Central Anticholinergic Effects Research Articles

Polypharmacy and potentially inappropriate medications (PIMs) in older adults referred to a memory clinic

AimsThe older adult is more likely to be prescribed a lot of medications (polypharmacy) on account of multi-morbidity and consequently being under the care of several specialists. Adverse drug events and reactions account for significant morbidity and mortality in this population group. Common sequelae include confusional episodes, dementia syndromes, falls, and higher rates of acute hospital admissions.Medications are not routinely reviewed in elderly care. We sought to estimate the prevalence of polypharmacy, and potentially inappropriate medications (e.g. anticholinergics or medications with central anticholinergic effects) in those referred to the Cognitive Impairment and Dementia Service (Elm Lodge), Older Persons Mental Health, West London NHS Trust.MethodAll referrals between 01/10/2020 and 30/11/2020 were screened for medications prescribed. Polypharmacy was defined as prescription of 5 or more medications. Medications with anticholinergic properties were considered examples of Potentially Inappropriate Medications (PIMs). The Anticholinergic Effect on Cognition (AEC) Tool, ‘Medichec’, was used to identify and rate anticholinergic burden. Anticholinergic load was also compared using the Anticholinergic Burden Scale (ABS).ResultTotal number of patients referred – 19311 patients excluded due to unavailable/incomplete medication records.Study number: 182Polypharmacy: 79.67% (n = 145) were prescribed 5 or more medications.44.51% (n = 81) prescribed 5–9 medications.23.08% (n = 42) prescribed 10–14 medications.8.79% (n = 16) prescribed 15–19 medications.1.67% (n = 3) prescribed more than 20 medications.Anticholinergics prescribed (AEC Tool): 37.36% (n = 68) prescribed an anticholinergic.6.59% (n = 12) prescribed more than 1 anticholinergic.Anticholinergics (ABS): 29.67% (n = 54) prescribed an anticholinergic.7.699% (n = 14) prescribed more than 1 anticholinergic.ConclusionPolypharmacy and potentially inappropriate prescribing (e.g. anticholinergics) remain widespread within the older adult population. Anticholinergic load was broadly similar with the Anticholinergic Effect on Cognition tool and the Anticholinergic Burden Scale. Increased anticholinergic burden further compounds risks of cognitive impairment, delirium and death.Other categories of Potentially Inappropriate Medications, including those no longer needed, ought to be identified and reviewed. Over-the-counter medications also need to be screened for.Elimination or reduction of anticholinergic burden may improve quality of life for patients, as well as cost burden on services.Pharmacovigilance, collaborative working, and regular training are needed across services providing care for the older adult.

