Anticholinergic Side Effects Research Articles

Expanded Followup of Intravesical Oxybutynin Chloride Use in Children with Neurogenic Bladder

We evaluated the long-term results of intravesical oxybutynin chloride use in children with neurogenic bladders who could not tolerate or whose conditions were refractory to oral therapy. We reviewed our experience with 28 children (myelomeningocele in 27 and imperforate anus in 1) who presented with urinary incontinence and/or elevated bladder pressures refractory to intermittent catheterization and oral anticholinergic medication. Intravesical oxybutynin was administered to each child by instillation of 5 mg. crushed oxybutynin chloride in 10 cc sterile saline 2 times daily during catheterization. Seven patients (25%) could not tolerate intravesical oxybutynin secondary to anticholinergic side effects. The remaining 21 children have been followed on intravesical oxybutynin for a mean of 35 months (range 3 to 67). Of these 21 children 12 (57%) became completely dry day and night, 5 (24%) achieved daytime continence between catheterizations and 4 (19%) remained clinically unchanged with 2 in diapers. On urodynamics these 21 patients had increased bladder capacity of up to 1,150% (mean 237%, p < 0.0001) and decreased mean maximum filling pressures of -31% (p = 0.002). Although a number of patients continued to have anticholinergic side effects, a majority had significant improvement in urodynamic parameters and continence. The response appears to be durable, and it spares many of these children from undergoing bladder augmentation.

Clinical relevance of serum nortriptyline and 10-hydroxy-nortriptyline measurements in the depressed elderly: A multicenter pharmacokinetic and pharmacodynamic study

In a recent placebo-controlled multicenter study, 38 patients, ranging in age between 62 and 88 years (median, 71) were treated with nortriptyline (NT) for up to 7 weeks. NT was administered in a divided dose of 75 mg daily and serum NT (se NT), and its 10-hydroxy-metabolites (se OH-NT) were determined at various intervals. Several clinical measures of efficacy, including the 17-item Hamilton Rating Scale for Depression, were evaluated weekly as well as side effects (anticholinergic) and electrocardiogram (ECG) changes. Eighty-one percent of patients had NT levels in the previously defined therapeutic range of 50 to 170 ng/ml, with steady state reached between 1 and 3 weeks. There was little individual variation in drug kinetics and metabolism over the study period. In general se OH-NT levels were not greater than those of se NT. Pharmacodynamic analyses showed that patients with moderate to severe anticholinergic side effects [CSE(+)] had significantly higher NT levels than those with mild or no symptoms [CSE(-)]. Furthermore, repeated-measures ANOVA modeled over time showed a highly significant decrease in clinical measures in both CSE groups of patients and also a highly significant group-time interaction. Higher se OH-NT levels were associated with less anticholinergic side effects. No ECG changes were observed.

Newer antipsychotics and antidepressants for elderly people

The newer antipsychotics and antidepressants offer distinct clinical advantages over older agents.Specifically, treatment with the atypical antipsychotic agents clozapine and risperidone has resulted in greater reduction in negative symptoms associated with schizophrenia. Also, the atypical antipsychotic drugs have been associated with a lower risk of extrapyramidal symptoms, such as parkinsonism and tardive dyskinesia, relative to typical agents. For antidepressants, the safety profile of the selective serotonin reuptake inhibitors nefazodone and venlafaxine, in terms of anticholinergic side effects, cardiac toxicity, and overdose lethality, is superior to the older tricyclic antidepressants and monoamine oxidase inhibitors.

A pharmacoepidemiological evaluation of anticholinergic prescribing patterns in the elderly.

