Peripheral Anticholinergic Effects Research Articles

Synthesis and Pharmacological Activity of 2-(Diethylamino)Ethyl 9-Hydroxy-9H-Fluorene-9-Carboxylate Hydrochloride

New fluorenecarboxylic acid derivatives (structural analogs of amizil) were synthesized. A compound with low toxicity (LD50 = 45 ± 9.9 mg/kg) and antidepressant and antianxiety effects was identified. The central and peripheral muscarinic anticholinergic properties of 2-dimethylaminoethyl 9-hydroxyfluorene-9-carboxylate were studied using an arecoline tremor model. Apharmacological analysis showed that the new amizil structural analog exhibited pronounced central muscarinic anticholinergic activity and did not possess peripheral muscarinic anticholinergic effects. The advantages of the tested compound over amizil, amitriptyline that is widely used in the clinic, and the benzodiazepine tranquilizer diazepam were discussed. The results indicated that 2-diethylaminoethyl 9-hydroxyfluorene-9-carboxylate was promising for further development for the treatment of depressive and anxiety disorders.

Atropa belladonna and associated anticholinergic toxic syndrome: a case report

Atropa belladonna causes poisoning by its anticholinergic effects. Excessive ingestion of this plant may cause peripheral anticholinergic effects, and moreover, a more severe clinical picture can be seen due to its central effects which can result in lethargy, coma or even death. In this article, we aimed to present a case with Atropa belladonna intoxication and to emphasize that Atropa belladonna poisoning should be kept in mind in cases with anticholinergic findings.

Postoperative Anticholinergic Poisoning: Concealed Complications of a Commonly Used Medication

BackgroundScopolamine is a potent anticholinergic compound used commonly for the prevention of postoperative nausea and vomiting. Scopolamine can cause atypical anticholinergic syndromes due to its prominent central antimuscarinic effects. Case ReportA 47-year-old female presented to the emergency department (ED) 20 h after hospital discharge for a right-knee meniscectomy, with altered mental status (AMS) and dystonic extremity movements that began 12 h after her procedure. Her vital signs were normal and physical examination revealed mydriasis, visual hallucinations, hyperreflexia, and dystonic movements. Laboratory data, lumbar puncture, and computed tomography were unrevealing. The sustained AMS prompted a re-evaluation that revealed urinary overflow with 500 mL of retained urine discovered on ultrasound and a scopolamine patch hidden behind her ear. Her mental status improved shortly after patch removal and physostigmine, with complete resolution after 24 h with discharge diagnosis of scopolamine-induced anticholinergic toxicity. Why Should an Emergency Physician Be Aware of This?Although therapeutically dosed scopolamine transdermal patches rarely cause complications, incomplete toxidromes can be insidiously common in polypharmacy settings. Providers should thoroughly evaluate the skin of intoxicated patients for additional adherent medications that may result in a delay in ED diagnosis and curative therapies. Our case, as well as rare case reports of therapeutic scopolamine-induced anticholinergic toxicity, demonstrates that peripheral anticholinergic effects, such as tachycardia, dry mucous membranes, and hyperpyrexia are often not present, and incremental doses of physostigmine may be required to reverse scopolamine's long duration of action. This further complicates identification of the anticholinergic toxidrome and diagnosis.

Datura poisoning, clinical and laboratory findings. Report of five cases

Introduction. Plants of Datura species contain belladonna alkaloids that can cause central and peripheral anticholinergic effects. Abuse of Datura plants for their hallucinogenic effects is growing among adolescents and young adults. Datura poisoning has caused a diagnostic challenge in medical emergency wards. In this article we report 5 cases of Datura toxicity at Clinical Toxicology Emergency of Baharloo Hospital, Tehran, Iran during Summer-Fall 2015, and discuss their clinical presentations and laboratory findings. Cases Description. All 5 cases with Datura toxicity were young males and had intentionally used the plants. Mean duration of hospitalization was 3.2 days. ree cases were multiple drug abusers. Mydriasis, tachycardia, tachypnea and ushing alongside with psychotic-like signs and symptoms were observed in all cases. Elevation of liver enzymes was present in three of cases but without clinical signi cance. Raised LDH or CPK in four patients were without myoglubinuria and evidence of rhabdomyolysis and these biomarkers returned to normal by supportive care. All patients discharged with complete recovery and there was no need to ICU admission. Discussion. With the absence of routine laboratory screening tests for alkaloids and complex and confusing presentations of Datura intoxication, diagnosis of such cases is difficult. Physicians' clinical suspicion and su cient knowledge plays the mainstay role in appropriate and timely diagnosis and management of cases with Datura toxicity. Since regulatory legislation wouldn't be successful in halting the availability of natural plants, the best strategy to prevent Datura abuse is informing people about the adverse e ects of these plants. Key Words: datura stramonium, poisoning, abuse, anticholinergic, laboratory ndings, liver function tests, rhabdomyolysis. Language: en

