Cholinergic medications are a category of pharmaceutical agents which 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, tacrine) 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, tabun, sarin, soman, carbaryl, propoxur). The use of cholinergic agonists is limited 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:
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 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.
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 the parasympathetic nervous systems. The parasympathetic nervous system regulates various organ and gland functions, and primarily uses acetylcholine as its main neurotransmitter so does all the cholinomimetics.
Anticholinesterase medications are agents which inhibit choline esterase, protect acetylcholine from hydrolysis, and produce cholinergic effects. Anticholinesterases further classify into reversible (carbamates) and irreversible agents (organophosphates).
Cholinergic medications are available in various formulations. For example, pilocarpine and physostigmine when used as a miotic are administered as ophthalmic eye drops. For the treatment of myasthenia gravis, pyridostigmine is given orally. It can be given parenterally to patients who cannot take it orally. Rivastigmine, donepezil, and galantamine are administered orally in Alzheimer disease. Organophosphates are 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. The other anticholinesterase agents used for treating various other conditions are usually administered parenterally.
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 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.
M3 receptors present on the blood vessels are dilated causing a fall in blood pressure and flushing. 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 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 prominent.
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.
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:
If an employee's RBC or serum cholinesterase levels fall more than 20% below the baseline, evaluate the employee's work practices to identify and correct potential sources of pesticide poisoning.
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. Some of these agents have also been used 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 cholinergic and glutamatergic nervous system causing some chronic adverse health effects.
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.' Hence, the treatment should initiate as early as possible.
Further exposure should be terminated 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 oximes. Atropine competes with acetylcholine at muscarinic receptors, preventing cholinergic activation. Oximes such as pralidoxime and others are cholinesterase reactivating agents that are effective in treating both muscarinic and nicotinic symptoms. Oximes work as specific antidotes for organophosphate poisoning.
Cholinergic medications are employed for a variety of medical conditions. Healthcare workers, 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 levels. 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 procedure at all institutions receiving presentations of intoxication. Patients should also be educated, in detail, regarding the common potential adverse effects of all new medications.
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