Muscarinic antagonist

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Muscarinic acetylcholine receptor antagonist
Drug class
Scopolamine
Skeletal formula of Scopolamine, a nonselective antagonist of the muscarinic receptors
Class identifiers
Use Allergies, Asthma, Bradycardia, Motion sickness, Parkinson's disease, etc.
ATC code V
Biological target Metabotropic acetylcholinergic receptors.
External links
MeSH D018727
In Wikidata

A muscarinic receptor antagonist (MRA) is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. Acetylcholine (often abbreviated ACh) is a neurotransmitter whose receptor is a protein 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.

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

Certain substances are known as long-acting muscarinic receptor antagonists (LAMAs).[1]

Effects[edit]

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. 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. In addition to increased activity to dopaminergic neurons from anticholinergics, antagonists of the muscarinic-acetylcholine receptors produce a sense of happiness and euphoria. This led to the discovery of various tricyclic antidepressants.

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, which is overcome by MRA and thus increases the heart rate. If atropine is given by intramuscular or subcutaneous injection, it causes initial bradycardia. This is because by i.m/s.c it acts on presynaptic M1 receptors (autoreceptors). Intake of acetylcholine in axoplasm is prevented and the presynaptic nerve releases more acetylcholine into the synapse that initially causes bradycardia.

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

Important[2] muscarinic antagonists include atropine, Hyoscyamine, hyoscine butylbromide and hydrobromide, ipratropium, tropicamide, cyclopentolate, and pirenzepine.

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[edit]

Overview[edit]

Substance Trade names Mechanism Clinical use Adverse effects
Atropine (D/L-Hyoscyamine) Symax, HyoMax, Anaspaz, Egazil, Buwecon, Cystospaz, Levsin, Levbid, Levsinex, Donnamar, NuLev, Spacol T/S and Neoquess non-selective antagonism, CNS depression[2]
Scopolamine (L-Hyoscine) Scopace, Transderm-Scop, Maldemar, Buscopan non-selective antagonism, CNS depression[2]
Hydroxyzine Vistaril, Atarax Very mild/negligible mechanism of action
Ipratropium Atrovent and Apovent non-selective antagonism, without any mucociliary excretion inhibition.[2] in asthma and bronchitis[2]
  • Bronchial vasodilation
Tropicamide short acting non-selective antagonism, CNS depression[2]
Pirenzepine M1 receptor-selective antagonist[2] (fewer than non-selective ones)[2]
Diphenhydramine Benadryl, Nytol Non-selective antagonism in the central nervous system, blood vessels and smooth muscle tissues
  • sedation
  • dry mouth
  • constipation
  • urinary retention
Doxylamine Unisom
  • antihistamine[4]
  • antiemetic
  • sleep aid
  • dizziness
  • dry mouth
Dimenhydrinate Dramamine Combination of diphenhydramine with a methylxanthine salt
Dicyclomine
Flavoxate Urispas
Oxybutynin Ditropan
Tiotropium Spiriva
Cyclopentolate short acting non-selective antagonism, CNS depression[2]
Atropine methonitrate non-selective antagonism, blocks transmission in ganglia.[2] Lacks CNS effects[5]
Trihexyphenidyl/Benzhexol Artane Targets the M1 Muscarinic receptor Parkinson's disease Drug at relative dose has 83% activity of atropine, thus has the same side-effects
Tolterodine Detrusitol, Detrol
Solifenacin Vesicare Competitive muscarinic acetylcholine receptor antagonist
Darifenacin Enablex Selective for M3 receptors [5] Urinary incontinence [5] Few side effects[5]
Benztropine Cogentin Reduces the effects of the relative central cholinergic excess that occurs as a result of dopamine deficiency. Parkinson's disease
Mebeverine Colofac, Duspatal, Duspatalin A muscolotropic spasmolytic with a strong and selective action on the smooth muscle spasm of the gastrointestinal tract, in particular of the colon.
  • Irritable bowel syndrome 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
Procyclidine Antimuscarinic
  • Drug-induced parkinsonism, akathisia and acute dystonia
  • Parkinson disease
  • 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
Aclidinium bromide Tudorza Selective long acting muscarinic antagonist
  • Bronchospasm
  • Chronic Obstructive Pulmonary Disease

Binding affinities[edit]

Anticholinergics[edit]

