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Muscarinic Antagonists


Muscarinic Antagonists

Article Author:
Abdullah Naji
Article Editor:
Jason Gatling
Updated:
5/6/2020 10:16:12 AM
For CME on this topic:
Muscarinic Antagonists CME
PubMed Link:
Muscarinic Antagonists

Indications

Muscarinic receptor antagonists (MRAs) are a group of agents that function by competitively blocking the cholinergic response manifested by acetylcholine (ACh) binding muscarinic receptors on exocrine glandular cells, cardiac muscle cells, and smooth muscle cells. Therefore, MRAs are heavily involved with the parasympathetic nervous system and act on different types of muscarinic receptors resulting in a wide array of clinical indications.

Chronic obstructive pulmonary disease (COPD) encompasses a group of lung diseases that share the same pathophysiology of airway obstruction. These diseases include emphysema, bronchiectasis, asthma, and chronic bronchitis. In COPD, the increased parasympathetic activity via the vagus nerve results in increased secretion of ACh. The high levels of ACh act on bronchial smooth muscle and submucosal glandular cells, resulting in increased bronchial inflammation, mucus plugging, and bronchial smooth muscle constriction. Hence, part of the therapy for COPD focuses on blocking the surge of ACh on muscarinic receptors on the bronchial smooth muscles of the airway. As a result, COPD therapy involves the use of MRA, such as ipratropium.  Ipratropium is a Food and Drug Administration (FDA) approved MRA inhaler that attenuates the vagal-induced airway obstruction by competitively inhibiting muscarinic receptors on the bronchial smooth muscles.[1][2][3]

Organophosphates are chemicals that function as acetylcholinesterase inhibitors leading to hyperstimulation of cholinergic nicotinic and muscarinic receptors due to increased levels of ACh. Common scenarios that involve organophosphate toxicity include pediatric ingestion, suicide attempts, and farmers who suffer exposure to organophosphates in pesticides. Moreover, organophosphates can be used as nerve agents in bioterrorism. Organophosphate toxicity presents as outcomes of muscarinic receptor hyperstimulation: diarrhea, diaphoresis, increased urination, miosis, bronchospasm, bradycardia, emesis, lacrimation, and salivation. Organophosphate toxicity also causes increased nicotinic receptor hyperstimulation resulting in muscle paralysis. An immediate administration of FDA-approved MRA known as atropine treats the cholinergic muscarinic side effects of organophosphate toxicity. Atropine alleviates the signs and symptoms of organophosphate muscarinic toxicity by acting as a competitive antagonist of the muscarinic receptor.[4][5]

Anesthesiologists frequently use mRAs in the reversal of non-depolarizing neuromuscular blocking agents (NMBA) after a surgical procedure. Neostigmine is the most common agent employed for the reversal of non-depolarizing NMBA and functions by inhibiting acetylcholinesterase, resulting in an increased amount of ACh in the neuromuscular junction. Clinicians can administer the MRA glycopyrrolate to attenuate the muscarinic side effects from the increased ACh from neostigmine administration. Glycopyrrolate minimizes the muscarinic side effects of neostigmine such as salivation, lacrimation, diarrhea, bradycardia, and bronchoconstriction. Therefore, neostigmine with glycopyrrolate results in overcoming the paralysis of skeletal muscles caused by non-depolarizing NMBA without the manifestation of the cholinergic muscarinic side effects. Moreover, atropine and glycopyrrolate are MRA agents used by anesthesiologists to induce bronchodilation for the management of severe bronchospasm that is refractory to treatment. Such efforts include 100% oxygen with hand ventilation, deepening of the anesthetic via administering a bolus of intravenous (IV) propofol or ketamine, and albuterol administration.[6][7][8]

Other indications of MRA agents include use in the treatment of Parkinson disease, nausea, motion sickness, urinary incontinence, and irritable bowel syndrome.

Mechanism of Action

Muscarinic receptors are predominately on glandular cells, smooth muscle cells, and cardiac muscle cells. The parasympathetic nervous system releases ACh, which binds to and activates muscarinic receptors. MRAs function by competitively blocking the binding of ACh to muscarinic receptors resulting in an anticholinergic response.