The elderly are high consumers of both prescription and over-the-counter medications. As a result of age-related changes in drug pharmacokinetics and pharmacodynamics, they experience twice the number of adverse effects than in the general population. Using the health insurance data bases of the province of Saskatchewan, the prescribing pattern of drugs which have anticholinergic properties, was studied in the elderly. Of patients less than or equal to (< or =) 64 years of age 3.8% compared to 11.3% of patients greater than or equal to (> or =) 65 years of age were prescribed an anticholinergic medication. In the elderly group, 9.3% of the ambulatory subjects and 43.8% of the special care home (SCH) residents received a prescription for an anticholinergic drug. The concurrent prescribing of two or more anticholinergic medications was also higher in the elderly (0.16% of patients < or = 64 versus 0.54% of patients > or = 65). All differences between patients < or = 64 and those > or = 65, as well as between the ambulatory elderly subjects and the SCH elderly residents, were statistically significant. Approximately 25% of all anticholinergic medications were prescribed in the high to excessive dosage range. The study also looked at prescribing patterns for individuals with a diagnosis of dementia. Despite the potential detrimental adverse effect of anticholinergic therapy in that patient group, 35.5% received a prescription for anticholinergic medication. These data confirm that the elderly are at high risk for receiving a prescription for anticholinergic medications. The high prevalence of anticholinergic prescribing in a patient population known to be sensitive to anticholinergic side-effects has the potential to cause significant adverse clinical consequences.

Treatment of neurogenic bladder dysfunction in infants and children with neurospinal dysraphism with clean intermittent (self)catheterisation and optimized intravesical oxybutynin hydrochloride therapy.

Clean intermittent (self)catheterisation (CIC) in combination with oral anticholinergic drugs (oxybutynin hydrochloride [OH] is the present standard therapy for neurogenic bladder dysfunction (NBD) with detrusor hyperactivity. However, complete suppression of detrusor contractions and complete urinary continence is not always obtained despite maximal dosage, and the high incidence of severe systemic anticholinergic side-effects often impairs therapeutic compliance, resulting in dose reduction or even discontinuation of therapy. The intravesical administration of OH has been shown recently to be an effective alternative for treating persistent detrusor hyperactivity, and occurrence and severity of systemic side-effects appeared to be significantly decreased. However, available data are limited from a paediatric view. Furthermore, it is our belief that the use of crushed OH tablets with consequent problems of impracticability accounts for the variable long-term patient compliance reported to be the only disadvantage to intravesical OH. Using an optimized drug preparation we demonstrate the superiority of intravesical OH for treatment of NBD in 15 children (range 0.6-13.75 years, mean 6.1) with incomplete detrusor activity suppression and/or intolerable systemic side-effects on oral OH therapy. Since the previous reported problems of impracticability and variable long-term patient compliance can be resolved by optimized drug preparation, we therefore conclude that the era of crushing OH tablets should be over in order to allow the intravesical OH therapy on a long-lasting and large-scale basis.

The use of medicines with anticholinergic effects in older people: a population study in an urban area of Sweden.

To investigate the use of medicines with anticholinergic properties among older people in an urban population in Sweden. A cross-sectional survey. Ordinary homes, sheltered accommodations, nursing homes, and geriatric departments. All residents aged 75 and older in a district of Stockholm, Sweden. Structured interviews with older persons, their relatives and/or health care personnel; prescription forms; medical records. The overall use of medicines with anticholinergic effects was comparatively low. Doses of these medicines were also generally low. Concurrent use of several such medicines was uncommon. The most prevalent therapeutic/pharmacological group was neuroleptics. In contrast, antidepressants were used by few older people. The prevalence of medicines with anticholinergic effects was highest at institutions, where neuroleptics were frequent and use of low-potency neuroleptics was not uncommon. Our results indicate that the risk of anticholinergic side effects may be quite low in the present population as a whole. However, there may be grounds for revising the therapy in institutions, where the use of neuroleptics was shown to be high and low-potency neuroleptics, known to have a higher incidence of anticholinergic side effects, were not avoided.

