Muscle ADRs PDF

Musclo skeletal adverse drug reactions  Drug-induced muscle and bone injuries may be due to a primary direct drug action, or may be part of a more generalized drug-induced disease (e.g. drug-induced polyneuropathy). Musculoskeletal ADRs may be only temporarily disabling, su...

Musclo skeletal adverse drug reactions  Drug-induced muscle and bone injuries may be due to a primary direct drug action, or may be part of a more generalized drug-induced disease (e.g. drug-induced polyneuropathy). Musculoskeletal ADRs may be only temporarily disabling, such as muscle cramps, Myalgia as well as may be a serious and life threatening conditions in other cases, such as rhabdomyolysis. Statins Statins considered the drug of choice for reducing abnormal elevation of cholesterol levels. Also, reduction risk of death because of congestive heart failure and nonfatal myocardial infarction, revascularization procedures, strokes and cardiovascular mort.  Myalgia is clinically associated with muscle pain and weakness, it may be accompanied by an increase in the enzyme creatinine phosphokinase (CPK) in serum and is associated with several drugs, as a very common complaint. Rhabdomyolysis Rhabdomyolysis is among the best-recognized and most feared complications of statins; it occurs when muscle damage is severe, leading to a marked elevation of CK (e.g. in excess of 10 times the upper limit of normal) It results from the death of muscle fibers and release of their contents into the bloodstream. This can lead to serious complications such as renal (kidney) failure and occasionally renal failure and death  Muscle pain specifically related to statins metabolized by CYP3A4, simvastatin, lovastatin and atorvastatin, which considered more toxic to muscle cells. Pravastatin and fluvastatin not metabolized by liver enzyme, therefore, their effect on muscle will be lower.  In conclusion, statin types associated with increased incidence and severity of ADRs. Therefore it recommended using low doses of statins and frequent checking, especially for patients on chronic use of statin. Mechanism of action Statins inhibit the enzyme HMG-CoA reductase, at a stage early in the mevalonate pathway. This pathway generates a range of other products in addition to cholesterol, such as coenzyme Q10, heme-A, and isoprenylated proteins, which have pivotal roles in cell biology and human physiology and potential relevance to benefits as well as risks of statins. Additionally, cholesterol itself is not merely a final product but also an intermediate to additional products of fundamental importance to health and well-being, such as sex steroids, corticosteroids, bile acids and vitamin D, several of which have been shown to be affected with statin administration.  Several mechanisms are probably involved: supplementation studies showed that farnesol and geranylgeraniol, but not squalene, are able to prevent these effects induced by statins The potential mechanism may be therefore through blockade of farnesyl pyrophosphate and geranylgeranyl pyrophosphate production (enzymatic steps in the cholesterol synthetic pathway).  These two enzymes, however, contribute to activate regulatory proteins, small GTP-binding proteins (e.g., Ras, Rac, Rho, etc.) which promote cell maintenance and growth, and attenuate apoptosis. Therefore, statins may induce skeletal myocytes apoptosis through inhibition of their formation.  A decrease in muscle Coenzyme Q10 (CoQ10), a component of the mitochondrial respiratory chain, may have a role in the pathogenesis of statin-related myopathy. CoQ10 supplementation ameliorate the symptoms of statin- associated myopathy, but there is no sufficient evidence to support its routine use for preventing the ADRs of statin therapy or to link statin therapy to pathologically decreased CoQ10 tissue level.  Statins may also modify the electrophysiological properties of muscle cell membrane. Decreased Na+/K+ ATPase pump density, with an elevated sarcoplasmic Ca++ and myofibre necrosis and apoptosis, has been shown to occur in skeletal muscle after lovastatin. Simvastatin has been reported to reduce Cl- conductance, an effect that may limit after-hyperpolarization and facilitate hyperthermia. Fibrates  Fibrates also induced skeletal muscle ADRs, but the mechanisms involved may be different. The interaction between fibrates (HMG CoA synthase depletion) and statins (HMG CoA reductase inhibition) may also have a downstream synergistic influence on mevalonate pathway at the level of isopentenyl pyrophosphate (IPP) synthesis for the production of selenoproteins. Sec-tRNA selenocysteine isopentylation governs the expression of all selenoproteins but it is functional (mature form) only after isopentylation of adenosine.  