Hyoscyamus niger Intoxication: A Case Report

Aims: To present the clinical findings and intensive care management of Hyoscyamus niger (HN) intoxication in a 7-year-old patient. Presentation of Case: A seven-year-old girl was admitted to the emergency department who had eaten a plant in large amounts. She had psychomotor agitation, inability to recognize her family, slurred speech, dry mouth, flushing, over-distended urinary bladder, visual and hearing hallucinations. After a nasogastric tube was inserted, gastric lavage was performed and activated charcoal was administered. Symptomatic treatment including oxygen, fluid-electrolyte balance, and gastric protective drugs was established. Physostigmine infusion (0.02 mg/kg) was given due to tachycardia at the second hour of hospitalization. The plant that was responsible for the clinical picture was confirmed as ‘deli bat bat grass’. The clinical symptoms resolved after 2-hours administration of physostigmine. She was transferred to pediatric ward after 24 hours of monitorization in intensive care unit. Discussion: HN is commonly known as black henbane or deli bat bat grass in the Eastern Anatolian Region in Turkey. Oral intake of this plant can cause central and peripheral anticholinergic effects. This clinical picture described as ‘central anticholinergic syndrome’ is characterized by thought impairment, hallucinations, hyperpyrexia, ataxia, excitement, drowsiness, Case Study

Life-threatening poisoning associated with henbane plant

Hyoscyamus Niger (HN) is a very common and highly hallucinogenic plant which contains anticholinergic agents. The HN is found in every region in Turkey. It is 25-80 cm tall with yellowish, purple flowers. As an annual herbaceous plant, it opens up with a lid-like cover when it is ripe and contains many seeds in its fruits. HN is commonly known as stinking nightshade or black henbane; in Turkey, HN is defined as Ban Plant (Ban Otu) or Crazy Bat (Deli Bat). There are 6 different types of henbane in Turkey. Black henbane and maize henbane are the kinds used in medicine. Maize henbane grows in and around Malatya in Turkey. Its leaves contain hyoscyamine, scopolamine (hyoscine), and several tropane alkaloids. Glycosides is found in the entire body of the plant, though it is dense in the seeds (1). The oral intake can cause central and peripheral anticholinergic effects. It is known that HN poisoning leads to anticholinergic syndromes. In this case report, we are presenting the life-threatening poisoning of a family of four after the accidental oral intake of HN.

Mechanism of Action of Antipsychotic Medications

Article AbstractA variety of antipsychotic medications exist for treating patients with schizophrenia. Knowledge of pharmacokinetics (the body's effect on the drug) and pharmacodynamics (the drug's effect on the body) can help clinicians select antipsychotics and make timely dose adjustments to improve patient outcomes. Currently, the only known effective mechanism to reduce positive psychotic symptoms is dopamine D2 blockade. However, several relevant dopamine pathways exist, and increasingly sophisticated insight into the role of subsections of the striatum has helped link dopamine D2 blockade in specific pathways to the beneficial and adverse effects of antipsychotics, including extrapyramidal side effects (EPS) and secondary negative or cognitive effects. Antipsychotics with low D2 affinity (partial D2 agonism) that modulate dopamine transmission via blockade of histamine or cholinergic receptors or that bind more tightly to serotonin 5-HT2A receptors than D2 receptors generally have less risk for EPS. However, some of the mechanisms that balance dopamine tone can be associated with sedation, central and peripheral anticholinergic effects, weight gain and metabolic abnormalities. Thus, treatment selection needs to be individualized based on the pharmacokinetic and pharmacodynamic profiles of available antipsychotics as well as their effects in a given patient with past treatment response patterns, comorbidities, and preferences. Importantly, new medications with either additional or exclusive nondopaminergic pharmacologic mechanisms need to be developed that can address not only positive symptoms of schizophrenia but also negative and cognitive symptoms, which do not appear to be primarily related to dopamine dysfunction.See the entire activity.

