Continuing Education Activity

Glycopyrrolate, also known as glycopyrronium, is an anticholinergic drug. Glycopyrrolate has been widely used as a preoperative medication to inhibit salivary gland and respiratory secretions. The most frequent reasons for administering anticholinergics include producing an antisialagogue effect, creating a sedative and amnesic effect, and preventing reflex bradycardia. Glycopyrrolate is among the more common anticholinergic medications. It is used perioperatively as a muscarinic receptor antagonist. This activity outlines the indications, mechanism of action, dosing, important adverse effects, contraindications, monitoring, the toxicity of glycopyrrolate. It increases practitioners' knowledge regarding how to approach and use this medication and monitor it effectively to drive better patient outcomes.

Objectives:

• Explain the mechanism of action of glycopyrrolate.
• Identify the indications for using glycopyrrolate on a patient.
• Review the necessary monitoring that must take place when utilizing glycopyrrolate.
• Outline interprofessional team strategies for improving care coordination and communication to advance improved outcomes using glycopyrrolate when indicated.

Indications

Glycopyrrolate, also known as glycopyrronium, is an anticholinergic drug. It is a synthetically created quaternary amine with pyridine and a cyclopentane moiety within the compound's structure. Glycopyrrolate has been widely used as a preoperative medication to inhibit salivary gland and respiratory secretions. The most frequent reasons for administering anticholinergics include producing an antisialagogue effect, creating a sedative and amnesic effect, and preventing reflex bradycardia. Anticholinergics are not predictably effective in increasing gastric fluid pH or decreasing gastric fluid volume. Glycopyrrolate is among the most commonly used anticholinergic medications.

• It is used perioperatively as a muscarinic receptor antagonist.[1][2]
• The topical formulation of glycopyrrolate is indicated to treat primary axillary hyperhidrosis in nine and older patients.[3] 
• It is also helpful to reduce severe or chronic drooling in pediatric patients with neurologic conditions, such as cerebral palsy. The intravenous formulation of glycopyrrolate classically works to reverse vagal reflexes and bradycardia intraoperatively and reverse the muscarinic effects of cholinergic agents such as neostigmine or pyridostigmine.[4]
• Glycopyrrolate may be administered to reverse the neuromuscular blockade due to nondepolarizing muscle relaxants postoperatively and is frequently used in conjunction with neostigmine, a cholinesterase inhibitor.[5]
• Various oral inhalation formulations of glycopyrrolate are indicated for the long-term maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD).[6][7]

Other commonly used anticholinergics include atropine and scopolamine. Most frequently, clinicians use glycopyrrolate to reduce pharyngeal, tracheal, bronchial, and sialagogue effects preoperatively; decreased secretions are the desired effect during anesthesia when a tracheal tube is in place. A blockade of reflexive vagal cardiac inhibition reflexes during intubation and anesthetic induction may also occur.

Mechanism of Action

Glycopyrrolate's primary mechanism of action is the blockage of acetylcholine's effects at the parasympathetic sites in various tissues. This blockage primarily occurs in the central nervous system, smooth muscle, and secretory glands. It also reduces the rate of salivation by preventing the stimulation of the acetylcholine receptors themselves. Glycopyrrolate does not cross the blood-brain barrier or the placenta. It has a slower diffusion rate relative to other anticholinergic drugs such as atropine and scopolamine.[8][9]

Pharmacokinetics

Glycopyrrolate exhibits onset of action within 1 minute when given intravenously and an elimination half-life of approximately 50 minutes. Glycopyrrolate undergoes urinary excretion and elimination. It differs from atropine in being a quaternary amine and has both cyclopentane and pyridine moieties in the compound.[10]  Glycopyrrolate has a 2 to the 4-hour duration of action after intravenous administration, while atropine has 30 minutes.

Administration

Glycopyrrolate administration can be intravenous, intramuscular, oral, or topical.

