How Do Muscarinic Agonists Work?

Muscarinic agonists are medications used in the treatment of diverse conditions such as glaucoma, urinary retention, paralysis of intestinal muscles (ileus), Alzheimer’s disease, and others. Muscarinic agonists work by stimulating the contraction of smooth muscles that enable the function of organs such as the heart, bladder, intestines and eyes, and activity of glands that secrete body fluids.

Muscarinic agonists are known as parasympathomimetic drugs because they enhance the activity of the parasympathetic nervous system. The sympathetic nervous system activates the “fight or flight” response to stress by increasing blood pressure, respiratory rate, heart rate and pupil size, while the parasympathetic system brings the body back to normal state with the opposite actions.

Muscarinic receptors are protein particles on the cell membranes of heart muscles, smooth muscles around various organs, and exocrine glands which secrete saliva, sweat, tears, milk and digestive enzymes. Muscarinic receptors initiate smooth muscle contraction and fluid secretion when activated by acetylcholine, a chemical (neurotransmitter) secreted by nerve endings in smooth muscles and exocrine glands.

Muscarinic agonists work by increasing the activity of muscarinic receptors. Muscarinic agonists are of two types, direct agonists and indirect agonists, classified by the way they work:

Direct muscarinic agonists: They work by acting like acetylcholine and stimulating the muscarinic receptors. They resist being broken down by the enzyme acetylcholinesterase, a natural enzyme in the body that breaks down acetylcholine to prevent its buildup.

Indirect muscarinic agonists: These work by inhibiting the activity of acetylcholinesterase enzyme, which prevents the breakdown of the natural acetylcholine in the body and prolongs its action. Indirect muscarinic agonists may be used also to treat conditions that involve nicotinic receptors, the other type of receptors activated by acetylcholine.

Muscarinic receptors are classified into 5 types M1-M5, and the clinically important ones that are targeted by muscarinic agonists are M1, M2 and M3. The type of muscarinic agonist chosen and the administration route used will depend on the condition that is treated. Each direct muscarinic agonist is designed to stimulate specific muscarinic receptors.

M1 muscarinic receptors: These are located in the central nervous system and play a key role in neurological functions. Muscarinic agonists that stimulate M1 receptors are used to treat Alzheimer’s disease. They prevent acetylcholine breakdown, which helps reduce memory loss and formation of abnormal beta-amyloid proteins in patients with Alzheimer’s. They slow down disease progression but cannot cure Alzheimer’s.

M2 muscarinic receptors: M2 receptors are found on specialized cells in the heart muscles that regulate the heart rate and rhythm. Muscarinic agonists designed to stimulate M2 receptors help slow down the heart rate and contractility of the heart.

M3 muscarinic receptors: M3 receptors are in the smooth muscles of intestines, bladder, airway, blood vessels, eyes, and exocrine glands. Muscarinic agonists that stimulate M3 receptors are used to treat urinary retention, ileus, glaucoma and dry mouth, and to diagnose asthma.

Muscarinic agonists may be administered through various routes depending on the condition treated. These include:

• Oral tablets, capsules, syrups or solutions
• Ophthalmic solutions
• Inhalation solutions
• Skin (transdermal) patches
• Injections into the tissue beneath skin (subcutaneous), into the muscle (intramuscular), or into the vein (intravenous)

Following are FDA-approved and off-label uses of muscarinic agonists:

Direct agonists:

• Bethanechol (Adult):
  • Postpartum nonobstructive urinary retention
  • Acute postoperative urinary retention (off-label in children)
  • Gastroesophageal reflux disease (off-label in adults and children)
• Carbachol (Adult and Pediatric):
  • Increase in intraocular during surgery
  • Open-angle glaucoma
  • Acute angle-closure glaucoma
• Pilocarpine ophthalmic (Adult):
  • High intraocular pressure (ocular hypertension)
  • Open-angle glaucoma
  • Acute angle-closure glaucoma
  • Postoperative increase in intraocular pressure
  • To induce pupil contraction (miosis)
  • Primary congenital glaucoma in children
• Pilocarpine oral (Adult):
  • Radiation-induced dry mouth (xerostomia)
  • Xerostomia caused by Sjogren’s syndrome
• Methacholine (Adult and Pediatric):
  • Diagnosis of bronchial airway hyperreactivity in patients over 5 years old who do not have clinically apparent asthma

Indirect agonists:

• Neostigmine (Adult and Pediatric):
  • Reversal of nondepolarizing neuromuscular blockade
  • Neostigmine (Adult)
  • Post-operative urinary retention (off-label)
  • Neurogenic urinary retention (off-label)
  • Neostigmine with atropine (Adult and Pediatric)
  • Myasthenia gravis diagnosis (off-label)
  • Myasthenia gravis treatment (off-label)
• Physostigmine (Adult and Pediatric):
  • Anticholinergic toxicity
• Galantamine (Adult):
  • Alzheimer’s disease dementia
• Donepezil (Adult):
  • Alzheimer’s disease dementia
• Rivastigmine (Adult):
  • Alzheimer’s disease dementia
  • Parkinson’s disease dementia
• Pyridostigmine:
  • Myasthenia gravis
  • Reversal of nondepolarizing neuromuscular blockade
  • Pretreatment for Soman nerve gas exposure (for military use only)
  • Disopyramide-induced anticholinergic adverse effects (off-label)
  • Postural orthostatic tachycardia syndrome (off-label)

Common side effects of muscarinic agonists include the following:

• Diarrhea
• Urination
• Spasm of the airway muscles (bronchospasm)
• Slow heart rate (bradycardia)
• Excitation of the central nervous system (CNS)
• Excitation of skeletal muscles
• Excessive constriction of pupils (miosis)
• Watering eyes (lacrimation)
• Excessive salivation
• Sweating

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of muscarinic agonists include:

Direct agonists:

• bethanechol
• Urecholine
• carbachol
• Miostat
• cevimeline
• Evoxac
• pilocarpine
• Pilocarpine PO
• Salagen
• pilocarpine ophthalmic
• Isopto Carpine
• Qlosi
• Vuity
• methacholine inhaled
• Provocholine

Indirect agonists:

• neostigmine
• Bloxiverz
• Prostigmin
• physostigmine
• galantamine
• donepezil
• Aricept
• donepezil transdermal
• Adlarity
• Edrophonium (discontinued) 
• rivastigmine
• Exelon
• Exelon Patch
• Prevduo
• pyridostigmine
• Mestinon