CYCLOBENZAPRINE OVERDOSE PRESENTING WITH RHABDOMYOLYSIS, DISTRIBUTIVE SHOCK, AND MULTIORGAN FAILURE

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Few cases of cyclobenzaprine (CBZ) overdose exist in the literature, and the range of toxicity is not well-defined. We report a case of CBZ overdose with life-threatening shock and multiorgan failure. CASE PRESENTATION: A 51-year-old woman with type 2 diabetes, hypertension, chronic back pain, and depression presented to the emergency department after being found unresponsive near an empty bottle of CBZ. She was hypotensive and mildly tachycardic with a Glasgow coma score of 8. She was intubated and admitted to the intensive care unit. She had multiorgan failure with acute kidney injury (blood urea nitrogen: 57 mg/dL, creatinine: 7.1 mg/dL), elevated liver enzymes, anion gap metabolic acidosis (arterial blood gas pH 7.1, pCO2: 34, pO2: 80, HCO3: 10), creatine kinase level of 39K IU/L, and myoglobin >3000 ng/mL. Her urine drug screen was positive for TCA; her serum qualitative screen was positive for CBZ. Her electrocardiogram (ECG) showed widened QRS with no acute ST changes. Given her hypotension refractory to intravenous (IV) fluid resuscitations, she received 2 inotropic agents for 2 days, maintenance IV fluids, and NaHCO3 infusion. Her QRS interval normalized after 6 hours. She was extubated on day 3 with subsequent normalization of both her kidney and liver functions (Graph 1, 2). Later she reported ingesting the CBZ as a suicide attempt. DISCUSSION: Cyclobenzaprine is a centrally acting muscle relaxant, that is structurally similar to amitriptyline (TCA), differing by only one double bond. CBZ and TCA cause reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Toxic effects can be mild (e.g., confusion, visual hallucination, agitation, drowsiness, dry mouth, dizziness) or severe (e.g., cardiac arrhythmias, hypotension, convulsions, stupor, coma). Spiller et al.'s analysis of 402 cases of CBZ toxicity found respiratory failure requiring mechanical ventilation in 12 cases (3%). Only 2 cases had refractory hypotension requiring inotropic support. Rhabdomyolysis is an uncommon complication, reported only in 2 independent case reports. The management of a CBZ overdose is like that of any TCA. Gastrointestinal decontamination by lavage and activated charcoal is time sensitive. QRS widening or intraventricular conduction abnormalities should be treated with NaHCO3. CONCLUSIONS: To our knowledge, this is the first case report of life-threatening shock resulting in concurrent multiorgan failure, including acute renal insufficiency, hepatic injury, rhabdomyolysis, metabolic encephalopathy, and respiratory failure from CBZ overdose. Health care professionals should realize that CBZ overdose can present as a spectrum of toxicities, including life-threatening complications. Early recognition and appropriate intervention can help reverse this otherwise possible fatal condition Reference #1: Spiller HA, Winter ML, Mann KV, Borys DJ, Muir S, Krenzelok EP. Five-year multicenter retrospective review of cyclobenzaprine toxicity. J Emerg Med. 1995;13(6):781–785. doi:10.1016/0736-4679(95)02019-5 Reference #2: Chabria SB. Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity. J Occup Med Toxicol. 2006;1:16. doi:10.1186/1745-6673-1-16 DISCLOSURES: No relevant relationships by Meily Arevalo, source=Web Response No relevant relationships by Mohamed Elmassry, source=Web Response No relevant relationships by John Makram, source=Web Response No relevant relationships by Haneen Mallah, source=Web Response No relevant relationships by Arunee Motes, source=Web Response No relevant relationships by Kenneth Nugent, source=Web Response No relevant relationships by Pablo Paz, source=Web Response

Anticholinergic Drug Burden in Persons with Dementia Taking a Cholinesterase Inhibitor: The Effect of Multiple Physicians.

ObjectivesTo explore the association between the number of physicians providing care and anticholinergic drug burden in older persons newly initiated on cholinesterase inhibitor therapy for the management of dementia.DesignPopulation‐based cross‐sectional study.SettingCommunity and long‐term care, Ontario, Canada.ParticipantsCommunity‐dwelling (n = 79,067, mean age 81.0, 60.8% female) and long‐term care residing (n = 12,113, mean age 84.3, 67.2% female) older adults (≥66) newly dispensed cholinesterase inhibitor drug therapy.MeasurementsAnticholinergic drug burden in the prior year measured using the Anticholinergic Risk Scale.ResultsCommunity‐dwelling participants had seen an average of eight different physicians in the prior year. The odds of high anticholinergic drug burden (Anticholinergic Risk Scale score ≥ 2) were 24% higher for every five additional physicians providing care to individuals in the prior year (adjusted odds ratio = 1.24, 95% confidence interval = 1.21–1.26). Female sex, low‐income status, previous hospitalization, and higher comorbidity score were also associated with high anticholinergic drug burden. Long‐term care facility residents had seen an average of 10 different physicians in the prior year. After a sensitivity analysis, the association between high anticholinergic burden and number of physicians was no longer statistically significant in the long‐term care group.ConclusionIn older adults newly started on cholinesterase inhibitor drug therapy, greater number of physicians providing care was associated with higher anticholinergic drug burden scores. Given the potential risks of anticholinergic drug use, improved communication among physicians and an anticholinergic medication review before prescribing a new drug are important strategies to improve prescribing quality.

Central Anticholinergic Adverse Effects and Their Measurement.

