Muscarinic Agonists

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Continuing Education Activity

Muscarinic agonists are parasympathomimetic drugs and are indicated for ileus, urinary retention, glaucoma, Alzheimer disease, and other symptoms. This activity describes the indications, contraindications, and possible adverse effects of muscarinic agonists and how the interprofessional team can work together to improve outcomes using these agents. This activity will also highlight the different mechanisms of action of different muscarinic receptors in different parts of the body.


  • Identify the mechanism of action of muscarinic agonists.
  • Describe the potential adverse effects of muscarinic agonists.
  • Outline the appropriate monitoring for muscarinic agonists.
  • Review interprofessional team strategies for improving care coordination and communication to advance muscarinic agonists and improve outcomes.


Muscarinic receptors are primarily on the postsynaptic cell membrane of smooth muscle, cardiac muscle, and exocrine gland cells. Muscarinic receptors are activated by acetylcholine and increase the activity of the parasympathetic nervous system. Muscarinic agonists mimic the action of acetylcholine on muscarinic receptors and cause cardiac slowing, contraction of smooth muscles (intestinal tract, bronchioles, detrusor muscle, urethra, and iris muscle), and increased secretion from exocrine glandular tissues (salivary, gastric acid, and airway mucosal gland). Muscarinic agonist has different indications depending on how potent and selective each agonist is.

Muscarinic agonists divide into two groups: direct agonist and indirect agonist. Direct agonists resist acetylcholinesterase, thus preventing its breakdown. Indirect agonists work by inhibiting the acetylcholinesterase enzyme preventing the degradation of acetylcholine. Direct and indirect agonists both increase acetylcholine concentration in the synapse, prolonging acetylcholine effects on the receptor. 

Direct Agonists

Bethanechol's indications include postoperative ileus, neurogenic ileus, and urinary retention. Bethanechol increases the smooth muscle tone of the gastrointestinal tract to promote motility and restores peristalsis in the absence of obstruction. Bethanechol also increases the tone of the detrusor muscle to increase bladder emptying.[1][2]

Carbachol is indicated to treat open-angle glaucoma, acute angle-closure glaucoma, and increased intraocular pressure. Carbachol contracts the ciliary body muscle and opens the trabecular meshwork. Opening the meshwork increases aqueous humor outflow from the eye to reduce intraocular pressure.[3] 

Pilocarpine is indicated for open-angle glaucoma, acute angle-closure glaucoma, and ocular hypertension. When given topically, pilocarpine contracts the ciliary body muscle and opens the trabecular meshwork to increase the outflow of aqueous humor. Oral pilocarpine can be used to increase secretion of the salivary glands to treat dry mouth in patients with Sjogren's syndrome or salivary gland dysfunction.[4][5]

Methacholine is most commonly used to diagnose asthma or bronchial hyperactivity. Methacholine stimulates the muscarinic receptor in the airway when inhaled and induces bronchoconstriction, and increases tracheobronchial secretions. The lower the dose it takes for methacholine to induce bronchoconstriction, the more reactive the bronchial airway is.[6] 

Indirect Agonists (Cholinesterase Inhibitors)

Neostigmine is indicated for postoperative and neurogenic ileus, urinary retention, myasthenia gravis, and reversal of neuromuscular junction blockade.[7]

Physostigmine indications include glaucoma and anticholinergic toxicity, such as atropine overdose.[8] 

Galantamine, donepezil, and rivastigmine are indicated for Alzheimer disease. The medications help with memory loss as well as decrease plaque build-up. Galantamine, donepezil, and rivastigmine do not cure Alzheimer disease and can only delay the progression of the disease.[9][10]

The indirect agonists listed below have indications that that require activity on nicotinic receptors of the skeletal muscle rather than muscarinic receptors.

Edrophonium is a short and rapid-acting anticholinesterase commonly used to evaluate and diagnose patients with myasthenia gravis.[11] 

Pyridostigmine is indicated for the treatment of myasthenia gravis.[12] 

Mechanism of Action

Muscarinic agonists are agents that activate the muscarinic acetylcholine receptor. There are five different muscarinic receptors labeled M1-M5. Muscarinic agonists are parasympathomimetics, and their mechanism of action is different depending on which receptor is activated. 

