Anticholinergic

An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. Anticholinergics inhibit parasympathetic nerve impulses by selectively blocking the binding of the neurotransmitter acetylcholine to its receptor in nerve cells. The nerve fibers of the parasympathetic system are responsible for the involuntary movement of smooth muscles present in the gastrointestinal tract, urinary tract, lungs, etc. Anticholinergics are divided into three categories in accordance with their specific targets in the central and/or peripheral nervous system: antimuscarinic agents, ganglionic blockers, and neuromuscular blockers.^[1]

Medical uses

Anticholinergic drugs are used to treat a variety of conditions:

• Gastrointestinal disorders (e.g., gastritis, diarrhea, pylorospasm, diverticulitis, ulcerative colitis, nausea, and vomiting)
• Genitourinary disorders (e.g., cystitis, urethritis, and prostatitis)
• Respiratory disorders (e.g., asthma, chronic bronchitis, and chronic obstructive pulmonary disease [COPD])
• Sinus bradycardia due to a hypersensitive vagus nerve.
• Insomnia, although usually only on a short-term basis.
• Dizziness (including vertigo [a.k.a. 'the spins'] and motion sickness-related symptoms)

Anticholinergics generally have antisialagogue effects (decreasing saliva production), and most produce some level of sedation, both being advantageous in surgical procedures.^[2][3]

Recreational uses

When a significant amount of an anticholinergic is taken into the body, a toxic reaction known as acute anticholinergic syndrome may result. This may happen accidentally or intentionally as a consequence of recreational drug use. Anticholinergic drugs are usually considered the least enjoyable by many recreational drug users,^[4] possibly due to the lack of euphoria caused by them. There have been reported cases of users experiencing what they attribute to "euphoria" from the use of this substance. In terms of recreational use, these drugs are commonly referred to as deliriants.^[5] The risk of addiction is low in the anticholinergic class. The effects are usually more pronounced in the elderly, due to natural reduction of acetylcholine production associated with its use.

Side effects

Long term use increases the risk of both mental and physical decline.^[6] It is unclear if they affect the risk of death generally.^[6] However, in older adults they do appear to increase the risk of death.^[7] Possible effects of anticholinergics include:

• Poor coordination
• Dementia^[8]
• Decreased mucus production in the nose and throat; consequent dry, sore throat
• Dry-mouth with possible acceleration of dental caries
• Stopping of sweating; consequent decreased epidermal thermal dissipation leading to warm, blotchy, or red skin
• Increased body 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
• Diminished bowel movement, sometimes ileus (decreases motility via the vagus nerve)
• Increased intraocular pressure; dangerous for people with narrow-angle glaucoma.

Possible effects in the central nervous system resemble those associated with delirium, and may include:

• Confusion
• Disorientation
• Agitation
• Euphoria or dysphoria
• Respiratory depression
• Memory problems^[9]
• Inability to concentrate
• Wandering thoughts; inability to sustain a train of thought
• Incoherent speech
• Irritability
• Mental confusion (brain fog)
• Wakeful myoclonic 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 sensory hallucinations
  • 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
• Rarely: seizures, coma, and death
• Orthostatic hypotension (sudden dropping of systolic blood pressure when standing up suddenly) and significantly increased risk of falls in the elderly population.^[10]

A common mnemonic for the main features of anticholinergic syndrome is the following:^[11]

• Blind as a bat (dilated pupils)
• Red as a beet (vasodilation/flushing)
• Hot as a hare (hyperthermia)
• Dry as a bone (dry skin)
• Mad as a hatter (hallucinations/agitation)
• Bloated as a toad (ileus, urinary retention)
• And the heart runs alone (tachycardia)

Toxicity

Acute anticholinergic syndrome is reversible and subsides once all of the causative agent has been excreted. Reversible Acetylcholinesterase inhibitor agents such as physostigmine can be used 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.^[12]

Piracetam (and other racetams), α-GPC and choline are known to activate the cholinergic system and alleviate cognitive symptoms caused by extended use of anticholinergic drugs.

