There are more than 30 drugs in current clinical use (other than anesthetic agents) that may, under certain circumstances, interfere with neuromuscular transmission in otherwise normal individuals. Of these, the most important are the aminoglycoside and quinolone antibiotics. Myasthenic weakness has been reported with 18 different antibiotics but particularly neomycin, kanamycin (less so with gentamicin), colistin, streptomycin, polymyxin B, and certain tetracyclines (McQuillen et al; Pittinger et al). It has been shown that these drugs impair transmitter release by interfering with calcium ion fluxes at nerve terminals. The fluorinated quinolones (fluoroquinolones)—typified by ciprofloxacin—affect both preand postsynaptic activity. They are especially hazardous when given to patients with myasthenia but they may be used if necessary to treat infections in patients who are already receiving ventilatory support.
Other agents—particularly the organophosphate insecticides and nerve gases—cause paralysis by binding to cholinesterase and blocking the hydrolysis of ACh. The endplate remains depolarized and is refractory to neural stimuli. The most notable of these agents are (1) botulinum toxin, which binds to cholinergic motor endings, blocking quantal release of ACh; (2) black widow spider venom, which causes a massive release of ACh, resulting in muscular contraction and then paralysis from a lack of ACh; (3) d-tubocurarine, which binds to AChR; (4) suxamethonium and decamethonium, which also bind to AChR; (5) organophosphates, which bind irreversibly to AChE; and (6) malathion and parathion, which inhibit AChE. The actions of all these agents except for the organophosphate “nerve gases” are transitory.
The administration of d-penicillamine has also caused an unusual type of myasthenia. The weakness is typical in that rest increases strength—as do neostigmine and edrophonium—and the electrophysiologic findings are also the same. In such cases, Vincent and associates (1978) found anti-AChR antibodies in the serum; hence, one must assume that this is a form of induced autoimmune myasthenia gravis. In these respects it differs from the weakness caused by aminoglycosides (see review by Swift). Rarely, typical autoimmune myasthenia gravis develops as part of a chronic graft-versus-host disease in long-term (2to 3-year) survivors of allogeneic marrow transplants.
A large group of naturally occurring environmental neurotoxins are known to act at the neuromuscular junction and to induce muscle paralysis of a pattern like that of myasthenia gravis. Venoms of certain snakes, spiders, and ticks are common and well-known animal poisons, as are ciguatera and related toxins (from fish that have ingested certain dinoflagellates), curare (from plants), and Clostridium botulinum—all of which are discussed in other parts of this book, particularly Chap. 41. Poisoning by these natural neurotoxins constitutes an important public health hazard in many parts of the world. This class of disorders of neuromuscular transmission has been reviewed by Senanayake and Roman.
MYOTONIAS, PERIODIC PARALYSES, AND STATES OF PERSISTENT MUSCLE FIBER ACTIVITY (CHANNELOPATHIES)