BACKGROUND: Intrathecal gabapentin is effective on nociceptive states evoked by tissue injury. In addition, gabapentin interacts synergistically with clonidine at the spinal level, suggesting that a mechanism of gabapentin may be related to spinal adrenoceptors. However, it has not been established whether this drug is associated with cholinergic receptors. The aim of this study was to examine the role of spinal adrenergic and cholinergic receptors on the antinociceptive action of intrathecal gabapentin. METHODS: Rats were implanted with lumbar intrathecal catheters. For a nociceptive test, 50nl of 5% formalin solution was injected into the hindpaw. The effect of intrathecal gabapentin, administered 10 min before the formalin injection, was assessed. Next, antagonistic effects of intrathecal prazosin, yohimbine, atropine and mecamylamine for the action of intrathecal gabapentin were evaluated. RESULTS: Formalin injection caused a biphasic incidence of flinching of the injected paw. Intrathecal gabapentin produced a dose-dependent suppression of only the phase 2 flinching response in the formalin test. Intrathecal atropine, but not prazosin, yohimbine nor mecamylamine, reversed the antinociception of intrathecal gabapentin. CONCLUSIONS: The antinociceptive effect of intrathecal gabapentin on facilitated states may be mediated through the muscarinic receptor but by neither the nicotinic receptor nor the adrenergic receptor at the spinal level.
Animals ; Atropine ; Catheters ; Cholinergic Antagonists* ; Clonidine ; Formaldehyde ; Incidence ; Mecamylamine ; Nociception ; Pain Measurement ; Prazosin ; Rats ; Receptors, Adrenergic ; Receptors, Cholinergic ; Receptors, Muscarinic ; Receptors, Nicotinic ; Spinal Cord ; Yohimbine

Overactive bladder is a chronic condition defined by bothersome urgency with or without urgency incontinence, usually associated with daytime frequency and nocturia. The treatment of this condition is to control bothersome urinary symptoms and is therefore to improve quality of life. The Korean Continence Society published the overactive bladder guideline in 2007, which suggested the mainstay of management is behavioral therapy and antimuscarinic pharmacotherapy. With growing awareness toward overactive bladder and quality of life, clinical information regarding antimuscarinic agents should be updated. There are several agents with good level of evidence and good grade of recommendation. Newer antimuscarinic agents are available or will be available in near future. The pharmacological properties, efficacy and tolerability of oxybutynin, trospium, propiverine, tolterodine, darifenacin, solifenacin, fesoterodine and imidafenacin are reviewed and discussed here. The results of major clinical studies are summarized.
Cholinergic Antagonists* ; Drug Therapy ; Muscarinic Antagonists ; Nocturia ; Quality of Life ; Urinary Bladder, Overactive* ; Solifenacin Succinate ; Tolterodine Tartrate

The prevention of and the controlling of symptoms, reductions in the frequency of exacerbations, and disease severity are central to the pharmacologic therapy of chronic obstructive pulmonary disease (COPD). COPD patients are inclined to be older, have more comorbidities, and use polypharmacy as a result. Long-acting inhaled muscarinic antagonists (LAMAs) is a preferred treatment modality. However, the cardiovascular (CV) safety of anti-cholinergics, including LAMA, has been an issue. In contrast, the results of the UPLIFT trial and a pooled analysis of data from 30 trials of tiotropium illustrates the association of tiotropium with reductions in the risk of all cause mortality, CV mortality and CV events. And, the UPLIFT trial provides clues regarding the additive advantages of tiotropium in COPD patients who already are using long-acting inhaled beta2 agonists and inhaled corticosteroids. Following the contribution of tiotropium as a first LAMA, new LAMAs such as aclidinium and glycopyrrolate (NVA-237) seem to be emerging.
Adrenal Cortex Hormones ; Cholinergic Antagonists ; Comorbidity ; Glycopyrrolate ; Humans ; Muscarinic Antagonists ; Polypharmacy ; Pulmonary Disease, Chronic Obstructive ; Scopolamine Derivatives ; Tiotropium Bromide

AIMTo investigate the roles of acetylcholine (ACh) receptors in the rapid effects of corticosterone (CORT) on the presympathetic neurons in the rostral ventrolateral medulla (RVLM) of rats, and study the non-genomic mechanism of glucocorticoid (GC) in the integration of sympathetic cardiovascular activity.

