# Muscarinic antagonist

A muscarinic acetylcholine receptor antagonist, also simply known as a muscarinic antagonist or as an antimuscarinic agent, is a type of anticholinergic drug that blocks the activity of the muscarinic acetylcholine receptors (mAChRs). The muscarinic receptors are proteins 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:
* muscarinic, which respond to muscarine
* nicotinic, which respond to nicotine
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.
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.

## 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. 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 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 | During anesthesia Antidote to anticholinesterase poisoning Atrial fibrillation with bradycardia Antispasmodic in gastrointestinal hypermotility | UR xerostomia blurred vision | CD | Symax, HyoMax, Anaspaz, Egazil, Buwecon, Cystospaz, Levsin, Levbid, Levsinex, Donnamar, NuLev, Spacol T/S and Neoquess |
| Atropine methonitrate | NS | antispasmodic in gastrointestinal hypermotility | | Blocks transmission in ganglia. Lacks CNS effects | |
| Aclidinium bromide | Selective | Bronchospasm COPD | | Long acting antagonist | Tudorza |
| Benztropine | M1-selective | PD EPS caused by typical and atypical antipsychotics | | Reduces the effects of the relative central cholinergic excess that occurs as a result of dopamine deficiency. | Cogentin |
| Cyclopentolate | NS | produce mydriasis and cycloplegia in diagnostics | may cause ocular hypertension | Short acting, CD | |
| Diphenhydramine | NS | for EPS from typical and atypical antipsychotic medications antihistamine sleep aid PD management of asthma symptoms | sedation dry mouth constipation UR | Acts in the central nervous system, blood vessels and smooth muscle tissues | Benadryl, Nytol |
| Doxylamine | NS | antihistamine antiemetic sleep aid | dizziness dry mouth | | Unisom |
| Dimenhydrinate | | motion sickness | | Combination of diphenhydramine with a methylxanthine salt | Dramamine, Gravol |
| Dicyclomine | | IBS | | | Bentyl |
| Darifenacin | Selective for M3 | Urinary incontinence | Few side effects | | Enablex |
| Flavoxate | | Urinary bladder antispasmodic | | | Urispas |
| Glycopyrrolate (Glycopyrronium bromide) | NS | Prior to anesthesia to reduce salivary, tracheobronchial, and pharyngeal secretions In combination with neostigmine to prevent muscarinic effects such as bradycardia Sialorrhea Hyperhidrosis COPD | Dry mouth UR Headache Vomiting | Does not cross the blood–brain barrier and has few to no central effects. | Robinul, Cuvposa, Seebri |
| Hydroxyzine | | | | Very mild/negligible action | Vistaril, Atarax |
| Ipratropium bromide | NS | Asthma and bronchitis | Bronchial vasodilation | Lacks mucociliary excretion inhibition. | 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 | overactive bladder urge incontinence | | | Ditropan |
| Pirenzepine | M1-selective | in peptic ulcer (not much anymore) | (fewer than non-selective ones) | Inhibits gastric secretion | |
| 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 | Same uses as atropine Motion sickness | as atropine sedation | CD | Scopace, Transderm-Scop, Maldemar, Buscopan |
| Solifenacin | | overactive bladder (OAB) Urgency (urge incontinence) | | Competitive antagonist | Vesicare |
| Tropicamide | NS | produce mydriasis and cycloplegia in diagnostics | may cause ocular hypertension | Short acting, CD | |
| Tiotropium | | COPD | | | Spiriva |
| Trihexyphenidyl/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 |
The muscarinic acetylcholine receptor subtype sectivities of a large number of antimuscarinic drugs have been reviewed.

