Usage
Glycopyrrolate + Neostigmine is prescribed for the reversal of residual non-depolarizing (competitive) neuromuscular blockade induced by non-depolarizing neuromuscular blocking agents (NMBAs) used during surgical procedures. These NMBAs, such as rocuronium, vecuronium, and pancuronium, cause muscle paralysis to facilitate intubation, surgery, and mechanical ventilation. Glycopyrrolate + Neostigmine helps restore spontaneous breathing and muscle function postoperatively.
This drug combination falls under the pharmacological classifications of:
- Neostigmine: Cholinesterase inhibitor, parasympathomimetic.
- Glycopyrrolate: Antimuscarinic, anticholinergic.
The mechanism of action involves neostigmine inhibiting acetylcholinesterase, the enzyme that breaks down acetylcholine at the neuromuscular junction. This leads to increased acetylcholine levels, which compete with the NMBA and restore muscle function. Glycopyrrolate is included to counteract the muscarinic side effects of neostigmine, such as bradycardia, salivation, and bronchospasm.
Alternate Names
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Glycopyrronium Bromide + Neostigmine Metilsulfate (International Nonproprietary Name - INN)
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Brand Name: Prevduo (US), Robinul-Neostigmine
How It Works
Pharmacodynamics: Neostigmine increases acetylcholine concentration at the neuromuscular junction, antagonizing the effects of non-depolarizing NMBAs. Glycopyrrolate blocks the muscarinic effects of acetylcholine, reducing the side effects associated with neostigmine.
Pharmacokinetics:
- Neostigmine: Poorly absorbed orally. Administered intravenously. Metabolized by cholinesterases in the liver and plasma. Excreted primarily through the kidneys.
- Glycopyrrolate: Quaternary ammonium compound, poorly absorbed from the gastrointestinal tract. Administered intravenously. Not significantly metabolized. Primarily excreted unchanged in urine.
Mode of Action: Neostigmine inhibits acetylcholinesterase, thereby increasing acetylcholine levels at the neuromuscular junction. This allows acetylcholine to outcompete the NMBA for receptor binding, restoring muscle function. Glycopyrrolate competitively blocks acetylcholine at muscarinic receptors, thereby minimizing undesirable cholinergic side effects like bradycardia and excessive secretions.
Receptor binding, enzyme inhibition or neurotransmitter modulation: Neostigmine inhibits acetylcholinesterase. Glycopyrrolate competitively binds to and blocks muscarinic receptors.
Elimination pathways: Neostigmine is primarily eliminated through renal excretion, with some hepatic metabolism. Glycopyrrolate is primarily eliminated through renal excretion.
Dosage
Standard Dosage
Adults:
0.03 mg/kg to 0.07 mg/kg neostigmine methylsulfate (0.006 mg/kg to 0.014 mg/kg of glycopyrrolate) intravenously. The dose is typically given over 10-30 seconds.
Children:
For children over 2 years old, use adult guidelines. Doses similar to adult dosing are recommended.
Special Cases:
- Elderly Patients: No specific dosage adjustments are generally recommended, but caution should be exercised due to potential age-related decline in organ function.
- Patients with Renal Impairment: Caution should be exercised, and dose adjustments may be needed.
- Patients with Hepatic Dysfunction: Caution should be exercised, and dose adjustments may be needed.
- Patients with Comorbid Conditions: Caution is advised in patients with conditions such as bronchospasm, bradycardia, recent myocardial infarction, epilepsy, hypotension, vagotonia, peptic ulcer, hyperthyroidism. Patients with a prolonged QT interval should avoid the use of this combination.
Clinical Use Cases
Dosage recommendations are provided in the Standard Dosage section above. The specific use cases are all related to the reversal of neuromuscular blockade after surgery:
- Intubation
- Surgical Procedures
- Mechanical Ventilation
- Intensive Care Unit (ICU) Use
Dosage Adjustments
Dose adjustment might be necessary for patients with renal or hepatic dysfunction. Close monitoring of patient response and vital signs is essential in such cases.
Side Effects
Common Side Effects
Nausea, vomiting, bradycardia, miosis, increased salivation, diarrhea, abdominal cramps, excessive sweating.
