QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of astemizole and olanzapine. Please also consult the relevant specialist information.
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for astemizole, when combined with olanzapine (100%). We did not detect any change in exposure to olanzapine. We currently cannot estimate the influence of astemizole.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Astemizole has a low oral bioavailability [ F ] of 3%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is 22 hours and constant plasma levels [ Css ] are reached after approximately 88 hours. The protein binding [ Pb ] is 97% strong. The metabolism takes place via CYP2D6 and CYP3A4, among others.
Olanzapine has a mean oral bioavailability [ F ] of 63%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather long at 32 hours and constant plasma levels [ Css ] are only reached after more than 128 hours. The protein binding [ Pb ] is moderately strong at 93% and the volume of distribution [ Vd ] is very large at 445 liters, Since the substance has a low hepatic extraction rate of 0.24, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. The metabolism takes place via CYP1A2 and CYP2D6, among others and the active transport takes place partly via PGP and UGT1A4.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither astemizole nor olanzapine increase serotonergic activity.
|Kiesel & Durán b||1||Ø||+|
Recommendation: As a precaution, attention should be paid to anticholinergic symptoms, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Olanzapine only has a mild effect on the anticholinergic system. The risk of anticholinergic syndrome with this medication is rather low if the dosage is in the usual range. According to our knowledge, astemizole does not increase anticholinergic activity.
QT time prolongation
Rating: In combination, astemizole and olanzapine can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||ast||ola|
|Weight gain||43.1 %||n.a.||43.1|
|Increased appetite||13.5 %||n.a.||13.5|
Dizziness (9.8%): olanzapine
Dystonia (2.5%): olanzapine
Status epilepticus: olanzapine
Constipation (7.5%): olanzapine
Peripheral edema (4.5%): olanzapine
Orthostatic hypotension: olanzapine
Sudden cardiac death: olanzapine
Diabetes mellitus: olanzapine
Hypersensitivity reaction: olanzapine
Diabetic ketoacidosis: olanzapine
Pulmonary embolism: olanzapine
Venous thromboembolism: olanzapine
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: Astemizole is a long-acting, highly selective histamine1-receptor antagonist with minimal central and anticholinergic effects. Comparison studies have shown astemizole to be equal or superior to currently available antihistamines, beclomethasone nasal spray, and cromolyn sodium in relieving allergic symptoms of seasonal and perennial allergic rhinitis. Other uses include treatment of allergic conjunctivitis and chronic urticaria. Astemizole is not as effective for treatment of acute allergic symptoms because of its delayed onset of action. Astemizole and its active metabolite, desmethylastemizole, have long elimination half-lives permitting once-daily dosing. The incidence of sedation is lower than with conventional antihistamines, but increased appetite and weight gain do occur. Astemizole should be useful for both maintenance and prophylactic therapy in patients with chronic allergic conditions who cannot tolerate the sedative or anticholinergic effects of conventional antihistamines.
Abstract: Astemizole is an H1-histamine receptor antagonist with a long duration of action permitting once daily administration. Its efficacy in seasonal and perennial allergic rhinitis has been convincingly demonstrated, and several comparative studies suggest that astemizole is at least as effective as some other H1-histamine receptor antagonists. A few smaller studies have shown beneficial effects on the symptoms of allergic conjunctivitis and chronic urticaria (but not atopic dermatitis). While astemizole appears to share with other H1-histamine receptor antagonists a tendency to increase appetite and cause weight gain after prolonged use, it offers the important advantage of an absence of significant central nervous system depression or anticholinergic effects with usual doses. Thus, astemizole offers a worthwhile improvement in side effect profile over 'traditional' H1-histamine receptor antagonists, especially in patients bothered by the sedative effects of these drugs.
