In clinical disorders that involve depression of smooth muscle activity without obstruction, cholinomimetic drugs with direct or indirect muscarinic effects may be helpful. These disorders include postoperative ileus (atony or paralysis of the stomach or bowel following surgical manipulation) and congenital megacolon. Urinary retention may occur postoperatively or postpartum or may be secondary to spinal cord injury or disease (neurogenic bladder). Cholinomimetics were also sometimes used to increase the tone of the lower esophageal sphincter in patients with reflux esophagitis but proton pump inhibitors are usually indicated (see Chapter 62). Of the choline esters, bethanechol is the most widely used for these disorders. For gastrointestinal problems, it is usually administered orally in a dose of 10–25 mg three or four times daily. In patients with urinary retention, bethanechol can be given subcutaneously in a dose of 5 mg and repeated in 30 minutes if necessary. Of the cholinesterase inhibitors, neostigmine is the most widely used for these applications. For paralytic ileus or atony of the urinary bladder, neostigmine can be given subcutaneously in a dose of 0.5–1 mg. If patients are able to take the drug by mouth, neostigmine can be given orally in a dose of 15 mg. In all of these situations, the clinician must be certain that there is no mechanical obstruction to outflow before using the cholinomimetic. Otherwise, the drug may exacerbate the problem and may even cause perforation as a result of increased pressure.
Pilocarpine has long been used to increase salivary secretion. Cevimeline, a quinuclidine derivative of acetylcholine, is a newer direct-acting muscarinic agonist used for the treatment of dry mouth associated with Sjögren’s syndrome or caused by radiation damage of the salivary glands.
C. Neuromuscular Junction
Myasthenia gravis is an autoimmune disease affecting skeletal muscle neuromuscular junctions. In this disease, antibodies are produced against the main immunogenic region found on α1 subunits of the nicotinic receptor-channel complex. Antibodies are detected in 85% of myasthenic patients. The antibodies reduce nicotinic receptor function by (1) cross-linking receptors, a process that stimulates their internalization and degradation; (2) causing lysis of the postsynaptic membrane; and (3) binding to the nicotinic receptor and inhibiting function. Frequent findings are ptosis, diplopia, difficulty in speaking and swallowing, and extremity weakness. Severe disease may affect all the muscles, including those necessary for respiration. The disease resembles the neuromuscular paralysis produced by d-tubocurarine and similar nondepolarizing neuromuscular blocking drugs (see Chapter 27). Patients with myasthenia are exquisitely sensitive to the action of curariform drugs and other drugs that interfere with neuromuscular transmission, eg, aminoglycoside antibiotics.
Cholinesterase inhibitors—but not direct-acting acetylcholine receptor agonists—are extremely valuable as therapy for myasthenia. Patients with ocular myasthenia may be treated with cholinesterase inhibitors alone (Figure 7–4B). Patients having more widespread muscle weakness are also treated with immunosuppressant drugs (steroids, cyclosporine, and azathioprine). In some patients, the thymus gland is removed; very severely affected patients may benefit from administration of immunoglobulins and from plasmapheresis.