Continuing Education Activity

Cholinergic medications are a category of pharmaceutical agents that act upon the neurotransmitter acetylcholine, the primary neurotransmitter within the parasympathetic nervous system (PNS). There are two broad categories of cholinergic drugs: direct-acting and indirect-acting. The direct-acting cholinergic agonists work by directly binding to and activating the muscarinic receptors. Examples of direct-acting cholinergic agents include choline esters (acetylcholine, methacholine, carbachol, bethanechol) and alkaloids (muscarine, pilocarpine, cevimeline). Indirect-acting cholinergic agents increase the availability of acetylcholine at the cholinergic receptors. These include reversible agents (physostigmine, neostigmine, pyridostigmine, edrophonium, rivastigmine, donepezil, galantamine) and irreversible agents (echothiophate, parathion, malathion, diazinon, sarin, soman). This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of cholinergic agents, which is a topic of significant complexity and with far-reaching clinical implications, as is pertinent for members of the interprofessional team in dealing with the effects of these agents, both therapeutic and toxic.

Objectives:

• Outline indications for cholinergic medications.
• Summarize the presentation of a patient with cholinergic medication toxicity.
• Describe the potential contraindications for cholinergic drugs.
• Review the importance of improving care coordination amongst interprofessional team members to improve outcomes for employees who handle organophosphates or patients receiving cholinergic medications.

Indications

Cholinergic medications are a category of pharmaceutical agents that act upon the neurotransmitter acetylcholine, the primary neurotransmitter within the parasympathetic nervous system (PNS). There are two broad categories of cholinergic drugs: direct-acting and indirect-acting. The direct-acting cholinergic agonists work by directly binding to and activating the muscarinic receptors. Examples of direct-acting cholinergic agents include choline esters (acetylcholine, methacholine, carbachol, bethanechol) and alkaloids (muscarine, pilocarpine, cevimeline). Indirect-acting cholinergic agents increase the availability of acetylcholine at the cholinergic receptors.[1] These include reversible agents (physostigmine, neostigmine, pyridostigmine, edrophonium, rivastigmine, donepezil, galantamine) and irreversible agents (echothiophate, parathion, malathion, diazinon, tabun, sarin, soman, carbaryl, propoxur).[2] The use of cholinergic agonists has limitations because of their tendency to cause adverse effects in any organ under the control of the parasympathetic nervous system. Some indications for use are listed below:

Indications

• Myasthenia gravis: The initial first-line therapy for most patients is anticholinesterase medication, usually pyridostigmine. Neostigmine is also available but not commonly used.

• Dementia: Cholinesterase inhibitors like rivastigmine, donepezil, galantamine are the available medications for cognition and global functioning in patients with dementia of all causes. Their primary use is in mild to moderate Alzheimer disease. These medications have off label use for dementia from Parkinson disease and Lewy body dementia.

• Ophthalmology: Pilocarpine and carbachol work by increasing the aqueous outflow and hence decrease the intra-ocular tension in open-angle glaucoma. Miotics are used as an add on therapy and are now third-choice drugs. Carbachol has utility with intraocular use as a miotic in surgery. Sequential use of atropine (mydriatic) and pilocarpine (miotic) is used to break iris-lens adhesions. Pilocarpine is used off label to counter the effects of cycloplegics. 

• Reversal of nondepolarizing neuromuscular blockade after surgery: Neostigmine preceded by atropine to block muscarinic effects, rapidly reverses muscle paralysis induced by neuromuscular blockers and is approved by the FDA.

• Postoperative urinary retention: For both prevention and treatment of urinary distention and retention, neostigmine is a common option. Bethanechol is the indicated pharmaceutical treatment of acute postoperative and postpartum non-obstructive urinary retention.

• Neurogenic bladder: Bethanechol may help complete bladder emptying in those with a hypotonic bladder. 

• Acute colonic pseudo-obstruction: Off-label use of neostigmine is acute colonic pseudo-obstruction.

• Xerostomia: Use of muscarinic agonists in patients with an inadequate response to artificial saliva and mechanical stimulation in Sjogren syndrome or patients post-radiation treatment associated with head and neck cancer. Cevimeline is FDA approved for the treatment of symptoms of dry mouth in Sjogren syndrome.

• Anticholinergic overdose: Physostigmine is the specific antidote for poisoning with belladonna or other anticholinergics. It should only be used to reverse toxic, life-threatening delirium caused by an anticholinergic agent (atropine, scopolamine, diphenhydramine).

• Tensilon test: Edrophonium was previously a bedside test in patients with suspected myasthenia gravis, has been discontinued and is no longer available in the United States of America.

• Snakebite: Neostigmine also has found use in patients with neurotoxic snakebite for who antivenom is not available or is ineffective.