Pharmacology

Anticholinergics are classified according to the receptors that are affected:

• Antimuscarinic agents operate on the muscarinic acetylcholine receptors. The majority of anticholinergic drugs are antimuscarinics.
• Antinicotinic agents operate on the nicotinic acetylcholine receptors. The majority of these are non-depolarising skeletal muscle relaxants for surgical use that are structurally related to curare. Several are depolarizing agents.

Examples

Examples of common anticholinergics:

• Antimuscarinic agents
  • Atropine
  • Benzatropine (Cogentin)
  • Biperiden
  • Chlorpheniramine (Chlor-Trimeton)
  • Dicyclomine (Dicycloverine)
  • Dimenhydrinate (Dramamine)
  • Diphenhydramine (Benadryl, Sominex, Advil PM, Unisom, etc.)
  • Doxepin (Sinequan, Deptran)
  • Doxylamine (Restavit)
  • Glycopyrrolate (Robinul)
  • Hydroxyzine (Atarax, Vistaril)
  • Ipratropium (Atrovent)
  • Orphenadrine (Norflex)
  • Oxitropium (Oxivent)
  • Oxybutynin (Ditropan, Driptane, Lyrinel XL)
  • Tolterodine (Detrol, Detrusitol)
  • Tiotropium (Spiriva)
  • Tricyclic antidepressants (28 compounds with numerous trade names)
  • Trihexyphenidyl
  • Scopolamine
  • Solifenacin
  • Tropicamide^[4]
• Antinicotinic agents
  • Bupropion (Zyban, Wellbutrin) - Ganglion blocker^[13][14][15]
  • Dextromethorphan - Cough suppressant and ganglion blocker^[16][17][18]
  • Doxacurium - Nondepolarizing skeletal muscular relaxant
  • Hexamethonium - Ganglion blocker
  • Mecamylamine - Ganglion blocker and occasional smoking cessation aid^[19]
  • Tubocurarine - Nondepolarizing skeletal muscular relaxant

Plants of the Solanaceae family contain various anticholinergic tropane alkaloids, such as scopolamine, atropine, and hyoscyamine.

Physostigmine is one of only a few drugs that can be used as an antidote for anticholinergic poisoning. Nicotine also counteracts anticholinergics by activating nicotinic acetylcholine receptors. Caffeine (although an adenosine receptor antagonist) is able to counteract the anticholinergic symptoms by reducing sedation and increasing acetylcholine activity, thereby causing alertness and arousal.

Plant sources

The most common plants containing anticholinergic alkaloids (including atropine, scopolamine, and hyoscyamine among others) are:

• Atropa belladonna (deadly nightshade)
• Brugmansia species
• Datura species
• Garrya species
• Hyoscyamus niger (henbane)
• Mandragora officinarum (mandrake)

Use as a deterrent

Several narcotic and opiate-containing drug preparations, such as those containing hydrocodone and codeine are combined with an anticholinergic agent to deter intentional misuse.^[20] Examples include Hydromet/Hycodan (hydrocodone/homatropine), Lomotil (diphenoxylate/atropine) and Tussionex (hydrocodone polistirex/chlorpheniramine). However, it is noted that opioid/antihistamine combinations are used clinically for their synergistic effect in the management of pain and maintenance of dissociative anesthesia (sedation) in such preparations as Meprozine (meperidine/promethazine) and Diconal (dipipanone/cyclizine), which act as strong anticholinergic agents.^[21]