### Binding affinities
#### Anticholinergics

| Compound | M$_1$ | M$_2$ | M$_3$ | M$_4$ | M$_5$ | Species |
| 3-Quinuclidinyl benzilate | 0.035–0.044 | 0.027–0.030 | 0.080–0.088 | 0.034–0.037 | 0.043–0.065 | Human |
| 4-DAMP | 0.57–0.58 | 3.80–7.3 | 0.37–0.52 | 0.72–1.17 | 0.55–1.05 | Human |
| AF-DX 250 | 427 | 55.0 | 692 | 162 | 3020 | Human |
| AF-DX 384 | 30.9 | 6.03 | 66.1 | 10.0 | 537 | Human |
| AQ-RA 741 | 28.8 | 4.27 | 63.1 | 6.46 | 832 | Human |
| Atropine | 0.21–0.50 | 0.76–1.5 | 0.15–1.1 | 0.13–0.6 | 0.21–1.7 | Human |
| Benzatropine (benztropine) | 0.231 | 1.4 | 1.1 | 1.1 | 2.8 | Human |
| Biperiden | 0.48 | 6.3 | 3.9 | 2.4 | 6.3 | Human |
| Darifenacin | 5.5–13 | 47–77 | 0.84–2.0 | 8.6–22 | 2.3–5.4 | Human |
| Dicycloverine (dicyclomine) | 57 (IC$_{50}$) | 415 (IC$_{50}$) | 67 (IC$_{50}$) | 97 (IC$_{50}$) | 53 (IC$_{50}$) | Human/rat |
| Glycopyrrolate | 0.37 | 1.38 | 1.31 | 0.41 | 1.30 | Human |
| Hexahydrodifenidol | 11 | 200 | 16 | 76 (IC$_{50}$) | 83 | Human/rat |
| Hexahydrosiladifenidol | 44 | 249 | 10 | 298 (IC$_{50}$) | 63 | Human/rat |
| (R)-Hexbutinol | 2.09 | 20.9 | 2.14 | 3.02 | 5.50 | Human |
| Hexocyclium | 2.3 | 23 | 1.4 | 5.5 | 3.7 | Human/rat |
| Himbacine | 107 | 10.0 | 93.3 | 11.0 | 490 | Human |
| Ipratropium | 0.49 | 1.5 | 0.51 | 0.66 | 1.7 | Human |
| Methoctramine | 16–50 | 3.6–14.4 | 118–277 | 31.6–38.0 | 57–313 | Human |
| N-Methylscopolamine | 0.054–0.079 | 0.083–0.251 | 0.052–0.099 | 0.026–0.097 | 0.106–0.125 | Human |
| Orphenadrine | 48 | 213 | 120 | 170 | 129 | Human |
| Otenzepad (AF-DX 116) | 1300 | 186 | 838 | 1800 (IC$_{50}$) | 2800 | Human/rat |
| Oxybutynin | 0.66 | 13 | 0.72 | 0.54 | 7.4 | Human |
| pFHHSiD | 22.4 | 132 | 15.5 | 31.6 | 93.3 | Human |
| Pirenzepine | 6.3–8 | 224–906 | 75–180 | 17–37 | 66–170 | Human |
| Procyclidine | 4.6 | 25 | 12.4 | 7 | 24 | Human |
| Propiverine | 476 | 2970 | 420 | 536 | 109 | Human |
| Scopolamine (hyoscine) | 1.1 | 2.0 | 0.44 | 0.8 | 2.07 | Human |
| Silahexacyclium | 2.0 | 35 | 1.2 | 3.2 | 2.0 | Human/rat |
| Timepidium | 34 | 7.7 | 31 | 18 | 11 | Human |
| Tiquizium | 4.1 | 4.0 | 2.8 | 3.6 | 8.2 | Human |
| Trihexyphenidyl | 1.6 | 7 | 6.4 | 2.6 | 15.9 | Human |
| Tripitamine (tripitramine) | 1.58 | 0.27 | 38.25 | 6.41 | 33.87 | Human |
| Zamifenacin | 55 | 153 | 10 | 68 | 34 | Human |
| Values are K$_i$ (nM). The smaller the value, the more strongly the drug binds to the site. ||||||||

#### Antihistamines

| Compound | M$_1$ | M$_2$ | M$_3$ | M$_4$ | M$_5$ | Species |
| Brompheniramine | 25700 | 32400 | 50100 | 67600 | 28800 | Human |
| Chlorphenamine (chlorpheniramine) | 19000 | 17000 | 52500 | 77600 | 28200 | Human |
| Cyproheptadine | 12 | 7 | 12 | 8 | 11.8 | Human |
| Diphenhydramine | 80–100 | 120–490 | 84–229 | 53–112 | 30–260 | Human |
| Doxylamine | 490 | 2100 | 650 | 380 | 180 | Human |
| Mequitazine | 5.6 | 14 | 5.3 | 11.1 | 11.0 | Human |
| Terfenadine | 8710 | 8510 | 5250 | 30900 | 11200 | Human |
| Values are K$_i$ (nM). The smaller the value, the more strongly the drug binds to the site. ||||||||

