neostigmine and glycopyrrolate

Action and Spectrum

Actions and Spectrum: 

neostigmine: 

Action: 

neostigmine is a cholinesterase inhibitor, meaning it blocks the action of the enzyme acetylcholinesterase. This enzyme breaks down the neurotransmitter acetylcholine at the neuromuscular junction. By inhibiting acetylcholinesterase, neostigmine increases the levels of acetylcholine, leading to enhanced cholinergic (parasympathomimetic) activity in the body. 

Spectrum: 

Reversal of Neuromuscular Blockade: One of the primary uses of neostigmine is to reverse the effects of non-depolarizing neuromuscular blockers, which are often used during surgery to induce muscle relaxation. neostigmine can restore muscle function and reverse the paralysis caused by these drugs. 

Myasthenia Gravis: neostigmine is also used in the treatment of myasthenia gravis, a neuromuscular disorder characterized by muscle weakness and fatigue. By increasing acetylcholine levels, neostigmine helps improve muscle strength in these patients. 

Gastrointestinal Disorders: neostigmine may be used to treat certain gastrointestinal conditions, such as paralytic ileus, by stimulating bowel movements. 

glycopyrrolate 

Action: glycopyrrolate functions as an anticholinergic medication, exhibiting specific inhibition of acetylcholine activity at muscarinic receptors. It is a quaternary ammonium compound, which means it has poor penetration through the blood-brain barrier and primarily acts on peripheral (or peripheral-central) muscarinic receptors. 

Spectrum: 

Reducing Secretions: One of the main uses of glycopyrrolate is to reduce excessive secretions during surgery, particularly saliva and respiratory tract secretions. It helps prevent complications related to increased airway and oral secretions during anesthesia. 

Bradycardia: glycopyrrolate can be used to counteract bradycardia (abnormally slow heart rate) caused by excessive parasympathetic stimulation. It increases heart rate by blocking the effect of acetylcholine on cardiac muscarinic receptors. 

Drug Interaction

Adverse Reaction

Frequency defined  

1-10% 

≥1% (neostigmine) 

Procedural pain 

Procedural complication 

Pharyngolaryngeal pain 

Incision site complication 

Vomiting 

Postprocedural nausea 

Nausea 

Dry mouth 

Tachycardia/increase heart rate 

Hypotension 

Bradycardia 

Frequency Not Defined 

glycopyrrolate 

Drowsiness 

Nervousness 

Headache 

Loss of taste 

Decreased sweating 

Palpitation 

Tachycardia 

Increased ocular tension 

Cycloplegia 

mydriasis 

Xerostomia  

Black Box Warning

Black Box Warning:  

None

Contraindication / Caution

Contraindication/Caution:  

neostigmine: 

Hypersensitivity: neostigmine is contraindicated in individuals with a known hypersensitivity or allergic reaction to the drug or any of its components.  

Mechanical Intestinal or Urinary Obstruction: neostigmine should not be administered to patients with mechanical intestinal or urinary obstruction. The drug’s cholinergic effects may exacerbate the obstruction and lead to further complications. 

Bradycardia or Heart Block: neostigmine is contraindicated in patients with bradycardia (heart rate <60 beats per minute) or heart block, as the drug can worsen the cardiac conduction abnormalities and potentially result in cardiovascular collapse. 

Asthma or Chronic Obstructive Pulmonary Disease (COPD): neostigmine may cause bronchoconstriction in patients with asthma or COPD, leading to respiratory distress. It is contraindicated in these individuals due to the potential for exacerbation of respiratory symptoms. 

Active Peptic Ulcer Disease: neostigmine can increase gastric acid secretion and motility, potentially aggravating peptic ulcers and causing gastrointestinal bleeding. It should be avoided in patients with active peptic ulcer disease. 

glycopyrrolate: 

Glaucoma: glycopyrrolate is contraindicated in patients with narrow-angle glaucoma as the drug can induce mydriasis (pupil dilation) and increase intraocular pressure, worsening the condition and potentially leading to vision loss. 

Bowel Obstruction: glycopyrrolate should not be administered to individuals with mechanical bowel obstruction as it may further impede gastrointestinal motility and exacerbate the obstruction. 

Myasthenia Gravis: glycopyrrolate is contraindicated in patients with myasthenia gravis, The drug’s anticholinergic effects can worsen muscle weakness and interfere with neuromuscular transmission. 

Severe Ulcerative Colitis: glycopyrrolate may lead to decreased gastrointestinal motility, potentially worsening the symptoms of severe ulcerative colitis. It is contraindicated in patients with this condition. 

Hypersensitivity: Individuals with a history of hypersensitivity or allergic reactions to glycopyrrolate or related anticholinergic drugs should avoid its use due to the risk of allergic responses. 

Pregnancy / Lactation

Pregnancy warnings:     

Pregnancy category: AU TGA pregnancy category: B2
US FDA pregnancy category: Not assigned 

Lactation: Excreted into human milk is unknown 

Pregnancy Categories:         

Category A: Studies that were well-controlled and met expectations revealed no risk to the fetus in either the first or second trimester. 

