Mitochondrial disorder aggravated by propranolol.

Abstract: Although there are indications that [beta]-blockers affect the skeletal muscle in therapeutic dosages, their influence on mitochondrial disorders is unknown. A 52-year-old woman developed double vision, myalgias, muscle cramps, and hip and thigh muscle stiffness. Clinical neurologic examination revealed ptosis, dysarthria, sore neck muscles, weakness and wasting of the thighs, and generally brisk tendon reflexes. Lactate stress testing was significantly abnormal. Needle electromyography was nonspecifically abnormal and myopathic. Muscle biopsy showed mild myopathic changes, target fibers, and a single COX-negative fiber. Probable mitochondrial disorder was diagnosed. The patient had been on 30 mg of propranolol during 7 years for arterial hypertension. Shortly after discontinuation of the drug, her double vision gradually disappeared, myalgias and muscle cramps gradually resolved, and the patient reported an increase in muscle mass on repeated follow-ups. Long-term administration of propranolol may aggravate a mitochondrial disorder. Discontinuation of propranolol may result in a gradual resolution of these adverse reactions.

Key Words: metabolic myopathy, mitochondrial myopathy, side effect, adverse reaction, neuromuscular disorder, respiratory chain

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Various drugs adversely affect patients with mitochondrial disorders (MCDs). (1-6) Although there are indications that [beta]-blockers in therapeutic dosages also affect the skeletal muscle, inducing cramps, weakness, myotonia, elevation of creatine kinase (CK) levels, myofibrillar disruption, or myopathy, (7-12) worsening of a MCD by a [beta]-blocker has not, to our knowledge, been reported.

Case Report

We report on a 52-year-old HIV-negative woman, height of 163 cm, weight 65 kg, with an individual history as listed in Table 1. The patient's mother, who was 165 cm tall, had suffered from arterial hypertension, chronic heart failure, a cataract, and diabetes and her father had chronic heart failure. Drugs administered during the period of interest are listed in Table 2. The patient had taken propranolol for 7 years for arterial hypertension and tachycardia. For pulmonary granulomatosis, she had received corticosteroids between June 2003 and April 2004, without effect (Table 2).

Clinical neurologic examination in May 2004 revealed bilateral ptosis, double vision when looking in any direction, dysarthria, sore neck muscles, generally brisk tendon reflexes with contralateral cocontraction of the lower limbs, weak elbow extension (M5-) on the right side, weak hip flexion bilaterally (M5-), wasting of the thighs and reduced Achilles tendon reflexes. Blood sedimentation rate was repeatedly increased. Blood work revealed hyperlipidemia, hyperuricemia, and occasional eosinophilia, elevated [gamma]-glutamyl-transpeptidase, and elevated CK levels. Protein electrophoresis, antistreptoly-sin-O-titer, complement C3 and C4, circulating immune complexes, antinuclear antibodies, p- and c-antineutro-phil-cytoplasmic antibodies, antimitochondrial antibodies, and antiacetylcholine-receptor antibodies were negative and/or normal. Blood pressure was repeatedly normal. Chest x-ray and high-resolution CT scan showed disseminated, small granulomas of the lung bilaterally with slightly thickened interlobar septs. Bronchoscopy and biopsy of these granulomas did not reveal malignancy or a specific granulomatous infection. Transthoracic echocardiography revealed myocardial thickening despite a well-controlled blood pressure, a pericardial effusion of 4 to 10 mm, and mitral insufficiency, grade 2. MRI of the brain disclosed multiple, subcortical, small white matter lesions bilaterally. Nerve conduction studies of various nerves were normal. Needle electromyography of the right anterior tibial muscle was nonspecifically abnormal and myogenic in the right biceps brachii muscle. Muscle biopsy from the left lateral vastus muscle showed mild myopathic changes, target fibers, and a single COX-negative muscle fiber (Fig. 1). MCD was suspected. MtDNA analysis for deletions and the point mutations T8993C and A3243G were negative.

To exclude a possible relation between certain drugs and the skeletal muscle abnormalities, various drugs were discontinued between April and October 2004: in April 2004, pravastatin, corticosteroids, and candesartan; in June 2004, clomipramine; in September 2004, acetylsalicylic acid; and in October 2004, paroxetine and propranolol (Table 2). Despite the discontinuation of these drugs, neuromuscular manifestations remained unchanged until October 2004 compared with May 2004. After discontinuation of propranolol, however, the patient's double vision disappeared almost completely within 2 weeks and myalgias, muscle cramps, and muscle stiffness diminished and finally resolved within eight weeks on repeated neurologic follow-ups. Since December 2004, the patient repeatedly reported an increase in muscle mass. Clinical neurologic examination in February 2005, however, revealed double vision when looking in any direction, right-sided ptosis, dysarthria, weakness for hip flexion (M5-), exaggerated tendon reflexes and increased diffuse wasting of the lower limbs.

