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). 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 . 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.
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 Page 147 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.
Comparison table
Overview SubstanceSelectivityClinical useAdverse effectsNotesTrade names Atropine (D/L-Hyoscyamine) During anesthesia Antidote to anticholinesterase poisoning Atrial fibrillation with bradycardia Antispasmodic in gastrointestinal hypermotility xerostomia blurred visionSymax, HyoMax, Anaspaz, Egazil, Buwecon, Cystospaz, Levsin, Levbid, Levsinex, Donnamar, NuLev, Spacol T/S and Neoquess Atropine methonitrate antispasmodic in gastrointestinal hypermotility Blocks transmission in ganglia. Lacks CNS effectsTable 10-5 in: Aclidinium bromideSelective Bronchospasm COPD Long acting antagonist Tudorza BenztropineM1-selective caused by typical and atypical antipsychoticsReduces the effects of the relative central cholinergic excess that occurs as a result of dopamine deficiency. Cogentin Cyclopentolate produce mydriasis and cycloplegia in diagnostics may cause ocular hypertension Short acting, Diphenhydramine for from typical and atypical antipsychotic medications antihistamine sleep aid
management of asthma symptoms antiemetic sedation dry mouth constipation Acts in the central nervous system, blood vessels and smooth muscle tissues Benadryl, Nytol Doxylamine antihistamine antiemetic sleep aid dizziness dry mouth Unisom Dimenhydrinate motion sickness Combination of diphenhydramine with a methylxanthine salt Dramamine, Gravol Dicyclomine IBS BentylDarifenacinSelective for M3Urinary incontinence Few side effectsEnablex Flavoxate Urinary bladder antispasmodic Urispas Glycopyrrolate (Glycopyrronium bromide) 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
Headache Vomiting Does not cross the blood–brain barrier and has few to no central effects. Robinul, Cuvposa, Seebri HydroxyzineVery mild/negligible action Vistaril, Atarax Ipratropium bromideAsthma 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 rashesA 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 OxybutyninM1/3/4 selective overactive bladder urge incontinence Ditropan PirenzepineM1-selective in peptic ulcer (not much anymore) (fewer than non-selective ones) Inhibits gastric secretionProcyclidine Drug-induced parkinsonism, akathisia and acute dystonia
Idiopathic or secondary dystoniaOverdose 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) Same uses as atropine Motion sickness as atropine sedation Scopace, Transderm-Scop, Maldemar, Buscopan Solifenacin overactive bladder (OAB) Urgency (urge incontinence) Competitive antagonist Vesicare Tropicamide produce mydriasis and cycloplegia in diagnostics may cause ocular hypertension Short acting, Tiotropium COPD SpirivaTrihexyphenidyl/BenzhexolM1 selectiveDrug at relative dose has 83% activity of atropine, thus has the same side-effectsArtane 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 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 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 (IC50) 415 (IC50) 67 (IC50) 97 (IC50) 53 (IC50) Human/rat Glycopyrrolate 0.37 1.38 1.31 0.41 1.30 Human Hexahydrodifenidol 11 200 16 76 (IC50) 83 Human/rat Hexahydrosiladifenidol 44 249 10 298 (IC50) 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 (IC50) 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 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 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 Ki (nM). The smaller the value, the more strongly the drug binds to the site.
Antidepressants