Chemical structure of acetylcholine

Cholinergic blocking drugs are a group of drugs that block the action of acetylcholine (ACh), a neurotransmitter, in synapses of the cholinergic nervous system.[1] They block acetylcholine from binding to cholinergic receptors, namely the nicotinic and muscarinic receptors.

These agents have broad effects due to their actions in nerves located vastly over the body. These nerves include motor nerves in somatic nervous system which innervate skeletal muscles as well as nerves in the sympathetic and parasympathetic nervous systems.[1] Organs that receive innervations from these systems include exocrine glands, heart, eyes, gastrointestinal tract etc. Antimuscarinic and antinicotinic agents can increase heart rate, inhibit secretions, and gastrointestinal motility.[1][2]

Naturally occurring antimuscarinics were found in alkaloids from Belladonna (Solanaceae) plants. They were used as deadly poison and pupil-dilating cosmetics. While curare, the naturally occurring antinicotinics derived from Chondrodendron and Strychnos, was a poison used by South American Indians for hunting.[1][3][4]

According to their site of actions, cholinergic blocking drugs can be classified into two general types — antimuscarinic and antinicotinic agents.[1] Antimuscarinic agents (also known as muscarinic antagonists), including atropine and hyoscine, block acetylcholine at the muscarinic acetylcholine receptors. Antinicotinic agents (also known as ganglionic blockers, neuromuscular blockers), including tubocurarine and hexamethonium, block acetylcholine action at nicotinic acetylcholine receptors. Their effects are based on the expression of corresponding receptors in different parts of the body.

There are many adverse effects, interactions and contraindications for antinicotinic and antimuscarinic agents. Adverse effects include hypotension, dry mouth, dry eyes etc. They interact with grapefruit juice and various medications, e.g. warfarin, metoclopramide. Therefore, cautions should be exercised and advice from medical professionals should be sought before using medications.

History

Discovery of cholinergic nervous system

In 1900, Reid Hunt, a pharmacologist (1870-1948), realised a fall in blood pressure in rabbits after removing adrenaline (epinephrine) from adrenal glands extract. While he initially attributed this effect to choline, he later discovered acetylcholine was 100 000 times more potent in lowering blood pressure.[2]

Sir Henry Hallett Dale

British physiologist Sir Henry Hallett Dale (1875-1968) observed acetylcholine for causing blood vessel dilation and slowing down heart rate. In 1914, Dale noted that the physiological effect of acetylcholine resembled the stimulation of parasympathetic nervous system and hypothesized acetylcholine as the neurotransmitter. Later, Dale named substances that mimic acetylcholine action as “cholinergics”.[5]

In 1914, Dale also distinguished two types of activities of acetylcholine, namely muscarinic and nicotinic, as they mimic the effects of injecting muscarine, extracted from poisonous mushroom Amanita muscaria, and nicotine.[2]

Antimuscarinic agents

Naturally occurring antimuscarinics were found in alkaloids from Belladonna (Solanaceae) plants. They were used as deadly poison in Roman Empire and Middle Ages. The name Belladonna, meaning beautiful ladies, was derived from women using berry juice from the plant cosmetically to dilate their pupils.[4]

The mydriatic effect was studied by the German chemist Friedlieb Ferdinand Runge (1795-1867), in which the active ingredient, atropine, was first discovered by Vaquelin in 1809 and was first isolated by Heinrich F. G. Mein in 1813.[4]

In the 1850s, atropine was used as antispasmodic in asthma treatment and as morphine antidote for its mydriatic effect.[4] Bezold and Bloebaum showed that atropine blocked the effects of vagal stimulation on the heart in 1867. Subsequently in 1872, Heidenhain found its ability to prevent salivary secretion.[6]

Antinicotinic agents

Curare, derived from Chondrodendron and Strychnos, was used as poison by South American Indians to coat arrow tips or blow-pipe darts for hunting animals. It is first identified when Spanish soldiers were attacked by these indigenous tribes in the 16th century.[1][3]

In 1906, Langley studied the actions of nicotine and curare on chicken and frog muscles. Curare was found to block the stimulant action of nicotine in both innervated and chronically denervated muscles. In 1940, Jenkinson identified tubocurarine as a competitive antagonist of acetylcholine.  

