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Chapter: Modern Pharmacology with Clinical Applications: Directly and Indirectly Acting Cholinomimetics

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Cholinesterase Inhibitors: Clinical Uses

Myasthenia gravis is an autoimmune disease in which antibodies recognize nicotinic cholinoreceptors on skeletal muscle.

Clinical Uses

Myasthenia Gravis

Myasthenia gravis is an autoimmune disease in which antibodies recognize nicotinic cholinoreceptors on skeletal muscle. This decreases the number of functional receptors and consequently decreases the sensitivity of the muscle to ACh. Muscle weakness and rapid fatigue of muscles during use are characteristics of the disease. Anticholinesterase agents help to alleviate the weak-ness by elevating and prolonging the concentration of ACh in the synaptic cleft, producing a greater activation of the remaining nicotinic receptors. By contrast, thymectomy, plasmapheresis, and corticosteroid administration are treatments directed at decreasing the au-toimmune response.

Anticholinesterase agents play a key role in the di-agnosis and therapy of myasthenia gravis, because they increase muscle strength. During diagnosis, the patient’s muscle strength is examined before and immediately af-ter the intravenous injection of edrophonium chloride. In myasthenics, an increase in muscle strength is ob-tained for a few minutes.

The pronounced weakness that may result from in-adequate therapy of myasthenia gravis (myasthenic crisis) can be distinguished from that due to anti-cholinesterase overdose (cholinergic crisis) by the use of edrophonium. In cholinergic crisis, edrophonium will briefly cause a further weakening of muscles, whereas improvement in muscle strength is seen in the myasthenic patient whose anticholinesterase therapy is inadequate. Means for artificial respiration should be available when patients are being tested for cholinergic crisis.

Pyridostigmine and neostigmine are the major anti-cholinesterase agents used in the therapy of myasthenia gravis, but ambenonium can be used when these drugs are unsuitable. When it is feasible, these agents are given orally. Pyridostigmine has a slightly longer duration of action than neostigmine, with smoother dos-ing, and it causes fewer muscarinic side effects. Ambenonium may act somewhat longer than pyri-dostigmine, but it produces more side effects and tends to accumulate.

Smooth Muscle Atony

Anticholinesterase agents can be employed in the treat-ment of adynamic ileus and atony of the urinary blad-der, both of which may result from surgery. Neostigmine is most commonly used, and it can be administered sub-cutaneously or intramuscularly in these conditions. Cholinesterase inhibitors are, of course, contraindicated if mechanical obstruction of the intestine or urinary tract is known to be present. myasthenic patient whose anticholinesterase therapy is inadequate. Means for artificial respiration should be available when patients are being tested for cholinergic crisis.

Pyridostigmine and neostigmine are the major anti-cholinesterase agents used in the therapy of myasthenia gravis, but ambenonium can be used when these drugs are unsuitable. When it is feasible, these agents are given orally. Pyridostigmine has a slightly longer duration of action than neostigmine, with smoother dos-ing, and it causes fewer muscarinic side effects. Ambenonium may act somewhat longer than pyri-dostigmine, but it produces more side effects and tends to accumulate.

Smooth Muscle Atony

Anticholinesterase agents can be employed in the treat-ment of adynamic ileus and atony of the urinary blad-der, both of which may result from surgery. Neostigmine is most commonly used, and it can be administered sub-cutaneously or intramuscularly in these conditions. Cholinesterase inhibitors are, of course, contraindicated if mechanical obstruction of the intestine or urinary tract is known to be present.

Antimuscarinic Toxicity

A number of drugs in addition to atropine and scopol-amine have antimuscarinic properties. These include tri-cyclic antidepressants, phenothiazines, and antihista-mines. Physostigmine has been used in the treatment of acute toxicity produced by these compounds. However, physostigmine can produce cardiac arrhyth-mias and other serious toxic effects of its own, and therefore, it should be considered as an antidote only in life-threatening cases of anticholinergic drug overdose.

Alzheimer’s Disease

Alzheimer’s disease is a slowly developing neurodegen-erative disease that produces a progress loss of memory and cognitive function, that is, dementia. These func-tional changes appear to result primarily from the loss of cholinergic transmission in the neocortex. The four cholinesterase inhibitors that have been approved for use in the palliative treatment of Alzheimer’s disease are tacrine, donepezil, rivastigmine, and galanthamine. These agents can cross the blood-brain barrier to pro-duce a reversible inhibition of AChE in the CNS. These compounds produce modest but significant improve-ment in the cognitive function of patients with mild to moderate Alzheimer’s disease, but they do not delay progression of the disease. Donepezil, rivastigmine, and galanthamine are as effective as tacrine in increasing cognitive performance but do not share tacrine’s hepa-totoxic effects.

Glaucoma

Long-lasting AChE inhibitors, such as demecarium (Humorsol ), echothiophate, and physostigmine are also effective in treating open-angle glaucoma, although they have now been largely replaced by less toxic drugs. Topical application of long-acting cholinesterase in-hibitors to the eye not only presents the risk of systemic effects, but they can cause cataracts; this is a primary rea-son for reluctance to use these drugs even in resistant cases of glaucoma. Pilocarpine should be used rather than AChE inhibitors for treating angle-closure glaucoma.

Strabismus

Drug treatment of strabismus (turning of one or both eyes from the normal position) is largely limited to cer-tain cases of accommodative esotropia (inward devia-tion). Long-acting anticholinesterase agents, such as echothiophate or demecarium, are employed to poten-tiate accommodation by blocking ACh hydrolysis at the ciliary muscle and decreasing the activity of extraocular muscles of convergence. This results in reduced accom-modative convergence. The same side effects and pre-cautions mentioned for the use of these drugs in glau-coma apply to the therapy of strabismus.

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