Compound M1 M2 M3 M4 M5 Species Ref
3-Quinuclidinyl benzilate 0.035–0.044 0.027–0.030 0.080–0.088 0.034–0.037 0.043–0.065 Human [6][7]
4-DAMP 0.57–0.58 3.80–7.3 0.37–0.52 0.72–1.17 0.55–1.05 Human [8][9]
AF-DX 250 427 55.0 692 162 3020 Human [8]
AF-DX 384 30.9 6.03 66.1 10.0 537 Human [8]
AQ-RA 741 28.8 4.27 63.1 6.46 832 Human [8]
Atropine 0.21–0.50 0.76–1.5 0.15–1.1 0.13–0.6 0.21–1.7 Human [6][10][9]
Benzatropine (benztropine) 0.231 1.4 1.1 1.1 2.8 Human [6]
Biperiden 0.48 6.3 3.9 2.4 6.3 Human [6]
Darifenacin 5.5–13 47–77 0.84–2.0 8.6–22 2.3–5.4 Human [9][11]
Dicycloverine (dicyclomine) 57 (IC50) 415 (IC50) 67 (IC50) 97 (IC50) 53 (IC50) Human/rat [10]
Hexahydrodifenidol 11 200 16 76 (IC50) 83 Human/rat [10]
Hexahydrosiladifenidol 44 249 10 298 (IC50) 63 Human/rat [10]
(R)-Hexbutinol 2.09 20.9 2.14 3.02 5.50 Human [8]
Hexocyclium 2.3 23 1.4 5.5 3.7 Human/rat [10]
Himbacine 107 10.0 93.3 11.0 490 Human [8]
Ipratropium 0.49 1.5 0.51 0.66 1.7 Human [11]
Methoctramine 16–50 3.6–14.4 118–277 31.6–38.0 57–313 Human [10][8][12]
N-Methylscopolamine 0.054–0.079 0.083–0.251 0.052–0.099 0.026–0.097 0.106–0.125 Human [8]
Orphenadrine 48 213 120 170 129 Human [7]
Otenzepad (AF-DX 116) 1300 186 838 1800 (IC50) 2800 Human/rat [10]
Oxybutynin 0.66 13 0.72 0.54 7.4 Human [9]
pFHHSiD 22.4 132 15.5 31.6 93.3 Human [8]
Pirenzepine 6.3–8 224–906 75–180 17–37 66–170 Human [6][10][8][9]
Procyclidine 4.6 25 12.4 7 24 Human [6]
Propiverine 476 2970 420 536 109 Human [9]
Scopolamine (hyoscine) 1.1 2.0 0.44 0.8 2.07 Human [6]
Silahexacyclium 2.0 35 1.2 3.2 2.0 Human/rat [10]
Timepidium 34 7.7 31 18 11 Human [9]
Tiquizium 4.1 4.0 2.8 3.6 8.2 Human [9]
Trihexyphenidyl 1.6 7 6.4 2.6 15.9 Human [6]
Tripitamine (tripitramine) 1.58 0.27 38.25 6.41 33.87 Human [12]
Zamifenacin 55 153 10 68 34 Human [9]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Antihistamines[edit]

Compound M1 M2 M3 M4 M5 Species Ref
Brompheniramine 25700 32400 50100 67600 28800 Human [13]
Chlorphenamine (chlorpheniramine) 19000 17000 52500 77600 28200 Human [13]
Cyproheptadine 12 7 12 8 11.8 Human [7]
Diphenhydramine 80–100 120–490 84–229 53–112 30–260 Human [6][14]
Doxylamine 490 2100 650 380 180 Human [14]
Mequitazine 5.6 14 5.3 11.1 11.0 Human [7]
Terfenadine 8710 8510 5250 30900 11200 Human [13]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Antidepressants[edit]

Compound M1 M2 M3 M4 M5 Species Ref
Amitriptyline 14.7 11.8 12.8 7.2 15.7 Human [7]
Bupropion >35,000 >35,000 >35,000 >35,000 >35,000 Human [7]
Citalopram 1430 ND ND ND ND Human [15]
Desipramine 110 540 210 160 143 Human [7]
Desmethylcitalopram >10000 >10000 >10000 >10000 >10000 Human [16]
Desmethyldesipramine 404 927 317 629 121 Human [16]
Desvenlafaxine >10000 >10000 >10000 >10000 >10000 Human [17]
Dosulepin 18 109 38 61 92 Human [7]
Doxepin 18–38 160–230 25–52 20–82 5.6–75 Human [14][7]
Escitalopram 1242 ND ND ND ND Human [15]
Etoperidone >35000 >35000 >35000 >35000 >35000 Human [7]
Femoxetine 92 150 220 470 400 Human [7]
Fluoxetine 702–1030 2700 1000 2900 2700 Human [7][15]
Fluvoxamine 31200 ND ND ND ND Human [15]
Imipramine 42 88 60 112 83 Human [7]
Lofepramine 67 330 130 340 460 Human [7]
Norfluoxetine 1200 4600 760 2600 2200 Human [7]
Nortriptyline 40 110 50 84 97 Human [7]
Paroxetine 72–300 340 80 320 650 Human [7][15]
Sertraline 427–1300 2100 1300 1400 1900 Human [7][15]
Tianeptine >10000 >10000 >10000 >10000 >10000 Human [18]
Trazodone >35,000 >35,000 >35,000 >35,000 >35,000 Human [14][7]
Venlafaxine >35000 >35000 >35000 >35000 >35000 Human [7]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Antipsychotics[edit]