tRNA isopentenyl transferase is the enzyme responsible for such maturation. IPP is a direct metabolite of mevalonate and substrate of tRNA isopentyltransferase. Statins block the formation of mevalonate as a downstream consequence of HMG CoA reductase inhibition, as well as fibrates do. In vitro, selenoproteins synthesis was shown to be reduced by lovastatin. Since statins and se-lenium deficiency show similar symptoms of myopathy, this concomitant imbalance may enhance statin ADRs. FLUOROQUINOLONES Fluoroquinolones are an important group of antibiotics widely used in the treatment of various infectious diseases in adults. Their use is currently contraindicated in children and adolescents because animal studies have shown lesions and destruction of cartilage in weight-bearing joints in immature animals. Although long-term effects on articular function and growth are generally unknown, many Authors presently recommend that contraindications in children should be reconsidered based on analysis between risk factors and benefits that quinolones offer in pediatrics.  Data from spontaneous reporting suggest that general musculoskeletal-related ADRs occur more frequently in association with fluoroquinolones than other antimicrobial. Arthralgia and myalgia are frequently reported by patients, but the most severe disorders include arthropathies and tendinopathies. In clinical studies, quinolone associated arthropathy has been reported to occur in about 1% of patients, causing pain, stiffness and swelling of involved joints, usually within the first few days of therapy.  After quinolone discontinuation, arthropathy usually resolves within days to weeks. Quinolones have an inhibitory effect on DNA, collagen and proteoglycan synthesis and on the formation of oxygenderived reactive molecules. Chondrotoxicity is also explained by their chelating properties for bi- and tri-valent ions, causing formation of radicals in immature joint cartilage, and eventually irreversible lesions.  Recently, it was suggested that quinolone-induced arthropathy is possibly associated with the magnesium- chelating properties of these drugs leading to an altered functionality of integrin receptors on chondrocyte surface. The first cases of tendon disorders related to fluoroquinolones were described in men in 1983 ; over the last few years the number of clinical reports on tendinopathies related to fluoroquinolones is increased.  Among fluoroquinolones, levofloxacin was associated with the highest tendinitis reporting rate , an observation supported also by the WHO database in which levofloxacin ranked first for tendon ruptures.  In spite of the relatively large volume of case-based evidence, the pathophysiology of fluoroquinolone-induced tendinitis and tendon rupture is still unclear. Since there are similarities between tendons and cartilage, common mechanisms might exist for chondrotoxicity and tendontoxicity. As mentioned above, the imbalance of nutrients and electrolytes produced by quinolones and other chelating agents may alter the function of regulating proteins (e.g., integrins) of both chondrocytes and tenocytes. Furthermore, tendons can not easily compensate these altered functions because of their poor vascularization.  Recent results on cultured human tendons provided evidence that apoptosis, a consequence of changes in beta-1 integrin receptors and Map-kinase pathway, has to be considered as a final event in the pathogenesis of fluoroquinolone-induced tendinopathies. The findings that quinolone-induced damage on connective tissue is partially due to magnesium chelation also support the observation that patients with a latent magnesium deficiency could be at an increased risk of tendon disorders. CORTICOSTEROIDS Corticosteroids play a major role in the treatment of asthma, inflammatory joint disorders and other inflammatory and autoimmune diseases affecting gastrointestinal tract and central nervous system. In spite of prescription and warning messages, they are often administered for long-term, as well as for short- term (e.g., high dosage regime during short-term treatment for asthma) period of time. Corticosteroids induce musculoskeletal ADRs such as tendinopathies, myopathy, and osteoporosis.  