Recognition and Management of Anxiety and Depression in Elderly Patients

To describe important aspects of the recognition and management of anxiety and depression in elderly patients. We reviewed pertinent recent articles in the medical literature and compiled guidelines for diagnosing and treating anxiety and depression in the geriatric population. Depression and anxiety are common in the elderly population. The development of depression in elderly subjects is associated with a higher risk of death from suicide than for any other age-group. Recognition of depression in elderly patients is often hampered by an inability or reluctance on the part of these patients to report depressive symptoms. In addition, anxiety and depression are often attributed to organic illness in this age-group. Pharmacotherapy is effective; however, older patients are probably more likely than young patients to experience adverse effects. Using medications at lower doses, choosing drugs with shorter half-lives, and avoiding drugs with potent anticholinergic side effects are often advisable. Anxiety and depression are common conditions among the elderly population. Correct recognition, attention to underlying precipitating factors, and compassionate, supportive care can vastly improve the quality of the lives of these patients.

Histologic Studies of Intravesical Oxybutynin in the Rabbit

Intravesically applied oxybutynin has been reported to have no significant systemic anticholinergic side effects, with excellent efficacy in the treatment of neurogenic bladder dysfunction. Currently, the morphologic effects of intravesical oxybutynin on the local bladder tissue are not well established. It is the purpose of this study to address this issue in an animal model. Thirty-nine New Zealand White female rabbits were catheterized daily and intravesical solutions instilled for as long as 30 days. In part A of the study, the overall histologic effects of intravesical oxybutynin were examined by comparing oxybutynin with saline administration. Part B of this study compared the relative effects of crushed oxybutynin tablets and pure oxybutynin powder. The bladder histology and urine microbiological studies were analyzed in a blinded fashion. We found that the crushed oxybutynin tablets and saline administered intravesically produced similarly mild inflammation in the bladders (p less than 0.05). When we compared the crushed oxybutynin tablets and pure oxybutynin powder, however, the crushed tablet group was found to have a mild eosinophilic infiltrate seen in 5 of 9 animals, which was not observed in any of the animals in the other groups (p = 0.029). Qualitative and quantitative analyses of the microbiological findings were not different among the different groups (p greater than 0.05). Our findings support the clinical use of intravesical oxybutynin as being safe for local tissue. However, consideration should be given to the use of the pure powdered form of oxybutynin, since the crushed oxybutynin tablets may lead to allergic reactions.

Critical flicker fusion threshold and anticholinergic effects of chronic antidepressant treatment in remitted depressives

The persistence of deficits in cognitive performance in major depressive patients taking maintenance antidepressant medication was assessed by examining groups of patients in clinical remission, stable on one of a range of tricyclics or selective serotonin re-uptake inhibitors (SSRIs) for at least 3 months, compared with controls. Measures of critical flicker fusion (CFF), choice reaction time (CRT), subjective sedation, and anticholinergic side-effect score were made. Tricyclic antidepressants (TCAs) produce a significant deficit in critical flicker fusion threshold compared both to controls and SSRIs. Similar effects were seen with choice reaction times which were significantly affected by age. Sedation scores were significantly higher with TCAs than SSRIs. Anticholinergic side effects were strongly related to CFF, less so to visual analogue sedating scales and not significantly to CRT. The effect measured by CFF is different from sedation, and may be related to the anticholinergic potency of the drug; it may be considered a drug-induced pseudodementia. This effect represents a risk factor for accidents during maintenance therapy and may impair work and leisure performance. The relative risk of weight gain with TCAs compared to SSRIs in women was 5.92 (95% CI 1.79-19.50).

Long-term treatment of perennial allergic rhinitis with ipratropium bromide nasal spray 0.06%

The purpose of this study was to assess the safety and efficacy of ipratropium bromide nasal spray 0.06% (aqueous solution), 84 μg per nostril three times a day, in reducing nasal hypersecretion in the long-term treatment of patients with perennial allergic rhinitis (PAR). This was an open-label 1-year trial. In the first 6 months all patients were treated with two puffs ipratropium bromide nasal spray 0.06%, 84 μg per nostril three times per day, unless they were unable to tolerate the dose. In the last 6 months the dose could be reduced to the lowest amount required to control rhinorrhea. Ninety-six patients entered the trial, and 47 completed it. Sixty-three patients completed more than 6 months of treatment. Patient and physician global evaluation suggested that ipratropium bromide nasal spray 0.06% is effective in controlling rhinorrhea associated with PAR and can contribute to control of congestion, postnasal drip, and sneezing. There was also a trend toward reduction of mucosal edema and improvement in quality of life. The most common drug-related adverse events were nasal dryness, epistaxis/nose bleed, and increased rhinitis. Most adverse events were mild and resulted in drug discontinuation in less than 10% of patients. Ipratropium bromide nasal spray was well tolerated and not associated with serious drug-related adverse events or clinically significant anticholinergic side effects. Use of ipratropium bromide nasal spray alone or with other standard medications should be considered in treating patients with PAR. (J A LLERGY C LIN I MMUNOL 1995;95:1128-32.)

