Muscarinic antagonist

Muscarinic acetylcholine receptor antagonist
Drug class
Scopolamine
Skeletal formula of scopolamine, a nonselective antagonist of the muscarinic receptors
Class identifiers
UseAllergies, asthma, atrial fibrillation with bradycardia,[1] motion sickness, Parkinson's disease, etc.
ATC codeV
Biological targetMetabotropic acetylcholinergic receptors.
External links
MeSHD018727
In Wikidata

A muscarinic receptor antagonist (MRA) is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. The muscarinic receptor is a protein involved in the transmission of signals through certain parts of the nervous system, and muscarinic receptor antagonists work to prevent this transmission from occurring. Notably, muscarinic antagonists reduce the activation of the parasympathetic nervous system. The normal function of the parasympathetic system is often summarised as "rest-and-digest", and includes slowing of the heart, an increased rate of digestion, narrowing of the airways, promotion of urination, and sexual arousal. Muscarinic antagonists counter this parasympathetic "rest-and-digest" response, and also work elsewhere in both the central and peripheral nervous systems.

Drugs with muscarinic antagonist activity are widely used in medicine, in the treatment of low heart rate, overactive bladder, respiratory problems such as asthma and COPD, and neurological problems such as Parkinson's disease and Alzheimer's disease. A number of other drugs, such as antipsychotics and the tricyclic family of antidepressants, have incidental muscarinic antagonist activity which can cause unwanted side effects such as difficulty urinating, dry mouth and skin, and constipation.

Acetylcholine (often abbreviated ACh) is a neurotransmitter whose receptors are proteins found in synapses and other cell membranes. Besides responding to their primary neurochemical, neurotransmitter receptors can be sensitive to a variety of other molecules. Acetylcholine receptors are classified into two groups based on this:

Most muscarinic receptor antagonists are synthetic chemicals; however, the two most commonly used anticholinergics, scopolamine and atropine, are belladonna alkaloids, and are naturally extracted from plants such as Atropa belladonna, the deadly nightshade. The name "belladonna", Italian for "beautiful lady", is thought to derive from one of the antimuscarinic effects of these alkaloids: they were used by women for cosmetic purposes, to promote dilation of the pupils.[2]

Muscarinic antagonist effects and muscarinic agonist effects counterbalance each other for homeostasis.

Certain muscarinic antagonists can be classified into either long-acting muscarinic receptor antagonists (LAMAs) or short-acting muscarinic receptor antagonists (SAMAs), depending on when maximum effect occurs and for how long the effect persists.[3]

Effects

Scopolamine and atropine have similar effects on the peripheral nervous system. However, scopolamine has greater effects on the central nervous system (CNS) than atropine due to its ability to cross the blood–brain barrier.[4] At higher-than-therapeutic doses, atropine and scopolamine cause CNS depression characterized by amnesia, fatigue, and reduction in rapid eye movement sleep. Scopolamine (Hyoscine) has anti-emetic activity and is, therefore, used to treat motion sickness.

Antimuscarinics are also used as anti-parkinsonian drugs. In parkinsonism, there is imbalance between levels of acetylcholine and dopamine in the brain, involving both increased levels of acetylcholine and degeneration of dopaminergic pathways (nigrostriatal pathway). Thus, in parkinsonism there is decreased level of dopaminergic activity. One method of balancing the neurotransmitters is through blocking central cholinergic activity using muscarinic receptor antagonists.

Atropine acts on the M2 receptors of the heart and antagonizes the activity of acetylcholine. It causes tachycardia by blocking vagal effects on the sinoatrial node. Acetylcholine hyperpolarizes the sinoatrial node; this is overcome by MRAs, and thus they increase the heart rate. If atropine is given by intramuscular or subcutaneous injection, it causes initial bradycardia. This is because when administered intramuscularly or subcutaneously atropine acts on presynaptic M1 receptors (autoreceptors). Uptake of acetylcholine in axoplasm is prevented and the presynaptic nerve releases more acetylcholine into the synapse, which initially causes bradycardia.

In the atrioventricular node, the resting potential is lowered, which facilitates conduction. This is seen as a shortened PR-interval on an electrocardiogram. It has an opposite effect on blood pressure. Tachycardia and stimulation of the vasomotor center causes an increase in blood pressure. But, due to feedback regulation of the vasomotor center, there is a fall in blood pressure due to vasodilation.