Mechanism of Action

Acetylcholine is a major neurotransmitter in the body. Depending on the type of receptors through which it undergoes mediation, the peripheral actions of acetylcholine classify as working on muscarinic (M1, M2, M3, M4, M5) or nicotinic (Nm, Nn) receptors. M1 receptors are present on the gastric parietal cells and in the central nervous system. M2 receptors are present on the heart, visceral smooth muscle. M3 receptors on the smooth muscle, exocrine glands, and receptors of the bladder. Nicotinic receptors are present in the central nervous system, adrenal medulla, autonomic ganglia, and neuromuscular junction.[3]

The peripheral nervous system consists of the autonomic and the somatic nervous system. The autonomic nervous system can be further broken down into sympathetic and parasympathetic nervous systems. The parasympathetic nervous system regulates various organ and gland functions and primarily uses acetylcholine as its primary neurotransmitter, as do all the cholinomimetics.

Anticholinesterase medications are agents that inhibit choline esterase, protect acetylcholine from hydrolysis, and produce cholinergic effects. Anticholinesterases further classify into reversible (carbamates) and irreversible agents (organophosphates).[4]

Administration

Cholinergic medications are available in various formulations. For example, pilocarpine and physostigmine, when used as a miotic agent, the administration is via ophthalmic eye drops. For the treatment of myasthenia gravis, pyridostigmine dosing is oral. It can be given parenterally to patients who cannot take it orally. Rivastigmine, donepezil, and galantamine are administered orally in Alzheimer disease. Organophosphates get absorbed from all sites, including intact skin and lungs. Transdermal administration of neostigmine by iontophoresis appears to be effective to induce bowel evacuation in individuals with spinal cord injury.[5] The other anticholinesterase agents used for treating various other conditions are usually parenterally administered.

Adverse Effects

Cholinergic medications can cause muscarinic and/or nicotinic adverse effects. Acetylcholine hyperpolarizes the SA nodal cells through M2 receptors of the heart. As a result, bradycardia or even cardiac arrest may occur. At the A-V node and Purkinje fibers, conduction slows, and a complete A-V block may occur. Due to non-uniform vagal innervation of atrial fibers, people may have a predisposition to atrial fibrillation or flutter.[6]

M3 receptors present on the blood vessels mediate dilation, causing a fall in blood pressure and flushing. The stimulation of cholinergic nerves to the penis causes an erection. However, this response is minimal with injected cholinomimetic drugs. The contraction of the smooth muscle in various organs of the body gets mediated through M3 receptors. Tone and peristalsis in the gastrointestinal tract increase and sphincters relax, causing abdominal cramps and evacuation of the bowel. The detrusor muscle contracts while the bladder trigone and sphincter relax, leading to the voiding of the bladder. Bronchial muscles constrict, precipitating an attack of bronchial asthma.

Secretions from glands are increased through the M3 and M2 receptors, resulting in salivation, sweating, lacrimation, gastric, and tracheobronchial secretions.

Pilocarpine eye drops results in contraction of the iris, causing miosis and spasm of accommodation. 

Acetylcholine, if given intravenously, does not cross the blood-brain barrier and has no effects. However, cholinergic drugs which enter the brain, produce a complex pattern of stimulation followed by depression. 

The ganglia are primarily stimulated by anticholinesterases via muscarinic receptors present there. After treatment with an anticholinesterase, acetylcholine released by nerve impulse in skeletal muscles may cause twitching and fasciculations by repetitive firing. Higher doses of anticholinesterase medications block the transmission of impulses in the neuromuscular junction; weakness or even paralysis of the muscle.   

Physostigmine and organophosphates have more marked muscarinic and CNS effects; stimulate ganglia, but action on skeletal muscles is less prominent. Neostigmine and the other agents produce a more pronounced effect on the skeletal muscles, stimulate ganglia, but the muscarinic effects are less noticeable. 

The most common etiology of the cholinergic crisis is from inappropriate or elevated doses of medication or accidental exposure to insecticides such as malathion, parathion. Other sources include nerve gas such as sarin.[7][8]

Contraindications

1. Pulmonary disease (COPD/bronchial asthma)
2. Peptic ulcer disease (may use with caution)
3. Arrhythmias (atrial fibrillation)
4. Coronary vascular disease 
5. Angle-closure glaucoma
6. Hyperthyroidism 
7. Intestinal resection or anastomosis
8. Urinary obstruction
9. Orthostatic hypotension
10. Severe miosis

Monitoring

Agricultural employees who handle organophosphates for a prolonged period should have medical monitoring. Appropriate testing is recommended to identify overexposure before the occurrence of clinical illness. Both serum and RBC cholinesterase must be determined. Baseline blood samples may be obtained and compared with the samples according to one of the following schedules:

• On a routine 30-day basis

(or)

• Within three days at the end of each qualifying period where the employee meets the exposure threshold.