Corticosteroid-associated tendinopathies are prevalent with oral and parenteral routes of administration, and rarely with topical applications. The incidence of myopathy varies from 7 to 60% and can occur after short term high-dose steroid administration (e.g., in exacerbation of asthma) as well as after chronic treatment. Corticosteroid-induced myopathy is correlated with increased CK level in type II fibres, with high glycolytic and low oxidative activities. At a microscopic level, there are non specific histological changes, including variation of fibre size (type II fibre atrophy), centralization of nuclei, inflammation and occasional necrosis.  At a biochemical level, the inhibition of protein synthesis in type II muscle fibres appears as the most detrimental event. This correlates with lower levels of initiation factor eIF4E, which control mRNA binding to the 43S pre-initiation complex, and reduction of IGF-1 expression with a consequent decrease of its anti-apoptotic effects. The net result is an enhancement of protein catabolism and muscle apoptosis. Glutamine synthetase activity is also increased by both corticosteroid - induced protein synthesis inhibition, and by proteolysis.  Glutamine synthetase activity has a pathogenic significance (imbalance of energy production) which is counteracted by glutamine supplementation. Also note that glutamine synthetase activity in skeletal myocytes is under the control of IGF-1 factor, whose levels are lowered by corticosteroids. Glycogen phosphorylase activity is significantly decreased by corticosteroid treatment. This effect, which is associated to muscular atrophy and weakness induced by increased levels of glycogen concentration, may be an additional mechanism of corticosteroid-associated myopathy.  Osteoporosis is one of the serious complications of oral corticosteroid treatment. Several studies report a decrease in bone mineral density irrespective of the disease being treated. A meta-analysis shows that oral corticosteroids treatment using more than 5 mg daily leads to a reduction in bone mineral density and a rapid increase in the risk of fracture Fracture risk has been associated both with oral and with inhaled corticosteroids.  Bone loss is dose and time dependent even though there are discrepancies on the involvement of the different glucocorticoids. Long-term glucocorticoid treatment impairs intestinal calcium absorption, suppresses osteoblastic formation, and stimulates osteocyte apoptosis. The possible mechanisms involved may be different, since the pathophysiology is complex and still unclear (Fig. 1). One potential major mechanism is imbalance of calcium and phosphate metabolism. Calcium absorption is reduced in the intestine and renal excretion is increased. The effects are not mediated by changes in vitamin D metabolism or of levels of vitamin binding protein.  Dexamethasone increases the proresorption ratio in marrow stromal cells, but data on bone resorption are still inconsistent. Increased trabecular perforation by bone microarchitecture studies suggests a marked decrease in bone formation as a potential mechanism underlying glucocorticoids-induced osteoporosis. Modulation of synthesis of bone-specific proteins, including the early transcription factor cbfa-1 - involved in osteoblastic differentiation - has been reported. The glucocorticoid ADRs effect on marrow mesenchymatous cells is complex.  Other effects are decreased synthesis of type I collagen by mature osteoblasts, reduced expression of IGF-1 (an autocrine growth factor for osteoblasts) and of its binding proteins 3, 4 and 5 , decreased osteoblasts adhesion to extracellular matrix , promotion of matrix breakdown and stimulation of collagenase activity by inhibition of collagenase inhibitor TIMP-1 [(Fig. 1). There is evidence that glucocorticoids may enhance the response of osteoblast to PTH by increasing the number of PTH receptors.  Very recent data suggest an involvement of nitric oxide (NO) synthase in glucocorticoid-induced osteoporosis. The mechanistic link is still not elucidated, but studies in rats showed that NO improves osteoporosis induced by methylprednisolone. This evidence suggests a potential role for the NO mechanisms but more data are needed. BISPHOSPHONATES Bisphosphonates (BPs) is an important class of drugs used to treat osteoporosis, Paget disease, multiple myeloma and metastatic cancer to the bones. BPs have a potent inhibitory effect on osteoclastic activity and induce apoptosis. The novel aminobisphosphonates, alendronate, pamidronate, risedronate, zoledronic acid, and ibandronate, have higher potency due to nitrogen in the side chain of the molecule. These drugs also have antiangiogenenic and antitumor effects.  