Analysis of Indirect-acting Cholinergic Stimulants: Pyridostigmine and Neostigmine
Vanessa Rhule

Drugs can be are related by their chemical structure, the way they work or if they are used for the same purpose (Pubmed Health, 2012). A cholinergic stimulant is a class of drugs used to increase activity at acetylcholine synapses and can be further subdivided into two categories; direct and indirect acting cholinergic stimulants. This categorization is based on their mechanisms of action and specificity for clinical use (Ciccone, 2007). Direct-acting cholinergic stimulants increase activity at the acetylcholine synapses by binding directly with the cholinergic receptor on the other hand; indirect-acting cholinergic stimulants put forth the same effect by inhibiting the acetylcholinesterase enzyme situated on the cholinergic synapse. For the purpose of this paper, an analysis of indirect acting cholinergic stimulants will be completed, with focus on Pyridosigmine and Prostigmin and their implications to physical therapy practice.
Indirect-Acting Cholinergic Stimulants
Indirect-acting cholinergic stimulants are also known as Cholinesterase inhibitors or Anticholinesterase agents. Cholinesterase inhibitors increase activity at cholinergic synapses by preventing the acetylcholinesterase enzyme from breaking down acetylcholine (ACh) after its release from the presynaptic terminal. Cholinesterase inhibitors inhibit acetylcholinesterase thus allowing more acetylcholine to remain at the synapse which results in an increase in cholinergic synaptic transmission (Ciccone, 2007). For circumstances where acetylcholine supply is low, the resulting high concentration of ACH increases the communication between nerve cells and subsequently stabilizes the symptoms associated of the condition being treated (Australia, nd). Ciccone (2007) stated that Cholinesterase Inhibitors specificity is low in regards to which cholinergic synapse to stimulate as they inhibit the acetylcholinesterase found at all cholinergic synapses. Cholinesterase inhibitors are therefore used to treat symptoms of various conditions for example, Alzheimer disease, Myasthenia Gravis, Glaucoma, Postoperative Gastrointestinal and Bladder Atony as well as to reverse the effects of Anticholinergic- induced CNS toxicity (Ciccone, 2007).
Pyridosigmine and Prostigmin
Myasthenia gravis is defined by Mehndiratta, Pandey and Kuntzer (2011) as “a disease in which antibodies directed against acetylcholine receptors block the transmission of nerve impulses to muscles, causing fluctuation muscle weakness and fatigability”. Indirect acting cholinergic stimulants’ effect at the neuromuscular junction is used to alleviate symptoms of muscular fatigue associated with myasthenia gravis. The increased availability of ACH stimulates the ACH receptors resulting in muscle activation and contraction (Mehdiratta et al, 2011). An article Schwab and Timberlake (1954) reported that 1935 myasthenia gravis was a condition unresponsive to therapy and carried high mortality rates. They went ahead to report that that year, a neostigmine injection was introduced as a rapid and specific diagnostic test. A year later it was discovered that patients with the condition could be maintained on neostigmine tablets and this started the successful treatment of myasthenia gravis.
Pyridosigmine and Neostigmine are two cholinesterase inhibitors commonly used in the treatment of myasthenia gravis today. Neostigmine is taken orally, daily (15 to 375 mg) but can also be administered subcutaneously or intramuscularly via solution (0.5mg) usually over twenty-four (24) hours when the patient is more prone to fatigue (Drugs.com, 2014). Pyridosigmine can also be orally administered with immediate release tablets or syrup (6mg three times daily), sustained- release tablets (180-540 mg once or twice daily)or via intramuscular or slow intravenously (2 – 5mg every two – three hours) methods. Generic names are those names that can vary from country to country based on the authorized bodies. Trade/Brand names are names chosen by the manufacturers and are usually easier to remember and pronounce. Pyridosimine has trade name Mestinon while Neostigmine is Prostgmin. Neostigmine is also used to treat GI and Bladder Atony while both drugs can also be used in the treatment of reversal of neuromuscular blocking drugs.