The M1, M3, and M5 are transmembrane receptors that couple to a Gq protein. The Gq protein upregulates phospholipase C (PLC). PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into 1,2- diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG activates protein kinase C, which activates downstream protein and causes calcium influx. IP3 causes the sarcoplasmic reticulum to release stored calcium. Increased intracellular calcium causes smooth muscle contraction and exocrine glandular secretions.[13][14]   

The M2 and M4 receptors are Gi receptor, which inhibits adenylyl cyclase. Inhibition of adenylyl cyclase decreases cyclic adenosine 3’,5’-monophosphate (cAMP) production from ATP. The decrease in cAMP concentration subsequently decreases the activation of protein kinase A.[15][16]

The clinically significant muscarinic receptors are the M1, M2, and M3 receptors.

The M1 muscarinic receptor is clinically significant in the central nervous system, and it influences neurologic functions. Muscarinic agonists play an important role in the treatment of Alzheimer disease(AD). Memory loss in Alzheimer disease patients is associated with a cholinergic deficit due to the reduced activity of choline acetyltransferase, which synthesizes acetylcholine. Another important feature of AD is the accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are aggregates of amyloid-beta derived from cleaving amyloid precursor protein. Muscarinic agonists appear to increase the activity of a protease enzyme that cleaves amyloid precursor protein in such a manner that there is no production of amyloid-beta. Through such mechanisms, muscarinic agonists treat memory deficit and amyloid deposition in AD.[17][18]

The M2 muscarinic receptor is the predominant receptor found in the sinoatrial and atrioventricular nodal cells of the heart. The downstream effect, once the M2 receptor is activated, allows potassium efflux. Potassium efflux results in hyperpolarization and reduction of the action potential duration in the nodal cells. Therefore, the activation of the M2 receptor in the heart causes decreased heart rate and atrial contractility.[19] 

The M3 muscarinic receptor is clinically significant in the intestine's smooth muscle, bladder, airway, eye, exocrine glands, and blood vessels. Smooth muscle of the intestine, bladder, airway, and eye contracts when calcium concentration increase within the cell. Calcium binds with calmodulin to form a complex that can now activate the enzyme myosin light chain kinase. Myosin light chain kinase phosphorylates myosin resulting in contraction. Muscarinic agonists' action on blood vessels results in vasodilatation rather than vasoconstriction. Calcium in the endothelial cells activates nitric oxide synthase, converting L-arginine into nitric oxide. Nitric oxide diffuses into the underlying smooth muscle causing an increase in cGMP. cGMP activates myosin light chain phosphatase resulting in smooth muscle relaxation. When the endothelium is damaged, it does not produce nitric oxide and acetylcholine results in smooth muscle contraction.[20][21]


  • Bethanechol is administered orally on an empty stomach two to four times a day to prevent stomach upset and nausea. 
  • Carbachol is commonly administered topically ocularly. 
  • Pilocarpine is administered topically, ocularly, or orally.
  • Methacholine is administered through inhalation.
  • Neostigmine is administered through intramuscular, intravenous, and subcutaneous injection.
  • Physostigmine is administered intravenously.
  • Galantamine, donepezil, and rivastigmine are administered orally.
  • Edrophonium is administered through intramuscular injection.
  • Pyridostigmine is administered orally.

Adverse Effects

Adverse effects of muscarinic agonists can be memorized using the mnemonic "DUMBBELSS." 

  • Diarrhea
  • Urination
  • Miosis
  • Bronchospasm
  • Bradycardia
  • Excitation of skeletal muscle and CNS
  • Lacrimation
  • Sweating
  • Salivation


Asthma or Chronic Obstructive Pulmonary Disease (COPD)

COPD is a chronic, inflammatory lung disease that results in airflow obstruction in the lungs. Muscarinic agonists cause bronchoconstriction, increase mucous secretion, and can exacerbate chronic obstructive pulmonary disease (COPD) or asthma.  

Peptic Ulcer

Peptic ulcers occur when acid erodes the protective mucous layer of the stomach and other parts of the digestive tract. Muscarinic agonists can cause an increase in gastric acid secretion and can worsen the complication of peptic ulcers.[22] 

Coronary Vascular Disease

Coronary vascular disease occurs when the blood vessels that supply the heart are damaged. Damaged vessels can build up cholesterol plaque that narrows the coronary arteries resulting in chest pain and shortness of breath.[23] The decreased blood flow can worsen when taking a muscarinic agonist through the mechanism, as mentioned above. 


