Drug that binds to but does not activate muscarinic cholinergic receptors
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 chronic obstructive pulmonary disease (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 (LAMA s) or short-acting muscarinic receptor antagonists (SAMA s), 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[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[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[clarification needed ] Long acting antagonist Tudorza Benztropine M1 -selectiveReduces 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 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 bromideNS Asthma and bronchitis [5] 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.). 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 Antihistamines 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 See also References External links
Psychedelics (5-HT2A agonists)
Benzofurans Lyserg‐ amides Phenethyl‐ amines
2C-x 25x -NBx
25x -NB 25x -NB3OMe 25B-NB3OMe 25C-NB3OMe 25D-NB3OMe 25E-NB3OMe 25H-NB3OMe 25I-NB3OMe 25N-NB3OMe 25P-NB3OMe 25T2-NB3OMe 25T4-NB3OMe 25T7-NB3OMe 25TFM-NB3OMe 25x -NB4OMe 25B-NB4OMe 25C-NB4OMe 25D-NB4OMe 25E-NB4OMe 25H-NB4OMe 25I-NB4OMe 25N-NB4OMe 25P-NB4OMe 25T2-NB4OMe 25T4-NB4OMe 25T7-NB4OMe 25TFM-NB4OMe 25x -NBF 25x -NBMD 25B-NBMD 25C-NBMD 25D-NBMD 25E-NBMD 25F-NBMD 25H-NBMD 25I-NBMD 25P-NBMD 25T2-NBMD 25T7-NBMD 25TFM-NBMD 25x -NBOH 25x -NBOMe Atypical structures
25x -NMx 25B-NMe7BF 25B-NMe7BT 25B-NMe7Bim 25B-NMe7Box 25B-NMe7DHBF 25B-NMe7Ind 25B-NMe7Indz 25B-NMePyr 25I-NMe7DHBF 25I-NMeFur 25I-NMeTHF 25I-NMeTh N-(2C)-fentanyl N-(2C-B) fentanyl N-(2C-C) fentanyl N-(2C-D) fentanyl N-(2C-E) fentanyl N-(2C-G) fentanyl N-(2C-H) fentanyl N-(2C-I) fentanyl N-(2C-IP) fentanyl N-(2C-N) fentanyl N-(2C-P) fentanyl N-(2C-T) fentanyl N-(2C-T-2) fentanyl N-(2C-T-4) fentanyl N-(2C-T-7) fentanyl N-(2C-TFM) fentanyl
3C-x 4C-x DOx HOT-x MDxx Mescaline (subst.) TMAs TMA TMA-2 TMA-3 TMA-4 TMA-5 TMA-6 Others
Piperazines Tryptamines
alpha -alkyltryptaminesx -DALT x -DET x -DiPT x -DMT 4,5-DHP-DMT 2,N,N-TMT 4-AcO-DMT 4-HO-5-MeO-DMT 4,N,N-TMT 4-Propionyloxy-DMT 5,6-diBr-DMT 5-AcO-DMT 5-Bromo-DMT 5-MeO-2,N ,N -TMT 5-MeO-4,N ,N -TMT 5-MeO-α,N,N-TMT 5-MeO-DMT 5-N ,N -TMT 7,N,N-TMT α,N,N-TMT (Bufotenin) 5-HO-DMT DMT Norbaeocystin (Psilocin) 4-HO-DMT (Psilocybin) 4-PO-DMT x -DPT Ibogaine-related x -MET x -MiPT Others
Others
Dissociatives (NMDAR antagonists )
Deliriants (mAChR antagonists ) Others
mAChRs Tooltip Muscarinic acetylcholine receptors
Agonists Antagonists 3-Quinuclidinyl benzilate 4-DAMP Aclidinium bromide (+formoterol )Abediterol AF-DX 250 AF-DX 384 Ambutonium bromide Anisodamine Anisodine Antihistamines (first-generation) (e.g., brompheniramine , buclizine , captodiame , chlorphenamine (chlorpheniramine) , cinnarizine , clemastine , cyproheptadine , dimenhydrinate , dimetindene , diphenhydramine , doxylamine , meclizine , mequitazine , perlapine , phenindamine , pheniramine , phenyltoloxamine , promethazine , propiomazine , triprolidine )AQ-RA 741 Atropine Atropine methonitrate Atypical antipsychotics (e.g., clozapine , fluperlapine , olanzapine (+fluoxetine ), rilapine, quetiapine , tenilapine , zotepine )Benactyzine Benzatropine (benztropine) Benzilone Benzilylcholine mustard Benzydamine BIBN 99 Biperiden Bornaprine Camylofin CAR-226,086 CAR-301,060 CAR-302,196 CAR-302,282 CAR-302,368 CAR-302,537 CAR-302,668 Caramiphen Cimetropium bromide Clidinium bromide Cloperastine CS-27349 Cyclobenzaprine Cyclopentolate Darifenacin DAU-5884 Desfesoterodine