BPs are generally considered welltolerated drugs with minimal ADRs, even though long-term risks associated with prolonged BP exposure have not been fully described yet. One of the concerns is the very prolonged half-life of these compounds which are incorporated into the skeleton without being degraded; for example the estimated half-life for alendronate is up to 12 years. After BPs use in oncology, approved in 1995, and with novel more potent drugs available, the major concern for BPs long-term therapy is osteonecrosis of the jaw (ONJ).  Clinically, ONJ appears as an area of exposed yellow-white hard bone with smooth or ragged borders, extraoral or intraoral sinus tracts may be present. The ONJ can develop spontaneously or more often after dental treatment. The disorder is usually painful, but sometime is asymptomatic. The first bisphosphonates-associated ONJ cases were reported in 2003. After this alert, several papers appeared in the literature describing other cases of ONJ mainly in oncologic patients treated with IV BPs. In particular, Durie and coll. reported the results of a survey by the International Myeloma Foundation on 1203 patients, the estimated incidence of ONJ among the patients receiving zoledronic acid or pamidronate was 10% and 4% respectively.  The mechanisms of bisphosphonate-associated ONJ have not been fully elucidated. Physiologically, bone microfracture and microcracks signal the need for new bone formation. This signal can be detected by osteoblasts which will initiate new bone mineralization. Since BPs strongly inhibit osteoclastic activity, no bone resorption takes place after the formation of microfractures. This process results in accumulation of the non-vital bone that is usually resorbed by osteoclasts. The jaws are covered only by thin mucosa and periosteum, so the bones are more exposed to microtrauma and infection, leading to osteonecrosis. However, some cases of avascular necrosis of the hip have been reported in patients treated with BPs, raising the possibility that bisphosphonates- associated osteonecrosis is a true systemic complication at the bone level. RETINOIDS Retinoids are potent derivatives of retinol (the basic molecule of vitamin A), and have been proven to be important to improve the quality of life of many thousands of patients. However, a careful use of these important drugs is needed because of their side effects, many of which are similar to the clinical signs of the hypervitaminosis A syndrome. Musculoskeletal symptoms of vitamin A toxicity include muscle weakness, bone pain, bone abnormalities, hyperostosis, muscular stiffness and pain.  The precise mechanism of bone toxicity of vitamin A is not sufficiently clear. Retinol is released in target cells and converted to retinoic acid, which exerts its effects by binding to specific nuclear receptors. These retinoic acid receptors have been identified in nearly every cell including osteoblasts, osteoclasts and chondrocytes. Retinoic acid suppresses osteoblast activity, stimulates osteoclast formation, and antagonizes the ability of vitamin D to maintain normal serum calcium levels. All of which may contribute to bone resorption and skeletal fractures.  Hyperostosic changes or calcification of tendons and ligaments, resembling those observed in diffuse idiopathic skeletal hyperostosis (DISH), are the most frequently reported skeletal ADRs associated with retinoids. DISH is common in the general population and increases with aging; patients receiving chronic retinoid therapy, particularly with higher doses, have a very high likelihood to develop DISH like hyperostosis. Monitoring skeletal toxicity during a single course of retinoid therapy is generally not indicated, while repeated short courses or long-term use of retinoids may require monitoring for skeletal toxicity.  Another relevant retinoid bone toxicity is the premature epiphyseal closure in children. It has been suggested that this isotretinoin effect may be related to alterations in the characteristic pattern of chondrocyte gene expression. Animal data indicate that activation of the retinoic acid receptors is necessary and sufficient to cause epiphyseal dysfunction or destruction.  Arthralgia, back pain, musculoskeletal aches and pain are frequently observed in patients receiving isotretinoin , however the discontinuation of therapy is only occasionally required. Myalgia occurs in up to 15% of treated patients with isotretinoin in some of the cases showing elevated creatinine phosphokinase levels , more myalgia than expected is reported if patients perform physical activities. Some cases of aseptic arthritis associated with isotretinoin therapy have been reported. A possible explanation of these cases involves the induction of lysosomal membrane solubilization and resultant cytopathic destruction of the synovia leading to increased sensitivity to mechanical injury. Arthralgia, back pain and myalgia are also reported for acitretin and alitretinoin.  