Muscarinic antagonist

Source: Wikipedia, the free encyclopedia.

A muscarinic receptor antagonist (MRA), also called an antimuscarinic, 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

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

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

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 feedback regulation of the vasomotor center, there is a fall in blood pressure due to vasodilation
.

Important

scopalamine
.

Muscarinic antagonists such as

bronchi
.

Further information: Cholinergic crisis § Treatment

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
  • hypermotility[5]
 Blocks transmission in
ganglia.[5] Lacks CNS effects[7]
Aclidinium bromide Selective[clarification needed]
  • Bronchospasm
  • COPD
 Long acting antagonist Tudorza
Benztropine
M1
-selective
  • PD
  • antipsychotics
 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
Nytol
Doxylamine NS
  • antihistamine[8]
  • antiemetic
  • sleep aid
  • dizziness
  • dry mouth
 Unisom
Dimenhydrinate Combination of diphenhydramine with a methylxanthine salt Dramamine, Gravol
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]
  • in
    peptic ulcer (not much anymore)[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
Benzhexol
 M1 selective PD Drug at relative dose has 83% activity of atropine, thus has the same side-effects Artane
Tolterodine
  • urge incontinence
 Detrusitol, Detrol

Binding affinities

Anticholinergics

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 [10][11]
4-DAMP 0.57–0.58 3.80–7.3 0.37–0.52 0.72–1.17 0.55–1.05 Human [12][13]
AF-DX 250 427 55.0 692 162 3020 Human [12]
AF-DX 384 30.9 6.03 66.1 10.0 537 Human [12]
AQ-RA 741 28.8 4.27 63.1 6.46 832 Human [12]
Atropine 0.21–0.50 0.76–1.5 0.15–1.1 0.13–0.6 0.21–1.7 Human [10][14][13]
Benzatropine (benztropine) 0.231 1.4 1.1 1.1 2.8 Human [10]
Biperiden 0.48 6.3 3.9 2.4 6.3 Human [10]
Darifenacin 5.5–13 47–77 0.84–2.0 8.6–22 2.3–5.4 Human [13][15]
Dicycloverine (dicyclomine) 57 (IC50) 415 (IC50) 67 (IC50) 97 (IC50) 53 (IC50) Human/rat [14]
Glycopyrrolate
 0.37 1.38 1.31 0.41 1.30 Human [9]
Hexahydrodifenidol 11 200 16 76 (IC50) 83 Human/rat [14]
Hexahydrosiladifenidol 44 249 10 298 (IC50) 63 Human/rat [14]
(R)-Hexbutinol 2.09 20.9 2.14 3.02 5.50 Human [12]
Hexocyclium 2.3 23 1.4 5.5 3.7 Human/rat [14]
Himbacine 107 10.0 93.3 11.0 490 Human [12]
Ipratropium
 0.49 1.5 0.51 0.66 1.7 Human [15]
Methoctramine 16–50 3.6–14.4 118–277 31.6–38.0 57–313 Human [14][12][16]
N-Methylscopolamine
 0.054–0.079 0.083–0.251 0.052–0.099 0.026–0.097 0.106–0.125 Human [12]
Orphenadrine 48 213 120 170 129 Human [11]
Otenzepad (AF-DX 116) 1300 186 838 1800 (IC50) 2800 Human/rat [14]
Oxybutynin 0.66 13 0.72 0.54 7.4 Human [13]
pFHHSiD 22.4 132 15.5 31.6 93.3 Human [12]
Pirenzepine 6.3–8 224–906 75–180 17–37 66–170 Human [10][14][12][13]
Procyclidine 4.6 25 12.4 7 24 Human [10]
Propiverine 476 2970 420 536 109 Human [13]
Scopolamine (hyoscine) 1.1 2.0 0.44 0.8 2.07 Human [10]
Silahexacyclium 2.0 35 1.2 3.2 2.0 Human/rat [14]
Timepidium
 34 7.7 31 18 11 Human [13]
Tiquizium 4.1 4.0 2.8 3.6 8.2 Human [13]
Trihexyphenidyl 1.6 7 6.4 2.6 15.9 Human [10]
Tripitamine (tripitramine) 1.58 0.27 38.25 6.41 33.87 Human [16]
Zamifenacin 55 153 10 68 34 Human [13]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Antihistamines

Compound M1 M2 M3 M4 M5 Species Ref
Brompheniramine 25700 32400 50100 67600 28800 Human [17]
Chlorphenamine (chlorpheniramine) 19000 17000 52500 77600 28200 Human [17]
Cyproheptadine 12 7 12 8 11.8 Human [11]
Diphenhydramine 80–100 120–490 84–229 53–112 30–260 Human [10][18]
Doxylamine 490 2100 650 380 180 Human [18]
Mequitazine 5.6 14 5.3 11.1 11.0 Human [11]
Terfenadine 8710 8510 5250 30900 11200 Human [17]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Antidepressants