Important[5] muscarinic antagonists include atropine, Hyoscyamine, hyoscine butylbromide and hydrobromide, ipratropium, tropicamide, cyclopentolate, pirenzepine and scopalamine.

Muscarinic antagonists such as ipratropium bromide can also be effective in treating asthma, since acetylcholine is known to cause smooth muscle contraction, especially in the bronchi.

Comparison table

Overview

Substance Selectivity Clinical use Adverse effects Notes Trade names
Atropine (D/L-Hyoscyamine) NS CD[5] Symax, HyoMax, Anaspaz, Egazil, Buwecon, Cystospaz, Levsin, Levbid, Levsinex, Donnamar, NuLev, Spacol T/S and Neoquess
Atropine methonitrate NS Blocks transmission in ganglia.[5] Lacks CNS effects[7]
Aclidinium bromide Selective
  • Bronchospasm
  • COPD
 Long acting antagonist Tudorza
Benztropine M1-selective Reduces the effects of the relative central cholinergic excess that occurs as a result of dopamine deficiency. Cogentin
Cyclopentolate NS Short acting, CD[5]
Diphenhydramine NS
  • sedation
  • dry mouth
  • constipation
  • UR
 Acts in the central nervous system, blood vessels and smooth muscle tissues Benadryl, Nytol
Doxylamine NS
  • antihistamine[8]
  • antiemetic
  • sleep aid
  • dizziness
  • dry mouth
 Unisom
Dimenhydrinate Combination of diphenhydramine with a methylxanthine salt Dramamine
Dicyclomine Bentyl
Darifenacin Selective for M3[7] Urinary incontinence [7] Few side effects[7] Enablex
Flavoxate Urispas
Glycopyrrolate (Glycopyrronium bromide) NS Does not cross the blood-brain barrier and has few to no central effects.[9] Robinul, Cuvposa, Seebri
Hydroxyzine Very mild/negligible action Vistaril, Atarax
Ipratropium bromide NS Asthma and bronchitis[5]
  • Bronchial vasodilation
 Lacks mucociliary excretion inhibition.[5] Atrovent and Apovent
Mebeverine
  • IBS in its primary form (e.g., Abdominal Pain, Bloating, Constipation, and Diarrhea).
  • Irritable bowel syndrome associated with organic lesions of the gastrointestinal tract. (e.g., diverticulosis & diverticulitis, etc.).
  • skin rashes
 A muscolotropic spasmolytic with a strong and selective action on the smooth muscle spasm of the gastrointestinal tract, in particular of the colon. Colofac, Duspatal, Duspatalin
Oxybutynin M1/3/4 selective Ditropan
Pirenzepine M1-selective[5] (fewer than non-selective ones)[5] Inhibits gastric secretion[5]
Procyclidine NS
  • Drug-induced parkinsonism, akathisia and acute dystonia
  • PD
  • Idiopathic or secondary dystonia
 Overdose produces confusion, agitation and sleeplessness that can last up to or more than 24 hours. Pupils become dilated and unreactive to light. Tachycardia (fast heart beat), as well as auditory and visual hallucinations
Scopolamine (L-Hyoscine) NS CD[5] Scopace, Transderm-Scop, Maldemar, Buscopan
Solifenacin Competitive antagonist Vesicare
Tropicamide NS Short acting, CD[5]
Tiotropium Spiriva
Trihexyphenidyl/Benzhexol M1 selective PD Drug at relative dose has 83% activity of atropine, thus has the same side-effects Artane
Tolterodine Detrusitol, Detrol

