Available online at www.sciencedirect.com Drug induced rhabdomyolysis Martin Hohenegger Rhabdomyolysis is a clinical condition of potential life Statins are the only class of drugs that commonly lead threatening destruction of skeletal muscle caused by diverse to skeletal muscle injury, in particular when combined mechanisms including drugs and toxins. Given the fact that with drugs interacting on the level of pharmacokinetics. structurally not related compounds cause an identical However, an excellent review on the mechanisms behind phenotype pinpoints to common targets or pathways, statins myotoxicity already exists in this journal [5 ]. responsible for executing rhabdomyolysis. A drop in myoplasmic ATP paralleled with sustained elevations in Generally, symptoms of myalgia and muscle weakness 2+ cytosolic Ca concentration represents a common signature precede rhabdomyolysis. However, no laboratory of rhabdomyolysis. Interestingly, cardiac tissue is hardly parameters are available that might help to estimate a affected or only secondary, as a consequence of imbalance in patients risk for the development of further muscle electrolytes or acid–base equilibrium.This dogma is now injury. Slight cases of rhabdomyolysis might exist that impaired by compounds, which show up with combined are subclinical, but still show up elevations of serum toxicity in heart and skeletal muscle. In this review, cases of creatine kinase (CK). The ill defined conditions of myal- rhabdomyolysis with novel recently approved drugs will be gia and myopathy are often seen by clinicians, but only a explored for new target mechanisms in the light of previously very small number of these patients exacerbate rhabdo- described pathomechanisms. myolysis. Once skeletal muscle injury exceeds 100 g, myoglobin is massively released and detectable before Address CK raises [2 ]. Consequently, myoglobinuria, elevated Medical University of Vienna, Center for Physiology and Pharmacology, CK and serum potassium levels, hyperuricosuria and Institute of Pharmacology, Wa¨ hringerstrasse 13A, A-1090 Vienna, acidosis come along with the progression of tissue Austria destruction. Conversely, the decline of these parameters Corresponding author: Hohenegger, Martin may also serve as control of recovery and therapeutic ([email protected]) success [1,2 ,3,4 ]. Leakage of the muscle protein myo- globin into the urine plugs the kidney in particular under acidic conditions. Thus, extensive and early fluid resus- Current Opinion in Pharmacology 2012, 12:335–339 citation is crucial to stabilize circulation, buffer acidosis This review comes from a themed issue on and control serum potassium. Moreover, suggested Musculoskeletal volumes of 12 litres a day should flush the tubular system Edited by Martin Hohenegger to keep it protected from damage by hyperuricosuria and/ or myoglobin [1]. Thus, rapid and aggressive therapeutic Available online 5th May 2012 intervention helps to prevent fatal complications like 1471-4892 arrhythmias, renal failure and disseminated vascular # 2012 Elsevier Ltd.Open access under CC BY-NC-ND license. coagulation [1,2 ,3,4 ]. http://dx.doi.org/10.1016/j.coph.2012.04.002 Organelles and rhabdomyolysis Central to all forms of rhabdomyolysis are decline in intracellular ATP levels and elevation in myoplasmic 2+ Introduction Ca concentration (Figure 1) [6 ]. Thus, sufficient Luckily, rhabdomyolysis is a rare event of rapid destruc- ATP supply by mitochondrial respiratory chain fails 2+ tion of skeletal muscle cells. The range of trigger mech- and as a consequence replenishing Ca stores and extru- 2+ anisms is wide and span from mechanical injury, sion of Ca to the extracellular space is reduced. It is 2+ ischemia, infections, genetic alterations to drugs and assumed that these long-lasting Ca elevations activate toxins. Excellent reviews exist on the various aspects calpain proteases, which further degrade proteins that 2+ of rhabdomyolysis [1,2 ,3,4 ]. Here, I will concentrate participate in Ca homeostasis and thereby aggravate 2+ on recently approved drugs that have been associated myoplasmic Ca overload, as has been shown for statins with clinical cases of rhabdomyolysis. [5 ,7]. This scenario is also corroborated by the finding that the dihydropyridine nifedipine and the ryanodine Currently, no algorithm exists that would predict a receptor blocker dantrolen are capable to attenuate exer- patients risk to develop rhabdomyolysis. The only cise and hyperthermia induced skeletal muscle damage manoeuvre to prevent skeletal muscle destruction [6 ,8–10]. Additionally, the skeletal muscle specific cal- represents avoidance of a drug in individuals that already pain 3 protease may contribute a further pathomechanism suffered from rhabdomyolysis