Myasthenia gravis acetylcholinesterase inhibitors

ACh receptors are destroyed by endocytosis via coated pits and proteolysis in lysosomes. In myasthenia gravis, the receptors are crosslinked by antireceptor antibodies, which facilitate the rate-limiting endocytosis step receptor destmction occurs in less than half the normal time, resulting in net receptor loss. The chronic disease is characterized clinically by such muscular weakness and abnormal fatigue that patients cannot even keep their eyes open. Acetylcholinesterase inhibitors increase the ACh concentration and excitation of the neuromuscular junction, resulting in increased strength and endurance. As expected, AChE inhibitors are also potent curare antidotes because the increased ACh levels displace the blocker more readily. 

One of the best-understood autoimmune diseases is myasthenia gravis, a condition associated with a decrease in the number of functional post-synaptic nicotinic acetylcholine receptors (Fig. 30-23) in neuromuscular junctions. e The resulting extreme muscular weakness can be fatal. Myasthenia gravis is not rare and affects about one in 10,000 peopled An interesting treatment consists of the administration of physostigmine, diisopropyl-phosphofluoridate (Chapter 12, Section C,l), or other acetylcholinesterase inhibitors (Box 12-E). These very toxic compounds, when administered in controlled amounts, permit accumulation of higher acetylcholine concentration with a resultant activation of muscular contraction. The same compounds... 

As mentioned in Part 2, there are drugs that can interfere with the inactivation of neurotransmitters. In that particular case the reversible cholinesterase inhibitor neostigmine was discussed within the context of treating myasthenia gravis. Excessive blockade of acetylcholinesterase at both muscarinic and nicotinic synapses results in a sustained excess of acetylcholine, which persistently activates the effector they innervate. Muscarinic stimulation results in excessive salivation, lacrimation, bronchiolar secretions, and bronchoconstriction. Nicotinic stimulation produces effects such as those described earlier for nicotine. 

Myasthenia gravis is treated with acetylcholinesterase (AChE inhibitors) ... 

The physiological activity of acetylcholine relies on local release, stimulation of the receptor, then rapid hydrolysis (deacetylation) by acetylcholinesterase, which results in deactivation. The indole alkaloid physostigmine, from the West African calabar bean, and the relatively simple synthetic compound pyridostigmine, which has a more obvious relationship to choline, are reversible inhibitors of acetylcholinesterase. Controlled inhibition of the enzyme by such drugs, which results in a build-up of ACh, is useful in conditions such as myasthenia gravis, a muscle weakness, which is caused by insufficient production of ACh. 

P. is used in opthalmic practice in the same way as pilocarpine, for pupil contraction and for the reduction of intraocular pressure. It is an inhibitor of acetylcholinesterase, a property shared by certain other basic urethanes, such as neostigmine (prostigmine) these urethanes presumably acylate, and therefore block, the enzyme. P. and neostigmine have been used in surgery to counteract the action of curare, and both have been used for the relief of Myasthenia gravis, a disease characterized by muscular weakness associated with a rapid breakdown of acetylcholine. These have now been largely replaced by other synthetic compounds. 

One of the clinical signs associated with MeHg intoxication is a myasthenia gravis-like muscle weakness in adults (Rustam et al. 1975), a syndrome which responded well to therapy with neostigmine, a reversible acetylcholinesterase inhibitor. In this syndrome, two effects of MeHg on synaptic transmission at the neuromuscular junction were demonstrated using intracellular microelectrode recording techniques (Atchison and Narahashi 1982 Atchison et al. 1984). First, nerve-evoked, synchronous quantal release of acetylcholine (ACh) is inhibited, as indicated by a decrease in end-plate potential (EPP) amplitude. Second, spontaneous quantal release... 

---