Hyperthyroidism is a condition where the thyroid gland produces excessive thyroxine hormone. Hyperthyroidism accelerates the body's metabolism resulting in weight loss and irregular heartbeat.[24] Muscarinic agonists' action on the heart and blood vessels causes bradycardia and hypotension. In response to bradycardia and hypotension, the body release norepinephrine from the sympathetic nerves. Norepinephrine in hyperthyroid patients can induce cardiac arrhythmias.[25] 


Monitor adverse effects and possible signs of contraindications as described above to change medication. 


Organophosphate agents are used for insecticides and work by irreversibly inhibiting acetylcholine esterase. Excess acetylcholine act on muscarinic and nicotinic receptors and present with signs of acetylcholine toxicity. Toxicity characteristically demonstrates overactive parasympathetic stimulation and presents with symptoms of diarrhea, urination, miosis, bronchospasm, bradycardia, excitation of skeletal muscle and CNS, lacrimation, sweating, and salivation.[26][27]

Organophosphate poisoning antidotes are atropine and pralidoxime. Atropine is a muscarinic antagonist, and pralidoxime can regenerate acetylcholinesterase.[28] 

Enhancing Healthcare Team Outcomes

Patient care is most successful when physicians, nurses, pharmacists, and other healthcare professionals exercise effective teamwork and coordination. Everyone, including the patients, needs to be aware of the possible adverse effects of muscarinic agonists. Physicians need to communicate goals, plans, and adverse effects with the patients and everyone involved in their care. Nurses will also need to familiarize themselves with goals, treatment plans, and adverse effects to inform the physician when there is a noticeable change. Pharmacists can educate the patient on taking the drug, educating them on other possible drug-drug interactions, and keeping the prescriber informed if there are any issues. The patient also needs to notify the physician if adverse effects are developing. Through effective teamwork, managing the adverse effects of muscarinic agonists can be performed. [Level 5]

Article Details

Article Author

Toai Bui

Article Editor:

Hieu Duong


4/26/2023 5:00:51 PM



Zgourides GD. Bethanechol chloride as a suggested adjunct to prolonged in vivo exposure therapy in the treatment of paruresis. Perceptual and motor skills. 1988 Feb:66(1):319-22     [PubMed PMID: 2896331]


Diokno AC, Koppenhoefer R. Bethanechol chloride in neurogenic bladder dysfunction. Urology. 1976 Nov:8(5):455-8     [PubMed PMID: 982732]


Bolton TB. The depolarizing action of acetylcholine or carbachol in intestinal smooth muscle. The Journal of physiology. 1972 Feb:220(3):647-71     [PubMed PMID: 5016040]


Vivino FB, Al-Hashimi I, Khan Z, LeVeque FG, Salisbury PL 3rd, Tran-Johnson TK, Muscoplat CC, Trivedi M, Goldlust B, Gallagher SC. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. P92-01 Study Group. Archives of internal medicine. 1999 Jan 25:159(2):174-81     [PubMed PMID: 9927101]


Wiseman LR, Faulds D. Oral pilocarpine: a review of its pharmacological properties and clinical potential in xerostomia. Drugs. 1995 Jan:49(1):143-55     [PubMed PMID: 7705213]


Fetters LJ, Matthews JI. Methacholine challenge test. Archives of internal medicine. 1984 May:144(5):938-40     [PubMed PMID: 6370167]


Neely GA, Sabir S, Kohli A. Neostigmine. StatPearls. 2023 Jan:():     [PubMed PMID: 29261883]


Andrade OA, Zafar Gondal A. Physostigmine. StatPearls. 2023 Jan:():     [PubMed PMID: 31424845]


Santoro A, Siviero P, Minicuci N, Bellavista E, Mishto M, Olivieri F, Marchegiani F, Chiamenti AM, Benussi L, Ghidoni R, Nacmias B, Bagnoli S, Ginestroni A, Scarpino O, Feraco E, Gianni W, Cruciani G, Paganelli R, Di Iorio A, Scognamiglio M, Grimaldi LM, Gabelli C, Sorbi S, Binetti G, Crepaldi G, Franceschi C. Effects of donepezil, galantamine and rivastigmine in 938 Italian patients with Alzheimer's disease: a prospective, observational study. CNS drugs. 2010 Feb:24(2):163-76. doi: 10.2165/11310960-000000000-00000. Epub     [PubMed PMID: 20088621]


Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C, Jiang T, Zhu XC, Tan L. Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. Journal of Alzheimer's disease : JAD. 2014:41(2):615-31. doi: 10.3233/JAD-132690. Epub     [PubMed PMID: 24662102]


Pascuzzi RM. The edrophonium test. Seminars in neurology. 2003 Mar:23(1):83-8     [PubMed PMID: 12870109]


Maggi L, Mantegazza R. Treatment of myasthenia gravis: focus on pyridostigmine. Clinical drug investigation. 2011 Oct 1:31(10):691-701. doi: 10.2165/11593300-000000000-00000. Epub     [PubMed PMID: 21815707]


Okamoto H, Unno T, Arima D, Suzuki M, Yan HD, Matsuyama H, Nishimura M, Komori S. Phospholipase C involvement in activation of the muscarinic receptor-operated cationic current in Guinea pig ileal smooth muscle cells. Journal of pharmacological sciences. 2004 Jun:95(2):203-13     [PubMed PMID: 15215645]


Lin JY, Chung KK, de Castro D, Funk GD, Lipski J. Effects of muscarinic acetylcholine receptor activation on membrane currents and intracellular messengers in medium spiny neurones of the rat striatum. The European journal of neuroscience. 2004 Sep:20(5):1219-30     [PubMed PMID: 15341594]


Ostrom RS,Ehlert FJ, M2 muscarinic receptor inhibition of agonist-induced cyclic adenosine monophosphate accumulation and relaxation in the guinea pig ileum. The Journal of pharmacology and experimental therapeutics. 1997 Jan;     [PubMed PMID: 8996196]


Ethier MF, Schaefer OP, Samant N, Yamaguchi H, Madison JM. Muscarinic receptor reserve for inhibition of cAMP accumulation in bovine trachealis cells. The American journal of physiology. 1996 Feb:270(2 Pt 1):L199-207     [PubMed PMID: 8779988]


Messer WS Jr. The utility of muscarinic agonists in the treatment of Alzheimer's disease. Journal of molecular neuroscience : MN. 2002 Aug-Oct:19(1-2):187-93     [PubMed PMID: 12212779]


Avery EE, Baker LD, Asthana S. Potential role of muscarinic agonists in Alzheimer's disease. Drugs & aging. 1997 Dec:11(6):450-9     [PubMed PMID: 9413702]


Sakmann B, Noma A, Trautwein W. Acetylcholine activation of single muscarinic K+ channels in isolated pacemaker cells of the mammalian heart. Nature. 1983 May 19-25:303(5914):250-3     [PubMed PMID: 6302520]


Kellogg DL Jr, Zhao JL, Coey U, Green JV. Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin. Journal of applied physiology (Bethesda, Md. : 1985). 2005 Feb:98(2):629-32     [PubMed PMID: 15649880]


Ehlert FJ, Ostrom RS, Sawyer GW. Subtypes of the muscarinic receptor in smooth muscle. Life sciences. 1997:61(18):1729-40     [PubMed PMID: 9365220]


Vatier J. [MI cholinergic receptors of gastric secretion: current status]. Journal de pharmacologie. 1985:16 Suppl 2():145-69     [PubMed PMID: 2867250]


Cassar A, Holmes DR Jr, Rihal CS, Gersh BJ. Chronic coronary artery disease: diagnosis and management. Mayo Clinic proceedings. 2009 Dec:84(12):1130-46. doi: 10.4065/mcp.2009.0391. Epub     [PubMed PMID: 19955250]


Mathew P, Kaur J, Rawla P. Hyperthyroidism. StatPearls. 2023 Jan:():     [PubMed PMID: 30725738]


Iwata T, Honda H. Acute hyperthyroidism alters adrenoceptor- and muscarinic receptor-mediated responses in isolated rat renal and femoral arteries. European journal of pharmacology. 2004 Jun 16:493(1-3):191-9     [PubMed PMID: 15189782]


Feuer G, de la Iglesia F. Effect of amphetamine on the hepatic endoplasmic reticulum of the pregnant rat. Toxicology. 1977 Feb:7(1):99-105     [PubMed PMID: 841587]


Robb EL, Baker MB. Organophosphate Toxicity. StatPearls. 2023 Jan:():     [PubMed PMID: 29261901]


Tush GM, Anstead MI. Pralidoxime continuous infusion in the treatment of organophosphate poisoning. The Annals of pharmacotherapy. 1997 Apr:31(4):441-4     [PubMed PMID: 9101007]