MRAs function by acting as competitive inhibitors on the numerous muscarinic receptors. There are five different muscarinic receptors: M1, M2, M3, M4, and M5. The M1, M4, and M5 receptors are in the central nervous system (CNS), and the MRA action on these receptors can manifest as cognitive impairment. The M2 receptors are found in cardiac tissue and are predominately in the atrioventricular (AV) and sinoatrial (SA) nodal cells that results in decreased heart rate and reduced atrial contractility. Therefore, MRA binding to M2 receptors leads to an increase in heart rate. M3 receptors are on the smooth muscle of the gastrointestinal tract, urinary tract, airway, and blood vessels. MRA binding to M3 receptors are responsible for reducing intestinal peristalsis and bladder contraction, reducing salivary and gastric secretions, reducing bronchial secretions, and increasing bronchodilation.[9][10]

Administration

Ipratropium administration is via a metered-dose inhaler (MDI). The recommended dose is two puffs up to four times per day. Each puff of MDI provides 17 micrograms of ipratropium. Also available is a 0.02% nebulized solution of ipratropium. The dose of the nebulized solution can start as low as 50 to 125 micrograms (mcg).[3]

Clinicians routinely administer glycopyrrolate with neostigmine for the reversal of non-depolarizing NMBA. The recommended reversal dose of glycopyrrolate is 0.2 mg of IV for every 1 mg of IV neostigmine. These medications are administered simultaneously since they both have a similar onset of action. For the management of severe bronchospasm, 3.2 mcg/kg of glycopyrrolate, and 6 to 10 mcg/kg of atropine can facilitate bronchodilation.[11]

For organophosphate toxicity, the clinicians should administer 2 to 5 mg of IV atropine for adults and 0.05 mg/kg of IV atropine for children. However, if no signs of relief occur, the dose is doubled every 3 to 5 minutes until respiratory muscarinic signs and symptoms resolve.[12][13]

Adverse Effects

The adverse effects of MRAs are due to the competitive inhibition of muscarinic M1-M5 receptors on various tissues and organ systems in the human body. MRAs acting on M1, M4, and M5 receptors in the CNS result in adverse effects of confusion and disorientation. MRAs acting on M2 receptors in cardiac tissue lead to tachycardia. MRAs acting on M3 receptors in exocrine glands can lead to dry mouth, dry skin, and sore throat. Moreover, MRAs act on receptors in the eyes resulting in mydriasis and photophobia. MRAs also cause decreased smooth muscle tone that can result in constipation, ileus, urinary retention, and gastroesophageal reflux.[14][15][16][17]

Contraindications

Contraindications for MRAs include a variety of underlining diseases or conditions that can become exacerbated with the use of MRAs. These contraindications include acute asthma, myocardial infarction, hyperthyroidism, paralytic ileus, benign prostatic hyperplasia, urinary retention, narrow-angle glaucoma, and myasthenia gravis.

Monitoring

Physicians and other healthcare providers must educate the patient about the adverse effects and toxicity of MRAs. Patients need to be cognizant and monitor the adverse effects of MRAs to have dose or medication changes to prevent serious morbidity or mortality.

Toxicity

Toxicity from MRA can manifest when patients consume medications or products that have anticholinergic muscarinic properties. Such products include Belladonna plants and Jimson weed, which contain MRAs, such as atropine and scopolamine. Medications with anticholinergic properties can induce toxicity such as tricyclic antidepressants (i.e., amitriptyline, imipramine), atypical antipsychotics (i.e., quetiapine, clozapine), and first-generation antihistamines (i.e., promethazine). Clinical features of MRA toxicity include dry mouth, blurry vision, hyperthermia, tachycardia, mydriasis, delirium, and hallucinations. Physostigmine, an acetylcholinesterase inhibitor, is used as the antidote for MRA toxicity.[14][15]

Enhancing Healthcare Team Outcomes

Improved quality of patient care is attainable when there are communication and collaborative planning between physicians, nurses, pharmacists, and other healthcare workers who are involved in patient care. Physicians should effectively assess the patient’s condition, comorbidities, and current medication list before prescribing MRAs. Furthermore, physicians must empower their patients by educating them about the adverse effects of MRAs when prescribing this class of medications. Patients must be cognizant of the adverse effects and immediately inform their physician regarding any signs and symptoms of MRA toxicity. Pharmacists contribute to the high quality of healthcare by being attentive to any possible drug-drug interactions that may lead to adverse outcomes and educating the patient on how to use the medication correctly. Ultimately, patients are more likely to receive effective and safe healthcare when they are managed by a multidisciplinary team that successfully collaborates to provide holistic and integrative care. [Level 5]


References

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