Curare and tubocurarine had important roles in establishing the concept of specific cholinoceptors in the motor end plate.[3] At right dose, they are used as general anesthetic for relaxing abdominal muscles in operations.[1]

General effects on body

Antimuscarinic agents

Muscarinic receptors are G-protein coupled receptors that present mainly in the parasympathetic system and sweat gland. Antimuscarinc agents, therefore, generally produce effects that are opposite to the stimulation of the parasympathetic system, which is responsible for “rest and digest”.[1][2]

Location Effects
Exocrine glands
  • Inhibition of secretions in salivary, lacrimal, bronchial and sweat glands
  • Dry mouth, dry skin
  • Gastric secretion is only slightly reduced
  • Bronchial mucociliary clearance inhibition leading to accumulation of residual secretion in lungs
Cardiovascular system
  • Increased heart rate (tachycardia)
  • Unaffected arterial blood pressure and response to exercise
Eye
Gastrointestinal tract
  • Inhibition of motility
Other smooth muscle
  • Relaxation of bronchial smooth muscle
  • Biliary and urinary tract smooth muscle only slightly affected, might precipitate urinary retention
Central Nervous System (CNS)
  • Restlessness, agitation, disorientation

Antinicotinic agent

Nicotinic receptors are ligand-gated ion channels that present in both parasympathetic and sympathetic ganglions, while the antagonistic effect of antinicotinic agents depend on which system predominates in a particular site. Nicotinic receptors are also present in neuromuscular junctions and the brain.[1][2]

Location Predominant system Effects
Exocrine glands Parasympathetic except sweat glands
  • Inhibition of secretions in salivary, lacrimal, bronchial and sweat glands
Heart Parasympathetic
  • Increased heart rate (tachycardia)
Blood vessels Sympathetic
Eye Parasympathetic
  • Pupil dilation (mydriasis) and unresponsive to light
  • Relaxation of ciliary muscle causes paralysis of accommodation (cycloplegia) and impaired near vision
Gastrointestinal tract Parasympathetic
Other smooth muscle Parasympathetic
  • Relaxation of bronchial, urinary bladder smooth muscle
Neuromuscular junction N/A
  • Muscle relaxation
  • Neuromuscular block or paralysis

Clinical uses

Listed below are some examples of antimuscarinic and antinicotinic agents according to the British National Formulary, including non-clinically one for better illustration of their site of actions.[7]

Antimuscarinic agents

Antimuscarinic agents are muscarinic antagonists and they bind to muscarinic cholinergic receptors postsynaptically without activating them. They occupy and prevent acetylcholine from binding to the active sites of receptors to elicit their effect.[1][2]

Examples Properties Clinical use Notes
Atropine
  • Non-selective antagonist
  • Good oral absorption
  • CNS stimulant (cross blood-brain barrier)
 Ophthalmologic examination
  • Cause cycloplegic effect, i.e. paralysis of ciliary muscle and loss of accommodation
  • Topical application

Surgery Premedication[8]

  • Inhibit saliva secretion
  • Maintain normal heartbeat

Myopia

  • Slow down Myopia progression in children.
  • New off-label treatment
  • Animal studies showed dopamine and DOPAC increase in the chick retina, important in ocular growth and myopia development.[9]

Acute symptomatic bradycardia

  • Increase heart rate, improve signs and symptoms
  • First-line treatment
  • Intravenous administration[10]
  • Belladonna alkaloid
  • Side effects include urinary retention, dry mouth, blurred vision
Glycopyrrolate
  • Quaternary ammonium compound
  • Does not cross blood-brain barrier
 Hyperhidrosis
  • Reduce rate of sweating by blocking parasympathetic receptors in the central nervous system, smooth muscle, and sweat glands[8]
  • First drug approved by FDA in 2018 for hyperhidrosis [11]
Dicycloverine (Dicyclomine)
  • Similar to atropine
 Bowel Colic
  • Relax intestinal smooth muscles and cramps by inhibiting parasympathetic system and intrinsic primary afferent nerves (IPAN)
  • Taken orally or intramuscularly
Hyoscine (Scopolamine)
  • Similar to atropine
  • CNS depressant
 Motion sickness

Bowel Colic

  • Similar to Dicycloverine
  • Belladonna alkaloid
  • Causes sedation
  • Side effects similar to atropine
  • Prevention drug for motion sickness instead of treatment medication
Tiotropium
  • Similar to atropine
  • Does not inhibit bronchial mucociliary clearance
  • Poor absorption
 Asthma and Chronic Obstructive Pulmonary Disease (COPD)
  • Dilate airway by relaxing bronchial smooth muscles
  • Quaternary ammonium compound
Ipratropium
Tropicamide
  • Similar to atropine
  • May increase intraocular pressure
 Ophthalmologic examination
  • Similar to atropine
  • Similar to atropine but shorter acting
Cyclopentolate
Darifenacin Urinary incontinence
  • Inhibit micturition by relaxing bladder smooth muscles
  • Used in urinary incontinence
  • Few side effects

Antinicotinic agents

Antinicotinic agents are classified into ganglionic blockers and neuromuscular blockers.