PROTON PUMP INHIBITORS Omeprazole and other proton pump inhibitors (PPIs) are drugs used worldwide for treating oesophageal reflux and dyspepsia. PPIs have been shown to be well tolerated by patients, with a frequency of mild side effects of about 1-3%. Headache, diarrhoea, skin rashes are the most frequently reported ADRs, while muscle cramps, myalgia, joint pain, and leg pain, developed in less than 1% of patients during treatment. In the literature, anedoctal case reports suggested the association between PPI and severe muscular injury, often as a result of drug interactions. A case of acute severe myopathy was recently observed after a single infusion of omeprazole, suggesting the need to moni-toring. ANTIPSYCHOTIC DRUGS Neuroleptic malignant syndrome (NMS) is a rare but life threatening disorder usually induced by antipsychotic drugs, characterized by hyperthermia, extrapyramidal symptoms as rigidity, altered consciousness, autonomic dysfunction, including diaphoresis and incontinence and elevated serum creatinine phosphokinase levels. Prospective studies have reported NMS occurrence rates ranging from 0.07% to 2.2% of patients receiving neuroleptics. Recent literature data suggest that NMS due to novel antipsychotics, with lower affinity for the dopamine D2 receptor, exhibits less muscle rigidity.  Severe muscle disorders as rhabdomyolysis – without evidence of NMS - has also been reported with typical and atypical antipsychotics such as haloperidol, clozapine and olanzapine. Some cases of rhabdomyolysis were related to the correction of hyponatremia in patients developing psychogenic polydipsia, possibly complicated by newer antipsychotic drugs. The Authors recommended regular monitoring of muscle enzyme concentrations in antipsychotic- treated patients with concomitant hyponatremia secondary to psychogenic polydipsia, in order to detect rhabdomyolysis  In a small study, decreased bone mineral density was observed in female, premenopausal schizophrenia patients receiving risperidone, but not in those receiving olanzapine. Age-adjusted bone speed of sound was significantly lower in women treated with risperidone as compared with patients treated with olanzapine when determined at radius and phalanx (p < 0.05), but not tibia. This effect is most likely due to persistent risperidone- induced hyperprolactinemia. ANTICOAGULANT DRUGS The use of heparins results in a risk of osteoporosis complicated by bone fractures, with low-molecular weight heparins (LMWHs) carrying a lower risk than unfractioned heparin (UFH). This effect has been correlated with long term use (greater than 6 months) and doses exceeding 15,000 IU per day. Osteoporosis has mostly been studied in pregnant women, where LMWHs appears to be safer than UFH, but they can still inhibit bone formation.Calcium, vitamin D supplementation and weight-bearing exercise are recommended to obviate heparin associated osteoporosis. It was suggested that osteoporosis may be due to heparin induced menhancement of collagenolysis or to enzyme inhibition. By using animal models, it was demonstrated that heparin causes bone loss by increasing osteoclast number and activity, and by enhancing osteoclast formation, through MAP kinase pathway upregulation.  Oral anticoagulants, such as warfarin, are vitamin K antagonists and exert an inhibition of theƔ -carboxylation of glutamic acid residues, conversion that activates clotting factors as well as bone proteins. On the basis of this mechanism and from growing bone observation in human and rat studies, the use of warfarin is considered a strong risk factor for osteoporosis. However, several observational studies aimed to answer the question of whether and how much warfarin exposure is associated with osteoporotic fracture in different patient populations, reached conflicting results.  In a very recent retrospective cohort study in more than 14,000 patients with atrial fibrillation, long term use of warfarin was associated with a 25% increased risk of osteoporotic fractures, whereas α-adrenergic antagonists may have a protective effect on bone density and risk of fracture. To minimize this risk, health care providers could give some advise when prescribing warfarin to elderly persons at high risk of falling, such as having adequate intake of calcium and vitamin D, regular exercise, to use walking aids and by discontinuing unnecessary drugs.