#### Antidepressants

| Compound | M$_1$ | M$_2$ | M$_3$ | M$_4$ | M$_5$ | Species |
| Amitriptyline | 14.7 | 11.8 | 12.8 | 7.2 | 15.7 | Human |
| Bupropion | >35,000 | >35,000 | >35,000 | >35,000 | >35,000 | Human |
| Citalopram | 1430 | ND | ND | ND | ND | Human |
| Desipramine | 110 | 540 | 210 | 160 | 143 | Human |
| Desmethylcitalopram | >10000 | >10000 | >10000 | >10000 | >10000 | Human |
| Desmethyldesipramine | 404 | 927 | 317 | 629 | 121 | Human |
| Desvenlafaxine | >10000 | >10000 | >10000 | >10000 | >10000 | Human |
| Dosulepin (dothiepin) | 18 | 109 | 38 | 61 | 92 | Human |
| Doxepin | 18–38 | 160–230 | 25–52 | 20–82 | 5.6–75 | Human |
| Escitalopram | 1242 | ND | ND | ND | ND | Human |
| Etoperidone | >35000 | >35000 | >35000 | >35000 | >35000 | Human |
| Femoxetine | 92 | 150 | 220 | 470 | 400 | Human |
| Fluoxetine | 702–1030 | 2700 | 1000 | 2900 | 2700 | Human |
| Fluvoxamine | 31200 | ND | ND | ND | ND | Human |
| Imipramine | 42 | 88 | 60 | 112 | 83 | Human |
| Lofepramine | 67 | 330 | 130 | 340 | 460 | Human |
| Norfluoxetine | 1200 | 4600 | 760 | 2600 | 2200 | Human |
| Nortriptyline | 40 | 110 | 50 | 84 | 97 | Human |
| Paroxetine | 72–300 | 340 | 80 | 320 | 650 | Human |
| Sertraline | 427–1300 | 2100 | 1300 | 1400 | 1900 | Human |
| Tianeptine | >10000 | >10000 | >10000 | >10000 | >10000 | Human |
| Trazodone | >35,000 | >35,000 | >35,000 | >35,000 | >35,000 | Human |
| Venlafaxine | >35000 | >35000 | >35000 | >35000 | >35000 | Human |
| Values are K$_i$ (nM). The smaller the value, the more strongly the drug binds to the site. ||||||||

#### Antipsychotics

| Compound | M$_1$ | M$_2$ | M$_3$ | M$_4$ | M$_5$ | Species |
| Amisulpride | >10,000 | >10,000 | >10,000 | >10,000 | >10,000 | Human |
| Aripiprazole | 6780 | 3510 | 4680 | 1520 | 2330 | Human |
| Asenapine | >10000 | >10000 | >10000 | >10000 | ND | Human |
| Bromperidol | 7600 | 1800 | 7140 | 1700 | 4800 | Human |
| Chlorprothixene | 11 | 28 | 22 | 18 | 25 | Human |
| Chlorpromazine | 25 | 150 | 67 | 40 | 42 | Human |
| Clozapine | 1.4–31 | 7–204 | 6–109 | 5–27 | 5–26 | Human |
| Cyamemazine (cyamepromazine) | 13 | 42 | 32 | 12 | 35 | Human |
| N-Desmethylclozapine | 67.6 | 414.5 | 95.7 | 169.9 | 35.4 | Human |
| Fluperlapine | 8.8 | 71 | 41 | 14 | 17 | Human |
| Fluphenazine | 1095 | 7163 | 1441 | 5321 | 357 | Human |
| Haloperidol | >10000 | >10000 | >10000 | >10000 | >10000 | Human |
| Iloperidone | 4898 | 3311 | >10000 | 8318 | >10000 | Human |
| Loxapine | 63.9–175 | 300–590 | 122–390 | 300–2232 | 91–241 | Human |
| Melperone | >15000 | 2400 | >15000 | 4400 | >15000 | Human |
| Mesoridazine | 10 | 15 | 90 | 19 | 60 | Human |
| Molindone | ND | ND | >10000 | ND | ND | Human |
| Olanzapine | 1.9–73 | 18–96 | 13–132 | 10–32 | 6–48 | Human |
| Perphenazine | ND | ND | 1848 | ND | ND | Human |
| Pimozide | ND | ND | 1955 | ND | ND | Human |
| Quetiapine | 120–135 | 630–705 | 225–1320 | 660–2990 | 2990 | Human |
| Remoxipride | >10000 | >10000 | >10000 | >10000 | ND | Human |
| Rilapine | 190 | 470 | 1400 | 1000 | 1100 | Human |
| Risperidone | 11000 | ≥3700 | 13000 | ≥2900 | >15000 | Human |
| Sertindole | ND | ND | 2692 | ND | ND | Human |
| Tenilapine | 260 | 62 | 530 | 430 | 660 | Human |
| Thioridazine | 2.7 | 14 | 15 | 9 | 13 | Human |
| Thiothixene | >10000 | >10000 | >10000 | >10000 | 5376 | Human |
| cis-Thiothixene | 2600 | 2100 | 1600 | 1540 | 4310 | Human |
| Tiospirone | 630 | 180 | 1290 | 480 | 3900 | Human |
| Trifluoperazine | ND | ND | 1001 | ND | ND | Human |
| Ziprasidone | ≥300 | >3000 | >1300 | >1600 | >1600 | Human |
| Zotepine | 18 | 140 | 73 | 77 | 260 | Human |
| Values are K$_i$ (nM). The smaller the value, the more strongly the drug binds to the site. ||||||||