Discussion

Various drugs may trigger, maintain, or worsen MCD. The adverse affect of these drugs on MCD is assumed to be due to induction of mtDNA mutations, direct blocking of the respiratory chain, or impairment of the nonrespiratory-chain mitochondrial metabolism. Propranolol, a blocker of [beta]-adrenergic receptors, also exhibits various muscular side effects, including myopathy, (8) weakness, (7) myotonia, (11) muscle cramps, (9) neuromuscular depression, (12) myofibrillar disruption, (10) or elevated CK levels. (9) In the presented patient, propranolol possibly aggravated double vision and triggered the development of myalgias, muscle cramps, and muscle stiffness. Arguments for propranolol as the inducing or worsening agent for these abnormalities are that the patient's double vision, myalgias, muscle cramps, and muscle stiffness almost completely disappeared within eight weeks after discontinuation of propranolol. In addition, previous experiments in felines also demonstrated a negative effect of propranolol on the hypothyroid myopathy in these animals. (13) Arguments against propranolol as a causative agent for the entire clinical picture are that the skeletal muscle manifestations did not disappear completely and in fact, some of them had occurred long before the initiation of propranolol. Whether propranolol exhibited its side effects only because of a pre-existing neuromuscular disorder or in combination with other myotoxic drugs remains speculative, but worthy of consideration.

Please refer to Table 1 for a complete list of the patient's symptoms. Whether myalgias of the thighs were solely attributable to propranolol, (14) due to arterial obstructive disease, or due to MCD remains speculative. Cold face is most likely also a side effect of propranolol since claudication and Raynaud phenomenon have been previously reported as side effects of propranolol. (14) The transient visual impairment was most likely also due to propranolol, as has been previously observed. (14) Although the dysphagia could be a direct side effect of the propranolol, it may also have derived from her chronic depression, or it may represent a smooth muscle manifestation of MCD. Also, the cause of pulmonary granulomatosis remains speculative. It may be attributable to varicella zoster pneumonia as a child, an unclassified collagenosis against which corticosteroids were ineffective, vasculitis, or the long-term administration of propranolol. Other differential diagnoses of the pulmonary granulomatosis considered were lymphoma, allergic alveolitis, miliary tuberculosis, metastasis, and eosinophilic granulomatosis. The generally brisk tendon reflexes were explained by the multiple, subcortical white matter lesions, which are a frequent finding in MCD. The chronic pericardial effusion was regarded as a residuum of a previous pericarditis. Possible explanations for the effect of propranolol are that carvedilol inhibits the activity of mitochondrial NADH-ubiquinone oxidoreductase in the rat and bovine species (15) or inhibits the mitochondrial ATPase activity in guinea pigs or rats. (16,17)

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Conclusion

This case shows that long-term intake of propranolol for arterial hypertension and tachycardia may induce muscular manifestations like myalgias, muscle cramps, and muscle stiffness, or may aggravate muscular manifestations, like double vision, in a pre-existing MCD. Discontinuation of propranolol may gradually relieve these skeletal muscle abnormalities, but may not reverse the manifestations and course of the MCD in the long run.

References

1. Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999;354:1084-1089.

2. Brunmair B, Staniek K, Gras F, et al. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 2004;53:1052-1059.

3. Fromenty B, Pessayre D. Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines. J Hepatol. 1997;26 (Suppl 2):43-53.

4. Goli AK, Goli SA, Byrd RP Jr, et al. Simvastatin-induced lactic acidosis: a rare adverse reaction? Clin Pharmacol Ther 2002;72:461-464.

5. Lebrecht D, Setzer B, Ketelsen UP, et al. Time-dependent and tissue-specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy. Circulation 2003;108:2423-2429.

6. Norman C, Howell KA, Millar AH, et al. Salicylic acid is an uncoupler and inhibitor of mitochondrial electron transport. Plant Physiol 2004;134:492-501.

7. Felmus MT, Patten BM, Hart A, et al. Catecholamine-induced muscle weakness. Arch Neurol 1977;34:280-284.

8. Forfar JC, Brown GJ, Cull RE. Proximal myopathy during beta-blockade. Br Med J 1979;2:1331-1332.

9. Imai Y, Watanabe N, Hashimoto J, et al. Muscle cramps and elevated serum creatine phosphokinase levels induced by beta-adrenoceptor blockers. Eur J Clin Pharmacol 1995;48:29-34.

10. Kuncl RW, Meltzer HY. Beta adrenergic-mediated myofibrillar disruption and enzyme efflux in an experimental myopathy related to isometric muscle activity. Exp Mol Pathol 1979;31:113-123.

11. Blessing W, Walsh JC. Myotonia precipitated by propranolol therapy. Lancet 1977;1:73-74.

12. Nirmala G, Brahmayya Sastry P. Neuro-muscular depressant action of pindolol in comparison with propranolol and procaine. Arch Int Pharmacodyn Ther 1979;238:196-205.