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.

Synthesis of a quaternary bis derivative of imipramine as a novel compound with potential anti-enuretic effect

Abstract Objectives Imipramine has been used for over four decades (early reports in 1960s) for the treatment of nocturnal enuresis, although the reason for its effect is not clear. Imipramine is a tertiary amine, which may act both in the periphery and/or pass through the blood-brain barrier (BBB) in unionized form and exhibit a central effect. Since imipramine has anti-cholinergic properties, some believe it may exert its anti-enuretic effect by affecting peripheral cholinergic receptors, i.e. its anti-enuretic effect may be due to peripheral anti-cholinergic properties, whereas others think it can pass through the BBB and interact with central nervous system (CNS) receptors. If the anti-enuretic effect of imipramine is due to its peripheral anti-cholinergic effects, its entrance into the CNS is unnecessary. Therefore, the synthesis of a form of imipramine that can exhibit peripheral anti-cholinergic effects but does not have CNS adverse effects would have a safer drug profile in this case. On the other hand, if the anti-enuretic effect of imipramine is primarily due to its action on the CNS, a form of imipramine that cannot pass through the BBB has no effect on nocturnal enuresis treatment and thus may help to clarify the mechanism of action of imipramine in nocturnal enuresis treatment. Methods This article describes the synthesis and evaluation of the anti-cholinergic effect of a new bis derivative of imipramine, which contains two imipramine units in its structure. Key findings The compound exhibited anti-cholinergic activity comparable with that of imipramine on isolated guinea pig ileum. Conclusions Being a quaternary ammonium, this compound is not expected to be able to cross the BBB and thus would cause fewer CNS side effects.

Synthesis of a quaternary bis derivative of imipramine as a novel compound with potential anti-enuretic effect

Imipramine has been used for over four decades (early reports in 1960s) for the treatment of nocturnal enuresis, although the reason for its effect is not clear. Imipramine is a tertiary amine, which may act both in the periphery and/or pass through the blood-brain barrier (BBB) in unionized form and exhibit a central effect. Since imipramine has anti-cholinergic properties, some believe it may exert its anti-enuretic effect by affecting peripheral cholinergic receptors, i.e. its anti-enuretic effect may be due to peripheral anti-cholinergic properties, whereas others think it can pass through the BBB and interact with central nervous system (CNS) receptors. If the anti-enuretic effect of imipramine is due to its peripheral anti-cholinergic effects, its entrance into the CNS is unnecessary. Therefore, the synthesis of a form of imipramine that can exhibit peripheral anti-cholinergic effects but does not have CNS adverse effects would have a safer drug profile in this case. On the other hand, if the anti-enuretic effect of imipramine is primarily due to its action on the CNS, a form of imipramine that cannot pass through the BBB has no effect on nocturnal enuresis treatment and thus may help to clarify the mechanism of action of imipramine in nocturnal enuresis treatment. This article describes the synthesis and evaluation of the anti-cholinergic effect of a new bis derivative of imipramine, which contains two imipramine units in its structure. The compound exhibited anti-cholinergic activity comparable with that of imipramine on isolated guinea pig ileum. Being a quaternary ammonium, this compound is not expected to be able to cross the BBB and thus would cause fewer CNS side effects.

The association between anticholinergic load and cognitive performance, elevated blood pressure and the presence of peripheral anticholinergic side effects.

Background: To quantify the association between anticholinergic drug use (burden or load) and cognitive function (MMSE), blood pressure and the presence of anticholinergic side effects.