Abstract: An overdose of astemizole predisposes the myocardium to ventricular dysrhythmias, including torsades de pointes. Herein we describe a case of astemizole-induced torsades de pointes ventricular tachycardia and also review previous case reports in the literature. All the patients were young, and dysrhythmias developed only in those with corrected QT intervals greater than 500 ms. Although several mechanisms have been postulated, no clear explanation has been provided for why astemizole promotes myocardial dysrhythmias. Treatment of astemizole-induced torsades de pointes includes discontinuing use of astemizole, intravenous administration of magnesium sulfate and isoproterenol, temporary cardiac pacing, and, when necessary, direct current cardioversion. A cardiac cause of syncope or convulsions must not be overlooked, especially in patients taking H1 antagonists because they often have these symptoms before hospitalization or detection of torsades de pointes (or both).
Abstract: No Abstract available
Abstract: A 26 year-old woman was admitted to the hospital two hours after astemizole overdose. Electrocardiograph showed a prolonged QT interval. Torsade de pointes occurred 13 h after ingestion. Plasma levels of astemizole plus hydroxylated metabolites showed an apparent plasma half-life of 17 h. The possible occurrence of torsade de pointes in astemizole overdose, and the long elimination time of astemizole and hydroxylated metabolites, makes it necessary to maintain ECG monitoring until QT interval has returned to normal.
Abstract: Disposition and biotransformation of the new antipsychotic agent olanzapine (OLZ) were studied in six male healthy volunteers after a single oral dose of 12.5 mg containing 100 microCi of [14C]OLZ. Biological fluids were analyzed for total radioactivity, the parent compound (GC/MS), and metabolites (electrospray LC/MS and LC/MS/MS). Mean radiocarbon recovery was approximately 87%, with 30% appearing in the faces and 57% excreted in the urine. Approximately half of the radiocarbon was excreted within 3 days, whereas > 70% of the dose was recovered within 7 days of dosing. Circulating radio-activity was mostly restricted to the plasma compartment of blood. Mean peak plasma concentration of OLZ was 11 ng/ml, whereas that of radioactivity was 39 ng eq/ml. Mean plasma terminal elimination half-lives were 27 and 59 hr, respectively, for OLZ and total radioactivity. With the help of NMR and MS data, a major metabolite of OLZ in humans was characterized as a novel tertiary N-glucuronide in which the glucuronic acid moiety is attached to the nitrogen at position 10 of the benzodiazepine ring. Another N-glucuronide was detected in urine and identified as the quaternary N-linked 4'-N-glucuronide. Oxidative metabolism on the allylic methyl group resulted in 2-hydroxymethyl and 2-carboxylic acid derivatives of OLZ. The methyl piperazine moiety was also subject to oxidative attack, giving rise to the N-oxide and N-deemethyl metabolites. Other metabolites, including the N-deemethyl-2-carboxy derivative, resulted from metabolic reactions at both the 4' nitrogen and 2-methyl groups. The 10-N-glucuronide and OLZ were the two most abundant urinary components, accounting for approximately 13% and 7% of the dose, respectively. In fecal extracts, the only significant radioactive HPLC peaks were due to 10-N-glucuronide and OLZ representing, respectively, approximately 8% and 2% of the administered dose. Semiquantitative data obtained from plasma samples from subjects given [14C]OLZ suggest that the main circulating metabolite is 10-N-glucuronide. Thus, OLZ was extensively metabolized in humans via N-glucuronidation, allylic hydroxylation, N-oxidation, N-dealkylation and a combination thereof. The 10-N-glucuronidation pathway was the most important pathway both in terms of contribution to drug-related circulating species and as an excretory product in feces and urine.
Abstract: AIMS: The aim of this study was to investigate the influence of chronic itraconazole treatment on the pharmacokinetics and cardiovascular effects of single dose astemizole in healthy subjects was studied. METHODS: Twelve male volunteers were taking orally 200 mg twice daily itraconazole or placebo for 14 days with a washout period of 4 weeks in between. Approximately 2 h after the morning dose of itraconazole or placebo on day 11, 10 mg astemizole was orally administered. The plasma concentrations of astemizole and desmethylastemizole were measured by radioimmunoassay up to 504 h after administration; electrocardiograms with analysis of the QTc interval were recorded up to 24 h post administration. RESULTS: Itraconazole treatment did not significantly change the peak concentration of astemizole (0.74 vs 0.81 ng ml-1) but it increased the area under the curve from 0 to 24 h (5.46 to 9.95 ng ml-1 h) and from 0 to infinity (17.4 to 48.2 ng ml-1 h), and the elimination half-life (2.1 to 3.6 days). The systemic bioavailability of desmethylastemizole was also increased. The QTc interval did not increase after astemizole administration and there was no difference in the QTc intervals between the itraconazole and placebo session. CONCLUSIONS: Chronic administration of itraconazole influences the metabolism of single dose astemizole in normal volunteers without changes of cardiac repolarization during the first 24 h after astemizole administration. However, the reduction in astemizole clearance under concomitant administration of itraconazole may result in a marked increase in astemizole plasma concentrations and QTc alterations during chronic combined intake of astemizole with itraconazole.