Drugs with anticholinergic properties are widely used. However, they may evoke a variety of adverse reactions (such as dry mouth and constipation, but also drowsiness and confusion), and therefore unnecessary use of drugs with anticholinergic properties should be avoided. In particular, older people are particularly vulnerable to the central anticholinergic effects of drugs. However, monitoring of drug-induced anticholinergic effects and drug concentrations in serum is challenging. In addition to the 'pure' anticholinergics such as atropine and oxybutynin, several other drugs whose principal mode of action is not anticholinergic, possess anticholinergic properties, thus increasing the risk of anticholinergic adverse effects. In this paper, we focus on the central anticholinergic effects of drugs, and on the usefulness of the serum anticholinergic assay (SAA) in the prediction of anticholinergic effects. Results on the anticholinergic effects of drugs on cognition are mixed. This may be because of differences in the populations as well as in the drugs used. In addition, the clinical conditions of the patients may affect the results. The SAA has been used in an attempt to measure anticholinergic burden. However, the results are variable and the SAA levels do not necessarily reflect the medication used by the patient. Therefore, its usefulness in determining anticholinergic adverse reactions is questionable.

A Randomized, Prospective, Double-Blinded Study of Physostigmine to Prevent Sedation-Induced Ventilatory Arrhythmias.

Physostigmine, a centrally acting acetylcholinesterase inhibitor, is most commonly used by anesthesiologists in the postanesthetic setting to reverse confusion caused by central anticholinergic medication effects. It has also been proposed as a treatment for sleep-disordered breathing. We investigated whether physostigmine was effective in decreasing the frequency of ventilatory arrhythmias produced during moderate sedation with midazolam and remifentanil during the conditions of breathing room air or 2 L/min nasal O2. Ten healthy male volunteers participated in this randomized, double-blind control trial of physostigmine (0.24 µg·kg·min) versus placebo. Moderate sedation was achieved with infusions of midazolam and remifentanil and monitored with full and processed electroencephalogram. Analgesia was quantified with subjective pain score to thermal stimulation. Ventilatory arrhythmias, as measured by the sedation apnea-hypopnea index (S-AHI), were scored as the number of apneas and hypopneas during two 1-hour periods on room air or 2 L/min nasal O2. All subjects tolerated the sedation and physostigmine without significant adverse effects. Sedation during placebo infusion resulted in clinically significant (S-AHI > 15) ventilatory arrhythmias in 5 conditions in 3 subjects (2 on room air and then O2, and 1 on O2 only). Physostigmine did not significantly (P > 0.46) reduce the total number of ventilatory arrhythmias on either room air or O2 (13.4 ± 18.8 events/h [mean ± SEM], 95% confidence interval [CI] = -9.9 to 62.7; and 6.2 ± 8.0, 95% CI = -3.1 to 28.7, respectively). Physostigmine did reduce the S-AHI in all 5 instances of clinically significant ventilatory arrhythmias (S-AHI decreased by 67.0 ± 22.2; CI = 29.2-111.7; P = 0.04). Physostigmine does not appear to be useful as a pretreatment to prevent ventilatory arrhythmias during moderate sedation. However, it may be useful as a treatment for clinically significant ventilatory arrhythmias during moderate sedation.

Use of desipramine for the treatment of overactive bladder refractory to antimuscarinic therapy.

To evaluate the use of desipramine in the treatment of overactive bladder (OAB). We retrospectively evaluated 43 patients who were treated with desipramine for OAB refractory to antimuscarinic therapy. These OAB patients were stratified by the presence or absence of bladder pain. Forty-three patients were evaluated with a mean follow up time of 12.2 ± 4.6 months. The mean age of the patients was 71 ± 16 years. Twelve patients (28%) discontinued desipramine, 9 due to perceived lack of efficacy, 2 due to central anticholinergic side effects, and 1 due to the development of oropharyngeal sores. Patients were stratified into two subgroups based upon treatment with desipramine for OAB alone (n = 29) or OAB and bladder pain (n = 14). There was no difference between the groups in regard to sex (P = .34), prior history of radiation (P = .19), side effects (P = .16), and specifically evaluated central anti-cholinergic side effects (P = .66). There was no statistical difference in the self-reported success rate of the medication (P = .48). In the OAB plus bladder pain subgroup, 71% of patients reported improvement in their pain. Overall, 13 (30%) patients had history of prior pelvic radiation and 10 of those (77%) reported improvement with desipramine. Desipramine is a potential useful treatment for patients with OAB. In addition, it can be used in patients with OAB and bladder pain and patients with complex OAB such as OAB caused by pelvic radiation.

Anticholinergic Drug Burden in Older People's Brain - How well is it Measured?

