Reversible selective ß2-adrenoceptor agonist-induced myopathy

J.-P. Hellier, M. Baudrimont1, J. C. Dussaule2 and F. Berenbaum

Department of Rheumatology,
1 Department of Pathology and
2 Department of Electrophysiology, Hôpital Saint-Antoine, 184, rue du fbg Saint-Antoine, 75012 Paris, France

SIR, Salbutamol and formoterol, two ß2-adrenergic agonists, are commonly prescribed in bronchospasm. Headache, shaking, palpitation and skin rash are the most common side-effects related to these compounds. Muscle cramps have also been reported but are usually mild and do not necessitate stoppage of the treatment. We report a patient with clinical, reversible ß2-adrenoceptor agonist myopathy. The myopathy was demonstrated electrically and histologically. He had received a well-documented high cumulative dose of ß2-adrenoceptor agonists, and in whom no other drug could be implicated.

A 76-yr-old Caucasian woman was admitted to our unit. Her symptoms included gradually increasing weakness, proximal muscle cramps and fatigue over a period of 4 months. Before the symptoms started she had been in her usual state of good health. She denied fever and weight loss. She had been receiving salbutamol spray (600 µg/day) and tablets (10 mg/day) for 2 yr for asthma. A flare-up of asthma occurred 6 months before admission, which led to additional treatment with the ß-adrenergic agonist formoterol (24 µg/day). No other treatment was recorded. The patient was not exposed to any environmental agents thought to be associated with myopathy. There was no history of recent infection.

On admission, the patient weighed 60 kg and her height was 1.65 m. Muscle examination showed marked weakness (4/5 on the Medical Research Council scale) that involved the proximal limbs, with myalgia on palpation. There was no amyotrophy and no rash. Otherwise the physical examination was normal.

Laboratory tests revealed a normal complete blood count with no elevation of the eosinophil count. The erythrocyte sedimentation rate was 10 mm/h. The creatine kinase (CK) concentration was 494 IU/l (normal range 0–130 IU/l) with 100% MM homodimer, lactate dehydrogenase (LDH) was 350 IU/l (normal range 0–300 IU/l), aldolase was 10 UI/l (normal range 0–7.5 IU/l), aspartate transaminase was 27 IU/l (normal range 0–30 IU/l) and alanine transaminase was 41 IU/l (normal range 0–35 IU/l). {gamma}-Glutamyl transpeptidase and alkaline phosphatase were normal. The patient was negative for antinuclear antibodies, anticardiolipin antibodies, rheumatoid factor and cryoglobulinaemia. Complement C3 and C4 and thyroid hormone status were within normal limits. Serological tests for HIV and hepatitis viruses B and C were negative.

An electromyogram performed on the four limbs showed increased polyphasic potentials with normal amplitude and duration, consistent with the diagnosis of polymyositis. An occult neoplasm was ruled out by chest X-ray, urinalysis, CT scanning of the abdomen and pelvis, and bronchoscopy. A biopsy of the left deltoid muscle revealed muscle atrophy with an infiltrate of lymphocytes and histiocytes (Fig. 1Go). There was no fibre necrosis or macrophage infiltrate.



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FIG. 1. Muscle biopsy. Haematoxylin–eosin staining. Magnification, x400.

 
The three drugs (the two forms of salbutamol and formoterol) were stopped at admission. Two days later the patient's clinical condition began to improve gradually. Muscle pain and weakness disappeared in 3 weeks, concomitantly with the recovery of normal values for CK, LDH and aldolase (Table 1Go). Five months later, CK values and a new electromyogram were normal. The patient was not treated again with salbutamol, formoterol or any other ß2-adrenergic agonist.


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TABLE 1. Biological data

 
Several drugs are known to induce myositis, such as corticosteroids, colchicine, chloroquine, D-penicillamine, cyclosporin, gold salts, zidovudine, hydroxymethylglutaryl coenzyme A reductase inhibitors, amiodarone and cimetidine [1]. The case of a 47-yr-old man who suffered from myalgia, muscle cramps and elevated CK while he was receiving inhaled and oral salbutamol twice daily has been reported [2]. However, exercise-induced myopathy existed before this treatment.

In a randomized, double-blind, cross-over study [3], the effects of selective ß-adrenoceptor partial agonist activity on plasma CK and skeletal muscle symptoms were investigated in 10 normal volunteers. One of the drugs used had ß1-selective partial agonist activity (xamoterol); the other had partial agonist activity and acted mainly through ß2-adrenoceptors (pindolol). Each drug was given for 3 weeks. During pindolol administration the plasma CK level rose above the pretreatment baseline, but during treatment with xamoterol the level did not rise. Muscle cramps were reported by five subjects during pindolol administration and by one subject, but to a lesser extent, during xamoterol administration.

Treatment with a high oral dose of albuterol (another ß2-adrenergic agonist) has been reported to cause focal myocardial necrosis and fibrosis in rats, as well as myocardial hypertrophy, as a result of the excessive ß-adrenergic stimulant action of the drug [4].

These results and our case report indicate that the deleterious effect on muscle is due to the specific ß2-adrenergic agonist activity of these compounds.

In conclusion, elevations in plasma CK and skeletal muscle symptoms can be produced by ß2-adrenergic agonists, and this may cause confusion in the diagnosis of muscle disease. We propose that ß2-adrenergic agonists should be added to the list of drugs that are able to induce myopathies.

Notes

Correspondence to: J-P. Hellier. Back

References

  1. Zuckner J. Drug-related myopathies. Rheum Dis Clin North Am1994;20:1017–32.[ISI][Medline]
  2. Craig TJ, Smits W, Soontornniyomkiu V. Elevation of creatine kinase from skeletal muscle associated with inhaled albuterol. Ann Allergy Asthma Immunol1996;77:488–90.[ISI][Medline]
  3. Tomlinson B, Cruickshanck JM. Selective beta-adrenoreceptor partial agonist effects of pindolol and xamoterol on skeletal muscle assessed by plasma creatinine changes in healthy subjects. Br J Clin Pharmacol1990;30:665–72.[ISI][Medline]
  4. Libretto SE. A review of the toxicology of salbutamol (albuterol). Arch Toxicol1994;68:213–6.[ISI][Medline]
Accepted 26 June 2001





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