Abstract: OBJECTIVE: Olanzapine is a novel antipsychotic, which is effective against both the positive and negative symptoms of schizophrenia and causes fewer extrapyramidal adverse effects than conventional antipsychotics. The purpose of the present study was to assess the potential for a pharmacokinetic interaction between olanzapine and carbamazepine, since these agents are likely to be used concomitantly in the treatment of manic psychotic disorder. METHOD: The pharmacokinetics of two single therapeutic doses of olanzapine were determined in 11 healthy volunteers. The first dose of olanzapine (10 mg) was taken alone and the second dose (10 mg) after 2 weeks of treatment with carbamazepine (200 mg BID). Measurement of urinary 6beta-hydroxycortisol/cortisol excretion was used as an endogenous marker to confirm that induction of CYP3A4 by carbamazepine had occurred. RESULTS: The dose of olanzapine given after a 2-week pretreatment with carbamazepine was cleared more rapidly than olanzapine given alone. Olanzapine pharmacokinetic values for Cmax and AUC were significantly lower after the second dose, the elimination half-life was significantly shorter, and the clearance and volume of distribution were significantly increased. CONCLUSION: Carbamazepine has been shown to induce several P450 cytochromes including CYP3A4 and CYP1A2. Since CYP1A2 plays a role in the metabolic clearance of olanzapine, the interaction may be attributed to induction of CYP1A2 by carbamazepine, leading to increased first-pass and systemic metabolism of olanzapine. The interaction is not considered to be of clinical significance because olanzapine has a wide therapeutic index, and the changes in plasma concentration of olanzapine are within the fourfold variation that occurs without concern for safety in a patient population.
Abstract: Second-generation histamine H1 receptor antagonists (antihistamines) have been developed to reduce or eliminate the sedation and anticholinergic adverse effects that occur with older H1 receptor antagonists. This article evaluates second-generation antihistamines, including acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, ketotifen, loratadine, mizolastine and terfenadine, for significant features that affect choice. In addition to their primary mechanism of antagonising histamine at the H1 receptor, these agents may act on other mediators of the allergic reaction. However, the clinical significance of activity beyond that mediated by histamine H1 receptor antagonism has yet to be demonstrated. Most of the agents reviewed are metabolised by the liver to active metabolites that play a significant role in their effect. Conditions that result in accumulation of astemizole, ebastine and terfenadine may prolong the QT interval and result in torsade de pointes. The remaining agents reviewed do not appear to have this risk. For allergic rhinitis, all agents are effective and the choice should be based on other factors. For urticaria, cetirizine and mizolastine demonstrate superior suppression of wheal and flare at the dosages recommended by the manufacturer. For atopic dermatitis, as adjunctive therapy to reduce pruritus, cetirizine, ketotifen and loratadine demonstrate efficacy. Although current evidence does not suggest a primary role for these agents in the management of asthma, it does support their use for asthmatic patients when there is coexisting allergic rhinitis, dermatitis or urticaria.
