Page 133 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 7 Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs 119

with urinary retention, bethanechol can be given subcutaneously in can be used to assess the adequacy of treatment with the longer-
a dose of 5 mg and repeated in 30 minutes if necessary. Of the cho- acting cholinesterase inhibitors usually prescribed in patients with
linesterase inhibitors, neostigmine is the most widely used for these myasthenia gravis. If excessive amounts of cholinesterase inhibitor
applications. For paralytic ileus or atony of the urinary bladder, have been used, patients may become paradoxically weak because
neostigmine can be given subcutaneously in a dose of 0.5–1 mg. of nicotinic depolarizing blockade of the motor end plate. These
If patients are able to take the drug by mouth, neostigmine can patients may also exhibit symptoms of excessive stimulation of
be given orally in a dose of 15 mg. In all of these situations, the muscarinic receptors (abdominal cramps, diarrhea, increased sali-
clinician must be certain that there is no mechanical obstruction vation, excessive bronchial secretions, miosis, bradycardia). Small
to outflow before using the cholinomimetic. Otherwise, the drug doses of edrophonium (1–2 mg intravenously) will produce no
may exacerbate the problem and may even cause perforation as a relief or even worsen weakness if the patient is receiving excessive
result of increased pressure. cholinesterase inhibitor therapy. On the other hand, if the patient
Pilocarpine has long been used to increase salivary secretion. improves with edrophonium, an increase in cholinesterase inhibi-
Cevimeline, a quinuclidine derivative of acetylcholine, is a newer tor dosage may be indicated.
direct-acting muscarinic agonist used for the treatment of dry Long-term therapy for myasthenia gravis is usually accom-
mouth associated with Sjögren’s syndrome or caused by radiation plished with pyridostigmine; neostigmine is an alternative. The
damage of the salivary glands. doses are titrated to optimum levels based on changes in muscle
strength. These drugs are relatively short-acting and therefore
C. Neuromuscular Junction require frequent dosing (every 6 hours for pyridostigmine and
Myasthenia gravis is an autoimmune disease affecting skeletal every 4 hours for neostigmine; Table 7–4). Sustained-release
muscle neuromuscular junctions. In this disease, antibodies are preparations are available but should be used only at night and
produced against the main immunogenic region found on α1 if needed. Longer-acting cholinesterase inhibitors such as the
subunits of the nicotinic receptor-channel complex. Antibodies organophosphate agents are not used, because the dose require-
are detected in 85% of myasthenic patients. The antibodies reduce ment in this disease changes too rapidly to permit smooth control
nicotinic receptor function by (1) cross-linking receptors, a process of symptoms with long-acting drugs.
that stimulates their internalization and degradation; (2) causing If muscarinic effects of such therapy are prominent, they can
lysis of the postsynaptic membrane; and (3) binding to the nico- be controlled by the administration of antimuscarinic drugs such
tinic receptor and inhibiting function. Frequent findings are ptosis, as atropine. Frequently, tolerance to the muscarinic effects of the
diplopia, difficulty in speaking and swallowing, and extremity cholinesterase inhibitors develops, so atropine treatment is not
weakness. Severe disease may affect all the muscles, including those required.
necessary for respiration. The disease resembles the neuromuscular Neuromuscular blockade is frequently produced as an adjunct
paralysis produced by d-tubocurarine and similar nondepolarizing to surgical anesthesia, using nondepolarizing neuromuscular relax-
neuromuscular blocking drugs (see Chapter 27). Patients with ants such as pancuronium and newer agents (see Chapter 27).
myasthenia are exquisitely sensitive to the action of curariform After surgery, it is usually desirable to reverse this pharmacologic
drugs and other drugs that interfere with neuromuscular transmis- paralysis promptly. This can be easily accomplished with cholin-
sion, eg, aminoglycoside antibiotics. esterase inhibitors; neostigmine and edrophonium are the drugs
Cholinesterase inhibitors—but not direct-acting acetylcho- of choice. They are given intravenously or intramuscularly for
line receptor agonists—are extremely valuable as therapy for prompt effect. Some snake venoms have curare-like effects, and
myasthenia. Patients with ocular myasthenia may be treated with the use of neostigmine as a nasal spray is under study to prevent
cholinesterase inhibitors alone (Figure 7–4B). Patients having respiratory arrest.
more widespread muscle weakness are also treated with immuno-
suppressant drugs (steroids, cyclosporine, and azathioprine). In D. Heart
some patients, the thymus gland is removed; very severely affected The short-acting cholinesterase inhibitor edrophonium was used
patients may benefit from administration of immunoglobulins to treat supraventricular tachyarrhythmias, particularly paroxys-
and from plasmapheresis. mal supraventricular tachycardia. In this application, edropho-
Edrophonium is sometimes used as a diagnostic test for myas- nium has been replaced by newer drugs with different mechanisms
thenia. A 2 mg dose is injected intravenously after baseline muscle (adenosine and the calcium channel blockers verapamil and diltia-
strength has been measured. If no reaction occurs after 45 seconds, zem, see Chapter 14).
an additional 8 mg may be injected. If the patient has myasthenia
gravis, an improvement in muscle strength that lasts about 5 minutes E. Antimuscarinic Drug Intoxication
can usually be observed. Atropine intoxication is potentially lethal in children (see Chapter 8)
Clinical situations in which severe myasthenia (myasthenic and may cause prolonged severe behavioral disturbances and
crisis) must be distinguished from excessive drug therapy (cho- arrhythmias in adults. The tricyclic antidepressants, when taken
linergic crisis) usually occur in very ill myasthenic patients and in overdosage (often with suicidal intent), also cause severe musca-
must be managed in hospital with adequate emergency support rinic blockade (see Chapter 30). The muscarinic receptor blockade
systems (eg, mechanical ventilators) available. Edrophonium produced by all these agents is competitive in nature and can be