Psychopharmacotherapy and adverse drug effects in old age psychiatry

The number of drug prescriptions is continuously increasing with age. Physiologic age-associated pharmacodynamic and pharmacokinetic changes influence drug metabolism and tolerability. Therefore, we analysed the pattern of adverse drug effects, that has been reported to AGATE. Since 1992/1995 AGATE spontaneously monitors adverse drug effects (ADE) and treatment regimen, respectively, in psychiatric state hospitals in Germany. Our analysis comprised >8000 drug prescriptions with >200 ADE-reports (~2,7%) of patients older than 65 years, that have been treated with psychopharmaca. The qualitative composition of the ADE-reports revealed no age-associated differences. However, statistical analysis revealed, that delirium, red blood cell count, peripheral anticholinergic side effects, elevated liver enzymes and extra-pyramidal motor signs were significantly more frequently reported in elderly patients as compared to patients <65 years of age. We conclude, that despite the use of rather low doses in psychopharmacological treatment regimen in old age psychiatry, there is still a high risk for the occurrence of ADE.

Anticholinergic effects of desloratadine, the major metabolite of loratadine, in rabbit and guinea-pig iris smooth muscle

Allergic conjunctivitis is the most common ocular allergic disease. Although very symptomatic it does not endanger vision, and topical antihistamines or chromones are the first choice treatment in clinical practice. Recently, equivalent nanomolar affinities for histamine H 1 and muscarinic M 1 and M 3 cloned human receptors have been reported for desloratadine, the active metabolite of loratadine, a widely prescribed antihistamine. This property might enhance its utility in the treatment of asthma, but could induce adverse anticholinergic effects after topical administration. In the present study, we compare the anticholinergic activity of desloratadine with other known muscarinic antagonists and antihistamines on rabbit and guinea-pig iris smooth muscle. Desloratadine was found to be a competitive antagonist (p A 2=6.67±0.09) of carbachol-induced contractions in isolated rabbit iris smooth muscle. Atropine (p A 2=9.44±0.02) and NPC-14695 (p A 2=9.18±0.03) also behaved as competitive antagonists, whereas tiotropium bromide (p D 2′=9.06±0.02) exhibited a non-competitive behaviour in this tissue. Carebastine (p A 2=5.64±0.04) and fexofenadine (p A 2<4.0) were also studied. After topical administration on the guinea-pig eye conjunctiva, desloratadine produced a potent (ED 50=2.3 mg/ml) and long lasting mydriasis (>120 min at the ED 50) in conscious animals. Fexofenadine and carebastine were inactive even at the highest concentration tested (10 mg/ml). Atropine (ED 50=30 μg/ml) and tiotropium bromide (ED 50=10 μg/ml) were much more potent than desloratadine or pirenzepine (ED 50=3 mg/ml) in this model. The competitive muscarinic antagonism of desloratadine in vitro, and its potency and duration of action in vivo, suggest that topical treatment of allergic conjunctivitis and rhinitis with desloratadine could produce undesirable peripheral anticholinergic side effects such as mydriasis and xerostomia.

Late-life depression--clinical features, treatment and prognosis

A generation ago, geriatric depression was regarded either as a natural reaction to the privations and multiple losses that accompany old age, or as an irreversible consequence of cerebral degeneration heralding dementia. Even if physicians overcame their expectation of the inevitability of depression in old age, an unhealthy nihilism concerning the effects of antidepressant treatment in this group held sway. Elderly depressed patients, probably more than any other group, have been helped by the remarkable advances in biological treatments for depression. Those of us too young to remember the advent of electroconvulsive therapy in the 1930s and the introduction of the tricyclics and monoamine oxidase inhibitors in the 1960s can only dimly imagine the extraordinary impact that such advances must have had on psychiatric practice. In the hands of experienced clinicians, these treatments offered safe and efficacious relief of depression. Introduction of the selective serotonin reuptake inhibitors in the 1980s was particularly welcome to geriatric psychiatrists. Although those drugs are probably no more effective than the tricyclics, they are significantly more benign with regard to side effects and to the consequences of overdose. This is an obviously important point in the treatment of elderly patients, who are so often exquisitely sensitive to the hypotensive, cardiotoxic, and central and peripheral anticholinergic effects of the tricyclics.