Abstract: Multicentre trials in patients with schizophrenia confirm that olanzapine is a novel antipsychotic agent with broad efficacy, eliciting a response in both the positive and negative symptoms of schizophrenia. Compared with traditional antipsychotic agents, olanzapine causes a lower incidence of extrapyramidal symptoms and minimal perturbation of prolactin levels. Generally, olanzapine is well tolerated. The pharmacokinetics of olanzapine are linear and dose-proportional within the approved dosage range. Its mean half-life in healthy individuals was 33 hours, ranging from 21 to 54 hours. The mean apparent plasma clearance was 26 L/h, ranging from 12 to 47 L/h. Smokers and men have a higher clearance of olanzapine than women and nonsmokers. After administering [14C]olanzapine, approximately 60% of the radioactivity was excreted in urine and 30% in faeces. Olanzapine is predominantly bound to albumin (90%) and alpha 1-acid glycoprotein (77%). Olanzapine is metabolised to its 10- and 4'-N-glucuronides, 4'-N-desmethylolanzapine [cytochrome P450 (CYP) 1A2] and olanzapine N-oxide (flavin mono-oxygenase 3). Metabolism to 2-hydroxymethylolanzapine via CYP2D6 is a minor pathway. The 10-N-glucuronide is the most abundant metabolite, but formation of 4'-N-desmethylolanzapine is correlated with the clearance of olanzapine. Olanzapine does not inhibit CYP isozymes. No clinically significant metabolic interactions were found between olanzapine and diazepam, alcohol (ethanol), imipramine, R/S-warfarin, aminophylline, biperiden, lithium or fluoxetine. Fluvoxamine, an inhibitor of CYP1A2, increases plasma concentrations of olanzapine; inducers of CYP1A2, including tobacco smoke and carbamazepine, decrease olanzapine concentrations. Orthostatic changes were observed when olanzapine and diazepam or alcohol were coadministered. Pharmacodynamic interactions occurred between olanzapine and alcohol, and olanzapine and imipramine, implying that patients should avoid operating hazardous equipment or driving an automobile while experiencing the short term effects of the combinations. Individual factors with the largest impact on olanzapine pharmacokinetics are gender and smoking status. The plasma clearance of olanzapine generally varies over a 4-fold range, but the variability in the clearance and concentration of olanzapine does not appear to be associated with the severity or duration of adverse effects or the degree of efficacy. Thus, dosage adjustments appear unnecessary for these individual factors. However, dosage modification should be considered for patients characterised by a combination of factors associated with decreased oxidative metabolism, for example, debilitated or elderly women who are nonsmokers.
Abstract: AIMS: The aims of the present study were to investigate the metabolism of astemizole in human liver microsomes, to assess possible pharmacokinetic drug-interactions with astemizole and to compare its metabolism with terfenadine, a typical H1 receptor antagonist known to be metabolized predominantly by CYP3A4. METHODS: Astemizole or terfenadine were incubated with human liver microsomes or recombinant cytochromes P450 in the absence or presence of chemical inhibitors and antibodies. RESULTS: Troleandomycin, a CYP3A4 inhibitor, markedly reduced the oxidation of terfenadine (26% of controls) in human liver microsomes, but showed only a marginal inhibition on the oxidation of astemizole (81% of controls). Three metabolites of astemizole were detected in a liver microsomal system, i.e. desmethylastemizole (DES-AST), 6-hydroxyastemizole (6OH-AST) and norastemizole (NOR-AST) at the ratio of 7.4 : 2.8 : 1. Experiments with recombinant P450s and antibodies indicate a negligible role for CYP3A4 on the main metabolic route of astemizole, i.e. formation of DES-AST, although CYP3A4 may mediate the relatively minor metabolic routes to 6OH-AST and NOR-AST. Recombinant CYP2D6 catalysed the formation of 6OH-AST and DES-AST. Studies with human liver microsomes, however, suggest a major role for a mono P450 in DES-AST formation. CONCLUSIONS: In contrast to terfenadine, a minor role for CYP3A4 and involvement of multiple P450 isozymes are suggested in the metabolism of astemizole. These differences in P450 isozymes involved in the metabolism of astemizole and terfenadine may associate with distinct pharmacokinetic influences observed with coadministration of drugs metabolized by CYP3A4.