Ganglionic blockers are of little clinical use as they act at all autonomic ganglions.[1][2] They act by:

  • Interfering acetylcholine release
  • Prolonged depolarization (depolarisation block), i.e. stimulation then block stimulation
  • Competitive inhibition of nicotinic receptor
Examples Mechanism of action Properties Clinical use
Nicotine Prolonged depolarization
  • Non-competitive block
 Smoking Cessation
  • Eliminate symptoms of nicotine withdrawing
  • Given in low dose
Acetylcholine (in presence of cholinesterase inhibitors) No clinical use as ganglionic blocker
Hexamethonium Competitive inhibition of nicotinic receptor
  • Selective
  • First effective hypertension drug treatment
 No longer clinically use due to side effect
Trimethaphan
  • Selective
  • Short duration of action
 Blood pressure lowering in surgery (rarely use)
Tubocurarine
  • Non-selective
  • Cause histamine release, so greater side effects comparing with Atracurium
 Rarely used
Atracurium
  • Safer alternative to tubocurarine with less side effects
 Surgical anaesthetic & intubation
  • facilitate endotracheal intubation and provide skeletal muscle relaxation to reduce the risk of laryngeal injury.[12]

Neuromuscular blockers act at neuromuscular junction by:[1][2]

  • Inhibiting acetylcholine synthesis
  • Inhibiting acetylcholine release
  • Blocking acetylcholine receptors postsynaptically
  • Prolonged depolarization of motor end plate
Examples Mechanism of action Onset Duration of action Properties Clinical use
Hemicholinium Inhibiting acetylcholine synthesis / /
  • Block choline transport into nerve terminal
  • Use experimentally only[13]
 No clinical use
Vesamicol No clinical use
Botulinum toxin Inhibiting acetylcholine release 3–5 days 3–4 months
  • Very potent
  • Botulinum poisoning cause parasympathetic and motor paralysis
 Muscle relaxants
  • Treat cervical dystonia, spasticity, blepharospasm and overactive bladder
  • Injected to paralyse muscles around face, hence reducing wrinkles (clinical or cosmetic uses)

Reduce secretion

  • Used in patients with hyperhidrosis and sialorrhoea

Headache prophylaxis

  • Intramuscular or subcutaneous administration can reduce migraine frequency and severity[14]
Beta-bungarotoxin / / No clinical use
Tubocurarine Blocking acetylcholine receptors postsynaptically Slow

(> 5mins)

 Long (1-2h)
  • Plant alkaloid
 Rarely used
Alcuronium
  • Semisynthetic derivative of tubocurarine
  • Fewer side effect than tubocurarine
 No clinical use currently[15]
Pancuronium Intermediate (2-3 min) Long (1-2h)
  • First steroid-based compound
 Surgery Premedication
  • Endotracheal intubation and to produce muscle relaxation in general anaesthesia during surgery

Euthanasic agent

Pipecuronium
  • Similar to pancuronium
 Surgery Premedication
  • Similar to pancuronium but with less cardiovascular side effect[17]
Vecuronium Intermediate Intermediate

(30-40min)
  • Widely used
 Surgery Premedication
  • Similar to pancuronium
Rocuronium
  • Similar to vecuronium with faster onset
Atracurium Intermediate Intermediate

(<30 min)
  • Widely used
Doxacurium
  • Chemically similar to atracurium
  • Stable in plasma
  • Longer duration of action
Cisatracurium
  • Pure active isomeric constituent of atracurium
  • More potent
Mivacurium Fast (~2mins) Short (~15 mins)
  • Chemically similar to atracurium
  • Rapidly inactivated by plasma cholinesterase
Suxamethonium Prolonged depolarization of motor end plate Fast Short
  • Rapidly inactivated by plasma cholinesterase
  • Used for brief procedure, e.g. intubation
Rocuronium
  • Fewer unwanted effect than suxamethonium

Adverse effects

Drug reactions

The following are some side effects after taking either antinicotinic or anticholinergic medications. They vary from mild to severe and some of these effects depends on the duration of drug usage.

Cognitive function decline (Confusion, memory loss and difficulty in concentration)[18] paralysis, Tachycardia,[19] Hypotension (Anticholinergics are histamine-inducing, leading to vasodilation during anaphylactic reaction, hence a dropping in blood pressure),[20] constipation, dry mouth, dry eyes, hypohidrosis/ anhidrosis, blurry vision, or Increase in intraocular pressure, increase in the risk of glaucoma.