The Effects of Intrathecal Neostigmine on Somatic and Visceral Pain

This study was designed to qualitatively evaluate the analgesic actions of intrathecal neostigmine alone and with intravenous (IV) N-butyl-scopolamine on somatic and visceral pain. Twenty-seven patients scheduled for both tubal ligation and vaginoplasty were divided into three groups. Patients received a standard anesthetic with thiopental, atracurium, and N2O/O2/enflurane. N-butyl-scopolamine, 20 mg, or saline was administered as a 2-mL IV bolus 20 min before the end of the surgical procedure. The control group (CG) received spinal and IV saline; the neostigmine group (NG), spinal neostigmine and IV saline; and the neostigmine-N-butyl-scopolamine group (NSG), spinal neostigmine and IV N-butyl-scopolamine. Postoperatively, patients assessed their pain on a 10-cm visual analog scale (VAS). The CG had both visceral and somatic pain at the first 30-min assessment, and all patients requested morphine. Patients from the NG had only visceral pain from the first assessment; however, they had lower VAS scores (P = 0.026) and requested less morphine (P = 0.037). Patients from the NSG were pain free during all assessment times (P < 0.0001). Neostigmine was more effective for somatic pain than visceral pain. N-butyl-scopolamine administration acted peripherally as an effective complement for treatment of visceral pain, reflecting an association between central cholinergic effects and peripheral anticholinergic effects in the treatment of visceral postoperative pain.

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.

Anticholinergic side-effects of antidepressants: studies of the inhibition of salivation.

Studies of the peripheral anticholinergic effects of antidepressants initiated by Ole J. Rafaelsen are reviewed. They were all cross-over trials, either in patients who received continuous medication or in which continuous medication was temporarily discontinued, or in volunteers given single doses. Anticholinergic effects were evaluated from the inhibition of salivation rate measured by a tampon method. In essence, the studies revealed that 1) the method was sufficiently reliable and sensitive, 2) inhibition of salivation by tricyclic antidepressants persisted during long-term treatment, and 3) the newer antidepressants Nomifensine, Zimeldine, Mianserin, Citalopram, and Femoxetine were less potent as to anticholinergic effects than tricyclic antidepressants. The results of the studies reviewed have generally been in good agreement with similar studies of other centers and with clinical between-group studies. Other authors have found a sufficient specificity of salivation rate measurements for anticholinergic effects, but other methods, for instance based on heart rate measurements, may prove to be more specific.

Central vs peripheral anticholinergic effects on repeated acquisition of behavioral chains

Monkeys that were required to repeatedly learn new sequences of responses to obtain food were injected with 0.2 mg/kg of atropine sulfate or methylatropine nitrate. Effects lasted 8 to 12 hr following injection. Both drugs decreased the rate at which the animals worked, but only atropine sulfate increased the number of attempts required to solve the problem and decreased overall accuracy, suggesting a peripheral mode of action for rate-decreasing effects, and a central mode of action for effects of atropine on qualitative aspects of performance.

Bupropion, d-amphetamine, and amitriptyline-induced conditioned taste aversion in rats: Dose effects

Nine groups of rats (n=6 per group) were adapted to a daily one-half hour period of water availability. When intake had stabilized, they were allowed access to a 0.1% (w/v) solution of saccharin, and immediately afterward were given IP injections of isotonic saline; bupropion HCl (10.0, 20.0, or 40.0 mg/kg); d-amphetamone-sulfate (0.5, 1.0, 2.0 mg/kg); or amitriptyline HCl (5.0, 10.0, or 20.0 mg/kg) in a volume of 1 ml. The lowest dose of each compound was chosen to be equipotent in screening tests used to identify potential antidepressants. Following 2 days of access to water alone, all groups were given a choice between water and saccharin for 3 consecutive days. All compounds induced taste aversions in a dose-related manner, but amitriptyline induced greater and longer-lasting aversions than either bupropion or d-amphetamine which were equipotent over the dose range studied. As such, this is the first demonstration that bupropion and amitriptyline, two clinically effective antidepressants, can induce taste aversions and replicates as well the common finding that d-amphetamine has substantial taste aversion-inducing properties. The ability of these compounds to induce taste aversions could be mediated through their effects on central catecholaminergic processes although amitriptyline has significant peripheral anticholinergic effects.

Meige Syndrome

A patient with Meige syndrome associated with spasmodic torticollis was treated with benztropine mesylate (Cogentin) at doses of 12-16 mg daily. Marked suppression of both oromandibular dystonia and the torticollis was obtained. Mild impairment of recent memory was the major side effect. Peripheral anticholinergic side effects were controlled by the concomitant administration of ambenonium chloride (Mytelase) 15 mg daily.