Anticholinesterase Inhibitors
Anticholinesterase inhibitors interfere with the degradation of acetylcholine (ACh) by AChE, thereby increasing the amount of ACh available at the neuromuscular junction (NMJ) and increasing the chance of activating the acetylcholine receptors (AChRs). Any medication that increases the activity of the AChRs can have an effect on MG.
AChE inhibitors continue to be used as first-line treatment of MG. The improvement is usually partial and frequently decreases after many weeks to months of treatment. Besides, these agents are not as beneficial for ocular MG as for generalized MG. Hence, they often are complemented (and sometimes replaced) with immunosuppressive therapy.
Pyridostigmine bromide (Mestinon, Regonol)
Pyridostigmine acts in smooth muscle, the central nervous system (CNS), and secretory glands, where it blocks the action of ACh at parasympathetic sites. An intermediate-acting agent, it is preferred in clinical use to the shorter-acting neostigmine bromide and the longer-acting ambenonium chloride. It starts working in 30-60 minutes; effects last 3-6 hours.
Individualize the dose; MG does not affect all skeletal muscles similarly, and all symptoms may not be controllable without adverse effects. In critically ill or postoperative patients, administer the drug intravenously (IV).
In the United States, pyridostigmine is available in 3 forms: 60-mg scored tab, 180-mg timespan tablet, and 60-mg/5 mL syrup. Dose should not typically exceed 600 mg a day in adults and 7 mg/kg in children. Dosing half hour before meals may help in swallowing and reduce the risk of aspiration. The effects of the timespan tablet last 2.5 times longer. The timespan form is a useful adjunct to regular pyridostigmine for nighttime control of myasthenic symptoms. The absorption and bioavailability of the timespan tablet vary among subjects. It should be used only at bedtime, and patients need close monitoring for cholinergic adverse effects.
Patients can develop cholinergic side effects secondary to the accumulation of ACh at muscarinic and nicotinic receptors. Muscarinic side effects include nausea, vomiting, abdominal cramping, diarrhea, increased oral and bronchial secretions, bradycardia, and sometimes confusion or psychosis. When patients develop significant side effects, pretreatment with anticholinergic medications is recommended (eg, propantheline, glycopyrrolate, or diphenoxylate with atropine) 30 minutes before taking pyridostigmine.
Neostigmine (Bloxiverz)
Neostigmine inhibits the destruction of ACh by AChE, thereby facilitating the transmission of impulses across the NMJ. It is a short-acting AChE inhibitor that is available in an oral form (15 mg tablet) and a form suitable for IV, intramuscular (IM), or subcutaneous (SC) administration. Its half-life is 45-60 minutes. It is poorly absorbed from the gastrointestinal (GI) tract and should be used only if pyridostigmine is unavailable. Individualize the dose for all patients.
Edrophonium (Enlon)
Edrophonium is primarily used as diagnostic tool to predict the response to longer-acting cholinesterase inhibitors. Like other cholinesterase inhibitors, it decreases the metabolism of ACh, increasing the cholinergic effect at the NMJ. It was used in the past to distinguish between cholinergic and myasthenic crisis. If IV edrophonium resultsed in worsening of symptoms, the increased weakness in patients is probably due to overdosing the anticholinesterase medication. If weakness, on the other hand, improves following edrophonium, the weakness is due to the underlying MG.
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Normal neuromuscular junction showing a presynaptic terminal with a motor nerve ending in an enlargement (bouton terminale): Synaptic cleft and postsynaptic membrane with multiple folds and embedded with several acetylcholine receptors.
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Acetylcholine receptor. Note 5 subunits, each with 4 membrane-spanning domains forming a rosette with a central opening. The central opening acts as an ion channel.
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CT scan of chest showing an anterior mediastinal mass (thymoma) in a patient with myasthenia gravis.
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Increasing left ptosis developing upon sustained upward gaze in patient with myasthenia gravis (A through F). Note limited elevation of left eye, denoting superior rectus palsy (A). A initially, C after around 20 seconds, F after 1 minute.
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Cogan sign. Patient changes gaze from downward position (A) to primary position (B). Both lids are seen to overshoot in twitch (B) before gaining their initial ptotic position (D). In this case, Cogan sign is seen more obviously on right, whereas left lid is more ptotic.
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CT scan of chest and mediastinum showing thymoma in patient with myasthenia gravis.
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Repetitive nerve stimulation at frequency of 2 Hz showing increasing decrement in amplitude of compound muscle action potential up to fourth response (42% amplitude loss), after which it stabilizes.
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Single-fiber electromyography showing so-called jitter phenomenon (second action potential wave group).
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What is myasthenia gravis? Myasthenia gravis is an autoimmune disease that's categorized as a type II hypersensitivity that involves autoantibodies binding acetylcholine receptors on skeletal muscle cells. Courtesy of Osmosis.org (https://www.osmosis.org/).
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Motor end plate and innervation. Courtesy of Wikimedia Commons.