Abstract: BACKGROUND: There may be a temporal association between some antipsychotics and prolongation of the heart-rate-corrected QT interval (QTc) representing a delay in ventricular repolarization. QTc prolongation significantly exceeding normal intra-individual and interindividual variation may increase the risk of ventricular tachydysrhythmias, especially torsade de pointes, and therefore, sudden cardiac death. METHOD: Electrocardiogram recordings obtained as part of the safety assessment of olanzapine in 4 controlled, randomized clinical trials (N = 2,700) were analyzed. These analyses were conducted to characterize any change in QTc temporally associated with olanzapine, compared with placebo, haloperidol, and risperidone, in acutely psychotic patients (DSM-III-R and DSM-IV) and to characterize variability and temporal course of the QTc in this patient population. Changes from baseline to minimum and maximum QTc were tested for significance, and baseline to acute-phase endpoint change in mean QTc was tested for significance within treatments and for differences between olanzapine and comparators. The possibility of a linear relationship between dose of olanzapine and mean change in QTc, as well as incidence of treatment-emergent prolongation of QTc (change from < 430 msec at baseline to > or =430 msec at endpoint), was tested. RESULTS: The incidence of maximum QTc > or = 450 msec during treatment was approximately equal to the incidence of QTc > or =450 msec at baseline. CONCLUSION: Results of these analyses suggest that olanzapine, as therapeutically administered to patients with schizophrenia and related psychoses, does not contribute to QTc prolongation resulting in potentially fatal ventricular arrhythmias.
Abstract: STUDY DESIGN: The metabolic pathways of most xenobiotics and endogenous compounds can be divided into phase 1 (oxidative, reductive, and hydrolytic) and phase 2 (glucuronidation, sulfate conjugation, glycine and glutathione conjugation, and acetylation and methylation) processes. Oxidative metabolism by the cytochrome P450 system has been intensively investigated compared with glucuronidation and other conjugation pathways. The primary aim of this study was to evaluate the disposition of olanzapine or risperidone in healthy volunteers with and without coadministration of the uridine diphosphoglucuronate-glucuronosyltransferase inhibitor probenecid. We hypothesized that olanzapine disposition would be altered as a result of decreased glucuronidation, whereas risperidone disposition would be relatively unaffected. METHODS: Our objective was to investigate whether this interaction would occur in 12 healthy volunteers, aged 22 to 42 years, who participated in a single-dose, randomized, 4-period, double-blind, crossover study receiving a single dose of either 5 mg olanzapine or 1 mg risperidone with and without 500 mg probenecid (8 doses over 4 days). Multiple blood samples were analyzed by means of liquid chromatography-tandem mass spectrometry or HPLC to assess the 48-hour time course of risperidone and olanzapine. Urine was assayed for free and glucuronidated drugs. RESULTS: When olanzapine was administered with probenecid, statistically significant differences were observed between plasma pharmacokinetic parameters compared with olanzapine administered alone (maximum concentration, P <.05; area under the plasma concentration-time curve from time zero to 24 hours, P <.01). Clearance was not significantly different between the treatment phases. Risperidone pharmacokinetic parameters were not significantly different (all parameters, P >.05). CONCLUSION: Inhibition of uridine diphosphoglucuronate-glucuronosyltransferase appeared to influence the disposition of olanzapine but not risperidone. Phase 2 metabolism may significantly influence the disposition of antipsychotic drugs and may be an important aspect of the variability in metabolism, participation in drug-drug interactions, and clinical response to some antipsychotic agents.
