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Antimyasthenics Antimyasthenics This chapter includes those drugs used for their their reaction to an anticholinesterase. Intravenous edro- • Plasma exchange provides a dramatic but short-lived anticholinesterase action in the treatment of myasthe- phonium preceded by atropine (Tensilon test) is the most improvement and is useful as a short-term measure in nia gravis and related neuromuscular disorders. Other commonly used anticholinesterase test because of its rapid myasthenic crisis to improve ill patients while other groups of drugs playing an important role in the man- onset and short duration of action. Severe adverse effects therapies take effect, but there is no evidence that repeat- agement of myasthenia are the corticosteroids (p.1490) can occasionally occur so testing should only be undertak- ed plasma exchange combined with immunosuppres- en when facilities for endotracheal intubation and control- sion is superior to immunosuppression alone. A similar and some drugs with immunosuppressant actions dis- led ventilation are immediately available. A positive result short-term benefit has been seen from the use of high- cussed in the chapters on Antineoplastics (p.635) and is considered to be a rapid but temporary increase in mus- dose intravenous normal immunoglobulins; however, a Immunosuppressants (p.1810). cle strength. Repetitive nerve stimulation is also used as a systematic review considered further study to be war- diagnostic test but, like the anticholinesterase test, is not ranted. Eaton-Lambert myasthenic syndrome specific for myasthenia gravis. Computed tomography or • Thymectomy may be offered to all patients sufficiently Eaton-Lambert myasthenic syndrome is a rare auto-im- magnetic resonance imaging may be used to detect thymo- fit to undergo surgery unless they have minimal symp- mune disease of the neuromuscular junction. Unlike ma. toms, purely ocular disease, or late onset or seronegative myasthenia gravis (below), in which autoantibodies affect Treatment of myasthenia gravis. disease. Thymectomy is usually avoided in prepubertal children because of concern over the effect on growth acetylcholine receptors, antibodies in Eaton-Lambert syn- • Symptomatic treatment is with an anticholinesterase; drome act presynaptically to reduce release of acetylcho- and the developing immune system; it has been suggest- pyridostigmine and neostigmine are those most com- ed that symptomatic treatment with anticholinesterases line. Weakness mostly affects the proximal muscles, par- monly used. Most patients prefer pyridostigmine as it ticularly those of the limbs; respiratory and ocular muscles should be continued until adolescence, when the disease produces less muscarinic adverse effects and has a long- often improves spontaneously. After thymectomy, re- are usually spared. Autonomic symptoms including dry er duration of action, although the quicker onset of ac- mouth, constipation, and impotence are common. Over mission or improvement may be expected in about 80% tion of neostigmine may offer an advantage at the begin- of patients without thymomas, although this may take half of patients also have small cell carcinoma of the lung. ning of the day. The dose must be adjusted to give the Successful treatment of the tumour often leads to some im- some years; the response is poorer in those with thymo- optimum therapeutic response but muscle strength may mas. provement in symptoms. not be restored to normal and some patients must live The symptomatic treatment of Eaton-Lambert syndrome with a degree of disability. The effect may vary for dif- References. involves the use of drugs that increase the availability of ferent muscles and the dosage should be adjusted so that 1. Evoli A, et al. A practical guide to the recognition and manage- acetylcholine at the neuromuscular junction. Response to ment of myasthenia gravis. Drugs 1996; 52: 662–70. the bulbar and respiratory muscles receive optimum 2. Yi Q, Lefvert AK. Current and future therapies for myasthenia treatment with anticholinesterases alone is poor and treat- treatment. Generally, anticholinesterases only provide gravis. Drugs Aging 1997; 11: 132–9. ment with amifampridine, which increases acetylcholine partial remission and their effects tend to diminish with 3. Newsom-Davis J. Myasthenia gravis. Prescribers’ J 2000; 40: release, appears to be more effective, particularly when continued treatment. Overdosage may lead to a ‘cholin- 93–8. given with an anticholinesterase such as pyridostigmine. 4. Vincent A, et al. Myasthenia gravis. Lancet 2001; 357: 2122–8. ergic crisis’ (see Adverse Effects of Neostigmine, 5. Pascuzzi RM. Myasthenia gravis and Lambert-Eaton syndrome. The use of similar drugs such as guanidine and fampridine p.631). Edrophonium may be employed to establish Ther Apher 2002; 6: 57–68. is limited by severe adverse effects. Low-dose guanidine whether the patient is underdosed or overdosed. 