If an employee's RBC or serum cholinesterase concentrations fall more than 20% below the baseline, evaluate the employee's work practices to identify and correct potential sources of pesticide poisoning.[9]

Toxicity

Anticholinesterases are readily available and extensively used as agricultural, and household insecticides (malathion, parathion); accidental as well as suicidal and homicidal poisoning is common, which may present as severe cholinergic toxicity following ingestion or cutaneous exposure to the substances.[10][11] Some of these agents have also seen use in chemical warfare, such as nerve gases (sarin, soman). Anticholinesterases have medical use for the treatment of myasthenia gravis, reversal of neuromuscular blockade, Alzheimer disease.

Acute toxicity from organophosphate agents presents with manifestations of cholinergic excess. Primary toxic effects involve the neuromuscular junction, autonomic nervous system, and the central nervous system. The clinical features of acute cholinergic toxicity include miosis, salivation, lacrimation, emesis, bradycardia, bronchospasm, bronchorrhea, urination, and diarrhea. Sympathetic activation of postganglionic muscarinic receptors regulates the sweat glands causing diaphoresis. As sympathetic ganglia contain nicotinic receptors, at times, however, mydriasis and tachycardia may be observed. The nicotinic effects include muscle weakness, fasciculations, and paralysis through acetylcholine stimulation of receptors at the neuromuscular junction. Muscarinic and nicotinic receptors have been identified in the brain also and may contribute to lethargy, seizures, central respiratory depression, and coma. Cardiac arrhythmias, including QTc prolongation and heart block, are sometimes observed in organophosphorus agent poisoning. Mortality from acute poisoning generally results from respiratory failure due to a combination of neuromuscular weakness, depression of the CNS respiratory center, bronchoconstriction, and excessive respiratory secretions. Oxidative stress causes overstimulation of the cholinergic and glutamatergic nervous system, causing some chronic adverse health effects.[12][13]

Organophosphorus agents bind to acetylcholinesterase and turn the enzyme non-functional. The acetylcholinesterase-organophosphorus compound becomes resistant to reactivation by antidote after some time, a process known as 'aging.'[14] Hence, the treatment should initiate as early as possible. 

Intoxication Management

Medical personnel should terminate exposure by complete removal of the patient's clothes, irrigation of the skin, and mucous membranes. Patients with altered mental status require 100 percent oxygen and endotracheal intubation. Maintain positive-pressure respiration if the patient has respiratory distress. Supportive measures like hydration, maintenance of blood pressure, and use diazepam for control of convulsions. Prophylactic diazepam has also been shown to prevent impairment of cognitive function after organophosphorus poisoning. Treatment for cholinergic toxicity due to organophosphate agents is with atropine and pralidoxime.[14] Atropine competes with acetylcholine at muscarinic receptors, preventing cholinergic activation. Pralidoxime is a cholinesterase reactivating agent that is effective in treating both muscarinic and nicotinic symptoms. Pralidoxime works as a specific antidote for organophosphate poisoning. An intramuscularly administered dosage form is available which contains both atropine and pralidoxime.

Enhancing Healthcare Team Outcomes

Cholinergic medications are useful for a variety of medical conditions. Healthcare professionals, including pharmacists and nurses, need to be aware of the common adverse effects of cholinergic medications. Patients who are on a cholinesterase inhibitor should be seen for follow-up at three and six months to assess drug response, tolerance, and to prevent any symptoms of cholinergic excess. Stringent measures should be in place for agricultural employers to avoid accidental exposure to insecticides with cholinergic properties. Upon establishing a baseline, periodic blood tests should be done to check cholinesterase concentrations. Timely intervention can help prevent cases of overexposure and poisoning.

All emergency department personnel, as well as primary care physician, should be trained and have easy access to drug intoxication procedures at all institutions receiving presentations of intoxication. Patients should receive education, in detail, regarding the common potential adverse effects of all new medications.

When prescribing cholinergic drugs, an interprofessional team approach is essential. As outlined above, the adverse effect profile of these agents mandates such. Clinicians need to be aware of the benefits and limitations of cholinergic drugs when prescribing them. A pharmacist consult is beneficial; the pharmacist can verify dosing, look for drug-drug interactions, and perform medication reconciliation, and report back to the prescriber is there are issues. Nurses will need to be familiar with the adverse effect profile as they will often have the first contact with patients on subsequent visits. They can monitor for these adverse effects as well as evaluate medication compliance as well as therapeutic effectiveness. An interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, is essential in cholinergic therapy to achieve optimal patient outcomes. [Level V]