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.

Muscarinic acetylcholine receptor antagonist
Drug class
Skeletal formula of scopolamine, a nonselective antagonist of the muscarinic receptors
Class identifiers
Synonyms	Muscarinic acetylcholine receptor antagonist; Antimuscarinic; Anti-muscarinic; mACh antagonist; mAChR antagonist; Muscarinic antagonist; Antimuscarinic agent; Antimuscarinic drug; Antimuscarinic medication
Use	Allergies, asthma, atrial fibrillation with bradycardia,[1] motion sickness, Parkinson's disease, etc.
ATC code	V
Biological target	Muscarinic acetylcholine receptors
External links
MeSH	D018727
Legal status
In Wikidata

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, commonly known as deadly nightshade. The name "belladonna", Italian for "beautiful woman", is thought to derive from one of the antimuscarinic effects of these alkaloids, having been put into use by women for the cosmetic purpose of promoting 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^{[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 scopolamine.

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.

Further information: Cholinergic crisis § Treatment

Comparison table

Overview

Substance	Selectivity	Clinical use	Adverse effects	Notes	Trade names
Atropine (D/L-Hyoscyamine)	NS	During anesthesia[5][6] Antidote to anticholinesterase poisoning[5] Atrial fibrillation with bradycardia[1][5] Antispasmodic in gastrointestinal hypermotility[5]	UR[5] xerostomia[5] blurred vision[5]	CD[5]	Symax, HyoMax, Anaspaz, Egazil, Buwecon, Cystospaz, Levsin, Levbid, Levsinex, Donnamar, NuLev, Spacol T/S and Neoquess
Atropine methonitrate	NS	antispasmodic in gastrointestinal 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 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[5]	may cause ocular hypertension[5]	Short acting, CD[5]
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[8] 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[7]	Urinary incontinence [7]	Few side effects[7]		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.[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	overactive bladder urge incontinence			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	Same uses as atropine[5] Motion sickness[5]	as atropine[5] sedation[5]	CD[5]	Scopace, Transderm-Scop, Maldemar, Buscopan
Solifenacin		overactive bladder (OAB) Urgency (urge incontinence)		Competitive antagonist	Vesicare
Tropicamide	NS	produce mydriasis and cycloplegia in diagnostics[5]	may cause ocular hypertension[5]	Short acting, CD[5]
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.^[10]