by this particular drug. helping to explain the destruction of the myofibrils. www.sciencedirect.com Current Opinion in Pharmacology 2012, 12:335–339 336 Musculoskeletal Figure 1 Ca2+ influx DHP-receptor muscular dystrophies (Duchhenne, Becker) myotonic dystrophies RyR malignant hyperthermia central core disease sarcomers Brody’s myopathy Ca2+ ATP defects in glycolysis defects in glycogenolysis SR ketoacidosis defects of lipid metabolism and fatty acid oxidation mitochondria deficiencies in succinate dehydrogenase, cytochrome c oxidase, coenzyme Q10, myoadenylate deaminase, glucose-6-P dehydrogenase, complex II and III Current Opinion in Pharmacology Schematic presentation of a skeletal muscle cell. Diseases label the location and site of injury and defect. Sarcoplasmic reticulum (SR), the ryanodine 2+ receptor (RyR), DHP receptor (the voltage sensitive L-Type Ca channel) and sarcomeres (myocontractile machinery). During rhabdomyolysis 2+ reduced myoplasmic ATP concentrations facilitate elevated Ca concentrations. Calpain 3 is tethered to the giant protein titin, in particu- Newly authorised drugs with risk of lar to the N2A line and contributes to sarcomeric remo- rhabdomyolysis delling under physiological exercise [11]. The list of drugs that are reported to exert elevated risk for rhabdomyolysis is very long and has been extensively 2+ Thus, mitochondria, sarcoplasmic reticulum and Ca reviewed by others [3,4 ,12,14]. In particular, HMG-CoA influx mechanisms, also besides excitation-contraction- reductase inhibitors have a higher risk to generate coupling contribute and take over in the development of skeletal muscle side effects alone or in combination with rhabdomyolysis. other drugs owing to interference on the level of uptake/ transport and metabolisation [5 ]. Therefore, I will focus Gene defects and rhabdomyolysis on novel compounds with recently described episodes of Genetic polymorphisms and defects accounting for rhabdomyolysis and their possible molecular targets. skeletal muscle diseases potentiate the risk for episodes of rhabdomyolysis (Figure 1). These defects include Multitargeted tyrosine kinase inhibitors enzymes from the glycolysis and glycogenolysis pathway The novel multitargeted tyrosine kinase inhibitor suni- and pentose phosphate pathway. Impaired mitochondrial tinib is beneficial in overall survival of renal and colon pathways involve fatty acid oxidation, the citric acid cycle cancer patients and shows remarkable activity in a variety and the mitochondrial respiratory chain [4 ]. And finally, of other tumor types even when given as a single agent 2+ defects in the Ca homeostasis are seen in patients with anti-cancer drug [15,16]. However, sunitinib is associated mutations in proteins involved in excitation-contraction with hypertension, left ventricular dysfunction and con- coupling, myotonias and skeletal muscle dystrophies gestive heart failure in up to 15% [16,17]. Human heart [4 ,12]. biopsies and off-target screening has identified disruption of the mitochondrial architecture and an IC50 for AMP- This is exemplified by a case of a two year old patient with kinase inhibition as low as 0.2 mM [18 ]. Thereby suni- recurrent hemolytic uremic syndrome and rhabdomyoly- tinib interferes with fatty acid b-oxidation and glycogen- sis. The child is diagnosed for succinate coenzyme Q olysis. The ATP concentration in sunitinib treated reductase (complex II) deficiency, which is directly cardiomyocytes is significantly reduced, which corrobo- linked to the Krebs cycle via succinate dehydrogenase rates abnormalities in energy generation. Under these [13]. Hence, ATP depletion by a defect of oxidative conditions AMP-kinase activity acts as a rescue pathway phosphorylation is likely to be causative in this individual (Figure 2). Hence, inhibition by sunitinib is therefore to trigger myotoxicity repetitively. deleterious. Surprisingly, rhabdomyolysis has been Current Opinion in Pharmacology 2012, 12:335–339 www.sciencedirect.com Pharmacological destruction of skeletal muscle Martin 337 Figure 2 2+ Ca influx Daptomycin ? DHP-receptor RyR sarcomers Ca2+ ATP AMP-kinase SR Sunitinib Sorafenib?, Erlotinib? mitochondria Leflunomide Propofol Current Opinion in Pharmacology Analogs to Figure 1 drugs label the site of action within a skeletal muscle cell to trigger rhabdomyolysis. Question marks indicate postulated targets. recently reported for sunitinib in two patients with meta- Taken together, tyrosine kinase inhibitors exert cardio- static renal cell cancer receiving 37.5–50 mg sunitinib per toxicity and myotoxicity, most probably by a common day for multiple cycles [19]. The two patients showed a target interaction. more than 50% reduction in left ventricular ejection fraction and massive