Abstract: The combination of atypical antipsychotics and selective serotonin reuptake inhibitors is an effective strategy in the treatment of certain psychiatric disorders. However, pharmacokinetic interactions between the two classes of drugs remain to be explored. The present study was designed to determine whether there were different effects of steady-state fluvoxamine on the pharmacokinetics of a single dose of olanzapine and clozapine in healthy male volunteers. One single dose of 10 mg olanzapine (n = 12) or clozapine (n = 9) was administered orally. Following a drug washout of at least 4 weeks, all subjects received fluvoxamine (100 mg/day) for 9 days, and one single dose of 10 mg olanzapine or clozapine was added on day 4. Plasma concentrations of olanzapine, clozapine, and N-desmethylclozapine were assayed at serial time points after the antipsychotics were given alone and when added to fluvoxamine. No bioequivalence was found in olanzapine alone and cotreatment with fluvoxamine for the mean peak plasma concentration (C(max)), the area under the concentration-time curve from time 0 to last sampling time point (AUC(0-t)), and from time 0 to infinity (AUC(0- infinity )). Under the cotreatment, C(max) of olanzapine was significantly elevated by 49%, with a 32% reduced time (t(max)) to C(max), whereas the C(max) and t(max) of clozapine were unaltered. The cotreatment increased the AUC(0-t) and AUC(0- infinity ) of olanzapine by 68% and 76%, respectively, greater than those of clozapine (40% and 41%). The presence of fluvoxamine also prolonged the elimination half-life (t(1/2)) of olanzapine by 40% and, to a much greater extent, clozapine by 370% but reduced the total body clearance (CL/F) of clozapine (78%) more significantly than it did for olanzapine (42%). The apparent volume of distribution (V(d)) was suppressed by 31% in olanzapine combined with fluvoxamine but was unaltered in the clozapine regimen. A significant reduction in the N-desmethylclozapine to clozapine ratio was present in the clozapine with fluvoxamine regimen. The effects of fluvoxamine on different aspects of pharmacokinetics of the two antipsychotics may have implications for clinical therapeutics.
Abstract: P-glycoprotein (PGP) is a polymorphic efflux transporter located on the blood brain barrier that potentially affects the penetration of atypical antipsychotics into the central nervous system. Increased antipsychotic penetration to the primary site of activity may result in greater symptom improvement or the occurrence of side effects. This investigation examined the relationship between three common PGP polymorphisms (C1236T, G2677TA, and C3435T) and response to 6 weeks of open-label olanzapine treatment in patients with schizophrenia. Individuals with a PGP T allele at any of these polymorphisms would be expected to have greater antipsychotic penetration through the blood brain barrier, due to lower PGP activity. Forty-one patients were included in this reanalysis. For subjects in the 3435T allele carrier group, the plasma olanzapine level alone was positively associated with percent change in Brief Psychiatric Rating Scale score (p = 0.02). This relationship was not seen for the 3435CC group (p = 0.583). A similar trend was observed for negative symptom reduction, olanzapine plasma concentration, and the 3435T allele (p = 0.06), but this relationship did not meet statistical significance. There was no relationship between the PGP genotypes and changes in weight over the course of this 6 week study. The analysis using C1236T or G2677AT genotypes gave similar results, due to linkage of these polymorphisms.PGP polymorphisms may affect the penetration of olanzapine into the central nervous system as seen by a relationship between the 3435T allele, olanzapine plasma levels, and reduction in the positive symptoms of schizophrenia. This may stem from greater olanzapine central nervous system latency due to the presence of the 3435T allele and reduced PGP activity. The PGP C3435T genotype may help to determine positive symptom reduction from olanzapine clinically, but these findings should be replicated in a larger sample of subjects.
