Cholinesterase Inhibitors


Article Author:
Ravneet Singh


Article Editor:
Nazia Sadiq


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
7/16/2019 10:32:40 AM

Indications

Cholinesterase inhibitors also have the names acetylcholinesterase (AChE) inhibitors or anticholinesterases. They are a group of drugs that block the normal breakdown of acetylcholine (ACh) into acetate and choline and thereby increase both the levels and duration of actions of acetylcholine found in the central and peripheral nervous system. The acetylcholinesterase inhibitors have a variety of indications. Most commonly, their use is in treating neurogenerative diseases such as Alzheimer disease, Parkinson disease, and Lewy body dementia. Different physiological processes in these degenerative disorders destroy cells that produce ACh and thereby reduce cholinergic transmission in different regions of the brain. The cholinesterase inhibitor drugs inhibit AChE activity and maintain ACh level by decreasing its breakdown rate.[1]

Also, cholinesterase inhibitors have frequent use in patients with myasthenia gravis. The raised level of acetylcholine in the neuromuscular junction consequently leads to increased activation of ACh receptors found on post-synaptic membranes resulting in improved muscle activation, contraction, and strength.

At the end of surgeries, cholinesterase inhibitors, most commonly neostigmine, are administered to reverse the effects of nondepolarizing muscle agents such as rocuronium.[2][3][4][5][6]

Cholinesterase inhibitors are also necessary to administer when anticholinergic poisoning is suspected. Symptoms of anticholinergic poisoning include vasodilation, anhidrosis, mydriasis, delirium, and urinary retention.[7]

Other less common indications of cholinesterase inhibitors include treatment of patients diagnosed with certain psychiatric disorders such as schizophrenia and treatment of glaucoma by relieving aqueous humor pressure.[8]

Mechanism of Action

Cholinesterase inhibitors function by inhibiting cholinesterase from hydrolyzing acetylcholine into its components of acetate and choline' this allows for an increase in the availability and duration of action of acetylcholine in neuromuscular junctions. The cholinesterase enzyme has two active sites: an anionic site formed by tryptophan and an esteractic site formed by serine. Cholinesterase inhibitors such as organophosphates inhibit cholinesterase from cleaving acetylcholine by interacting with the serine esteractic site. As a result, acetylcholine will continue to accumulate and activate associated receptors.[9]

Cholinesterase inhibitors classify as reversible, irreversible, or pseudo-reversible. Reversible cholinesterase inhibitors are generally utilized for therapeutic purposes. In contrast, irreversible and pseudo-reversible inhibitors are often used in pesticides and for biowarfare (nerve agents).[10][11]

Administration

Cholinesterase inhibitors come in many forms. The administration of many available cholinesterase inhibitors is by IM, IV, or oral routes. Different forms can be available for different types of cholinesterase inhibitors. For example, neostigmine has a solution form used to counteract muscle relaxants at the end of surgeries. For patients with myasthenia gravis, an oral form of neostigmine is available for treatment. Rivastigmine, used in patients with dementia, has a transdermal patch form that is also frequently used.[12]

Adverse Effects

Cholinesterase inhibitors increase the overall amount of acetylcholine available. Thus, symptoms of overstimulation of the parasympathetic nervous system such as increased hypermotility, hypersecretion, bradycardia, miosis, diarrhea, and hypotension may be present.

A major concern when prescribing cholinesterase inhibitors or exposure to organophosphates is potentially developing a cholinergic crisis, also known as SLUDGE syndrome.[13]

SLUDGE is a mnemonic that stands for the following:

  • S: Salivation
  • L: Lacrimation
  • U: Urination
  • D: Diaphoresis
  • G: Gastrointestinal upset
  • E: Emesis

Temporary adverse effects when starting patients on cholinesterase inhibitors include headaches, insomnia, and minor GI issues. Other more concerning effects include lightheadedness, weakness, and weight loss. Prolonged muscle contraction may also be a presenting feature in patients exposed to cholinesterase inhibitors.[14][15]