Overdose

Anticholinergic overdose, both antinicotinic and antimuscarinic, can exert toxic effects on both central and peripheral systems. The following symptoms could be presented:[21][22]

Mydriasis

Mild symptoms include tachycardia, flushed face, mydriasis and blurred vision, fever, dry mouth and skin, and urinary retention. Early stage of overdose can lead to central nervous system stimulation, for instance, hyperactivity, followed by depression, such as agitation (Anxiety or nervous), delirium, disorientation, hallucinations, seizures, hypertension, or hyperthermia. In late or severe stage of overdose, it could lead to coma, medullary paralysis, death.

Physostigmine structure

Supportive care is usually performed in anticholinergic toxicated patients. Intravenous benzodiazepine is used as a first-line treatment for agitation. Cooling measures are employed if there is any significant hyperthermia. Activated charcoal is only given within one hour of anticholinergic ingestion. Physostigmine is given only if presenting both peripheral and central signs and symptoms of anticholinergic poisoning.[23] Physostigmine is a central and peripheral acting acetylcholinesterase inhibitor and generally given to patients with pure anticholinergic poisoning.[24]

Interactions

Combined use of medications with anticholinergics may cause synergistic (supra-additive), additive, or antagonistic interactions, leading to no therapeutic effect or overdosing.[25][26] Below listed are some medications or food that can interact with anticholinergics.

Medications indicated for:

Contraindications

The followings are the common contraindications adopted from the British National Formulary.[7]

Antimuscarinic agents

Drooping of eyelid in myasthenia gravis

For all antimuscarinics,

Antinicotinic agents

For anticholinergics, such as

  • Trimethoprim:
  • Suxamethonium:
    • Hyperkalemia
    • Low plasma-cholinesterase activity e.g. severe liver disease
    • Major trauma
    • Personal or family history of congenital myotonic disease
    • Personal or family history of malignant hyperthermia
    • Prolonged immobilisation
    • Severe burns
    • Skeletal muscle myopathies e.g. Duchenne muscular dystrophy