Category B: There were a lack of studies on pregnant women and no evidence of risk to the fetus in animal experiments.   

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.   

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category

Pharmacology

Pharmacology: 

neostigmine is a cholinesterase inhibitor primarily used in medical settings to reverse the effects of neuromuscular blocking agents (NMBAs) post-surgery and manage myasthenia gravis. glycopyrrolate is an anticholinergic medication used to reduce excessive secretions and prevent bradycardia during surgical procedures. 

Pharmacodynamics:  

neostigmine 

neostigmine acts as a reversible inhibitor of acetylcholinesterase, preventing it from degrading acetylcholine at the neuromuscular junction. This leads to an accumulation of acetylcholine, promoting prolonged stimulation of cholinergic receptors, specifically nicotinic and muscarinic receptors. 

glycopyrrolate 

glycopyrrolate is a competitive antagonist of muscarinic receptors, particularly the M1 and M2 subtypes. By binding to these receptors, it inhibits the effects of acetylcholine, leading to decreased cholinergic stimulation. 

Pharmacokinetics: 

neostigmine 

Absorption 

neostigmine is primarily administered parenterally, either intravenously or intramuscularly, due to its poor oral bioavailability. After intramuscular administration, its absorption is relatively rapid, achieving therapeutic plasma concentrations within minutes. 

Distribution 

neostigmine exhibits a moderate volume of distribution, as it readily crosses the blood-brain barrier and distributes into tissues. It is distributed to various target sites, including cholinergic synapses, where it exerts its pharmacological effects. 

Metabolism 

neostigmine undergoes hepatic metabolism, primarily through hydrolysis by cholinesterases, into its active metabolite, neostigmine methylsulfate. This active metabolite is responsible for its cholinergic effects. The metabolic pathway ensures rapid termination of its pharmacological action, with a short duration of action. 

Excretion and Elimination 

Following metabolism, neostigmine and its active metabolite are excreted primarily via renal elimination. Renal clearance plays a significant role in eliminating neostigmine from the body. The relatively short half-life of neostigmine necessitates frequent dosing to maintain therapeutic efficacy. 

glycopyrrolate 

Absorption 

glycopyrrolate is available in various formulations, including oral, intramuscular, and intravenous routes. The oral bioavailability of glycopyrrolate is low due to significant first-pass metabolism. Therefore, intramuscular, and intravenous routes are preferred when rapid onset of action is required. 

Distribution 

glycopyrrolate exhibits a relatively small volume of distribution, with limited penetration across the blood-brain barrier. Its distribution is largely confined to the peripheral tissues, including the gastrointestinal tract, where it exerts its anticholinergic effects. 

Metabolism 

glycopyrrolate undergoes partial hepatic metabolism, primarily through enzymatic hydrolysis and ester hydrolysis, forming inactive metabolites. The metabolic process contributes to the termination of its pharmacological activity. 

Excretion and Elimination 

The excretion of glycopyrrolate occurs mainly through renal elimination, with a fraction excreted unchanged in the urine. Renal clearance plays a crucial role in its elimination from the body. glycopyrrolate’s longer elimination half-life allows for less frequent dosing compared to neostigmine. 

Adminstartion

Administration:  

Intravenous Administration: For both drugs, intravenous administration is the most common and preferred route in acute medical situations where a rapid onset of action is required. This is often the case in emergencies or during surgical procedures. 

Intramuscular Administration: In some cases, when intravenous access is not readily available, or the patient’s condition does not permit IV administration, neostigmine and glycopyrrolate can be administered through intramuscular injection. The absorption of the drugs may be slightly delayed compared to IV administration. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: neostigmine/glycopyrrolate 

Why do we use neostigmine/glycopyrrolate?  

Postoperative Reversal of Neuromuscular Blockade: One of the primary applications of the neostigmine/glycopyrrolate combination is the reversal of neuromuscular blockade after surgical procedures. During surgery, muscle relaxants, such as non-depolarizing neuromuscular blocking agents, are administered to induce muscle paralysis, facilitating surgical access. 

Management of Myasthenia Gravis: neostigmine/glycopyrrolate combination therapy is also employed in the management of Myasthenia Gravis, an autoimmune neuromuscular disorder characterized by muscle weakness and fatigue. neostigmine enhances neuromuscular transmission and strengthens muscle contractions, mitigating the weakness associated with the condition. Simultaneously, glycopyrrolate mitigates the undesirable muscarinic side effects of neostigmine, such as gastrointestinal disturbances and bronchoconstriction, while minimizing cholinergic overstimulation. 

Treatment of Urinary Retention: neostigmine/glycopyrrolate combination has found utility in the management of acute urinary retention due to its effects on the bladder and detrusor muscle. neostigmine aids in increasing bladder contraction strength, facilitating urine expulsion, while glycopyrrolate helps to prevent excessive stimulation of muscarinic receptors, which can lead to undesirable side effects in the urinary and gastrointestinal tracts.