Anticholinergics

Historical note and nomenclature

  Anticholinergics are substances that block the neurotransmitter acetylcholine in the central and peripheral nervous systems and are administered to reduce the effects mediated by acetylcholine on acetylcholine receptors in neurons through competitive inhibition. Antimuscarinic agents, a type of anticholinergics, are so called because they block muscarine, a poisonous substance found in the Amanita muscaria, a non-edible mushroom species. Muscarine is a toxic compound that competes with acetylcholine for the same receptors. Antimuscarinic agents are atropine, scopolamine, and ipratropium bromide. Atropine and scopolamine are alkaloids naturally occurring in Atropa belladonna and Datura stramoniumplants whereas ipratropium bromide is a derivative of atropine used to treat asthma.

  Anticholinergic drugs are used in treating a variety of conditions, such as disorders of gastrointestinal (including nausea and vomiting), genitourinary, and respiratory systems. Atropine, an anticholinergic agent, is used as premedication in anesthesia to reduce upper respiratory secretions. This clinical summary focuses on the neurologic applications of anticholinergic drugs, mainly in Parkinson disease, as well as adverse neurologic effects of anticholinergic agents–anticholinergic syndrome.

  Historically anticholinergic agents were known more for their toxicity than for their therapeutic effects. Datura stramonium was described as a poison by Homer in The Odyssey. Anticholinergics agents were introduced as the first effective drugs for Parkinson disease by Charcot at the end of 19th century. With the advent of levodopa and other new drugs for Parkinson disease, and also because of their adverse effects, the use of anticholinergics declined but continues in several other disorders.

  Another use of atropine that is of historical interest now is atropine-induced non-convulsivecoma for treatment of various psychoses and obsessive-compulsive disorder between 1950 and 1975 in the United States and some parts of Europe (Gazdag et al 2005). Although atropine use was eventually abandoned, initial therapeutic results with atropine coma were favorable, and it seemed to be safer and more effective than the widely used insulin coma.

Pharmacology

  Anticholinergic agents are classified into 2 categories according to the receptors that they act on:

  (1) Antimuscarinic agents constitute the majority of anticholinergic drugs; they act on the muscarinic acetylcholine receptors.

  (2) Antinicotinic agents act on the nicotinic acetylcholine receptors. The majority of these are non-depolarizing skeletal muscle relaxants for anesthetic use.

  Antimuscarinic agents. A classical example is atropine, which blocks acetylcholine receptor sites, opposes the actions of the vagus nerve, increases firing of the sinoatrial node and conduction through the atrioventricular node of the heart, and decreases bronchiole secretions. Overall effect of atropine is to lower the parasympathetic activity of all muscles and glands regulated by the parasympathetic nervous system because acetylcholine is the main neurotransmitter used by the parasympathetic nervous system. Therefore, it may cause swallowing difficulties and reduced secretions.

  In addition to classical antimuscarinic agents, drugs from other categories may have antimuscarinic effect. Examples of such drugs are antihistamines, cimetidine, prednisolone, theophylline, and digoxin. These agents are listed in Table 1 as causative agents of anticholinergic syndrome.

  The effects of scopolamine on the peripheral nervous system are similar to the effects of atropine. However, scopolamine is a central nervous system depressant and constitutes a highly effective treatment to prevent motion sickness although at high doses it causes excitement with side effects similar to those caused by high doses of atropine.

  Most of the approved anticholinergic agents for the treatment of Parkinson disease are nonselective antimuscarinic receptor antagonists.

  Antinicotinic agents. These anticholinergic agents are ganglionic blockers, which target nicotinic receptors in nerve cells of either sympathetic or parasympathetic systems. The most used ganglionic blockers are trimethaphan and mecamylamine, which is used to treat hypertension.

  Neuromuscular anticholinergic agents act on motor nerve choline receptors. They prevent the transmission of signals from motor nerves to neuromuscular structures of the skeletal muscle. Neuromuscular blockers are very useful as muscle relaxants in several surgical procedures, either as an adjuvant to anesthesia or as a premedication for anesthesia. Their main therapeutic use is in surgical procedures. Examples of the first group are mivacurium, tubocurarine, metocurine, doxacurium, and atracurium; the second group consists of rocuronium, vecuronium, pipecuronium, and pancuronium.

Clinical trials

  There are few trials of anticholinergic drugs in recent years for treatment of neurologic disorders. A randomized, double blind, placebo-controlled, crossover study of ipratropium bromide was conducted in subjects with Parkinson disease and bothersome drooling (Thomsen et al 2007). Although it did not affect objective measures of saliva production, there was a mild effect on subjective measures of sialorrhea. The treatment was well tolerated.

  A prospective, 12-week dose titration trial of controlled-release oxybutynin chloride evaluated the efficacy and tolerability of higher doses of the drug in patients with neurogenic bladder andmultiple sclerosis, spinal cord injury, or Parkinson disease (Bennett et al 2004).

