4. Neuromuscular junction—The cholinesterase inhibitors have important therapeutic and toxic effects at the skeletal muscle neuromuscular junction. Low (therapeutic) concentrations moderately prolong and intensify the actions of physiologically released acetylcholine. This increases the strength of contraction, especially in muscles weakened by curare-like neuromuscular blocking agents or by myasthenia gravis. At higher concentrations, the accumulation of acetylcholine may result in fibrillation of muscle fibers. Antidromic firing of the motor neuron may also occur, resulting in fasciculations that involve an entire motor unit. With marked inhibition of acetylcholinesterase, depolarizing neuromuscular blockade occurs and that may be followed by a phase of nondepolarizing blockade as seen with succinylcholine (see Table 27–2 and Figure 27–7).
Some quaternary carbamate cholinesterase inhibitors, eg, neostigmine and pyridostigmine, have an additional direct nicotinic agonist effect at the neuromuscular junction. This may contribute to the effectiveness of these agents as therapy for myasthenia.
The major therapeutic uses of the cholinomimetics are to treat diseases of the eye (glaucoma, accommodative esotropia), the gastrointestinal and urinary tracts (postoperative atony, neurogenic bladder), and the neuromuscular junction (myasthenia gravis, curare-induced neuromuscular paralysis), and to treat patients with Alzheimer’s disease. Cholinesterase inhibitors are occasionally used in the treatment of atropine overdosage and, very rarely, in the therapy of certain atrial arrhythmias.
A. The Eye
Glaucoma is a disease characterized by increased intraocular pressure. Muscarinic stimulants and cholinesterase inhibitors reduce intraocular pressure by causing contraction of the ciliary body so as to facilitate outflow of aqueous humor and perhaps also by diminishing the rate of its secretion (see Figure 6–9). In the past, glaucoma was treated with either direct agonists (pilocarpine, methacholine, carbachol) or cholinesterase inhibitors (physostigmine, demecarium, echothiophate, isoflurophate). For chronic glaucoma, these drugs have been largely replaced by prostaglandin derivatives and topical β-adrenoceptor antagonists.
Acute angle-closure glaucoma is a medical emergency that is frequently treated initially with drugs but usually requires surgery for permanent correction. Initial therapy often consists of a combination of a direct muscarinic agonist (eg, pilocarpine) and other drugs. Once the intraocular pressure is controlled and the danger of vision loss is diminished, the patient can be prepared for corrective surgery (laser iridotomy). Open-angle glaucoma and some cases of secondary glaucoma are chronic diseases that are not amenable to traditional surgical correction, although newer laser techniques appear to be useful. Other treatments for glaucoma are described in the Box: The Treatment of Glaucoma in Chapter 10.
Accommodative esotropia (strabismus caused by hypermetropic accommodative error) in young children is sometimes diagnosed and treated with cholinomimetic agonists. Dosage is similar to or higher than that used for glaucoma.
B. Gastrointestinal and Urinary Tracts