Effect of protriptyline, 10 mg daily, on chronic hypoxaemia in chronic obstructive pulmonary disease

A daily dose of 20 mg of protriptyline can improve daytime arterial blood gas tensions in chronic obstructive pulmonary disease (COPD). Its usefulness is limited by anticholinergic side-effects. This study examined whether a daily dose of 10 mg of protriptyline improved daytime arterial oxygen tension (PaO2) and quality of life in patients with stable mild or moderate hypoxaemia caused by COPD. Twenty six patients were randomized to receive protriptyline or placebo in a double-blind parallel-group trial for 12 weeks, following a run-in period of 4 weeks, in order to assess the stability of hypoxaemia. Patients with a change in PaO2 of > 0.7 kPa during the run-in were excluded. Spirometry, quality of life and dyspnoea score were measured at randomization and after 12 weeks, whilst arterial blood gas tensions were also measured 2 and 6 weeks after randomization. No improvement in arterial blood gas tensions, spirometry values, dyspnoea score, or quality of life was found in either the protriptyline or the placebo group. The majority of patients receiving protriptyline experienced anticholinergic side-effects, which necessitated the withdrawal of the drug in one patient. We conclude that there was no evidence that a daily dose of 10 mg of protriptyline had a significant effect on daytime arterial oxygen tension in stable mild and moderate hypoxaemia caused by COPD. Despite the low dose, anticholinergic side-effects occurred in most patients.

Small Bowel Obstruction in a Child on an Antipsychotic

Though decreased intestinal motility and constipation are well recognized anticholinergic side effects of antipsychotic medications, frank intestinal obstruction is an unusual complication. To our knowledge, this is the first report of a neuroleptic unmasking a previously unrecognized intestinal anomaly. A 7-year-old girl, with an asymptomatic congenital intestinal anomaly, developed an obstruction while on perphenazine and benztropine mesylate. Presenting with increasing abdominal pain within a few days of starting perphenazine, she required surgical correction of a jejunal ileus. Antipsychotics, and other medications with antiperistaltic activity, should be prescribed with caution, even in patients with asymptomatic gastrointestinal narrowing.

Long-Term Safety and Clinical Acceptability of

The antidepressant efficacy and safety of venlafaxine was shown previously in 6-week, placebocontrolled trials. We evaluated the long-term safety and clinical acceptability of venlafaxine and imipramine in a double-blind, parallel-group, comparative study. Two hundred ninety depressed outpatients were treated with venlafaxine, and an additional 91 received imipramine for as long as clinically necessary, up to 1 year. The total daily dose of each drug could vary from 75 to 225 mg. The Clinical Global Impressions Scale and a therapeutic response rate that was based on Clinical Global Impressions Scale-Improvement and incorporated discontinuation information were used to evaluate efficacy. Safety determinations and patient subjective ratings were used to evaluate safety and clinical acceptability. During the study, the adverse events were generally mild to moderate and most subsided with continued treatment; the most frequent were nausea for venlafaxine and dry mouth for imipramine. The anticholinergic side effect burden was significantly higher in the imipramine group than in the venlafaxine group. Venlafaxine was judged significantly more acceptable than imipramine, on the basis of the subjective ratings by patients. Fewer venlafaxinetreated patients than imipramine-treated patients withdrew because of adverse events and unsatisfactory response. There was a consistent trend in the therapeutic response rates in favor of venlafaxine that reached statistical significance at months 2, 6, and 12. In this long-term study, patient acceptability was greater for venlafaxine than for imipramine, suggesting therapeutic advantages for venlafaxine in the long-term treatment of depression. Additional studies with other active comparators are underway to confirm and extend these encouraging results.