13. Zaiton Z, Merican Z, Khalid BA, et al. The effects of propranolol on skeletal muscle contraction, lipid peroxidation products and antioxidant activity in experimental hyperthyroidism. Gen Pharmacol 1993;24:195-199.

14. Jasek W. Austria-Codex. Fachinformation. Osterreichische Apotheker-verlagsgesellschaft, Wien, 2004.

15. Cocco T, Cutecchia G, Montedoro G, et al. The antihypertensive drug carvedilol inhibits the activity of mitochondrial NADH-ubiquinone oxidoreductase. J Bioenerg Biomembr 2002;34:251-258.

16. Almotrefi AA, Dzimiri N. Effects of beta-adrenoceptor blockers on mitochondrial ATPase activity in guinea pig heart preparations. Eur J Pharmacol 1992;215:231-236.

17. Wei YH, Lin TN, Hong CY, et al. Inhibition of the mitochondrial Mg2+-ATPase by propranolol. Biochem Pharmacol 1985;34:911-917.

Know how to listen, and you will profit even from those who talk badly.
--Plutarch

Josef Finsterer, MD, PHD, and Ellen Gelpi, MD

From Krankenanstalt Rudolfstiftung, and the Clinical Institute of Neurology, Medical University of Vienna, Vienna, Austria.

Reprint requests to Univ.Doz. DDr. J. Finsterer, Postfach 20, 1180 Vienna, Austria. Email: [e-mail]

Accepted February 21, 2006

RELATED ARTICLE: Key Points

* Propranolol may aggravate skeletal muscle manifestations in mitochondrial disorder.

* Discontinuation of propranolol gradually relieves adverse reactions in patients with mitochondrial disorder.

* [beta]-blockers should be given with caution in mitochondrial disorder.

Table 1. Patient's symptom history

Suggestive of mitochondrial disorders

Premature delivery in the 7th month of gestation
Short stature
Hypercholesterolemia since 1973
Hypertriglyceridemia since 1973
Lumbago and cervicalgia since 1984
Right-sided hypacusis in 1993
Recurrent feeling of having fever since 1995
Chronic pericardial effusion of unknown etiology since 1997
Polyarthralgia since 1999
Swelling of the metacarpophalangeal joints since 1999
Right-sided macular degeneration detected in 2000
Intermittent double vision since 2000
Hyperhidrosis since 2000
Hyperuricemia since 2002
Permanent double vision since 2003
Bilateral cataracts since 2003
Dysphagia since September 2003
Exercise-induced myalgias, cramps, and stiffness of the hips and thighs
  since 2004

Other abnormalities

Chronic otitis media in infancy
Ocular herpes infection in 1974
Depression with panic attacks since 1982
Pneumonia from varicella zoster virus in 1985
Arterial hypertension since 1994
Pneumonia with concomitant heart failure in 1998
Feeling of a cold face since 1996
Myocardial thickening of unknown etiology since 1997
Bilateral "granulomatosis" of the lung, first detected in 1998
Urethral stenosis requiring recurrent extension since 1999
Right retinal ablation in 2000 requiring cryopexy and a radial seal
Left-sided herpes zoster infection Th10 in 2003
Arterial obliterating disease, type 2, detected in 2003
Right-sided nephrolithiasis detected in 2003
Transient left-sided visual impairment in June 2004

Table 2. Patient's medication list

                      Dose per day
Drug                  (mg)          Period of use

Acetylsalicylic acid    100         Until September 2004
Allopurinol             100         Since 2002
Alprazolam                0.5-0.75  Occasionally
Amitriptyline            20         Until 1990
Belladonna                0.75      Since summer 2004
Bezafibrate           NA            For 3 months until approximately
                                      2000
Bisoprolol                1.25      Since October 2004
Bromazepam            NA            Since 1986 for 2-3 years,
                                      occasionally since then
Budesonide                0.320     Since bronchoscopy in 2001
Candesartan           NA            Until April 2004
Celecoxib               200         July 2001 until July 2003
Cerivastatin          NA            Since 1995 until 1998
Chloroquine           NA            July 2001 until 2003
Clomipramine             12.5-75    From 1989 to June 2004
Clopidogrel              75         Only during 3 weeks in 2004
Cholestyramine        12000         Since December 2004
Corticosteroids       NA            June 2003 until April 2004
Diosmin                 500         Since October 2004
Escitalopram             10         Since November 2004
Enalapril                 5-10      Since December 1998 until March 2000
Flupentixol               1         From 1986 to April 1990
Lansoprazole             30         Since October 2003 regularly
Paroxetine               20         June 2003 until October 2004
Pravastatin              20         June 2003 until April 2004
Propranolol              30         June 1997 until October 2004
Rosuvastatin             10         Until June 2004
Simvastatin              20         Until 1998
Tiotropium bromide        0.018     Between 2001 and 2003
Tramadol                200         Repeatedly since 2004

NA, not available.