Indications

  In neurologic disorders, anticholinergic drugs are used for the following conditions:

  Parkinson disease. Anticholinergics are used for symptomatic treatment of certain manifestations of Parkinson disease, such as sialorrhea, drug-induced dyskinesia, and urinary urgency or frequency.

  Hyperactive bladder. Anticholinergics may be used for hyperactive bladder in neurologic disorders other than Parkinson disease, for example, oxybutynin in multiple sclerosis. However, a systematic review of clinical trials of anticholinergics versus other treatments showed no significant difference between the 2 treatments in any efficacy outcome measure, and the available evidence did not support the use of anticholinergics in multiple sclerosis (Nicholas et al 2009).

  Urinary incontinence is common in patients with dementia. Central cholinergic stimulation is the mainstay in the treatment of cognitive decline. The use of anticholinergic medications for detrusor overactivity in demented patients carries the risk of mental deterioration, and further studies are needed to define treatment regimens for elderly individuals with both dementia and urinary dysfunction (Sakakibara et al 2008).

  Drug-induced dyskinesias. Rabbit syndrome, a movement disorder generally associated with prolonged use of antipsychotics, responds favorably to anticholinergic drugs (Catena et al 2007).

  Treatment of nerve agent poisoning. Atropine is recommended as the first-line treatment of sarin poisoning, and the dose should be titrated, with the goal of drying secretions and the resolution of bronchoconstriction. Atropine autoinjection is indicated as an initial treatment of the muscarinic symptoms of nerve agent poisonings. Each prefilled autoinjector provides a dose of the antidote atropine, an anticholinergic drug that reduces secretions in the mouth and respiratory passages, relieves the constriction and spasm of respiratory passages, and may reduce the paralysis of respiration, which results from actions of the toxic agent on the central nervous system. Physostigmine is also an effective treatment against sarin intoxication.

  Diagnostic procedures in neurologic disorders. The pupillary light reflex test forAlzheimer disease involves tropicamide blockade of cholinergic oculomotor functions. Pupillary constriction amplitude correlates significantly with severity of dementia, and cholinesterase inhibitor therapy may partially normalize pupillary light reflex abnormalities in these patients(Granholm et al 2003).

Contraindications

  Anticholinergic drugs are contraindicated in patients with urinary retention due to bladder neck obstruction, myasthenia gravis, severe decreased gastrointestinal motility conditions, and uncontrolled narrow angle glaucoma.

Goals and duration of treatment

  Most anticholinergic therapies are short-term or intermittent. Chronic or long-term use is limited by neurotoxicity of many of these compounds. They are mostly symptomatic and do not correct the underlying pathology of the disease.

Dosing

  Numerous anticholinergic agents are in use. The Physician’s Desk Reference should be consulted for doses of individual agents.

Precautions and use in special groups

  Pediatric. Anticholinergic drugs have been used in children, for example in the treatment of overactive bladder. Although some of the drugs are approved, few clinical trials have been conducted specifically in pediatric populations. There are no specific precautions in children, and contraindications are the same as in adults.

  Geriatric. Although many of the conditions for which anticholinergic drugs are used occur more frequently in the elderly, several precautions are necessary in this age group. Cognitive decline, renal function impairment, slowing of gastrointestinal motility, urinary obstruction due to prostatic hyperplasia, and cardiac rhythm disorders are some of the conditions that are more common in the elderly and require caution in the use of anticholinergic drugs.

  Pregnancy. The effect of anticholinergic agents on pregnancy is not well documented due to the lack of animal experimental or human studies, and caution should be exercised for use during pregnancy. The administration of anticholinergics should be avoided in patients with severe preeclampsia. There are no available data on excretion in breast milk, but anticholinergics suppress lactation; use in breastfeeding mothers should be avoided.

  Anesthesia. Anticholinergics have been used extensively as pre-anesthetic medications, for muscle relaxation and for postoperative complications such as nausea and vomiting.

Interactions

  Patients with Alzheimer disease being treated with cholinesterase inhibitors have a greater decline in their mental status after taking concurrent anticholinergic drugs for prolonged periods. This combination should be avoided as anticholinergic drugs reduce the therapeutic efficacy of cholinesterase inhibitors. Moreover, anticholinergic drugs can interact with cholinesterase inhibitors to produce bradycardia.

  Use of anticholinergic drugs for overactive bladder together with those prescribed for psychiatric or neurologic indications that also have anticholinergic properties can lead to pharmacodynamic drug interactions that might produce an anticholinergic toxicity (Michel et al 2009).

  Levels of the anticholinergic drugs can be increased to high levels by CYP3A4 inhibitors such as macrolide antibiotics (eg, erythromycin, anti-HIV agents, antidepressants, and calcium channel blockers). Therefore, this combination is contraindicated.

