Anticholinergic

For cholinergic blocking drugs, seeCholinergic blocking drugs.

Not to be confused withAnti-cholinesterase.

Anticholinergics(anticholinergic agents) are substances that block the action of theacetylcholine(ACh)neurotransmitteratsynapsesin thecentralandperipheral nervous system.

These agents inhibit theparasympathetic nervous systemby selectively blocking the binding of ACh to its receptor innerve cells.Thenerve fibersof the parasympathetic system are responsible for the involuntary movement ofsmooth musclespresent in thegastrointestinal tract,urinary tract,lungs,sweat glands,and many other parts of the body.

In broad terms, anticholinergics are divided into two categories in accordance with their specific targets in the central and peripheral nervous system and at the neuromuscular junction:antimuscarinicagents andantinicotinicagents (ganglionic blockers,neuromuscular blockers).

The term "anticholinergic" is typically used to refer to antimuscarinics which competitively inhibit the binding of ACh tomuscarinic acetylcholine receptors;such agents do not antagonize the binding atnicotinic acetylcholine receptorsat theneuromuscular junction,although the term is sometimes used to refer to agents which do so.

Medical uses

Anticholinergic drugs are used to treat a variety of conditions:

• Dizziness(includingvertigoandmotion sickness-related symptoms)
• Extrapyramidal symptoms,a potential side-effect of antipsychotic medications
• Gastrointestinal disorders (e.g.,peptic ulcers,diarrhea,pylorospasm,diverticulitis,ulcerative colitis,nausea,andvomiting)
• Genitourinary disorders (e.g.,cystitis,urethritis,andprostatitis)
• Insomnia,although usually only on a short-term basis
• Respiratory disorders (e.g.,asthma,chronic bronchitis,andchronic obstructive pulmonary disease[COPD])
• Sinus bradycardiadue to a hypersensitivevagus nerve
• Organophosphatebasednerve agentpoisoning,such asVX,sarin,tabun,andsoman(atropine is favoured in conjunction with an oxime, usuallypralidoxime)

Anticholinergics generally haveantisialagogueeffects (decreasing saliva production), and most produce some level of sedation, both being advantageous in surgical procedures.

Until the beginning of the 20th century, anticholinergic drugs were widely used to treat psychiatric disorders.

Physiological effects

Effects of anticholinergic drugs include:

• Delirium(often withhallucinationsanddelusionsindistinguishable from reality)
• Ocular symptoms (fromeye drops):mydriasis,pupil dilation,andacute angle-closure glaucomain those with shallowanterior chamber
• Anhidrosis,dry mouth, dry skin
• Fever
• Constipation
• Tachycardia
• Urinary retention
• Cutaneousvasodilation

Clinically the most significant feature isdelirium,particularly in the elderly, who are most likely to be affected by thetoxidrome.

Side effects

Long-term use may increase the risk of both cognitive and physical decline.It is unclear whether they affect the risk of death generally.However, in older adults they do appear to increase the risk of death.

Possible effects of anticholinergics include:

• Poor coordination
• Dementia
• Decreased mucus production in the nose andthroat;consequent dry, sore throat
• Dry mouthwith possible acceleration ofdental caries
• Cessation ofsweating;consequent decreased epidermal thermal dissipation leading to warm, blotchy, or red skin
• Increasedbody temperature
• Pupil dilation;consequent sensitivity to bright light (photophobia)
• Loss of accommodation (loss of focusing ability, blurred vision –cycloplegia)
• Double vision
• Increased heart rate
• Tendency to be easily startled
• Urinary retention
• Urinary incontinencewhile sleeping
• Diminished bowel movement, sometimesileus(decreases motility via thevagus nerve)
• Increasedintraocular pressure;dangerous for people with narrow-angleglaucoma

Possible effects in thecentral nervous systemresemble those associated withdelirium,and may include:

• Confusion
• Disorientation
• Agitation
• Euphoriaordysphoria
• Respiratory depression
• Memory problems
• Inability to concentrate
• Wandering thoughts; inability to sustain atrain of thought
• Incoherent speech
• Irritability
• Mental confusion (brain fog)
• Wakefulmyoclonic jerking
• Unusual sensitivity to sudden sounds
• Illogical thinking
• Photophobia
• Visual disturbances
  • Periodic flashes of light
  • Periodic changes in visual field
  • Visual snow
  • Restricted or "tunnel vision"
• Visual, auditory, or other sensoryhallucinations
  • Warping or waving of surfaces and edges
  • Textured surfaces
  • "Dancing" lines; "spiders", insects;form constants
  • Lifelike objects indistinguishable from reality
  • Phantom smoking
  • Hallucinated presence of people not actually there (e.g.shadow people)
• Rarely: seizures, coma, and death
• Orthostatic hypotension(severe drop in systolic blood pressure when standing up suddenly) and significantly increased risk of falls in the elderly population

Older patients are at a higher risk of experiencing CNS side effects.The link possible between anticholinergic medication use and cognitive decline/dementia has been noted in weaker observational studies.Although there is no strong evidence from randomized controlled trials to suggest that these medications should be avoided, clinical guidelines suggest that a consideration be made to decrease the use of these medications if safe to do so and the use of these medications be carefully considered to reduce any possible adverse effects including cognitive decline.