Compound M1 M2 M3 M4 M5 Species Ref
Amisulpride >10,000 >10,000 >10,000 >10,000 >10,000 Human [19]
Aripiprazole 6780 3510 4680 1520 2330 Human [20]
Asenapine >10000 >10000 >10000 >10000 ND Human [21][21]
Bromperidol 7600 1800 7140 1700 4800 Human [6]
Chlorprothixene 11 28 22 18 25 Human [6]
Chlorpromazine 25 150 67 40 42 Human [6]
Clozapine 1.4–31 7–204 6–109 5–27 5–26 Human [6][21][22][23]
Cyamemazine (cyamepromazine) 13 42 32 12 35 Human [24]
N-Desmethylclozapine 67.6 414.5 95.7 169.9 35.4 Human [25]
Fluperlapine 8.8 71 41 14 17 Human [6]
Fluphenazine 1095 7163 1441 5321 357 Human [26]
Haloperidol >10000 >10000 >10000 >10000 >10000 Human [21][22]
Iloperidone 4898 3311 >10000 8318 >10000 Human [27]
Loxapine 63.9–175 300–590 122–390 300–2232 91–241 Human [6][28]
Melperone >15000 2400 >15000 4400 >15000 Human [6]
Mesoridazine 10 15 90 19 60 Human [6]
Molindone ND ND >10000 ND ND Human [29]
Olanzapine 1.9–73 18–96 13–132 10–32 6–48 Human [21][22][23]
Perphenazine ND ND 1848 ND ND Human [29]
Pimozide ND ND 1955 ND ND Human [29]
Quetiapine 120–135 630–705 225–1320 660–2990 2990 Human [21][22]
Remoxipride >10000 >10000 >10000 >10000 ND Human [21]
Rilapine 190 470 1400 1000 1100 Human [6]
Risperidone 11000 ≥3700 13000 ≥2900 >15000 Human [6][21]
Sertindole ND ND 2692 ND ND Human [29]
Tenilapine 260 62 530 430 660 Human [6]
Thioridazine 2.7 14 15 9 13 Human [6]
Thiothixene >10000 >10000 >10000 >10000 5376 Human [30]
cis-Thiothixene 2600 2100 1600 1540 4310 Human [6]
Tiospirone 630 180 1290 480 3900 Human [6]
Trifluoperazine ND ND 1001 ND ND Human [29]
Ziprasidone ≥300 >3000 >1300 >1600 >1600 Human [22][31]
Zotepine 18 140 73 77 260 Human [6]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

See also[edit]

References[edit]

  1. ^ Alagha, Khudar; et al. (March 2014). "Long-acting muscarinic receptor antagonists for the treatment of chronic airway diseases". Therapeutic Advances in Chrnoic Disease. 5 (2): 85–98. PMC 3926345Freely accessible. PMID 24587893. doi:10.1177/2040622313518227. Three long-acting muscarinic receptor antagonists (LAMAs) were approved ... 
  2. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.  Page 147
  3. ^ Mirakhur, RK (August 1991). "Preanaesthetic medication: a survey of current usage". Journal of the Royal Society of Medicine. 84 (8): 481–483. PMC 1293378Freely accessible. PMID 1886116. 
  4. ^ http://www.drugbank.ca/drugs/DB00366
  5. ^ a b c d Table 10-5 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5. 
  6. ^ a b c d e f g h i j k l m n o p q r s t u v w x 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. 
  7. ^ a b c d e f g h i j k l m n o p q r s t 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. PMID 8100134. 
  8. ^ a b c d e f g h i j Dörje F, Wess J, Lambrecht G, Tacke R, Mutschler E, Brann MR (1991). "Antagonist binding profiles of five cloned human muscarinic receptor subtypes". J. Pharmacol. Exp. Ther. 256 (2): 727–33. PMID 1994002. 
  9. ^ a b c d e f g h i 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. PMID 10374898. 
  10. ^ a b c d e f g h i 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. 
  11. ^ a b Hirose H, Aoki I, Kimura T, Fujikawa T, Numazawa T, Sasaki K, Sato A, Hasegawa T, Nishikibe M, Mitsuya M, Ohtake N, Mase T, Noguchi K (2001). "Pharmacological properties of (2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide: a novel mucarinic antagonist with M(2)-sparing antagonistic activity". J. Pharmacol. Exp. Ther. 297 (2): 790–7. PMID 11303071. 
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  13. ^ a b c Yasuda SU, Yasuda RP (1999). "Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes". Pharmacotherapy. 19 (4): 447–51. PMID 10212017. 
  14. ^ a b c d 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. PMID 23357028. doi:10.1016/j.smrv.2012.08.001. 
  15. ^ a b c d e f 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. 
  16. ^ a b 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. PMC 2231336Freely accessible. PMID 17850785. doi:10.1016/j.ejphar.2007.08.017. 
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  24. ^ 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. PMID 12527336. 
  25. ^ 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. 
  26. ^ 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. 
  27. ^ 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. PMID 11750183. doi:10.1016/S0893-133X(01)00285-8. 
  28. ^ 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. 
  29. ^ a b c d e 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. PMID 12629531. doi:10.1038/sj.npp.1300027. 
  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. ^ 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. 

External links[edit]