Adverse Effects / Side Effects
An adverse drug reaction is defined by Goodman and Fuller (2009) as unwanted and potentially harmful effects produced by medication or prescription drugs, excluding over-dosage causing accidental exposure or attempted suicide. Goodman and Fuller (2009) went further to define the side effects of a drug, as “predictable pharmacologic effects that occur within one dose range and are undesirable in the given therapeutic situation”. Cholinergic stimulants are frequently associated with a number of adverse effects caused by its non-specificity (Ciccone, 2007). Adverse effects of cholinesterase inhibitor drugs show similar effects that occur with exaggerated parasympathetic activity (Ciccone, 2007) and will affect the Gastrointestinal, Respiratory and Musculoskeletal system as well as the Endocrine, Ocular, Dermatologic, Hematologic, Cardiovascular, Genitourinary and Nervous systems. Both drugs have an extensive list of adverse and side effects.
Adverse and side effects of Pyridostigmine include; gastrointestinal distress such as nausea, diarrhea, vomiting, increased flatus and abdominal cramping, increased salivation, urinary urgency and frequency, dysmenorrhea, bronchoconstriction, bradycardia, tachycardia, hypotension, muscle weakness, fasciculation or cramps, Arthalgia, blurred vision, acniform skin rashes, toxic alopecia, alopecia areata, thrombophlebitis, headache, vertigo, increased sweating, flushing, loss of memory and hallucinations (Drugs.com). Leong, AIni-Ardena, Cheong and Norris (2009) conducted a study investigating the effect of Pyridostigmine on platelet aggregation. This study was initiated after a patient with myasthenia gravis presented with multiple bruises a week after starting Pyridostigmine. Results of the study showed that Pyridostigmine interferes with human platelet aggregation by inhibiting the response to ADP and collagen stimulation and may therefore result in bleeding. Consequently, healthcare workers, including physical therapists should be aware of this uncommon side effect of Pyridostigmine.
Adverse effects of Neostigmine are understandably similar to those of Pyridostigmine and includes; Muscle twitches visible under the skin, weakness, Abdominal cramps, diarrhea, difficulty speaking, dilation of pupils, dizziness, drowsiness, increased salivation, increased urgency and frequency of urination, increased flatus, headache, increased sweating, Arthalgia, fainting, bradycardia, tachycardia, seizures, vision changes, shortness of breath, swelling of face, mouth, lips or tongue and hives. (Drugs.com, 2014).
For both drugs, the incidence of these effects varies with each patient but once drug dose increases, the onset and severity increases. Neostigmine as stated by Westerberg and Magee (1954) was the drug of choice in the treatment of myasthenia gravis however it has many disadvantages. The effects from the medication will only last a few hours requiring the individual to ingestion of large quantities of the drug daily. Westerberg and Magee (1954) also indicated that some patients may experience a let-down feeling during the wearing-off period of the drug. The drug homologous to neostigmine, pyridostigmine, was therefore developed as a compound to give the same therapeutic effects without experiencing the let-down feeling.
Drug Interactions
Neostigmine has six major drug interactions as per Drugs.com (2014) that can affect physical therapy management of a patient. Tramadol/ Acetaminophen, Metrizamide, Bupropion, Iopamidol and Iohexol may increase the risk of seizures. Dexamethasone may decrease the therapeutic effects of Neostigmine resulting in a decline in muscle strength.