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	[11][12]
4-DAMP	0.57–0.58	3.80–7.3	0.37–0.52	0.72–1.17	0.55–1.05	Human	[13][14]
AF-DX 250	427	55.0	692	162	3020	Human	[13]
AF-DX 384	30.9	6.03	66.1	10.0	537	Human	[13]
AQ-RA 741	28.8	4.27	63.1	6.46	832	Human	[13]
Atropine	0.21–0.50	0.76–1.5	0.15–1.1	0.13–0.6	0.21–1.7	Human	[11][15][14]
Benzatropine (benztropine)	0.231	1.4	1.1	1.1	2.8	Human	[11]
Biperiden	0.48	6.3	3.9	2.4	6.3	Human	[11]
Darifenacin	5.5–13	47–77	0.84–2.0	8.6–22	2.3–5.4	Human	[14][16]
Dicycloverine (dicyclomine)	57 (IC50)	415 (IC50)	67 (IC50)	97 (IC50)	53 (IC50)	Human/rat	[15]
Glycopyrrolate	0.37	1.38	1.31	0.41	1.30	Human	[9]
Hexahydrodifenidol	11	200	16	76 (IC50)	83	Human/rat	[15]
Hexahydrosiladifenidol	44	249	10	298 (IC50)	63	Human/rat	[15]
(R)-Hexbutinol	2.09	20.9	2.14	3.02	5.50	Human	[13]
Hexocyclium	2.3	23	1.4	5.5	3.7	Human/rat	[15]
Himbacine	107	10.0	93.3	11.0	490	Human	[13]
Ipratropium	0.49	1.5	0.51	0.66	1.7	Human	[16]
Methoctramine	16–50	3.6–14.4	118–277	31.6–38.0	57–313	Human	[15][13][17]
N-Methylscopolamine	0.054–0.079	0.083–0.251	0.052–0.099	0.026–0.097	0.106–0.125	Human	[13]
Orphenadrine	48	213	120	170	129	Human	[12]
Otenzepad (AF-DX 116)	1300	186	838	1800 (IC50)	2800	Human/rat	[15]
Oxybutynin	0.66	13	0.72	0.54	7.4	Human	[14]
pFHHSiD	22.4	132	15.5	31.6	93.3	Human	[13]
Pirenzepine	6.3–8	224–906	75–180	17–37	66–170	Human	[11][15][13][14]
Procyclidine	4.6	25	12.4	7	24	Human	[11]
Propiverine	476	2970	420	536	109	Human	[14]
Scopolamine (hyoscine)	1.1	2.0	0.44	0.8	2.07	Human	[11]
Silahexacyclium	2.0	35	1.2	3.2	2.0	Human/rat	[15]
Timepidium	34	7.7	31	18	11	Human	[14]
Tiquizium	4.1	4.0	2.8	3.6	8.2	Human	[14]
Trihexyphenidyl	1.6	7	6.4	2.6	15.9	Human	[11]
Tripitamine (tripitramine)	1.58	0.27	38.25	6.41	33.87	Human	[17]
Zamifenacin	55	153	10	68	34	Human	[14]
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	[18]
Chlorphenamine (chlorpheniramine)	19000	17000	52500	77600	28200	Human	[18]
Cyproheptadine	12	7	12	8	11.8	Human	[12]
Diphenhydramine	80–100	120–490	84–229	53–112	30–260	Human	[11][19]
Doxylamine	490	2100	650	380	180	Human	[19]
Mequitazine	5.6	14	5.3	11.1	11.0	Human	[12]
Terfenadine	8710	8510	5250	30900	11200	Human	[18]
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	[12]
Bupropion	>35,000	>35,000	>35,000	>35,000	>35,000	Human	[12]
Citalopram	1430	ND	ND	ND	ND	Human	[20]
Desipramine	110	540	210	160	143	Human	[12]
Desmethylcitalopram	>10000	>10000	>10000	>10000	>10000	Human	[21]
Desmethyldesipramine	404	927	317	629	121	Human	[21]
Desvenlafaxine	>10000	>10000	>10000	>10000	>10000	Human	[22]
Dosulepin (dothiepin)	18	109	38	61	92	Human	[12]
Doxepin	18–38	160–230	25–52	20–82	5.6–75	Human	[19][12]
Escitalopram	1242	ND	ND	ND	ND	Human	[20]
Etoperidone	>35000	>35000	>35000	>35000	>35000	Human	[12]
Femoxetine	92	150	220	470	400	Human	[12]
Fluoxetine	702–1030	2700	1000	2900	2700	Human	[12][20]
Fluvoxamine	31200	ND	ND	ND	ND	Human	[20]
Imipramine	42	88	60	112	83	Human	[12]
Lofepramine	67	330	130	340	460	Human	[12]
Norfluoxetine	1200	4600	760	2600	2200	Human	[12]
Nortriptyline	40	110	50	84	97	Human	[12]
Paroxetine	72–300	340	80	320	650	Human	[12][20]
Sertraline	427–1300	2100	1300	1400	1900	Human	[12][20]
Tianeptine	>10000	>10000	>10000	>10000	>10000	Human	[23]
Trazodone	>35,000	>35,000	>35,000	>35,000	>35,000	Human	[19][12]
Venlafaxine	>35000	>35000	>35000	>35000	>35000	Human	[12]
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	[24]
Aripiprazole	6780	3510	4680	1520	2330	Human	[25]
Asenapine	>10000	>10000	>10000	>10000	ND	Human	[26]
Bromperidol	7600	1800	7140	1700	4800	Human	[11]
Chlorprothixene	11	28	22	18	25	Human	[11]
Chlorpromazine	25	150	67	40	42	Human	[11]
Clozapine	1.4–31	7–204	6–109	5–27	5–26	Human	[11][26][27][28]
Cyamemazine (cyamepromazine)	13	42	32	12	35	Human	[29]
N-Desmethylclozapine	67.6	414.5	95.7	169.9	35.4	Human	[30]
Fluperlapine	8.8	71	41	14	17	Human	[11]
Fluphenazine	1095	7163	1441	5321	357	Human	[31]
Haloperidol	>10000	>10000	>10000	>10000	>10000	Human	[26][27]
Iloperidone	4898	3311	>10000	8318	>10000	Human	[32]
Loxapine	63.9–175	300–590	122–390	300–2232	91–241	Human	[11][33]
Melperone	>15000	2400	>15000	4400	>15000	Human	[11]
Mesoridazine	10	15	90	19	60	Human	[11]
Molindone	ND	ND	>10000	ND	ND	Human	[34]
Olanzapine	1.9–73	18–96	13–132	10–32	6–48	Human	[26][27][28]
Perphenazine	ND	ND	1848	ND	ND	Human	[34]
Pimozide	ND	ND	1955	ND	ND	Human	[34]
Quetiapine	120–135	630–705	225–1320	660–2990	2990	Human	[26][27]
Remoxipride	>10000	>10000	>10000	>10000	ND	Human	[26]
Rilapine	190	470	1400	1000	1100	Human	[11]
Risperidone	11000	≥3700	13000	≥2900	>15000	Human	[11][26]
Sertindole	ND	ND	2692	ND	ND	Human	[34]
Tenilapine	260	62	530	430	660	Human	[11]
Thioridazine	2.7	14	15	9	13	Human	[11]
Thiothixene	>10000	>10000	>10000	>10000	5376	Human	[35]
cis-Thiothixene	2600	2100	1600	1540	4310	Human	[11]
Tiospirone	630	180	1290	480	3900	Human	[11]
Trifluoperazine	ND	ND	1001	ND	ND	Human	[34]
Ziprasidone	≥300	>3000	>1300	>1600	>1600	Human	[27][36]
Zotepine	18	140	73	77	260	Human	[11]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

See also

• Anticholinergic
• Muscarinic agonist
• Nicotinic acetylcholine receptor
• Nicotinic agonist
• Nicotinic antagonist
• Parasympatholytic