Compound M1 M2 M3 M4 M5 Species Ref
Amitriptyline 14.7 11.8 12.8 7.2 15.7 Human [11]
Bupropion >35,000 >35,000 >35,000 >35,000 >35,000 Human [11]
Citalopram 1430 ND ND ND ND Human [19]
Desipramine 110 540 210 160 143 Human [11]
Desmethylcitalopram >10000 >10000 >10000 >10000 >10000 Human [20]
Desmethyldesipramine 404 927 317 629 121 Human [20]
Desvenlafaxine >10000 >10000 >10000 >10000 >10000 Human [21]
Dosulepin (dothiepin) 18 109 38 61 92 Human [11]
Doxepin 18–38 160–230 25–52 20–82 5.6–75 Human [18][11]
Escitalopram 1242 ND ND ND ND Human [19]
Etoperidone >35000 >35000 >35000 >35000 >35000 Human [11]
Femoxetine 92 150 220 470 400 Human [11]
Fluoxetine 702–1030 2700 1000 2900 2700 Human [11][19]
Fluvoxamine 31200 ND ND ND ND Human [19]
Imipramine 42 88 60 112 83 Human [11]
Lofepramine 67 330 130 340 460 Human [11]
Norfluoxetine
 1200 4600 760 2600 2200 Human [11]
Nortriptyline 40 110 50 84 97 Human [11]
Paroxetine 72–300 340 80 320 650 Human [11][19]
Sertraline 427–1300 2100 1300 1400 1900 Human [11][19]
Tianeptine >10000 >10000 >10000 >10000 >10000 Human [22]
Trazodone >35,000 >35,000 >35,000 >35,000 >35,000 Human [18][11]
Venlafaxine >35000 >35000 >35000 >35000 >35000 Human [11]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Antipsychotics

Compound M1 M2 M3 M4 M5 Species Ref
Amisulpride >10,000 >10,000 >10,000 >10,000 >10,000 Human [23]
Aripiprazole 6780 3510 4680 1520 2330 Human [24]
Asenapine >10000 >10000 >10000 >10000 ND Human [25]
Bromperidol 7600 1800 7140 1700 4800 Human [10]
Chlorprothixene 11 28 22 18 25 Human [10]
Chlorpromazine 25 150 67 40 42 Human [10]
Clozapine 1.4–31 7–204 6–109 5–27 5–26 Human [10][25][26][27]
Cyamemazine (cyamepromazine) 13 42 32 12 35 Human [28]
N-Desmethylclozapine 67.6 414.5 95.7 169.9 35.4 Human [29]
Fluperlapine 8.8 71 41 14 17 Human [10]
Fluphenazine 1095 7163 1441 5321 357 Human [30]
Haloperidol >10000 >10000 >10000 >10000 >10000 Human [25][26]
Iloperidone 4898 3311 >10000 8318 >10000 Human [31]
Loxapine 63.9–175 300–590 122–390 300–2232 91–241 Human [10][32]
Melperone >15000 2400 >15000 4400 >15000 Human [10]
Mesoridazine 10 15 90 19 60 Human [10]
Molindone ND ND >10000 ND ND Human [33]
Olanzapine 1.9–73 18–96 13–132 10–32 6–48 Human [25][26][27]
Perphenazine ND ND 1848 ND ND Human [33]
Pimozide ND ND 1955 ND ND Human [33]
Quetiapine 120–135 630–705 225–1320 660–2990 2990 Human [25][26]
Remoxipride >10000 >10000 >10000 >10000 ND Human [25]
Rilapine 190 470 1400 1000 1100 Human [10]
Risperidone 11000 ≥3700 13000 ≥2900 >15000 Human [10][25]
Sertindole ND ND 2692 ND ND Human [33]
Tenilapine 260 62 530 430 660 Human [10]
Thioridazine 2.7 14 15 9 13 Human [10]
Thiothixene
 >10000 >10000 >10000 >10000 5376 Human [34]
cis-Thiothixene
 2600 2100 1600 1540 4310 Human [10]
Tiospirone 630 180 1290 480 3900 Human [10]
Trifluoperazine ND ND 1001 ND ND Human [33]
Ziprasidone ≥300 >3000 >1300 >1600 >1600 Human [26][35]
Zotepine 18 140 73 77 260 Human [10]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

See also

References

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External links