Dexetimide DIBD Dicycloverine (dicyclomine) Dihexyverine Difemerine Diphemanil metilsulfate Ditran Drofenine EA-3167 EA-3443 EA-3580 EA-3834 Emepronium bromide Etanautine Etybenzatropine (ethybenztropine) Fenpiverinium Fentonium bromide Fesoterodine Flavoxate Glycopyrronium bromide (+beclometasone/formoterol , +indacaterol , +neostigmine )Hexahydrodifenidol Hexahydrosiladifenidol Hexbutinol Hexocyclium Himbacine HL-031,120 Homatropine Imidafenacin Ipratropium bromide (+salbutamol )Isopropamide J-104,129 Hyoscyamine Mamba toxin 3 Mamba toxin 7 Mazaticol Mebeverine Meladrazine Mepenzolate Methantheline Methoctramine Methylatropine Methylhomatropine Methylscopolamine Metixene Muscarinic toxin 7 N-Ethyl-3-piperidyl benzilate N-Methyl-3-piperidyl benzilate Nefopam Octatropine methylbromide (anisotropine methylbromide) Orphenadrine Otenzepad (AF-DX 116) Otilonium bromide Oxapium iodide Oxitropium bromide Oxybutynin Oxyphencyclimine Oxyphenonium bromide PBID PD-102,807 PD-0298029 Penthienate Pethidine pFHHSiD Phenglutarimide Phenyltoloxamine Pipenzolate bromide Piperidolate Pirenzepine Piroheptine Pizotifen Poldine Pridinol Prifinium bromide Procyclidine Profenamine (ethopropazine) Propantheline bromide Propiverine Quinidine 3-Quinuclidinyl thiochromane-4-carboxylate Revefenacin Rociverine RU-47,213 SCH-57,790 SCH-72,788 SCH-217,443 Scopolamine (hyoscine) Scopolamine butylbromide (hyoscine butylbromide) Silahexacyclium Sofpironium bromide Solifenacin SSRIs Tooltip Selective serotonin reuptake inhibitors (e.g., femoxetine , paroxetine )Telenzepine Terodiline Tetracyclic antidepressants (e.g., amoxapine , maprotiline , mianserin , mirtazapine )Tiemonium iodide Timepidium bromide Tiotropium bromide Tiquizium bromide Tofenacin Tolterodine Tricyclic antidepressants (e.g., amitriptyline (+perphenazine ), amitriptylinoxide , butriptyline , cidoxepin , clomipramine , desipramine , desmethyldesipramine, dibenzepin , dosulepin (dothiepin) , doxepin , imipramine , lofepramine , nitroxazepine , northiaden (desmethyldosulepin) , nortriptyline , protriptyline , quinupramine , trimipramine )Tridihexethyl Trihexyphenidyl Trimebutine Tripitamine (tripitramine) Tropacine Tropatepine Tropicamide Trospium chloride Typical antipsychotics (e.g., chlorpromazine , chlorprothixene , cyamemazine (cyamepromazine) , loxapine , mesoridazine , thioridazine )Umeclidinium bromide (+vilanterol )WIN-2299 Xanomeline Zamifenacin
Precursors (and prodrugs )
nAChRs Tooltip Nicotinic acetylcholine receptors
Agonists (and PAMs Tooltip positive allosteric modulators )5-HIAA 6-Chloronicotine A-84,543 A-366,833 A-582,941 A-867,744 ABT-202 ABT-418 ABT-560 ABT-894 Acetylcholine Altinicline Anabasine Anatabine Anatoxin-a AR-R17779 Bephenium hydroxynaphthoate Butinoline Butyrylcholine Carbachol Choline Cotinine Cytisine Decamethonium Desformylflustrabromine Dianicline Dimethylphenylpiperazinium Epibatidine Epiboxidine Ethanol (alcohol) Ethoxysebacylcholine EVP-4473 EVP-6124 Galantamine GTS-21 Ispronicline Ivermectin JNJ-39393406 Levamisole Lobeline MEM-63,908 (RG-3487) Morantel Nicotine (tobacco )NS-1738 PHA-543,613 PHA-709,829 PNU-120,596 PNU-282,987 Pozanicline Pyrantel Rivanicline RJR-2429 Sazetidine A SB-206553 Sebacylcholine SIB-1508Y SIB-1553A SSR-180,711 Suberyldicholine Suxamethonium (succinylcholine) Suxethonium (succinyldicholine) TC-1698 TC-1734 TC-1827 TC-2216 TC-5214 TC-5619 TC-6683 Tebanicline Tribendimidine Tropisetron UB-165 Varenicline WAY-317,538 XY-4083 Antagonists (and NAMs Tooltip negative allosteric modulators )
Precursors (and prodrugs )