Concurrent use of several drugs with potential anticholinergic properties is highly prevalent in the elderly. Methods to determine the overall anticholinergic drug burden have been developed to estimate the risk of central anticholinergic adverse effects. The objective of this MiniReview was to critically appraise the clinical utility of the methods used to assess the anticholinergic drug burden in older people's brain. We evaluated the in vitro method used to measure the anticholinergic activity in a patient's serum and the four anticholinergic drug scales: Anticholinergic Risk Scale, Anticholinergic Cognitive Burden, Drug Burden Index and Anticholinergic Drug Scale. Medline searches of the literature from January 1988 to January 2013 were performed. Studies that related anticholinergic drug burden to central adverse outcomes in elderly people were included, while case reports and studies of single substances were excluded. Despite the consistently reported association between a high anticholinergic drug burden and negative cognitive and psychomotor outcomes in older patients, there are discrepancies in the literature. Furthermore, no significant cognitive improvements after the anticholinergic drug burden was reduced have been shown in randomized controlled trials. It is reasonable to question whether the estimated anticholinergic drug burden can predict the overall brain effects of multiple anticholinergic agents in older people.

Higher anticholinergic drug scale (ADS) scores are associated with peripheral but not cognitive markers of cholinergic blockade. Cross sectional data from 21 Norwegian nursing homes

This study evaluated a presumed gradual decline in cognitive function in nursing home residents when the anticholinergic drug scale (ADS) score increased above 3. The study population was recruited from 21 nursing homes in Norway. Criteria for inclusion were ADS score ≥ 3 and no severe dementia, defined as Clinical Dementia Rating (CDR) score < 3. Primary cognitive end points were CERAD 10-word lists for recall and Mini Mental State Examination (MMSE). Secondary end points were activity of daily living (ADL), mouth dryness and serum anticholinergic activity (SAA). The patients were stratified into subgroups according to ADS score, i.e. a reference group with score 3 and test groups with scores 4, 5 or ≥6. End points were compared by analyses of covariance (ancova). Overall, 230 of the 1101 screened nursing home residents (21%) had an ADS score ≥3. After exclusion 101 residents were recruited and among these, 87 managed to participate in the study. No significant differences were detected in cognitive function or ADL when ADS increased above 3 (P > 0.10), but in vivo (mouth dryness) and in vitro (SAA) measures of peripheral anticholinergic activity were significantly higher in patients with an ADS score ≥6 (P < 0.01). The present study does not support a progressive decline in cognitive function with ADS score above 3. This might indicate that the ADS score model has limited potential to predict the clinical risk of central anticholinergic side effects in frail elderly patients receiving multiple anticholinergic drugs.

Evaluation of Brain Anticholinergic Activities of Urinary Spasmolytic Drugs Using a High-Throughput Radio Receptor Bioassay

To compare the brain anticholinergic activities of five urinary spasmolytic drugs (USDs). In vitro study. Laboratory. None. A validated 96-well anticholinergic radio receptor bioassay using small incubation volumes (240 μL per well) was applied in the current study. The different USDs (tolterodine, oxybutynin, solifenacin, darifenacin, and 5-hydroxy-methyl-tolterodine (5-HMT; the active metabolite of fesoterodine) were dissolved in plasma in their respective therapeutic concentration ranges. The plasma samples were added directly to the wells of 96 filter plates, wherein the incubation, filtration, and counting of undisplaced radioactivity was performed. Standard curves with atropine were used as reference for estimations of anticholinergic activity (AA). 5-HMT and tolterodine displayed the highest AA of the tested USDs. In the middle of the therapeutic concentration range, the central anticholinergic potency of 5-HMT and tolterodine was more than 10 times as high as that of oxybutynin, solifenacin, and darifenacin. Darifenacin exhibited the lowest AA at therapeutic serum concentrations (< one-third the AA of oxybutynin and solifenacin). Tolterodine and fesoterodine appear to have the highest pharmacodynamic potential to induce central anticholinergic side effects of the tested USDs. Darifenacin displayed the lowest AA, and combined with a low degree of brain distribution, it has probably the most favorable pharmacological profile of the USDs with respect to risk of cognitive impairment in older adults.