6. Vincent A, Drachman DB. Myasthenia gravis. Adv Neurol 2002; has been tried with pyridostigmine where amifampridine 88: 159–88. is not readily available. Although there has been some im- • Corticosteroids are the main immunosuppressive drugs 7. Richman DP, Agius MA. Treatment of autoimmune myasthenia used for treatment. They are also useful in patients with gravis. Neurology 2003; 61: 1652–61. provement with the combination, the incidence of adverse 8. Thanvi BR, Lo TCN. Update on myasthenia gravis. Postgrad effects, especially gastrointestinal reactions, is still high. ocular myasthenia, who as a group respond poorly to Med J 2004; 80: 690–700. Immunosuppressants including azathioprine and corticos- anticholinesterases and to thymectomy, provided that 9. Saperstein DS, Barohn RJ. Management of myasthenia gravis. their disability is severe enough to warrant long-term Semin Neurol 2004; 24: 41–8. teroids are also used, and unlike in treatment for myasthe- 10. Kothari MJ. Myasthenia gravis. J Am Osteopath Assoc 2004; nia gravis, corticosteroids do not appear to induce an initial corticosteroid treatment with its attendant adverse ef- 104: 377–84. exacerbation of symptoms. Plasma exchange or high-dose fects. Many start with low doses such as 5 to 20 mg of 11. Romi F, et al. Myasthenia gravis: clinical, immunological, and intravenous normal immunoglobulin have been tried in pa- prednisolone daily or on alternate days, to reduce the therapeutic advances. Acta Neurol Scand 2005; 111: 134–41. risk of steroid-induced exacerbations of weakness, and 12. Schwendimann RN, et al. Management of myasthenia gravis. tients with severe weakness. Am J Ther 2005; 12: 262–8. References. increase the dose slowly thereafter according to re- 13. Schneider-Gold C, et al. Corticosteroids for myasthenia gravis. 1. Newsom-Davis J. Myasthenia gravis and the Lambert-Eaton sponse; an improvement is usually seen after a few Available in The Cochrane Database of Systematic Reviews; Is- myasthenic syndrome. Prescribers’ J 1993; 33: 205–12. weeks. Others use more aggressive regimens to obtain a sue 2. Chichester: John Wiley; 2005 (accessed 15/02/06). 2. Oh SJ, et al. Low-dose guanidine and pyridostigmine: relatively more rapid response and start with large doses such as 14. Benatar M, Kaminski H. Medical and surgical treatment for oc- safe and effective long-term symptomatic therapy in Lambert- ular myasthenia. Available in The Cochrane Database of Sys- 60 to 80 mg of prednisolone daily. Whichever method is tematic Reviews; Issue 2. Chichester: John Wiley; 2006 (ac- Eaton myasthenic syndrome. Muscle Nerve 1997; 20: 1146–52. cessed 26/05/06). 3. Seneviratne U, de Silva R. Lambert-Eaton myasthenic syn- used, once clinical benefit has been obtained the regi- drome. Postgrad Med J 1999; 75: 516–20. men should be modified to alternate-day dosage, with 15. Hart IK, et al. Immunosuppressive agents for myasthenia gravis. Available in The Cochrane Database of Systematic Re- 4. Pascuzzi RM. Myasthenia gravis and Lambert-Eaton syndrome. the dose being slowly tapered when the patient is in re- views; Issue 4. Chichester: John Wiley; 2007 (accessed Ther Apher 2002; 6: 57–68. 24/01/08). 5. Sanders DB. Lambert-Eaton myasthenic syndrome: diagnosis mission. Patients taking corticosteroids require less anticholinesterase therapy and, if the dosage of the anti- 16. Gajdos P, et al. Intravenous immunoglobulin for myasthenia and treatment. Ann N Y Acad Sci 2003; 998: 500–8. gravis. Available in The Cochrane Database of Systematic Re- 6. Newsom-Davis J. Lambert-Eaton myasthenic syndrome. Rev cholinesterase is not reduced, an initial deterioration in views; Issue 1. Chichester: John Wiley; 2008 (accessed Neurol (Paris) 2004; 160: 177–80. the myasthenia may occur in the first few weeks of treat- 28/05/08). 7. Maddison P, Newsom-Davis J. Treatment for Lambert-Eaton myasthenic syndrome. Available in The Cochrane Database of ment (see also under Interactions of Neostigmine, Systematic Reviews; Issue 2. Chichester: John Wiley; 2005 (ac- p.632). It is rarely possible to withdraw corticosteroids cessed 15/02/06). completely but some patients may be maintained satis- Ambenonium Chloride (BAN, rINN) factorily on as little as 10 mg on alternate days. If remis- Ambenonii Chloridum; Ambénonium, Chlorure d’; Ambenon- sion cannot be maintained on low-dose prednisolone, Myasthenia gravis iumklorid; Ambenoniumkloridi; Ambestigmini Chloridum; Cloru- Myasthenia gravis is an auto-immune disorder character- addition of azathioprine at a dosage of 2 to 3 mg/kg ro de ambenonio; Win-8077. N,N′-Oxalylbis(N-2-aminoethyl-N- ised by defective neuromuscular
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