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: In the past, the information about the dose-clinical effectiveness of typical antipsychotics was not complete and this led to the risk of extrapyramidal adverse effects. This, together with the intention of improving patients' quality of life and therapeutic compliance, resulted in the development of atypical or second-generation antipsychotics (SGAs). This review will concentrate on the pharmacokinetics and metabolism of clozapine, risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole and sertindole, and will discuss the main aspects of their pharmacodynamics. In psychopharmacology, therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding adverse effects by keeping long-term exposure to the minimal effective blood concentration. The rationale for using therapeutic drug monitoring in relation to SGAs is still a matter of debate, but there is growing evidence that it can improve efficacy, especially when patients do not respond to therapeutic doses or when they develop adverse effects. Here, we review the literature concerning the relationships between plasma concentrations of SGAs and clinical responses by dividing the studies on the basis of the length of their observation periods. Studies with clozapine evidenced a positive relationship between plasma concentrations and clinical response, with a threshold of 350-420 ng/mL associated with good clinical response. The usefulness of therapeutic drug monitoring is well established because high plasma concentrations of clozapine can increase the risk of epileptic seizures. Plasma clozapine concentrations seem to be influenced by many factors such as altered cytochrome P450 1A4 activity, age, sex and smoking. The pharmacological effects of risperidone depend on the sum of the plasma concentrations of risperidone and its 9-hydroxyrisperidone metabolite, so monitoring the plasma concentrations of the parent compound alone can lead to erroneous interpretations. Despite a large variability in plasma drug concentrations, the lack of studies using fixed dosages, and discrepancies in the results, it seems that monitoring the plasma concentrations of the active moiety may be useful. However, no therapeutic plasma concentration range for risperidone has yet been clearly established. A plasma threshold concentration for parkinsonian side effects has been found to be 74 ng/mL. Moreover, therapeutic drug monitoring may be particularly useful in the switch between the oral and the long-acting injectable form. The reviewed studies on olanzapine strongly indicate a relationship between clinical outcomes and plasma concentrations. Olanzapine therapeutic drug monitoring can be considered very useful in assessing therapeutic efficacy and controlling adverse events. A therapeutic range of 20-50 ng/mL has been found. There is little evidence in favour of the existence of a relationship between plasma quetiapine concentrations and clinical responses, and an optimal therapeutic range has not been identified. Positron emission tomography studies of receptor blockade indicated a discrepancy between the time course of receptor occupancy and plasma quetiapine concentrations. The value of quetiapine plasma concentration monitoring in clinical practice is still controversial. Preliminary data suggested that a therapeutic plasma amisulpride concentration of 367 ng/mL was associated with clinical improvement. A therapeutic range of 100-400 ng/mL is proposed from non-systematic clinical experience. There is no direct evidence concerning optimal plasma concentration ranges of ziprasidone, aripiprazole or sertindole.
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: 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: 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: 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: The antipsychotic drug, olanzapine, one of the most widely used drugs in clinical medicine, has a high rate of discontinuation due to inefficacy and/or adverse effects. We identified a single nucleotide polymorphism in the drug metabolizing enzyme, cytochrome P450 3A43 (CYP3A43; rs472660), that highly significantly predicted olanzapine clearance in the Clinical Antipsychotic Trials of Intervention Effectiveness trial (P=5.9e(-7)). Moreover, at standard antipsychotic doses, 50% of individuals with the high clearance genotype (AA) have trough blood levels below the therapeutic range. Interestingly, a much higher proportion of African Americans carry the A allele compared with Caucasians (allele frequency 67 vs 14%). After accounting for CYP3A43 genotype, race is no longer a significant predictor of olanzapine clearance. Olanzapine clearance was associated with measures of clinical response. Patients with greater clearance had higher symptom ratings and were more likely to discontinue treatment due to an inadequate response. Our data identify a genetic mechanism for variation in olanzapine response and demonstrate that blood level monitoring of olanzapine treatment is advisable.
Abstract: Olanzapine, a world leader in antipsychotic drugs, is used in the treatment of schizophrenia and bipolar disorder. There is considerable interpatient variability in its hepatic clearance. Polymorphic glucuronidation of olanzapine by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) was investigated retrospectively in patient samples taken for routine therapeutic drug monitoring (TDM) and in recombinant metabolic systems in vitro. Multivariate analyses revealed that patients who were heterozygous as well as those who were homozygous for the UGT1A4*3 allelic variant had significantly higher concentrations of the major metabolite olanzapine 10-N-glucuronide in serum (+38% (P = 0.011) and +246% (P < 0.001), respectively). This finding was in line with the significant increases in glucuronidation activity of olanzapine observed with recombinant UGT1A4.3 (Val-48) as compared with UGT1A4.1 (Leu-48) (1.3-fold difference, P < 0.001). By contrast, serum concentrations of the parent drug were not significantly influenced by UGT1A4 genotype. Our findings therefore indicate that UGT1A4-mediated metabolism is not a major contributor to interpatient variability in olanzapine levels. However, with respect to other drugs for which UGT1A4 has a dominant role in clearance, increased glucuronidation encoded by UGT1A4*3 might impact the risk for subtherapeutic drug exposure.
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: No Abstract available