• Glycopyrrolate for injection comes packaged as a solution of 0.2 mg/mL. Before intravenous administration, inspect the syringe to ensure no particulate matter. Intramuscular or intravenous administration requires no dilution and should be at 0.2 mg over 1 to 2 minutes. Additionally, it may be administered via the tubing of a running intravenous infusion of a compatible solution.[11] Storage of the drug should be in a cool, dry area protected from light before administration. Promptly discard unused solution as it is unstable at a pH greater than 6. The typical dose of glycopyrrolate is one-half that of atropine. For instance, the premedication dose is 0.005 to 0.01 mg/kg up to 0.2 to 0.3 mg in adults.
• Oral tablets are available in 1 mg, 1.5 mg, and 2 mg strength and oral solution is available in 1mg/5mL strength. The starting dose is 1 to 2 mg twice a day and titrated upward gradually based on patient response to the treatment.[12]
• The topical formulation is available as a single-use cloth pre-moistened with a 2.4% glycopyrronium solution. It is used no more than once every 24 hours on both underarms.[13] 
• Inhalation formulation available as the dry powder inhaler 15.6 mcg capsule twice daily and as the nebulization solution of one 25 mcg vial inhaled twice daily.[14]

Specific Patient Population

Pregnancy Considerations: Glycopyrrolate in usual doses does not influence fetal heart rate or fetal heart rate variability to a significant extent. After parenteral administration, there is a low concentration of glycopyrrolate in umbilical venous and arterial blood and the amniotic fluid. Glycopyrrolate does not seem to penetrate through the placental barrier significantly. As animal reproduction studies are not consistently predictive of human response, this drug should be used during pregnancy only if needed. In general, because of limited data in human pregnancy studies, both atropine and glycopyrrolate are considered acceptable anticholinergics, and usage varies based on the clinician's preference.[15]

Breastfeeding Considerations: Glycopyrrolate is a quaternary ammonium compound; it is not likely to be absorbed and reach the infant's bloodstream, particularly when given by inhalation or applied topically on the skin. Long-term oral use of glycopyrrolate might reduce milk production or milk letdown, but a single dose is unlikely to interfere with breastfeeding. Observe for signs of decreased lactation (e.g., insatiety, poor weight gain).[10]

Patients with Renal Impairment: According to product labeling, dose adjustment might be necessary. Clinicain should exercise caution when using glycopyrrolate in patients with renal impairment. 

Patients with Hepatic Impairment: According to product labeling, information on patients with hepatic impairment is unavailable. Use with caution.

Pediatrics Patients: Usage should generally be avoided in neonates. A hyperexcitability reaction can potentially occur with higher than recommended dosages; use with caution.

Adverse Effects

Adverse reactions after glycopyrrolate administration may include anticholinergic symptoms such as mydriasis, hyperthermia, tachycardia, and cardiac arrhythmia. They may also include blurred vision, constipation, cycloplegia, dry mouth, dry skin, flushing, photophobia, urinary retention, and xerophthalmia.[2][16]

Glycopyrrolate may affect the patient's ability to perform tasks requiring mental alertness. In addition, the medication may induce drowsiness or blurred vision, which is exacerbated by the consumption of alcohol. Usage also requires close monitoring in patients with hepatic impairment. For example, patients may not be able to operate heavy machinery safely.

Use with discretion in patients with autonomic neuropathy or hyperthyroidism. Heat prostration can occur in the presence of fever, high ambient temperature, or physical exercise. Take caution to avoid this effect by limiting or discontinuing usage with exercise or in situations with elevated ambient temperatures.

Patients under the age of 12 with pediatric spastic paralysis are more likely to exhibit an increased anticholinergic response, which elevates the risk for unwanted effects.[17]

Contraindications

Glycopyrrolate is contraindicated in patients with hypersensitivity to glycopyrronium, excipients, or other ingredients in the anticholinergic class. The following is a list of medical conditions that would preclude the use of anticholinergic therapy, categorized by the system:

• Ophthalmic: angle-closure glaucoma[18]
• Cardiovascular: mitral stenosis and cardiovascular instability in acute hemorrhage[19]
• Gastrointestinal: hiatal hernia, gastrointestinal obstruction, paralytic ileus, reflux esophagitis, severe ulcerative colitis, toxic megacolon, intestinal atony in elderly or debilitated patients[20][21]
• Neuromuscular: myasthenia gravis[22]
• Urologic: obstructive uropathy[23]
• Using solid oral formulations of potassium chloride needs close monitoring if considering coadministration with glycopyrrolate.[24]

Monitoring

Glycopyrronium reduces the body's ability to sweat. Therefore, it may cause hyperthermia and heat stroke in hot environments. Other observed adverse effects include dry mouth, difficulty urinating, headaches, diarrhea, and constipation. Monitor heart rate and maintain adequate hydration to avoid adverse events.