Toxicity

An acute anticholinergic syndrome is reversible and subsides once all of the causative agents have been excreted. Reversibleacetylcholinesterase inhibitoragents such asphysostigminecan be used as an antidote in life-threatening cases. Wider use is discouraged due to the significant side effects related to cholinergic excess including seizures, muscle weakness, bradycardia, bronchoconstriction, lacrimation, salivation, bronchorrhea, vomiting, and diarrhea. Even in documented cases of anticholinergic toxicity, seizures have been reported after the rapid administration of physostigmine. Asystole has occurred after physostigmine administration for tricyclic antidepressant overdose, so a conduction delay (QRS > 0.10 second) or suggestion of tricyclic antidepressant ingestion is generally considered a contraindication to physostigmine administration.

Pharmacology

Anticholinergics are classified according to the receptors that are affected:

• Antimuscarinicagents operate on themuscarinic acetylcholine receptors.The majority of anticholinergic drugs are antimuscarinics.
• Antinicotinicagents operate on thenicotinic acetylcholine receptors.The majority of these are non-depolarisingskeletal musclerelaxants for surgical use that are structurally related tocurare.Several are depolarizing agents.

Examples

Examples of common anticholinergics:

• Antimuscarinic agents
  • Antipsychotics(clozapine,quetiapine)
  • Atropine
  • Benztropine
  • Biperiden
  • Chlorpheniramine
  • CertainSSRIs(Paroxetine)
  • Dicyclomine(Dicycloverine)
  • Dimenhydrinate
  • Diphenhydramine
  • Doxepin
  • Doxylamine
  • Flavoxate
  • Glycopyrronium/-late
  • Hyoscyamine
  • Ipratropium
  • Orphenadrine
  • Oxitropium
  • Oxybutynin
  • Promethazine
  • Propantheline bromide
  • Scopolamine
  • Solifenacin
  • Tolterodine
  • Tiotropium
  • Tricyclic antidepressants
  • Trihexyphenidyl
  • Tropicamide
  • Umeclidinium
• Antinicotinic agents
  • Bupropion– Ganglion blocker
  • Dextromethorphan- Cough suppressant and ganglion blocker
  • Doxacurium– Nondepolarizing skeletal muscular relaxant
  • Hexamethonium– Ganglion blocker
  • Mecamylamine– Ganglion blocker and occasionalsmoking cessationaid
  • Tubocurarine- Nondepolarizing skeletal muscular relaxant

Antidotes

Physostigmineis one of only a few drugs that can be used as an antidote for anticholinergic poisoning.Nicotinealso counteracts anticholinergics by activatingnicotinic acetylcholine receptors.Caffeine(although anadenosinereceptor antagonist) can counteract the anticholinergic symptoms by reducing sedation and increasing acetylcholine activity, thereby causing alertness and arousal.

Psychoactive uses

When a significant amount of an anticholinergic is taken into the body, atoxic reactionknown as acute anticholinergic syndrome may result. This may happen accidentally or intentionally as a consequence of eitherrecreationalorentheogenicdrug use, though many users find the side effects to be exceedingly unpleasant and not worth the recreational effects they experience. In the context of recreational use, anticholinergics are often calleddeliriants.

Plant sources

The most common plants containing anticholinergicalkaloids(includingatropine,scopolamine,andhyoscyamineamong others) are:

• Atropa belladonna(deadly nightshade)
• Brugmansiaspecies
• Daturaspecies
• Garryaspecies
• Hyoscyamus niger(henbane)
• Mandragora officinarum(mandrake)

Use as a deterrent

Several narcotic andopiate-containing drug preparations, such as those containinghydrocodoneandcodeineare combined with an anticholinergic agent to deter intentional misuse.Examples includehydrocodone/homatropine(Tussigon, Hydromet, Hycodan),diphenoxylate/atropine(Lomotil), andhydrocodone polistirex/chlorpheniramine polistirex(Tussionex Pennkinetic, TussiCaps). However, it is noted that opioid/antihistamine combinations are used clinically for their synergistic effect in the management of pain and maintenance of dissociativeanesthesia(sedation) in such preparations asmeperidine/promethazine(Mepergan) anddipipanone/cyclizine(Diconal), which act as strong anticholinergic agents.