METHODSThe effects of microelectrophoresis of CORT on the discharge of the presympathetic neurons in the RVLM were observed by extracellular recording in urethane-anaesthetized rats. The responses of atropine (a blocker for M type of ACh receptor, ATR), d-tubocurarine (a blocker for N1 type of ACh receptor, d-TC) and hexamethonium (a blocker for N2 type of ACh receptor, C6) to the effects of CORT on the presympathetic neurons were investigated respectively.

RESULTSTotally 33 presympathetic neurons in the RVLM were recorded. Among them the firing rate of 25 (76%) presympathetic neurons was increased by microelectrophoresis of CORT. The effects of CORT were also positively correlated with the currents. In the other 8 presympathetic neurons, had was shown no effect after microelectrophoresis of CORT. In 10 presympathetic neurons, which discharge was increased by CORT, microelectrophoresis of ATR decreased the firing rate of these presympathetic neurons (P < 0.05), and did not fully block the excitatory effect induced by CORT. In both 7 and 6 presympathetic neurons, application of d-TC and C6 had no effect on these neurons respectively, and did not fully block the excitatory effect induced by CORT.

CONCLUSIONCORT had rapid excitatory effects on the presympathetic neurons in the RVLM, which effect might be independent on ACh receptors.

Animals ; Cholinergic Antagonists ; pharmacology ; Corticosterone ; pharmacology ; Electrophoresis, Microchip ; Male ; Medulla Oblongata ; drug effects ; physiology ; Neuromuscular Nondepolarizing Agents ; pharmacology ; Neurons ; drug effects ; physiology ; Nicotinic Antagonists ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Cholinergic ; physiology

The signal pathways involved in the regulation of AP-1 DNA binding activity in long-term nicotine stimulated bovine adrenal medullary chromaffin (BAMC) cells have not been well characterized. To understand the involvement of second messengers in the regulation of AP-1 DNA binding activity, the present study was designed to define the time-course for inhibition of nicotine-induced responses by cholinergic antagonists, Ca2+ and calmodulin (CaM) antagonists, and calcium/calmodulin-dependent protein kinase (CaMK) II inhibitor using electrophoretic mobility shift assay. Nicotine (10microM) stimulation increased AP-1 DNA binding activity at 24 hr after treatment. Posttreatment with hexamethonium (1 mM) plus atropine (1microM) (HA), nimodipine (1microM), or calmidazolium (1microM) at 0.5, 3, and 6 hr after the nicotine treatment significantly inhibited the AP-1 DNA binding activity increased by long-term nicotine stimulation. However, posttreatment with HA, nimodipine, or calmidazolium at 9 or 12 hr after the nicotine treatment did not affect the nicotine-induced increase of AP-1 DNA binding activity. The pretreatment of BAMC cells with various concentrations of KN-62 inhibited the increase of AP-1 DNA binding activity induced by nicotine in a concentration-dependent manner. KN-62 (10microM) posttreatment beginning at 0.5, 3, or 6 hr after the nicotine treatment significantly inhibited the increase of AP-1 DNA binding activity. However, KN-62 posttreatment beginning at 9 or 12 hr after the nicotine treatment did not affect the increase of AP-1 DNA binding activity. This study suggested that stimulation (for at least 6 hr) of nicotinic receptors on BAMC cells was necessary for increase of AP-1 DNA binding activity, and activation of Ca2+, CaM, and CaMK II up to 6 hr at least seemed to be required for the increase of nicotine-induced AP-1 DNA binding activity.
Atropine ; Calmodulin ; Cholinergic Antagonists ; Chromaffin Cells* ; DNA* ; Electrophoretic Mobility Shift Assay ; Hexamethonium ; Nicotine* ; Nimodipine ; Protein Kinases ; Receptors, Nicotinic ; Second Messenger Systems* ; Signal Transduction ; Transcription Factor AP-1*