Full recovery from a potentially lethal dose of orphenadrine ingestion using conservative treatment: A case report

Intoxication by orphenadrine is uncommon. The clinical features consist of both central and peripheral anticholinergic effects. Ingestion of 2 to 3 g orphenadrine in an adult has been associated with fatality. A 46-year-old female was brought to our emergency department 1.5 hours after ingesting 40 tablets of 100 mg orphenadrine. She became stuporous 3 hours post-ingestion and developed generalized convulsions 1 hour later. Fifty-five hours post-ingestion, she had recovered and was found to have anterior shoulder dislocation. In addition, severe rhabdomyolysis and persistent nausea were observed. All of the above-noted toxic effects resolved with conservative treatment. Although orphenadrine intoxication can cause convulsions and hemodynamic instability, there is no available antidote and treatment remains supportive.

Spectrum of Central Anticholinergic Adverse Effects Associated with Oxybutynin: Comparison of Pediatric and Adult Cases

We reviewed Food and Drug Administration postmarketing reports of central nervous system (CNS) anticholinergic effects in association with oxybutynin. Taking domestic usage by age group into account, there is a disproportionately higher number of CNS adverse event cases reported in pediatric patients as compared with adult patients. CNS stimulation was prominent in the pediatric cases.

Central Anticholinergic Syndrome: A Case Report

Postoperative central anticholinergic syndrome (CAS) is caused by anticholinergic medications that cross the blood-brain barrier. Medications with central anticholinergic effects block muscarinic cholinergic receptors, resulting in a wide array of symptoms. Symptoms may range from coma to a highly agitated state. CAS may be underdiagnosed because of its varying presentation and lack of awareness. Differential diagnosis for the patient presenting with abnormal neurological signs and symptoms should include CAS after the exclusion of other potential causes. This case report details the occurrence of CAS in a patient in her 20's. A review of CAS including causes, signs and symptoms, incidence, differential diagnosis, and treatment is discussed.

Jimson weed extract as a protective agent in severe organophosphate toxicity.

Treatment of patients following an organophosphate (OP) exposure can deplete a hospital's entire supply of atropine. Given the possibility of multiple severe exposures after a terrorist attack using OP nerve agents, there exists a need for either greater atropine stores or the development of alternative antidotes. Jimson weed (Datura stramonium) contains atropine and other anticholinergic compounds and is common and readily available. It is used recreationally for its central anticholinergic effects and is made easily into an extract by boiling the crushed seeds. The extract has rapid onset of effects and may be useful for treatment of OP poisoning. To determine whether pretreatment with an easily stored and prepared Datura seed extract (DSE) will increase survival following a severe OP poisoning. Datura stramonium seeds were collected, crushed, and then heated in water to make a 2-mg/mL atropine solution (100 seeds contain approximately 6 mg of atropine or 0.007 mg/seed). Male rats were randomized to pretreatment with either saline (n = 10) or 7.5 mg/kg DSE (n = 10) given as a single intraperitoneal injection 5 minutes prior to a subcutaneous injection of 25 mg/kg of dichlorvos. The endpoint was time to death recorded by a blinded observer. The Kaplan-Meier estimates of the 24-hour survival rate was 90% (95% CI = 56% to 100%) for the DSE-pretreated group and 10% (95% CI = 0% to 45%) for the control group. The log-rank test revealed a statistically significant longer survival for the Datura-treated animals (p = 0.0002). Median survival time was 22 minutes 30 seconds for the control group and greater than 24 hours for the DSE-pretreated group. Pretreatment with DSE significantly increases survival following severe dichlorvos exposure.