Cardiovascular Toxicity of Antihistamines

The efficacy of individual antihistamines is similar for most indications. The primary difference between traditional (first-generation) and nonsedating (second-generation) histamine1-receptor antagonists is the incidence and severity of adverse reactions. The first-generation drugs are associated with sedation, decreased psychomotor function, anticholinergic side effects, and other adverse reactions that are not observed with usual doses of second-generation agents. Since 1990 evidence has accumulated demonstrating that high doses of the second-generation drugs terfenadine and astemizole prolonged the cardiac QT interval and produced torsades de pointes, a rare but potentially lethal arrhythmia. Some first-generation agents also cause torsades de pointes. Concomitant administration of some drugs that inhibit the hepatic drug-metabolizing enzymes with either terfenadine or astemizole prevents the metabolism and increases the serum concentration of unchanged terfenadine and astemizole; this results in prolonged cardiac QT intervals and torsades de pointes. Interacting drugs include the macrolides (erythromycin and troleandomycin) and imidazole antifungals (ketoconazole and itraconazole). Also discussed are other factors that increase the likelihood of torsades de pointes after administration of terfenadine or astemizole and the pathophysiology of torsades de pointes, current therapy, and ways to avoid its occurrence. Preliminary studies indicate that two other second-generation agents, loratadine and cetirizine (an investigational agent), do not produce torsades de pointes.

A double-blind comparison of sertraline and clomipramine in the treatment of major depressive disorder and associated anxiety in general practice

In this double-blind study in primary care patients, the efficacy and safety of sertraline, an antidepressant which is a selective inhibitor of serotonin re-uptake, was compared with clomipramine. Patients with DSM-III-defined major depression and with significant anxiety randomly received 50-150 mg of either sertraline (N=51) or clomipramine (N=55) once daily for 6 weeks. The mean final daily dose was 63.5 mg sertraline and 60.6 mg clomipramine. Seventy five percent of sertraline-treated and 79% of clomipramine-treated patients were maintained on the lowest dose of 50 mg once daily. The mean scores of all the rating scales (HAM-D, HAM-A, HAD, CGI) showed similar efficacy between the treatments in reducing the symptoms of depression and anxiety. Clomipramine was less well tolerated than sertraline with a greater overall incidence of side effects, or significantly greater incidence of anticholinergic side effects and significantly more patient withdrawals due to side effects; 18% in the clomipramine group compared with 4% in the sertraline group. The results indicate that sertraline is an effective agent to use in primary care patients with depression and associated symptoms of anxiety and is better tolerated than the tricyclic comparator clomipramine.

Heart Rate Variability in Depressed Patients and Differential Effects of Paroxetine and Amitriptyline on Cardiovascular Autonomic Functions

Twenty-four unmedicated patients with episodes of major depression (DSM-III-R) and an age- and sex-matched group of 24 normal subjects underwent a heart rate analysis. The battery of cardiovascular reflex tests included the coefficient of variation while resting (CVr) and during deep breathing (CVdr), a spectral analysis of heart rate variability, the Valsalva test, and the posture index. The depressed patients showed no significant abnormalities in any of the tests as compared to the healthy subjects. The 24 patients were randomly allocated for treatment with either amitriptyline or paroxetine. During treatment with 20 mg paroxetine per day, patients showed no changes in cardiovascular autonomic function tests after 14 days. However, treatment with 150 mg amitriptyline per day decreased all heart rate parameters significantly due to anticholinergic side effects, except heart rate, which increased significantly. As autonomic side effects are a potential hazard of antidepressant therapy, the data suggest that paroxetine is an appropriate antidepressant for cases with pre-existing cardiovascular autonomic neuropathy.

