, and relevant physiological changes according to different CYP2D6 phenotypes, several PBPK models were built. In addition, an initial model was further evaluated based on the plasma concentrations of risperidone and 9-OH-RIS from a single-dose study including 71 genotyped healthy volunteers treated with 1 mg of oral risperidone. RESULTS: PBPK models were able to accurately describe risperidone exposure after single-dose administration, especially in the concentration range ≥ 1 µg/L, illustrated by a minimal bias and a good precision. About 90.3% of all weighted residuals versus observed plasma concentrations ≥ 1 µg/L were in the ± 30% range. The risperidone/9-OH-RIS ratio increased progressively according to reduced CYP2D6 activity, resulting in a mean ratio of 4.96 for poor metabolizers. Simulations demonstrate that dose adjustment of the drug by - 25% for poor metabolizers and by - 10% for intermediate metabolizers results in a similar exposure to that of extensive metabolizers. Conversely, the risperidone/9-OH-RIS ratio can be used to determine the phenotype of individuals. CONCLUSION: PBPK modelling can provide a valuable tool to predict the pharmacokinetics of risperidone and 9-OH-RIS in healthy volunteers, according to the different CYP2D6 phenotypes taking CYP3A4 into account. These models are able to ultimately support decision-making regarding dose-optimization strategies, especially for subjects showing lower CYP2D6 activity.