Binding affinities

Anticholinergics

CompoundM1M2M3M4M5SpeciesRef
3-Quinuclidinyl benzilate0.035–0.0440.027–0.0300.080–0.0880.034–0.0370.043–0.065Human[10][11]
4-DAMP0.57–0.583.80–7.30.37–0.520.72–1.170.55–1.05Human[12][13]
AF-DX 25042755.06921623020Human[12]
AF-DX 38430.96.0366.110.0537Human[12]
AQ-RA 74128.84.2763.16.46832Human[12]
Atropine0.21–0.500.76–1.50.15–1.10.13–0.60.21–1.7Human[10][14][13]
Benzatropine (benztropine)0.2311.41.11.12.8Human[10]
Biperiden0.486.33.92.46.3Human[10]
Darifenacin5.5–1347–770.84–2.08.6–222.3–5.4Human[13][15]
Dicycloverine (dicyclomine)57 (IC50)415 (IC50)67 (IC50)97 (IC50)53 (IC50)Human/rat[14]
Glycopyrrolate0.371.381.310.411.30Human[9]
Hexahydrodifenidol112001676 (IC50)83Human/rat[14]
Hexahydrosiladifenidol4424910298 (IC50)63Human/rat[14]
(R)-Hexbutinol2.0920.92.143.025.50Human[12]
Hexocyclium2.3231.45.53.7Human/rat[14]
Himbacine10710.093.311.0490Human[12]
Ipratropium0.491.50.510.661.7Human[15]
Methoctramine16–503.6–14.4118–27731.6–38.057–313Human[14][12][16]
N-Methylscopolamine0.054–0.0790.083–0.2510.052–0.0990.026–0.0970.106–0.125Human[12]
Orphenadrine48213120170129Human[11]
Otenzepad (AF-DX 116)13001868381800 (IC50)2800Human/rat[14]
Oxybutynin0.66130.720.547.4Human[13]
pFHHSiD22.413215.531.693.3Human[12]
Pirenzepine6.3–8224–90675–18017–3766–170Human[10][14][12][13]
Procyclidine4.62512.4724Human[10]
Propiverine4762970420536109Human[13]
Scopolamine (hyoscine)1.12.00.440.82.07Human[10]
Silahexacyclium2.0351.23.22.0Human/rat[14]
Timepidium347.7311811Human[13]
Tiquizium4.14.02.83.68.2Human[13]
Trihexyphenidyl1.676.42.615.9Human[10]
Tripitamine (tripitramine)1.580.2738.256.4133.87Human[16]
Zamifenacin55153106834Human[13]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Antihistamines

CompoundM1M2M3M4M5SpeciesRef
Brompheniramine2570032400501006760028800Human[17]
Chlorphenamine (chlorpheniramine)1900017000525007760028200Human[17]
Cyproheptadine12712811.8Human[11]
Diphenhydramine80–100120–49084–22953–11230–260Human[10][18]
Doxylamine4902100650380180Human[18]
Mequitazine5.6145.311.111.0Human[11]
Terfenadine8710851052503090011200Human[17]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Antidepressants

CompoundM1M2M3M4M5SpeciesRef
Amitriptyline14.711.812.87.215.7Human[11]
Bupropion>35,000>35,000>35,000>35,000>35,000Human[11]
Citalopram1430NDNDNDNDHuman[19]
Desipramine110540210160143Human[11]
Desmethylcitalopram>10000>10000>10000>10000>10000Human[20]
Desmethyldesipramine404927317629121Human[20]
Desvenlafaxine>10000>10000>10000>10000>10000Human[21]
Dosulepin (dothiepin)18109386192Human[11]
Doxepin18–38160–23025–5220–825.6–75Human[18][11]
Escitalopram1242NDNDNDNDHuman[19]
Etoperidone>35000>35000>35000>35000>35000Human[11]
Femoxetine92150220470400Human[11]
Fluoxetine702–10302700100029002700Human[11][19]
Fluvoxamine31200NDNDNDNDHuman[19]
Imipramine42886011283Human[11]
Lofepramine67330130340460Human[11]
Norfluoxetine1200460076026002200Human[11]
Nortriptyline40110508497Human[11]
Paroxetine72–30034080320650Human[11][19]
Sertraline427–13002100130014001900Human[11][19]
Tianeptine>10000>10000>10000>10000>10000Human[22]
Trazodone>35,000>35,000>35,000>35,000>35,000Human[18][11]
Venlafaxine>35000>35000>35000>35000>35000Human[11]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Antipsychotics