Rare but Serious Side Effects
Bronchospasm, hypotension, heart block, arrhythmias, fasciculations, paralysis, hypersensitivity reactions (including anaphylaxis), angioedema.
Long-Term Effects
No specific long-term effects have been identified, as the drug is used for acute, short-term reversal of neuromuscular blockade.
Adverse Drug Reactions (ADR)
Severe bradycardia, bronchospasm, and hypersensitivity reactions require immediate intervention.
Contraindications
- Hypersensitivity to either glycopyrrolate or neostigmine.
- Mechanical obstruction of the gastrointestinal or urinary tracts.
- Peritonitis.
Drug Interactions
Neostigmine may interact with drugs that alter metabolizing enzymes or transporters. Glycopyrrolate may interact with other anticholinergics, potentiating antimuscarinic effects. Other potential interacting drugs include certain antibiotics (e.g. aminoglycosides), muscle relaxants (e.g. suxamethonium), and antiarrhythmics.
Pregnancy and Breastfeeding
No adequate, well-controlled studies on the combined use of glycopyrrolate and neostigmine are available in pregnant women. Limited data for glycopyrrolate use during pregnancy haven’t identified a drug-associated risk of major birth defects or miscarriages. Neostigmine may cause uterine irritability and induce premature labor when given near term.
Whether neostigmine and glycopyrrolate are excreted in human milk is unknown. Glycopyrrolate may suppress lactation. It’s advisable to use caution and weigh the potential benefits and risks when administering during pregnancy and breastfeeding.
Drug Profile Summary
- Mechanism of Action: Neostigmine inhibits acetylcholinesterase, increasing acetylcholine; glycopyrrolate counters muscarinic side effects.
- Side Effects: Nausea, vomiting, bradycardia, excessive salivation, bronchospasm (rare).
- Contraindications: Hypersensitivity, GI/urinary obstruction, peritonitis.
- Drug Interactions: Other anticholinergics, certain antibiotics, muscle relaxants.
- Pregnancy & Breastfeeding: Caution advised, potential risks.
- Dosage: 0.03-0.07 mg/kg neostigmine IV; glycopyrrolate dosed proportionally.
- Monitoring Parameters: Respiratory rate, heart rate, blood pressure, muscle strength, train-of-four (TOF) monitoring.
Popular Combinations
Glycopyrrolate is specifically combined with neostigmine to counteract the muscarinic side effects of the latter.
Precautions
Close monitoring for respiratory and cardiovascular adverse events is required. Caution should be exercised in patients with pre-existing cardiovascular, respiratory, or gastrointestinal conditions.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Glycopyrrolate + Neostigmine for reversal of neuromuscular blockade?
A: 0.03 mg/kg to 0.07 mg/kg neostigmine intravenously, with a corresponding dose of glycopyrrolate (0.2 mg glycopyrrolate per 1 mg neostigmine).
Q2: What are the common side effects of this medication?
A: Common side effects include nausea, vomiting, bradycardia, miosis, increased salivation, and sweating.
Q3: What are the contraindications for using Glycopyrrolate + Neostigmine?
A: Contraindications include hypersensitivity to the drugs, gastrointestinal or urinary obstruction, and peritonitis.
Q4: How does this drug combination work to reverse neuromuscular blockade?
A: Neostigmine inhibits acetylcholinesterase, while glycopyrrolate reduces the muscarinic side effects of neostigmine.
Q5: Can Glycopyrrolate + Neostigmine be used in pregnant or breastfeeding women?
A: Use with caution. Limited data are available, and potential risks exist. Consult with a specialist.
Q6: What are the significant drug interactions to consider?
A: Other anticholinergics, certain antibiotics, and other drugs that affect metabolizing enzymes.
Q7: What should be monitored during and after drug administration?
A: Respiratory rate, heart rate, blood pressure, and muscle strength should be closely monitored. Train-of-four (TOF) monitoring is useful to assess the depth of neuromuscular blockade.
Q8: How is Glycopyrrolate + Neostigmine administered?
A: The drug is administered intravenously over 10-30 seconds.
Q9: How should I manage a patient experiencing severe bradycardia after administration?
A: Administer additional glycopyrrolate or atropine intravenously as needed.
Q10: Are there any specific considerations for pediatric patients?
A: For children over 2 years old, adult dosing guidelines can be followed.