Cholinesterase inhibitors such as neostigmine used post-operatively for reversal of neuromuscular blockade can result in a potential residual neuromuscular block.[16]

Contraindications

Due to the ability to increase vagal tone through activation of the parasympathetic nervous system, caution is necessary when administering cholinesterase inhibitors to individuals who have bradycardia or cardiac conduction diseases such as sick sinus syndrome. These individuals are at risk for syncope and falls. Caution is also advised in patients on antihypertensive medications due to the possibility of developing severe hypotension.[17]

Moreover, cholinesterase inhibitors are also contraindicated in patients who have gastric ulcers due to the increased risk of gastrointestinal bleeding. Patients with urinary retention should also not receive cholinesterase inhibitors due to the risk of increased retention. This effect is especially notable in patients undergoing treatment for dementia and Alzheimer disease as urinary incontinence is a frequent clinical feature in these patients.[18] 

Administration to patients with previous allergies or hypersensitivities to cholinesterase inhibitors and its derivatives is also contraindicated.[19]

Monitoring

The therapeutic index for each class of cholinesterase inhibitors vary. Physostigmine has a short half-life with a small therapeutic index and is known to cause adverse effects of nausea, vomiting, stomach cramps, and diarrhea, it is not currently recommended for the treatment of dementia. Donepezil, which also has use in Alzheimer disease, is well absorbed and relatively tolerated but produces adverse effects at higher dosages.  The oral capsule form of rivastigmine was known to cause gastrointestinal upset. However, research led to the development of a transdermal version, which has proved to be well tolerated in many studies. Donepezil and rivastigmine are FDA approved and are associated with less adverse effects compared to older generations of cholinesterase inhibitors. The efficacy and adverse effects of newer generations of cholinesterase inhibitors such as metrifonate are currently under investigation. Blood can be drawn to measure RBC cholinesterase activity if there is difficulty confirming the diagnosis.[20][21]

Toxicity

The potential toxicity of cholinesterase inhibitors is due to its mechanism of action. The spectrum of toxicity can vary from patient to patient, which is also complicated by the type of cholinesterase inhibitor to which a patient suffers exposure. SLUDGE syndrome, as described above, is the most recognized form of toxicity for cholinesterase inhibitors. Severe respiratory depression can also present.

Involuntary movements due to increased acetylcholine at neuromuscular junctions can also be a sign of toxicity. Muscle fibrillation, fasciculations, and paralysis should raise the suspicion of toxicity.[22]

Miosis is a common sign of cholinergic toxicity. The excess acetylcholine causes the contraction of the sphincter pupillae muscle that encompasses the iris. Miosis is considered one of the most sensitive signs of exposure to aerosol cholinesterase inhibitors (organophosphates, pesticides.)[23]

First-line treatments for suspected cholinesterase inhibitor toxicity include atropine, 2-PAM (pralidoxime), and diazepam. Atropine occupies muscarinic receptor sites, therefore reducing the binding of acetylcholine. However, it does not counteract nicotinic effects such as muscle fasciculations and weakness, so ventilation may still be necessary.[24] 

2-PAM functions by reversing the binding of cholinesterase inhibitors to acetylcholinesterase. When administered together, 2-PAM and atropine have a synergistic effect.[25]

Seizures due to cholinesterase inhibitor toxicity are more apparent in pediatric patients and adults exposed to nerve agents, and hence warrant immediate management with diazepam.

Enhancing Healthcare Team Outcomes

An interprofessional team is required to manage patients who are being treated with cholinesterase inhibitors successfully. Since the majority of patient with cholinesterase inhibitor toxicity first present to the emergency department, the triage nurse must be familiar with the symptoms; these patients need immediate admission to a monitored unit. To improve outcomes, a team of nurses, laboratory technicians, pharmacists, physicians, and other healthcare professionals are essential to optimize care, especially when considering cholinesterase inhibitor toxicity. Patients admitted under these circumstances need close monitoring by the nurses and other clinicians. Ordering labs, understanding patient symptoms, and being vigilant to the next treatment steps are necessary to manage patients who are experiencing toxicity due to cholinesterase inhibitor use. Pharmacists should be consulted about the use of atropine, pralidoxime, and benzodiazepines if cholinesterase inhibitor-toxicity is suspected. A toxicologist consult should also take place, with an intensivist to further manage a patient as many of these cases require further interventional management during the hospital course. Only through this type of interprofessional coordination can patients experiencing cholinergic toxicity achieve optimal clinical results. [Level V]