References

1. Sharee A. Wiggins; Tomas Griebling. "Urinary Incontinence". Landon Center on Aging.
2. Page 592 in: Cahalan, Michael D.; Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K. (2009). Clinical Anesthesia. Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-8763-7.
3. Clinical Anesthesia. Books.google.se. Retrieved 8 December 2014.
4. Bersani, F. S.; Corazza, O.; Simonato, P.; Mylokosta, A.; Levari, E.; Lovaste, R.; Schifano, F. (2013). "Drops of madness? Recreational misuse of tropicamide collyrium; early warning alerts from Russia and Italy". General Hospital Psychiatry 35 (5): 571–3. doi:10.1016/j.genhosppsych.2013.04.013. PMID 23706777.
5. "Erowid Dimenhydrinate (Dramamine) Vault : Dramamine (and other related Pharmaceuticals) FAQ 2.3". 2015-06-02. Archived from the original on June 2, 2015. Retrieved 2015-06-08.
6. Fox, C; Smith, T; Maidment, I; Chan, WY; Bua, N; Myint, PK; Boustani, M; Kwok, CS; Glover, M; Koopmans, I; Campbell, N (September 2014). "Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: a systematic review.". Age and ageing 43 (5): 604–15. doi:10.1093/ageing/afu096. PMID 25038833.
7. Ruxton, K; Woodman, RJ; Mangoni, AA (2 March 2015). "Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: A systematic review and meta-analysis.". British Journal of Clinical Pharmacology 80: 209–20. doi:10.1111/bcp.12617. PMID 25735839.
8. "Study suggests link between long-term use of anticholinergics and dementia risk". Alzheimer's Society. 2015-01-26. Retrieved 2015-02-17.
9. Talan, Jamie (July–August 2008). "Common Drugs May Cause Cognitive Problems". Neurology Now 4 (4): 10–11. doi:10.1097/01.NNN.0000333835.93556.d1. Retrieved 2008-08-17.
10. "Lifeline Learning Center". Lifeline.theonlinelearningcenter.com. Retrieved 8 December 2014.
11. "Anticholinergic Toxidrome". Life in the Fast Lane. Retrieved 2015-06-08.
12. Rosen, Peter, John A. Marx, Robert S. Hockberger, and Ron M. Walls. Rosen's Emergency Medicine: Concepts and Clinical Practice. 8th ed. Philadelphia, PA: Mosby Elsevier, 2014.
13. Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI (2014). "Bupropion and bupropion analogs as treatments for CNS disorders". Adv. Pharmacol. 69: 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. PMID 24484978.
14. Dwoskin, Linda P. (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 177–216. ISBN 978-0-12-420177-4.
15. Tasman, Allan, Kay, Jerald, Lieberman, Jeffrey A., First, Michael B., Maj, Mario (11 October 2011). Psychiatry. John Wiley & Sons. ISBN 978-1-119-96540-4.
16. Damaj, M. I.; Flood, P; Ho, K. K.; May, E. L.; Martin, B. R. (2004). "Effect of Dextrometorphan and Dextrorphan on Nicotine and Neuronal Nicotinic Receptors: In Vitro and in Vivo Selectivity". Journal of Pharmacology and Experimental Therapeutics 312 (2): 780–5. doi:10.1124/jpet.104.075093. PMID 15356218.
17. Lee, Jun-Ho; Shin, Eun-Joo; Jeong, Sang Min; Kim, Jong-Hoon; Lee, Byung-Hwan; Yoon, In-Soo; Lee, Joon-Hee; Choi, Sun-Hye; Lee, Sang-Mok; Lee, Phil Ho; Kim, Hyoung-Chun; Nah, Seung-Yeol (2006). "Effects of dextrorotatory morphinans on α3β4 nicotinic acetylcholine receptors expressed in Xenopus oocytes". European Journal of Pharmacology 536 (1–2): 85–92. doi:10.1016/j.ejphar.2006.02.034. PMID 16563374.
18. Hernandez, S. C.; Bertolino, M; Xiao, Y; Pringle, K. E.; Caruso, F. S.; Kellar, K. J. (2000). "Dextromethorphan and Its Metabolite Dextrorphan Block α3β4 Neuronal Nicotinic Receptors". The Journal of Pharmacology and Experimental Therapeutics 293 (3): 962–7. PMID 10869398.
19. Shytle, RD; Penny, E; Silver, AA; Goldman, J; Sanberg, PR (Jul 2002). "Mecamylamine (Inversine): an old antihypertensive with new research directions". Journal of Human Hypertension 16 (7): 453–7. doi:10.1038/sj.jhh.1001416. PMID 12080428.
20. "NIH DailyMed - Hydromet Syrup". Dailymed.nlm.nih.gov. Retrieved 2008-08-17.
21. "Characterizing the subjective, psychomotor, and physiological effects of a hydrocodone combination product (Hycodan) in non-drug-abusing volunteers". Link.springer.com. Retrieved 2008-08-17.