CompoundM1M2M3M4M5SpeciesRef
Amisulpride>10,000>10,000>10,000>10,000>10,000Human[23]
Aripiprazole67803510468015202330Human[24]
Asenapine>10000>10000>10000>10000NDHuman[25]
Bromperidol76001800714017004800Human[10]
Chlorprothixene1128221825Human[10]
Chlorpromazine25150674042Human[10]
Clozapine1.4–317–2046–1095–275–26Human[10][25][26][27]
Cyamemazine (cyamepromazine)1342321235Human[28]
N-Desmethylclozapine67.6414.595.7169.935.4Human[29]
Fluperlapine8.871411417Human[10]
Fluphenazine1095716314415321357Human[30]
Haloperidol>10000>10000>10000>10000>10000Human[25][26]
Iloperidone48983311>100008318>10000Human[31]
Loxapine63.9–175300–590122–390300–223291–241Human[10][32]
Melperone>150002400>150004400>15000Human[10]
Mesoridazine1015901960Human[10]
MolindoneNDND>10000NDNDHuman[33]
Olanzapine1.9–7318–9613–13210–326–48Human[25][26][27]
PerphenazineNDND1848NDNDHuman[33]
PimozideNDND1955NDNDHuman[33]
Quetiapine120–135630–705225–1320660–29902990Human[25][26]
Remoxipride>10000>10000>10000>10000NDHuman[25]
Rilapine190470140010001100Human[10]
Risperidone11000≥370013000≥2900>15000Human[10][25]
SertindoleNDND2692NDNDHuman[33]
Tenilapine26062530430660Human[10]
Thioridazine2.71415913Human[10]
Thiothixene>10000>10000>10000>100005376Human[34]
cis-Thiothixene26002100160015404310Human[10]
Tiospirone63018012904803900Human[10]
TrifluoperazineNDND1001NDNDHuman[33]
Ziprasidone≥300>3000>1300>1600>1600Human[26][35]
Zotepine181407377260Human[10]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