ROLE OF THE CENTRAL HISTAMINERGIC NEURONAL SYSTEM IN THE CNS TOXICITY OF THE FIRST GENERATION H1-ANTAGONISTS

First-generation H1-antagonist-induced central toxicity often includes psychiatric changes, seizures and hallucinations, commonly thought to result from their central anticholinergic effects. Interference with the central functions of histamine have not been adequately addressed, despite the identification of histamine as a central neurotransmitter and neuromodulator. A synthesis of data support antagonism of H1-receptors as critical to the CNS toxicity of these drugs. The histaminergic neuronal system (HNS) is involved in a variety of global brain functions. Inherent or induced alterations in the HNS are associated with behavioral disorders. Clinical and experimental evidence support a role for the HNS in seizure protection and a relationship exits between histamine regulated systems and seizures. Histamine has important neuromodulatory influences on the central electrophysiology which underlies normal thalamocortical function. H1-antagonists block the H1-receptor-mediated reduction of a background-leakage K + current (I KL) in central neurons. Secondary alterations in other ionic currents and alterations in synaptic responses to glutamate and GABA are produced. The non-H1 receptor-mediated effects of histamine persist in the presence of these drugs, contributing to imbalances in central electrophysiology. H1-antagonist-induced changes are similar to the electrical disturbances thought to underly epileptic seizures and may adequately explain their hallucinogenic activity. These data form the basis for this review and must be considered as a major mechanism for the CNS toxicity of the first-generation H1-antagonists. © 1997 Elsevier Science Ltd. All Rights Reserved.

Minimizing the non-extrapyramidal side-effects of antipsychotics.

Standard neuroleptic medications have been augmented by the introduction of risperidone and clozapine into clinical practice. A great deal of attention has also been focused on efficacy and the lower propensity to extrapyramidal side-effects associated with the new agents. However, antipsychotic medication, both old and new, can cause a range of other adverse effects, some of which are serious, and many of which have the potential greatly to diminish the quality of life of patients who need to take medication in the long term. Of particular significance are postural hypotension, cardiotoxicity, peripheral and central anticholinergic effects, sedation, weight gain, and endocrine and haematological effects. Various antipsychotic compounds differ substantially with regard to propensity to adverse effects. Side-effects can be minimized by optimization of clinical strategies, including choice of appropriate drug, slow titration and dosage reduction. It is also vital to explain carefully to both patients and carers the nature of the side-effects which can be anticipated. The choice of antipsychotic is often determined by evaluation of the potential impact of the various adverse effects on a particular patient. New drugs, such as risperidone, are well tolerated, with fewer side-effects, and should now be considered as a first-line option.

Avoiding and Managing Anticholinergic Effects of Antidepressants

The anticholinergic actions of antidepressants can have undesirable effects that affect patient’ well-being. These effects can be peripheral or central in origin. The most frequently occurring anticholinergic effects are sedation, psychomotor and memory impairment, dry mouth and blurred vision. One of the most prominent central anticholinergic effects is that on cognitive function. Effects that occur after a single dose consist of sedation (lowering of activation and arousal), psychomotor impairment [slowed sensorimotor processes that can adversely affect operational manual control (e.g. car driving)] and memory disturbances (forgetfulness, inability to store and retrieve information and recall events). After long term administration, tolerance to sedation and psychomotor impairment is likely to develop, but not to memory disturbances. Elderly patients can be assumed to be particularly sensitive to central anticholinergic effects on cognitive functioning and also to peripheral anticholinergic effects such as dryness of the mouth and loss of accommodation in the eye. It is argued that for this reason, prescription of the classical tricyclic antidepressants should be avoided in elderly depressed patients. The second generation, or atypical antidepressants, and the newer selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) are considered to be useful alternatives to tricyclics in elderly patients. These drugs possess greatly diminished anticholinergic activity, although the atypical antidepressants are very sedative and the effects of long term administration of SSRIs on cognition have rarely been studied. Another approach to avoiding anticholinergic effects is to use reversible inhibitors of monoamine oxidase (MAO)-A (RIMAs), such as moclobemide. These agents can attenuate scopolamine-induced cognitive dysfunction. An important point in managing and avoiding anticholinergic effects of antidepressants is to realise that not all so-called ‘anticholinergic effects’ are actually cholinergically determined. Many other pharmacological effects of antidepressants, such as antihistaminergic and anti-α1-adrenergic effects, can induce sedation, cognitive and psychomotor impairment, blurred vision and dry mouth.

Fluoxetine

The selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor fluoxetine is an effective antidepressant in elderly patients. Its efficacy is similar to that of other frequently used antidepressants, such as the tricyclic antidepressants. However, compared with the tricyclic antidepressants, fluoxetine has a more favourable tolerability profile and is less toxic in overdose. It is associated with fewer anticholinergic, cardiovascular and CNS adverse events, but greater numbers of gastrointestinal adverse events than have been reported for the tricyclic antidepressants. This is important in elderly patients who are more at risk of developing central anticholinergic and cardiovascular effects than are younger patients. Therefore, while its position relative to other selective serotonin reuptake inhibitors requires investigation, fluoxetine represents a major advance over tricyclic antidepressant agents in the treatment of elderly patients with depression, predominantly because of its favourable tolerability profile.