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 Patrick G (2019-10-10). "Introduction". Introduction, Medicinal Chemistry. Taylor & Francis. pp. 2–3. doi:10.1201/9780429188572-1. ISBN 978-0-429-18857-2. S2CID 243582955. {{cite book}}: |work= ignored (help)
  2. 1 2 3 4 5 6 7 8 "Preface". Rang and Dale's Pharmacology (7Th ed.). Elsevier. 2012. pp. xv. doi:10.1016/b978-0-7020-3471-8.00064-0. ISBN 978-0-7020-3471-8.
  3. 1 2 3 Bowman WC (January 2006). "Neuromuscular block". British Journal of Pharmacology. 147 Suppl 1 (S1): S277-86. doi:10.1038/sj.bjp.0706404. PMC 1760749. PMID 16402115.
  4. 1 2 3 4 Shutt LE, Bowes JB (May 1979). "Atropine and hyoscine". Anaesthesia. 34 (5): 476–90. doi:10.1111/j.1365-2044.1979.tb06327.x. PMID 382907. S2CID 41496486.
  5. ↑ Raju TN (2014). "Dale, Henry Hallett". Encyclopedia of the Neurological Sciences. Elsevier. pp. 926–927. doi:10.1016/b978-0-12-385157-4.00848-4. ISBN 978-0-12-385158-1.
  6. ↑ Behcet A (2014-03-25). "The Source-Synthesis- History and Use of Atropine 1". Journal of Academic Emergency Medicine. 13 (1): 2–3. doi:10.5152/jaem.2014.1120141. ISSN 1305-760X.
  7. 1 2 "Digital Medicines Information Suite". MedicinesComplete. Retrieved 2021-03-05.
  8. 1 2 Gallanosa A, Stevens JB, Quick J (2021). "Glycopyrrolate". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 30252291. Retrieved 2021-03-05.
  9. ↑ Upadhyay A, Beuerman RW (May 2020). "Biological Mechanisms of Atropine Control of Myopia". Eye & Contact Lens. 46 (3): 129–135. doi:10.1097/ICL.0000000000000677. PMC 7176345. PMID 31899695.
  10. ↑ "Part 7.3: Management of Symptomatic Bradycardia and Tachycardia". Circulation. 112 (24_suppl): IV–67-IV-77. 2005-11-28. doi:10.1161/circulationaha.105.166558. ISSN 0009-7322.
  11. ↑ "Assessment of Safety, Tolerability and Efficacy of 1% GPB Cream Versus Qbrexza® (Glycopyrronium) Cloth 2.4% Under Maximum-Use Conditions in Subjects With Primary Axillary Hyperhidrosis". Case Medical Research. 2019-11-11. doi:10.31525/ct1-nct04159610. ISSN 2643-4652. S2CID 243333125.
  12. ↑ Stein JM (September 1975). "The effect of adrenaline and of alpha- and beta-adrenergic blocking agents on ATP concentration and on incorporation of 32Pi into ATP in rat fat cells". Biochemical Pharmacology. 24 (18): 1659–62. doi:10.1016/0006-2952(75)90002-7. PMID 12.
  13. ↑ "Hemicholinium-3". PubChem. Retrieved 2021-03-05.
  14. ↑ Escher CM, Paracka L, Dressler D, Kollewe K (February 2017). "Botulinum toxin in the management of chronic migraine: clinical evidence and experience". Therapeutic Advances in Neurological Disorders. 10 (2): 127–135. doi:10.1177/1756285616677005. PMC 5367647. PMID 28382110.
  15. ↑ Hillier K (2007). "Alcuronium". X Pharm: The Comprehensive Pharmacology Reference. Elsevier. pp. 1–4. doi:10.1016/b978-008055232-3.61181-x. ISBN 978-0-08-055232-3. {{cite book}}: |work= ignored (help)
  16. ↑ Riley S (August 2017). "Navigating the new era of assisted suicide and execution drugs". Journal of Law and the Biosciences. 4 (2): 424–434. doi:10.1093/jlb/lsx028. ISSN 2053-9711.
  17. ↑ Preuss C (2010). "Pipecuronium". xPharm: The Comprehensive Pharmacology Reference. Elsevier. pp. 1–5. doi:10.1016/b978-008055232-3.63925-x. ISBN 978-0-08-055232-3.
  18. ↑ Fox C, Smith T, Maidment I, Chan WY, Bua N, Myint PK, et al. (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.
  19. ↑ Moss J (August 1995). "Muscle relaxants and histamine release". Acta Anaesthesiologica Scandinavica. Supplementum. 106: 7–12. doi:10.1111/j.1399-6576.1995.tb04301.x. PMID 8533551. S2CID 37305853.
  20. ↑ Hunter JM (July 1993). "Histamine release and neuromuscular blocking drugs". Anaesthesia. 48 (7): 561–3. doi:10.1111/j.1365-2044.1993.tb07114.x. PMID 7688493. S2CID 36119841.
  21. ↑ Broderick ED, Metheny H, Crosby B (2021). "Anticholinergic Toxicity". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 30521219.
  22. ↑ National Research Council (US) Panel on Anticholinesterase Chemicals; National Research Council (US) Panel on Anticholinergic Chemicals (1982-01-01). Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents. doi:10.17226/740. ISBN 978-0-309-07759-0. PMID 25032448.
  23. ↑ Derinoz O, Emeksiz HC (September 2012). "Use of physostigmine for cyclopentolate overdose in an infant". Pediatrics. 130 (3): e703-5. doi:10.1542/peds.2011-3038. PMID 22908101. S2CID 22609464.
  24. ↑ Pentel P, Peterson CD (November 1980). "Asystole complicating physostigmine treatment of tricyclic antidepressant overdose". Annals of Emergency Medicine. 9 (11): 588–90. doi:10.1016/s0196-0644(80)80232-0. PMID 7001962.
  25. ↑ Paśko P, Rodacki T, Domagała-Rodacka R, Owczarek D (December 2016). "A short review of drug-food interactions of medicines treating overactive bladder syndrome". International Journal of Clinical Pharmacy. 38 (6): 1350–1356. doi:10.1007/s11096-016-0383-5. PMC 5124029. PMID 27738922.
  26. ↑ Rosow CE (September 1997). "Anesthetic drug interaction: an overview". Journal of Clinical Anesthesia. 9 (6 Suppl): 27S–32S. doi:10.1016/S0952-8180(97)00124-4. PMID 9278852.
  27. ↑ "IBM Watson Health Products". www.micromedexsolutions.com. Retrieved 2021-03-26.
  28. ↑ Keisu M, Wiholm BE, Palmblad J (October 1990). "Trimethoprim-sulphamethoxazole-associated blood dyscrasias. Ten years' experience of the Swedish spontaneous reporting system". Journal of Internal Medicine. 228 (4): 353–60. doi:10.1111/j.1365-2796.1990.tb00245.x. PMID 2266345. S2CID 29753376.
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