See also

References

  1. 1 2 "Hyoscyamine Subs for Pacemaker in Afib with Bradycardia". www.medpagetoday.com. May 14, 2018.
  2. ↑ "Belladonna: MedlinePlus Supplements". medlineplus.gov. Retrieved 2020-08-13.
  3. ↑ Ritter, James (2020). Rang and Dale's pharmacology. R. J. Flower, Graeme Henderson, Yoon Kong Loke, David J. MacEwan, H. P. Rang (9th ed.). Edinburgh. p. 377. ISBN 978-0-7020-8060-9. OCLC 1081403059.
  4. ↑ Sanagapalli, Santosh; Agnihotri, Kriti; Leong, Rupert; Corte, Crispin John (2017). "Antispasmodic drugs in colonoscopy: A review of their pharmacology, safety and efficacy in improving polyp detection and related outcomes". Therapeutic Advances in Gastroenterology. 10 (1): 101–113. doi:10.1177/1756283X16670076. PMC 5330606. PMID 28286563.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 147
  6. ↑ Mirakhur, RK (August 1991). "Preanaesthetic medication: a survey of current usage". Journal of the Royal Society of Medicine. 84 (8): 481–483. doi:10.1177/014107689108400811. PMC 1293378. PMID 1886116.
  7. 1 2 3 4 Table 10-5 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-06911-6.
  8. ↑ "Doxylamine". www.drugbank.ca. Retrieved 21 March 2018.
  9. 1 2 Chabicovsky, Monika; Winkler, Swantje; Soeberdt, Michael; Kilic, Ana; Masur, Clarissa; Abels, Christoph (1 May 2019). "Pharmacology, toxicology and clinical safety of glycopyrrolate". Toxicology and Applied Pharmacology. 370: 154–169. doi:10.1016/j.taap.2019.03.016. ISSN 1096-0333. PMID 30905688. S2CID 85498396.
  10. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Bolden C, Cusack B, Richelson E (1992). "Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells". J. Pharmacol. Exp. Ther. 260 (2): 576–80. PMID 1346637.
  11. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Stanton T, Bolden-Watson C, Cusack B, Richelson E (1993). "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics". Biochem. Pharmacol. 45 (11): 2352–4. doi:10.1016/0006-2952(93)90211-e. PMID 8100134.
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  13. 1 2 3 4 5 6 7 8 9 Moriya H, Takagi Y, Nakanishi T, Hayashi M, Tani T, Hirotsu I (1999). "Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland". Life Sci. 64 (25): 2351–8. doi:10.1016/s0024-3205(99)00188-5. PMID 10374898.
  14. 1 2 3 4 5 6 7 8 9 Buckley NJ, Bonner TI, Buckley CM, Brann MR (1989). "Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells". Mol. Pharmacol. 35 (4): 469–76. PMID 2704370.
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  16. 1 2 Maggio R, Barbier P, Bolognesi ML, Minarini A, Tedeschi D, Melchiorre C (1994). "Binding profile of the selective muscarinic receptor antagonist tripitramine". Eur. J. Pharmacol. 268 (3): 459–62. doi:10.1016/0922-4106(94)90075-2. PMID 7805774.
  17. 1 2 3 Yasuda SU, Yasuda RP (1999). "Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes". Pharmacotherapy. 19 (4): 447–51. doi:10.1592/phco.19.6.447.31041. PMID 10212017. S2CID 39502992.
  18. 1 2 3 4 Krystal AD, Richelson E, Roth T (2013). "Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications". Sleep Med Rev. 17 (4): 263–72. doi:10.1016/j.smrv.2012.08.001. PMID 23357028.
  19. 1 2 3 4 5 6 Owens JM, Knight DL, Nemeroff CB (2002). "[Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine]". Encephale (in French). 28 (4): 350–5. PMID 12232544.
  20. 1 2 Deupree JD, Montgomery MD, Bylund DB (2007). "Pharmacological properties of the active metabolites of the antidepressants desipramine and citalopram". Eur. J. Pharmacol. 576 (1–3): 55–60. doi:10.1016/j.ejphar.2007.08.017. PMC 2231336. PMID 17850785.
  21. ↑ Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, Andree TH (2006). "Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor". J. Pharmacol. Exp. Ther. 318 (2): 657–65. doi:10.1124/jpet.106.103382. PMID 16675639. S2CID 15063064.
  22. ↑ Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  23. ↑ Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer HY, Roth BL (2009). "Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo". Psychopharmacology. 205 (1): 119–28. doi:10.1007/s00213-009-1521-8. PMC 2821721. PMID 19337725.
  24. ↑ Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R (2003). "Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology". Neuropsychopharmacology. 28 (8): 1400–11. doi:10.1038/sj.npp.1300203. PMID 12784105.
  25. 1 2 3 4 5 6 7 Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, Seeman P, Wong DT (1996). "Radioreceptor binding profile of the atypical antipsychotic olanzapine". Neuropsychopharmacology. 14 (2): 87–96. doi:10.1016/0893-133X(94)00129-N. PMID 8822531.
  26. 1 2 3 4 5 Bymaster FP, Felder CC, Tzavara E, Nomikos GG, Calligaro DO, Mckinzie DL (2003). "Muscarinic mechanisms of antipsychotic atypicality". Prog. Neuropsychopharmacol. Biol. Psychiatry. 27 (7): 1125–43. doi:10.1016/j.pnpbp.2003.09.008. PMID 14642972. S2CID 28536368.
  27. 1 2 Bymaster FP, Falcone JF (2000). "Decreased binding affinity of olanzapine and clozapine for human muscarinic receptors in intact clonal cells in physiological medium". Eur. J. Pharmacol. 390 (3): 245–8. doi:10.1016/s0014-2999(00)00037-6. PMID 10708730.
  28. ↑ Hameg A, Bayle F, Nuss P, Dupuis P, Garay RP, Dib M (2003). "Affinity of cyamemazine, an anxiolytic antipsychotic drug, for human recombinant dopamine vs. serotonin receptor subtypes". Biochem. Pharmacol. 65 (3): 435–40. doi:10.1016/s0006-2952(02)01515-0. PMID 12527336.
  29. ↑ Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  30. ↑ Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  31. ↑ Kalkman HO, Subramanian N, Hoyer D (2001). "Extended radioligand binding profile of iloperidone: a broad spectrum dopamine/serotonin/norepinephrine receptor antagonist for the management of psychotic disorders". Neuropsychopharmacology. 25 (6): 904–14. doi:10.1016/S0893-133X(01)00285-8. PMID 11750183.
  32. ↑ Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  33. 1 2 3 4 5 Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL (2003). "H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs". Neuropsychopharmacology. 28 (3): 519–26. doi:10.1038/sj.npp.1300027. PMID 12629531.
  34. ↑ Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  35. ↑ Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
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