Nocturnal enuresis is a heterogeneous disorder with various underlying pathophysiological mechanisms and causes a mismatch between the nocturnal bladder capacity and the amount of urine produced during sleep at night. It is associated with a simultaneous failure of conscious arousal in response to the sensation of bladder fullness. Generally, a complete history and physical examination, with a specific focus on the genitourinary, gastrointestinal, and neurologic systems, is sufficient to evaluate a patient with enuresis. The therapeutic focus is directed toward a differential approach based on the underlying mechanism and toward combination therapies such as alarm devices and desmopressin as well as anticholinergic agents and desmopressin. Children with increased nocturnal urine production usually have a good response to desmopressin therapy. Patients with a small bladder generally show a poor response to desmopressin treatment, but they would benefit more from combination therapy with enuretic alarm, urotherapy, and antimuscarinic agents in addition to desmopressin. Different types of bladder dysfunction, which result in a small nocturnal bladder capacity, probably contribute significantly to the pathogenesis of nocturnal enuresis, particularly in those with treatment failure and refractory symptoms. Because different clinical subgroups may show different responses to treatment, it is necessary to distinguish these subgroups before a decision on the specific treatment protocol can be made.
Arousal ; Child ; Cholinergic Antagonists ; Clinical Protocols ; Deamino Arginine Vasopressin ; Enuresis ; Humans ; Muscarinic Antagonists ; Nocturnal Enuresis ; Physical Examination ; Sensation ; Treatment Failure ; Urinary Bladder

BACKGROUND: Antimuscarinic agents are used to block undesirable muscarinic effects of `anticholinesterase given to reverse the residual neuromuscular blockade produced by muscle relaxants. However, besides antimuscarinic effects, atropine was known to have some positive effects on the recovery from neuromuscular blockade by acting at the presynaptic muscarinic receptor of the neuromuscular junction. But there have been few reports about the neuromuscular effects of glycopyrrolate. So we observed the neuromuscular effects of atropine and glycopyrrolate, and compared two. METHODS: Mivacurium(0.064 mg/kg) was administered intravenously and the experimental groups were divided into 5 groups: the control group (no antimuscarinic agent administered), Al group (0.02 mg/kg atropine administered), A2 group (0.04 m atropine administered), Gl group (0.01 mg/kg glycopyrrolate administered) and G2 group (0.02 mg/kg glycopyrrolate administered). The left cammon peroneal nerve was stimulated by the 0.1 Hz single twitch and 100 Hz tetanic stimuli. We manitored the mechanical activity of the anterior tibialis muscle and observed recovery index, tetanic fade, and post-tetanic potentiation. RESULTS: There were no significant differences in recovery indices and post-tetanic potentiations among the 5 groups. Significant differences were found in tetanic fades between the experimental groups(A1, A2, Gl, G2) and the control group(P<0.05). However no significant differences in tetanic fades were found among the experimental groups. CONCLUSIONS: Atropine and glycopyrrolate hastened the recovery from mivacurium induced neuromuscular blockade. The neuromuscular recovery effects of glycopyrmlate were found to be similar to atropine at equipotent dose.
Atropine* ; Cholinergic Agents ; Glycopyrrolate* ; Muscarinic Antagonists ; Neuromuscular Agents ; Neuromuscular Blockade* ; Neuromuscular Junction ; Parasympathetic Nervous System ; Peroneal Nerve ; Receptors, Muscarinic ; Refractory Period, Electrophysiological

Anticholinergic drugs block muscarinic receptors at the detrusor muscle of the bladder. It can cause urinary retention by contracting the bladder neck. Cases of hydronephrosis, bladder dilatation as a result of polydipsia while taking anticholinergic drugs have been reported, but very few cases of chronic renal failure can be found. We report a case of a polydipsic schizophrenic patient who, after taking anticholinergic drugs as antipsychotic drugs to treat his schizophrenia for a long time, presented with chronic renal failure due to functional obstructive uropathy in the absence of demonstrable anatomic causes of obstruction.
Antipsychotic Agents ; Cholinergic Antagonists ; Contracts ; Dilatation ; Humans ; Hydronephrosis ; Kidney Failure, Chronic ; Muscles ; Neck ; Polydipsia ; Receptors, Muscarinic ; Schizophrenia ; Urinary Bladder ; Urinary Retention