Apart from toxicity, cholinesterase inhibitor therapy for conditions such as dementia and Alzheimer disease also requires interprofessional collaboration. Given the status of patients with these conditions being unable to participate in their treatment, it is imperative that the dosing clinician, the administering nursing staff, and the pharmacist all have input and cross-communicate to ensure proper agent selection, dosing, administration, and monitoring of side effects. Again, interprofessional collaboration is crucial to patient outcomes. [Level V]

Outcomes

Patients who are managed immediately after poisoning have good outcomes, but delays in treatment can lead to adverse outcomes.


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A 69-year-old male patient arrives at the office with his wife complaining of continued difficulty learning and problems with his memory for the past 6 months. He was diagnosed with dementia more than a year ago and placed on donepezil. The patient's wife states that he is now unable to conduct activities of daily living without assistance. A mini-mental status examination (MMSE) is undertaken, and the patient scores 15. What is the next best stage in management?



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A 30-year-old female patient comes to the clinic complaining of constipation, urinary retention, and drying of skin for the past 2 weeks. Upon further questioning, the patient reports she is currently using atropine eye drops for myopia. On the physical examination, the physician notes mydriasis of the pupils and a pulse of 110 beats/min. Which of the following is the next step in management for this patient?



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A 65-year-old male with a past medical history of cholecystitis presents to the clinic after having a cholecystectomy. The patient informs you he is having difficulty urinating since his surgery. He reports he has the urge to void but is unable to empty his bladder. Vital signs are within normal limits. Physical examination shows distention in the suprapubic region. After further investigation, you diagnose him with postoperative urinary retention. Imaging shows removed gallbladder and no other abnormalities. Laboratory values are also within normal limits. What is the next best step in the management of this patient?



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A 36-year-old male combat soldier is brought to the hospital, unresponsive and stiff, by his squadmate. The squadmate states that he was exposed to gas during the combat and collapsed. He is noted to have a heart rate of 50/min and a respiratory rate of 10/ min. Physical exam shows excessive salivation, sweating and pinpoint pupils. Laboratory parameters are within normal limits. Atropine is administered. Which of the following organ system will be expected to have limited improvement after administration of atropine?



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A 60-year-old female patient presents to the clinic complaining of drooping of her eyelids, double vision, and muscle weakness for the past month. After conducting a thorough examination, including blood work and imaging, the patient is diagnosed with Myasthenia gravis. What is the next step in management?



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A 45-year-old female patient with a past medical history of myasthenia gravis is required to undergo thymectomy. She is currently on pyridostigmine. How should the patient be managed preoperatively?



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A 35-year-old male patient presents to the clinic for a follow-up visit for disease management. The patient is currently on physostigmine for treatment of glaucoma and amlodipine for hypertension. Upon asking the patient how he is doing on the glaucoma medication, the patient informs the physician that he has been experiencing diarrhea and watery eyes for the past few days. What is the next step in management?



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A 65-year-old male accompanied by his wife arrives at the emergency department with respiratory depression, bradycardia, and hypotension. On physical exam, pupillary constriction and excessive drooling are noted. The patient is feeling weak and cannot respond when questioned. He has the following vitals: blood pressure 90/60 mmHg and pulse 56 bpm. The patient's wife states that the patient is a farmer who was working outside on their farm when he collapsed. What is the next step in management?



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A 31-year-old female patient presents to the clinic complaining of eyelid drooping and also has noticed that she has been more fatigued. She states that the fatigue gets worse with physical activity and also admits to occasionally regurgitating food. When asked to look at a fixed point during the physical exam, the patient displays eyelid droop and use of forehead muscles. What is the next step in medical management?



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Cholinesterase Inhibitors - References

References

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