Intervallo QT lungo
Reazione avversa da farmaco (ADR)
Varianti ✨Per l'analisi computazionale dettagliata delle varianti, si prega di selezionare l'abbonamento standard a pagamento.
Informazioni dei farmaci per i pazienti
Non abbiamo ulteriori avvertenze per la co-somministrazione di galantamina e astemizolo. Si prega di consultare le informazioni specialistiche pertinenti.
I cambiamenti riportati in seguito all'esposizione corrispondono ai cambiamenti nell'area sottesa alla curva concentrazione plasmatica-tempo [ AUC ]. Non è stato possibile rilevare nessun tipo di cambiamento nell'esposizione alla galantamina. Allo stato attuale non è possibile valutare come influisce la astemizolo. Non ci aspettiamo nessun cambiamento nell'esposizione alla astemizolo, quando è co-somministrata con la galantamina (100%).
I parametri farmacocinetici della popolazione media sono utilizzati come punto di partenza per calcolare i cambiamenti del singolo individuo esposto alle interazioni farmacologiche
La galantamina ha un elevata biodisponibilità [ F ] orale pari al 85%, perciò nel corso di un'interazione farmacologica la concentrazione plasmatica massima [Cmax] tende a cambiare di poco. L'emivita [ t12 ] del farmaco è di 7 ore e la concentrazione allo stato stazionario [Css] si raggiunge dopo circa 28 ore. Il legame proteico [ Pb ] è molto debole al 18%. Poiché la sostanza ha un basso tasso di estrazione epatica di 0.13, lo spostamento dal legame proteico [Pb] nel contesto di un'interazione può portare a un aumento dell'esposizione. Tra l'altro, il metabolismo avviene rispettivamente attraverso gli enzimi CYP2D6 e CYP3A4..
La astemizolo ha una bassa biodisponibilità orale [ F ] del 3%, motivo per cui il livello plasmatico massimo [Cmax] tende a cambiare fortemente con un'interazione. L'emivita [ t12 ] del farmaco è di 22 ore e la concentrazione allo stato stazionario [Css] si raggiunge dopo circa 88 ore. Il legame proteico [ Pb ] è forte al 97%. Tra l'altro, il metabolismo avviene rispettivamente attraverso gli enzimi CYP2D6 e CYP3A4..
|Effetti serotoninergici a||0||Ø||Ø|
Valutazione: Sulla base dei dati a nostra disposizione, né la galantamina né la astemizolo potenziano l'attività serotoninergica.
|Kiesel & Durán b||0||Ø||Ø|
Valutazione: Sulla base dei dati a nostra disposizione, né la galantamina né la astemizolo causano un aumento dell'attività anticolinergica.
Intervallo QT lungo
Valutazione: La co-somministrazione di galantamina e astemizolo potrebbe causare tachicardia ventricolare a torsione di punta.
Effetti collaterali generali
|Effetti collaterali||∑ frequenza||gal||ast|
|Perdita di appetito||7.4 %||7.4||n.a.|
|Mal di testa||7.1 %||7.1||n.a.|
|Blocco atrioventricolare||0.9 %||0.9||n.a.|
|Pustolosi esantematica generalizzata||0.0 %||0.01||n.a.|
Sindrome di Stevens Johnson: galantamina
Emorragia gastrointestinale: galantamina
Abbiamo valutato il rischio individuale di effetti indesiderati in base alle risposte fornite ed alle informazioni scientifiche disponibili. Le informazioni contenute nel sito hanno esclusivamente scopo informativo e non sostituiscono il parere del medico. Si accomanda pertanto di chiedere sempre il parere del proprio medico curante e/o di specialisti riguardo qualsiasi indicazione riportata. Nella versione alpha test, il rischio di tutti i farmaci non è stato ancora completamente valutato.
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: 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: 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: 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: Galantamine is the most recently approved cholinergic drug for the treatment of Alzheimer's disease, the most common type of dementia. Vascular dementia and Alzheimer's disease with cerebrovascular disease are also common in older patients. Dementia affects cognition, causes losses in ability to perform activities of daily living and often results in the emergence of psychiatric and abnormal behavioural symptoms. Dementia also results in an ever-increasing burden and a decreased quality of life for caregivers. Treatments for dementia, particularly Alzheimer's disease, have focused on improving function in the cholinergic system. Vascular dementia and diffuse Lewy body dementia are also associated with significant defects in cholinergic function. Galantamine works by inhibiting acetylcholinesterase and by allosterically modulating nicotinic receptors. In clinical trials, galantamine has shown benefits in the domains of cognition, function in activities of daily living, and behaviour. Galantamine is about 90% bioavailable and displays linear pharmacokinetics. It has a relatively large volume of distribution and low protein binding. Metabolism is primarily through the cytochrome P450 system, specifically the CYP2D6 and CYP3A4 isoenzymes. Population pharmacokinetic modelling with galantamine has shown that the variables affecting clearance are age, sex, and bodyweight. Model simulations demonstrate the importance of a slower dose-escalation schedule in patients with moderate hepatic impairment. In several large trials, galantamine has been shown to be well tolerated, with most adverse events being mild-to-moderate and gastrointestinal in nature. Based on the literature and clinical trial experience, galantamine appears to be an excellent treatment option for patients with Alzheimer's disease, vascular dementia or Alzheimer's disease with cerebrovascular disease.