A double-blind comparison of amitriptylinoxide versus doxepine in the treatment of severe depression

1. In a double-blind parallel group study the efficacy and safety of amitriptylinoxide were evaluated vs. doxepine in the treatment of in-patients with severe depression. 2. Two groups of 22 patients each received amitriptylinoxide and doxepine respectively at a daily dosage of 120–360 mg for a period of 4 weeks. 3. The total score on the Hamilton Depression Scale (HAMD) was reduced with amitriptylinoxide on an average from 28 ± 5 before treatment to 12 ± 8 at the end of treatment, with doxepine from 29 ± 8 to 13 ± 11. Of the amitriptylinoxide-treated patients, 12 showed a more than 50 % reduction in this score compared with 15 under doxepine. The difference was not statistically significant. 4. Twenty patients in each group experienced adverse drug reactions, the percentage of anticholinergic side effects being equal in the two groups.

Transient sexual dysfunction observed during antiarrhythmic therapy by long-acting disopyramide in a male Wolff-Parkinson-White patient

Dear Sir, During antiarrhythmic drug therapy for various kinds of cardiac arrhythmias, not only arrhythmogenic effects, but also other minor adverse reactions, such as skin eruption, dry mouth, and urinary retention, have been recognized as causes of discontinuation and poor compliance of therapy. Recently we observed a case of another rare but significant adverse effect of an antiarrhythmic drug. The patient was a 46-year-old intellectual desk worker with intermittent Wolff-Parkinson-White syndrome. He had occasional episodes of paroxysmal supraventricular tachycardia while playing amateur baseball and drinking alcoholic beverages. We prescribed the long-acting disopyramide phosphate, 150 mg once in the morning daily, because of low efficacy of verapamil, 40 mg three times daily. On the first visit after administration of disopyramide, he complained of sexual dysfunction (impotence) without any other anticholinergic side effects. At the second visit (4 weeks after drug administration), he reported the disappearance of that adverse effect. The steady-state serum level of disopyramide in this case was 1.5 ~g/ml. Sexuality is woven into the everyday life of an individual. Sexual dysfunction is a matter of enormous importance and the cause of worry and concern. Several authors [1-4] have itemized and reviewed the characteristics of good sexual functioning and its dysfunction. Papadopoulos [3] described the significance of the actions of cardiovascular drugs as factors in sexual dysfunction of the cardiovascular patient. McHaffie et al. [2] reported a case of a 47-year-old man in whom impotence developed when the plasma concentration of the drug was 14 ~g/ml. There was full recovery of sexual function when the concentration was lowered to 3 ~g/ml. Although the anticholinergic properties of the drug may mainly impair sexual performance [2-4], the present case indicates the dependence on individual organ sensitivity to the anticholinergic action of the drug. Despite the low serum drug concentration, the adverse drug action happened as a first-dose phenomenon at the beginning of drug administration. This case also indicates that such adverse effects of the long-acting disopyramide at a low serum concentration may be transient and reversible with continued intake of the drug.

A double-blind controlled comparison of fluoxetine and lofepramine in major depressive illness

One hundred and eighty three patients with DSM-III-R major depressive illness were allocated randomly to treatment with one of two new generation antidepressants, fluoxetine and lofepramine. Both patient groups had significantly lower mean scores on the Hamilton Depression Rating Scale (HDRS) 6 weeks after entry to the trial (p < 0.001), but there were no differences between the groups, either at baseline or after 6 weeks, in total HRDS score or in subscores for anxiety or suicidality. Anticholinergic side effects were commoner with lofepramine; adverse effects were on the whole mild and few patients dropped out because of them. This study does not support previous claims of specific adverse effects of fluoxetine on anxiety and suicidality.

Choice of antidepressants by psychiatrists working with old people

In 1992, 46 consultants in old age psychiatry were asked to list their five most frequently used antidepressants, with reasons for their choices, and to comment on an information set for evaluating an antidepressant for use in older people. Lofepramine tied with dothiepin as the most popular antidepressant. The relatively new selective serotonin reuptake inhibitors (SSRis) were also widely used. Cardiovascular safety, lack of anticholinergic side effects and safety in overdose were important factors in choice. Some antidepressants were preferred for particular symptoms or circumstances. A modified information set for evaluating an antidepressant for use in older people is presented.