Palatability of a Meal Influences Release of Beta-Endorphin, and of Potential Regulators of Food Intake in Healthy Human Subjects

The effect of the palatability of a meal was tested on the post-prandial release of several gut hormones or neuropeptides which are known to have an effect on intake and satiety. Hormonal response was determined in plasma during the 3 h after a highly palatable and energy-rich meal or after the same meal served cold in a poorly acceptable form, as well as while fasting. The early post-prandial pancreatic polypeptide and neurotensin response was significantly higher after the highly palatable meal than after the cold one. Later responses differed only for pancreatic polypeptide. No difference was observed in cholecystokinin and neutropeptide Y levels. Post-prandial levels of beta-endorphin were elevated only after the cold meal and were associated with an elevated response of ACTH. We suggest that beta-endorphin might be secreted in response to an aversion towards the non-palatable cold meal. This could, subsequently, inhibit the cephalic phase of pancreatic polypeptide response and the early post-prandial response of neurotensin by a central anticholinergic effect. This study evidences an effect of palatability on the modulation of the digestive hormonal response after a meal.

The problems of anticholinergic adverse effects in older patients.

The old saying 'red as a beet, dry as a bone, blind as a bat, hot as a hare, mad as a hatter' is often quoted when describing the autonomic effects of drugs that block the muscarinic cholinergic system. These effects may be subtle or dramatic, yet can be overlooked or discounted as a natural consequence of old age. Elderly patients can be particularly sensitive to the anticholinergic action of drugs because of physiological and pathophysiological changes that often accompany the aging process. The use of multiple drugs, a common finding in older patients, may result in pharmacodynamic and pharmacokinetic drug interactions that heighten anticholinergic effects. While the classic anticholinergic problems of decreased secretions, slowed gastrointestinal motility, blurred vision, increased heart rate, heat intolerance, sedation and possibly mild confusion, may be uncomfortable for a younger patient in relatively good health, these effects can be disastrous for older patients. Even the most common peripheral anticholinergic complaint of dry mouth can reduce the ability to communicate, predispose to malnutrition, promote mucosal damage, denture misfit or dental caries, and increase the risk of serious respiratory infection secondary to loss of antimicrobial activity of saliva. Mydriasis and the inability to accommodate will impair near vision and may precipitate narrow angle glaucoma in predisposed patients, but less obviously could lead to an increased risk of accidents, including falls. Somatic complaints of constipation and urinary hesitancy, could, in the presence of anticholinergic challenge, result in faecal impaction or urinary retention. Cardiac effects may be poorly tolerated. Increases in heart rate may precipitate or worsen angina. Finally, thermoregulatory impairment induced by anticholinergics, which block the ability to sweat, may lead to life threatening hyperthermia. Central anticholinergic effects range from sedation, mild confusion and inability to concentration to frank delirium. Even mild effects can reduce function and increase dependency. At any level of care, the loss of independence increases the caregiver burden, costs, and most importantly, can negatively affect quality of life. Many age-related and disease-related conditions may predispose elderly patients to anticholinergic drug toxicity. Careful attention to anticholinergic effects when prescribing drugs, patient education, regular review of the entire drug regimen, and familiarity with the signs and symptoms of anticholinergic toxicity will help to reduce the risk of drug-induced problems.

Delirium From Transdermal Scopolamine in an Elderly Woman

<h3>To the Editor.—</h3> Perhaps too little attention is paid by practitioners to central anticholinergic effects of drugs in the elderly. <h3>Report of a Case.—</h3> Recently, a 77-year-old woman was hospitalized for sudden global loss of memory, disorientation, and clouded sensorium after a journey to a holiday resort. Clinical and diagnostic evaluation did not indicate any abnormality. The patient had no history of drug intake. She was released after two days owing to spontaneous remission of the symptoms. The woman remained well for the remaining 15 days of her vacation, after which she went back home. On reaching her home, she experienced the same global disturbance of cognition as previously and again had to be hospitalized. Results of diagnostic evaluation were normal. After a more detailed drug history was taken, however, it was found that the elderly woman had used a scopolamine transdermal preparation (retroauricular) to prevent car sickness on her