Adverse effects

  Adverse effects of anticholinergics may be neurologic or non-neurologic. Non-neurologic symptoms and signs of anticholinergic effect include: dry, sore throat due to decreased mucous production and cessation of perspiration leading to increased body temperature as well as tachycardia, urinary retention, constipation, and increased intraocular pressure, which may be dangerous for people with narrow-angle glaucoma.

  Neurologic signs of anticholinergic effect include ataxia, pupil dilation with blurred vision, anddiplopia. Effects in the central nervous system resemble those associated with delirium. Neurotoxicity of anticholinergics is termed “acute cholinergic syndrome,” and other manifestations besides those of delirium include cognitive impairment and visual, auditory, and sensory hallucinations. Seizures, coma, and death may occur rarely. Anticholinergic syndrome is more likely to be caused by drugs with central anticholinergic effects that cross the blood-brain barrier and block muscarinic cholinergic receptors (Moos 2007). Drugs reported to be associated with anticholinergic syndrome are listed in Table 1.

Table 1. Drugs That Can Produce Anticholinergic Syndrome

• Anesthesia, analgesia, and postoperative medications

  – Atropine sulfate

  – Benzodiazepines

  – Halothane

  – Hyoscine

  – Influrane

  – Ketamine

  – Opioids

  – Transdermal scopolamine

• Antiarrhythmics

  – Propafenone

  – Quinidine

• Antiasthmatics

  – Ipratropium bromide

• Antiemetics

  – Cyclizine

  – Meclizine

• Antihistaminics with anticholinergic activity

  – Brompheniramine

  – Chlorpheniramine

  – Cyclizine

  – Diphenylhydramine

  – Promezathine

• Anti-incontinence agents

  – Oxybutynin

  – Propantheline bromide

• Antiparkinsonian medications

  – Amantadine

  – Benzotropine

  – Biperiden

  – Ethopropazine

  – Procyclidine

  – Trihexyphenidyl

• Antipsychotics

  – Clozapine

  – Chlorpromazine

  – Chlorprothixene

  – Thioridazine

• Antispasmodics for the gastrointestinal tract

  – Hexocyclium

  – Hyoscyamine

  – Isopropamide

  – Oxyphenonium

  – Propantheline

  – Tridihexethyl

• Baclofen

• Ophthalmic preparations

  – Atropine 1% ophthalmic solution

  – Cyclopentolate

  – Eucatropine

  – Tropicamide

• Tricyclic antidepressants

  – Amitriptyline

  – Imipramine

  – Clomipramine

• Drug interactions

  – Desipramine and venlafaxine

  – Venlafaxine-fluoxetine

  – Paroxetine and clozapine

Source: Updated from (Jain 2001)

  Management. Acute anticholinergic syndrome is completely reversible and subsides once all of the toxin has been excreted. Usually no specific treatment is indicated, but in severe cases, especially those that involve severe distortions of mental state, a reversible cholinergic agent such as physostigmine may be used as 1 mg intravenous dose.

References cited

Bennett N, O’Leary M, Patel AS, Xavier M, Erickson JR, Chancellor MB. Can higher doses of oxybutynin improve efficacy in neurogenic bladder? J Urol 2004;171(2 Pt 1):749-51.

Catena M, Fagiolini A, Consoli G, et al. The rabbit syndrome: state of the art. Curr Clin Pharmacol 2007;2(3):212-6.

Gazdag G, Bitter I, Ungvári G, Gerevich J. Atropine coma: a historical note. J ECT 2005;21(4):203-6.

Granholm E, Morris S, Galasko D, Shults C, Rogers E, Vukov B. Tropicamide effects on pupil size and pupillary light reflexes in Alzheimer’s and Parkinson’s disease. Int J Psychophysiol 2003;47(2):95-115.

Jain KK. Drug-induced Neurological Disorders. 2nd edition. Hogrefe & Huber, 2001:380.

Michel MC, Schäfers RF, de la Rosette JJ. Drug-drug interactions in urology. Urologe A 2009;48(3):264-9.

Moos DD. Central anticholinergic syndrome: a case report. J Perianesth Nurs 2007;22(5):309-21.

Nicholas RS, Friede T, Hollis S, Young CA. Anticholinergics for urinary symptoms in multiple sclerosis. Cochrane Database Syst Rev 2009;(1):CD004193.**

Sakakibara R, Uchiyama T, Yamanishi T, Kishi M. Dementia and lower urinary dysfunction: with a reference to anticholinergic use in elderly population. Int J Urol 2008;15(9):778-88.**

Thomsen TR, Galpern WR, Asante A, Arenovich T, Fox SH. Ipratropium bromide spray as treatment for sialorrhea in Parkinson’s disease. Mov Disord 2007;22(15):2268-73.