During an interaction search for pyridostigmine, Drugs.com (2014) revealed an extensive list of moderate drug interaction with other medications. Betamethasone, Prednisone, Corticorelin, Corticotropin, Cortisone, Cosyntropin, Dexamethasone, Hydrocortisone, Methylperdnisolone, Prednisolone, may decrease the effects of Pyridostigmine, resulting in decreased muscle strength. Atropine, Belladonna, Benztropine, Biperiden, Clozapine, Clidinium, Dicyclomine, Darifenacin, Disopyramide, Flavoxate, Fludrocortisone, Glycopyrrolate, Hyoscyamine, Mepenzolate, Methscopolamine, Oxybutynin, Procyclidine, Propantheline, Quinidine, Scopolamine, Solifenacin, Trospium, can cause increase in muscle weakness and can mask the less serious signs of overdose of all medication listed, including pyridostigmine. Donepezil, Galantamine, Physostigmine, Rivastigmine, Tacrine, can increase the blood levels or add to the side effects of either medication. Echothiophate Iodide can increase the effects of both medications. Thalidomide can cause bradycardia or arrhythmias. The combination of Succinylcholine and Pyridostigmine can result in breathing difficulties and the patient should be closely monitored.
Research on Clinical Use of Pyridostigmine and Neostigmine
Mehndiratta et al (2011) from a review of literature concluded that several observational studies, case reports, case series and daily clinical experiences favor the use of Cholinesterase inhibitors in the treatment of all forms of myasthenia gravis.
Aquilonius, Eckernas, Hartvig, Lindstrom, Osterman and Stalberg (1983) completed a study to determine the relation between plasma concentration of pyridostigmine and a daily dose in twenty patients diagnosed with myasthenia gravis. The study also explored the possibility of pharmacokinetic interactions between pyridostigmine and neostigmine and the effects on muscle responses. Results suggested the dose response curve suggested maximal effects of pyridostigmine at a concentration of 30-60ng/ml and 5-15ng/ml for neostigmine.
As it relates to the desirable therapeutic effects of indirect-acting cholinesterase inhibitors, a study reviewed by Mehndiratta et al (2011) included the administration of intranasal neostigmine or placebo to three participants with ocular myasthenia gravis and seven with generalized myasthenia gravis. Of the ten participants, nine had improved symptoms of myasthenia gravis, in at least one muscle function, after the two‐week neostigmine treatment phase however after the placebo phase, no further improvement was noted.
Implications to Physical Therapy Practice
The APTA stated that it is within the physical therapist’s scope of practice “to perform a patient screen in which medication issues are assessed, even if the physical therapist does not perform the specific care needed to address the medication issue” (APTA, 2011). Physical therapists should carry out this screening process and remember that any drug reaction or interaction may affect different aspects of physical therapy management of that patient. Physical therapists may encounter patients taking indirect-acting cholinergic stimulants and should be aware of the reasoning for the drug administered, for example in treatment for myasthernia gravis.
The patient should therefore be monitored for any adverse effects so it can be noted and communicated with the physician for further management if necessary. For example, the increased risk of a decline in muscle function as a result of a drug interaction or, the uncommon side effect of spontaneous bleeding discovered by Leong et al (2009). All should be considered as a precaution during physical therapy intervention.
Dewland, Androne, Lee, Lampert and Katz (2007) explored the effects Pyridostgmine on cardiac parasympathetic function in sedentary adults and trained athletes. Results revealed a decrease in resting heart rate (66.7 to 58.1 beats per minute) as well as an increase in post-exercise heart rate at one minute recovery (40.7 to 45.1 beats per minute) in the sedentary adult, but no change for the athlete. The results of this study are one a physical therapist should be aware of as it may affect exercise/endurance training and possibly vital signs with patients taking this medication.
In addition, if the patient taking neostigmine shows signs of the let-down feeling, patient and caregiver education should be done and the physical therapist should suggest a time where the effects of the medication is most in effect.
In conclusion, Indirect- Acting Cholinesterase inhibitors can be used to treat various conditions but the associated side effects and possibility of adverse effects should be of great understanding to physical therapists that encounter patients taking medication of this drug class. Pyriostigmine and neostigmine have proved to be effective ways in the treatment of myasthenia gravis and in combination with physical therapy, the patient should have an improved quality of life.

References
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