A dose adjustment may be necessary if urinary retention occurs. Existing renal impairment may be further complicated. In the general population, usage may increase the risk of confusion, hallucinations, and anticholinergic effects.[25]

Use glycopyrrolate with caution in patients with a hiatal hernia and reflux esophagitis. It can worsen prostatic hyperplasia symptoms and/or bladder neck destruction as it may increase urinary retention. In ulcerative colitis cases, a high dose may inhibit intestinal motility and worsen toxic megacolon or ileus symptoms. Glycopyrrolate administration is contraindicated in patients with ulcerative colitis. Since gastrointestinal motility may decline, constipation or intestinal pseudo-obstruction may occur. If the latter condition arises, it may result in pain from abdominal distention, nausea, or vomiting. If intestinal obstruction of any type is suspected, it is imperative to discontinue use and simultaneously reevaluate. Symptoms presenting as diarrhea, particularly in patients who have undergone bowel resections of the ileum or colon, warrant a lower threshold for clinical suspicion. When an obstruction is suspected, or if the patient has diarrhea, promptly discontinue treatment.[11]

Because of its quaternary structure, glycopyrrolate cannot cross the blood-brain barrier and is almost devoid of the central nervous system and ophthalmic activity. Potent inhibition of salivary gland and respiratory tract secretions is the primary rationale for using glycopyrrolate as a premedication. Heart rate usually increases after intravenous administration but not intramuscular.[2]

Toxicity

Acute toxicity with glycopyrrolate is secondary to an extension of the pharmacologic effects on the muscarinic cholinergic receptors. Muscarinic receptor sites are located in the brain's cerebral cortex, thalamus, hippocampus, and reticular activating system. They are also present in the postganglionic parasympathetic nervous system and other sites like sweat glands. Anticholinergic agents block the effects of acetylcholine by competitively binding and blocking muscarinic receptors.

Central Nervous System Toxicity

CNS toxicity is also called a central anticholinergic syndrome, as central nervous system toxicity can be an undesirable side effect of any anticholinergic medication. It manifests as delirium or prolonged somnolence after anesthesia. While this is more likely to occur with scopolamine than atropine, the incidence should be low with the administration of proper dosages. However, elderly patients may be uniquely susceptible. Glycopyrrolate is less likely to cause this condition than other anticholinergic medications because it does not cross the blood-brain barrier.[26]

Tachycardia

The most likely response after intramuscular administration of atropine, glycopyrrolate, or scopolamine for premedication is an increase in heart rate, indicating a weak cholinergic antagonist effect of these drugs.

Treatment

According to product labeling, a quaternary ammonium anticholinesterase such as neostigmine (which does not cross the blood-brain barrier) can be given to combat peripheral anticholinergic effects parenterally in increments of 0.25 mg in adults. It may be repeated every five to ten minutes until anticholinergic overactivity is reversed or up to a maximum of 2.5 mg. If CNS symptoms (e.g., restlessness, excitement, psychotic behavior, convulsions) are present, physostigmine (which does cross the blood-brain barrier) should be administered. Physostigmine 0.5 to 2 mg can be administered intravenously and repeated up to 5 mg in adults. To combat hypotension, administer IV fluids and pressor agents and supportive care.

Enhancing Healthcare Team Outcomes

Glycopyrrolate is a frequently prescribed agent by the nurse practitioner, primary care provider, anesthesiologist, and internist. However, all healthcare workers who prescribe this agent should be aware of its potential adverse effects. Glycopyrronium may cause hyperthermia and heat stroke in hot environments as it reduces the body's ability to sweat. Clinicians should monitor liver function tests in patients with hepatic impairment. Nursing staff should monitor and inform the prescriber if urinary retention occurs and existing renal impairment worsens. The use of glycopyrrolate in the general population may increase the risk of confusion, hallucinations, and other anticholinergic effects.[25] Before administering glycopyrrolate therapy, nurses should counsel patients for common adverse effects like dry mouth, difficulty urinating, headaches, diarrhea, and constipation. Pharmacists should verify the dose and possible drug-disease interactions. Pharmacists should warn the patient that the medication may induce drowsiness or blurred vision, which is exacerbated by alcohol consumption. As health care team members, all MDs, DOs, PAs, NPs, nursing staff, and pharmacists should collaborate to improve care coordination and communicate to advance better outcomes using glycopyrrolate when indicated.