Abstract: No Abstract available
Abstract: OBJECTIVE: To describe a case of QT interval prolongation, syncope, and delirium associated with galantamine use and to analyze similar cases related to acetylcholinesterase inhibitors (AChIs) reported to the Australian Adverse Drug Reaction Advisory Committee (ADRAC). CASE SUMMARY: An 85-year-old man with dementia was treated with prolonged release galantamine 8 mg daily for 1.5 years. Three months prior to the current admission, he had a syncopal episode with low blood pressure and bradycardia. Two months later, galantamine was withdrawn, but within 2 weeks, the man developed marked cognitive, behavioral, and functional deterioration and galantamine was restarted. Three weeks later, he developed syncope, delirium, hypotension, and prolonged QT interval with serious cardiac arrhythmias, in addition to vomiting and diarrhea. A complete blood cell count and biochemistry panel performed on admission were normal. No infection was detected. Galantamine and irbesartan were ceased. The delirium fully resolved in 6 days, and the QT interval shortened from 503 to 443 msec (corrected by Bazett's formula) 4 days after discontinuation of galantamine and remained normal. DISCUSSION: In the ADRAC reports, galantamine was associated with 18 cases of delirium/confusion, 8 of syncope, 13 of bradycardia, 6 of other arrhythmias or conduction abnormalities, and 6 of hypotension. Donepezil was associated with 56, 15, 26, 15, and 5, and rivastigmine with 21, 8, 6, 2, and 2, respectively, of these reactions. Five fatal outcomes were reported in association with galantamine, 11 with donepezil, and 3 with rivastigmine, including 3, 6, and 0 sudden deaths, respectively. This case, along with previously published reports and cases identified from the ADRAC database, illustrates that AChIs may lead to delirium, syncope, hypotension, and life-threatening arrhythmias. The Naranjo probability scale indicated that galantamine was the probable cause of QT interval prolongation, syncope, and delirium in this patient. CONCLUSIONS: Administration of galantamine and other AChIs requires vigilance and assessment of risk factors that may precipitate QT interval prolongation, syncope, and delirium.
Abstract: Galantamine is a reversible inhibitor of acetylcholinesterase and an allosteric-potentiating ligand of the nicotinic acetylcholine receptors. It is used for treating mild-to-moderate Alzheimer's disease. Interestingly, QT interval prolongation on the electrocardiogram (ECG), malignant ventricular arrhythmias and syncope have been reported with galantamine. Our objective was to evaluate the effects of galantamine on cardiac ventricular repolarization. Three sets of experiments were undertaken: 1) Whole cell patch-clamp experiments: HERG- or KCNQ1+KCNE1-transfected cells were exposed to galantamine 0.1-1000 μmol/l (n=25 cells, total) to assess drug effect on HERG and KCNQ1+KCNE1 currents. 2) Langendorff perfusion experiments: Isolated hearts from male Hartley guinea pigs (n=9) were exposed to galantamine 1 μmol/l to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD(90)). 3) Cardiac telemetry experiments: Guinea pigs (n=7) implanted with wireless transmitters were injected a single intraperitoneal (i.p.) dose of galantamine 3mg/kg and 24h ECG recordings were made. 1) The estimated IC(50) for galantamine on HERG current was 760.2 μmol/l. Moreover, galantamine 10 μmol/l had a small inhibiting effect on KCNQ1+KCNE1 current (12.17 ± 2.19% inhibition, n=10 cells). 2) While pacing at cycle lengths of 150, 200 or 250 ms, galantamine 1 μmol/l prolonged MAPD(90) by respectively 5.1 ± 1.6 ms, 9.4 ± 1.9 ms and 12.1 ± 2.1 ms. 3) Galantamine 3 mg/kgi.p. caused a maximal 11.9 ± 2.7 ms prolongation of the corrected QT (QTc). Galantamine is a weak HERG blocker. This contributes to its mild QT-prolonging effect. Patients could be at risk of cardiac proarrhythmia during drug overdosage or interactions involving cytochrome 2D6 drug-metabolizing enzyme.
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.