Continuing Education Activity

The muscarinic antagonist is a class medication used to manage and treat numerous conditions, including COPD and organophosphate toxicity. This activity outlines the indications, action, and contraindications for muscarinic antagonists as a valuable class of medications used to manage COPD, organophosphate toxicity, and other conditions. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the management of patients with COPD and related conditions.

Objectives:

• Identify the mechanism of action of muscarinic antagonists.
• Describe the adverse effects associated with muscarinic antagonists.
• Review the appropriate monitoring of muscarinic antagonists.
• Summarize interprofessional team strategies for improving care coordination and communication to advance muscarinic antagonists and improve outcomes.

Indications

Muscarinic receptor antagonists (MRAs) 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, muscarinic receptor antagonists are heavily involved with the parasympathetic nervous system and act on different types of muscarinic receptors resulting in a wide array of clinical indications. The normal function of the parasympathetic nervous system is often recalled via the mnemonic device of "rest and digest." This is in contrast to the "fight or flight" nature of the sympathetic nervous system. Parasympathetic functions include decreasing heart rate, increasing digestive activity, permitting urination, narrowing pulmonary airways, and sexual arousal. Muscarinic antagonist agents counter these parasympathetic actions.

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.[1][2] 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 using muscarinic receptor antagonists, such as ipratropium. Ipratropium is a Food and Drug Administration (FDA) approved muscarinic receptor antagonist inhaler that attenuates vagal-induced airway obstruction by competitively inhibiting muscarinic receptors on the bronchial smooth muscles.[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 the FDA-approved muscarinic receptor antagonist 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 muscarinic receptor antagonists to reverse non-depolarizing neuromuscular blocking agents (NMBA) after a surgical procedure. Neostigmine is the most common agent employed for reversing non-depolarizing NMBA and functions by inhibiting acetylcholinesterase, resulting in an increased amount of ACh in the neuromuscular junction. Clinicians can administer the muscarinic receptor antagonist glycopyrrolate to attenuate the muscarinic side effects of 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 muscarinic receptor antagonistic agents used by anesthesiologists to induce bronchodilation to manage 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 muscarinic receptor antagonist agents include use in the treatment of Parkinson disease, nausea, motion sickness, urinary incontinence, and irritable bowel syndrome. These drugs can be categorized based on their duration of action into long-acting muscarinic antagonists (LAMAs) or short-acting muscarinic antagonists (SAMAs).

Antimuscarinic agents appear in multiple therapeutic drug classes, including anticholinergics, antihistamines, antidepressants, and antipsychotics.

Mechanism of Action

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

Muscarinic receptor antagonists 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 action of these agents 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, resulting in decreased heart rate and reduced atrial contractility. Therefore, muscarinic receptor antagonist 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. Muscarinic receptor antagonist binding to M3 receptors reduces intestinal peristalsis and bladder contraction, reduces salivary and gastric secretions, reduces bronchial secretions, and increases bronchodilation.[9][10]

Some of these effects can be adverse events (see below), and in some cases, they are used to promote a therapeutic outcome, such as antisialagogue medications. Therefore, it is incumbent on the prescriber to understand the full spectrum of antimuscarinic effects and how they will fit into the patient's clinical picture.

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. To manage 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.[12] However, if no signs of relief occur, the dose is doubled every 3 to 5 minutes until respiratory muscarinic signs and symptoms resolve.[13]

The administration of the various antimuscarinic agents will vary significantly based on the particular agent in question.

Adverse Effects

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

Contraindications

Contraindications to muscarinic receptor antagonists include a variety of underlining diseases or conditions that can become exacerbated with their use. These contraindications include acute asthma, myocardial infarction, hyperthyroidism, paralytic ileus, benign prostatic hyperplasia, urinary retention, narrow-angle glaucoma, and myasthenia gravis.[18]

Monitoring

Prescribing clinicians and other healthcare providers must educate the patient about the adverse effects and toxicity of muscarinic receptor antagonists. Patients need to be cognizant and monitor the adverse effects of these agents to have dose or medication changes to prevent serious morbidity or mortality.[19]

Toxicity

Toxicity from muscarinic receptor antagonists can manifest when patients consume medications or products with anticholinergic muscarinic properties. Such products include Belladonna plants and Jimson weed, which contain muscarinic receptor antagonists, 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 muscarinic receptor antagonist toxicity include dry mouth, blurry vision, hyperthermia, tachycardia, mydriasis, delirium, and hallucinations. Physostigmine, an acetylcholinesterase inhibitor, is used as the antidote for muscarinic antagonist toxicity.[14][15]

Enhancing Healthcare Team Outcomes

Improved quality of patient care is attainable when there are communication and collaborative planning between all interprofessional healthcare team members, including physicians, mid-level practitioners (NPS and PAs), nurses, pharmacists, and other healthcare workers involved in patient care. Before prescribing muscarinic receptor antagonists, clinicians should assess the patient’s condition, comorbidities, and current medication list. Furthermore, clinicians must empower their patients by educating them about the potential adverse effects of muscarinic receptor antagonists when prescribing this class of medications.

Patients must be cognizant of the adverse effects and immediately inform their clinician regarding any signs and symptoms of muscarinic antagonist toxicity. Nursing staff will often serve as the gateway to the prescriber and can provide valuable patient counseling and answer questions about new or existing antimuscarinic prescriptions. Pharmacists can contribute to the high quality of healthcare by being attentive to any possible drug-drug interactions that may lead to adverse outcomes, verifying appropriate dosing, educating the patient on the proper use of the medication, and answering patient questions. If the pharmacist or nurse notes a concerning adverse event or interaction, they must contact the prescribing clinician immediately to inform them so appropriate therapeutic intervention can occur.

Ultimately, patients are more likely to receive effective and safe healthcare, with improved outcomes and reduced adverse events, when managed by an interprofessional healthcare team successfully collaborating and communicating to provide integrative care. [Level 5]