PURPOSE: Anticholinergics suppress the muscarinic receptors in the bladder smooth muscle and, increase the level of urine storage. Their side effects include dry mouth, dry eyes, constipation, drowsiness, and tachycardia. These adverse effects limit the dosing and often decrease patient compliance. This study examined the effect of amitryptline as one of the first- line treatments for overactive bladder patients with nocturia. MATERIALS AND METHODS: Between June 2005 and June 2006, a prospective randomized study was carried out on 45 female patients with an overactive bladder. The mean age was 57.6 years and the patients were treated with doxazosin(Group I), doxazosin with tolterodine(Group II), doxazosin with amitriptyline(Group III). All 45(Group I: 15, Group II: 15, Group III: 15) were followed up for 4 weeks. The treatment efficacy was measured using the 3 days of voiding diaries. RESULTS: The actual number diurnal voids showed considerable improvement after treatment(p<0.05). However, there was no difference in treatment results between Groups II and III(p>0.05). The actual number of nightly voids improved after treatment(p<0.05), but there was no change in Group I. There was no difference between Groups II and III (p>0.05). There was no difference in the total voiding volume, functional bladder capacity, nocturnal bladder capacity index, nocturia index between pre-treatment and post-treatment in each group(p>0.05). CONCLUSIONS: There are some enhanced effects with the actual number of diurnal voids and the actual number nightly voids in patients treated with doxazosin with amitriptyline. Therefore, amitripyline is helpful as a first- line treatment in female overactive bladder patients with nocturia.
Amitriptyline ; Cholinergic Antagonists ; Constipation ; Doxazosin ; Eye ; Female ; Humans ; Mouth ; Muscle, Smooth ; Nocturia ; Patient Compliance ; Prospective Studies ; Receptors, Muscarinic ; Sleep Stages ; Tachycardia ; Treatment Outcome ; Urinary Bladder ; Urinary Bladder, Overactive

PURPOSE: Central nervous system (CNS) and cardiovascular system (CVS) side effects of anticholinergic agents used to treat overactive bladder (OAB) are underreported. Hence, this review aimed to focus on the mechanisms of CNS and CVS side effects of anticholinergic drugs used in OAB treatment, which may help urologists in planning the rationale for OAB treatment. MATERIALS AND METHODS: PubMed/MEDLINE was searched for the key words "OAB," "anticholinergics," "muscarinic receptor selectivity," "blood-brain barrier," "CNS," and "CVS side effects." Additional relevant literature was determined by examining the reference lists of articles identified through the search. RESULTS: CNS and CVS side effects, pharmacodynamic and pharmacokinetic properties, the metabolism of these drugs, and the clinical implications for their use in OAB are presented and discussed in this review. CONCLUSIONS: Trospium, 5-hydroxymethyl tolterodine, darifenacin, and solifenacin seem to have favorable pharmacodynamic and pharmacokinetic properties with regard to CNS side effects, whereas the pharmacodynamic features of darifenacin, solifenacin, and oxybutynin appear to have an advantage over the other anticholinergic agents (tolterodine, fesoterodine, propiverine, and trospium) with regard to CVS side effects. To determine the real-life situation, head-to-head studies focusing especially on CNS and CVS side effects of OAB anticholinergic agents are urgently needed.
Benzhydryl Compounds ; Benzilates ; Benzofurans ; Cardiovascular System* ; Central Nervous System* ; Cholinergic Antagonists* ; Cresols ; Mandelic Acids ; Metabolism ; Pyrrolidines ; Quinuclidines ; Receptors, Muscarinic ; Tetrahydroisoquinolines ; Urinary Bladder, Overactive* ; Solifenacin Succinate