B6.086 Prework: Statin Myopathy Flashcards
common drug related myopathies
statins
steroids
alcohol
most common defined cause of myalgia and hyperCKemia
statins
used in a widespread fashion
mechanism of statins
competitive inhibitors of HMG-CoA reductase
occupy a portion of the binding site of HMG-CoA and block access to the active site on the enzyme to decrease the rate of cholesterol synthesis
net effect of statins
decrease endogenous cholesterol synthesis (most common source of cholesterol in the body)
eventually increase LDL receptor expression
increased LDL taken up from blood and metabolized
net effect: less LDL circulation
toxicity of different statins
proportional to their lipophilicity and their dependence on cytochrome P450 (CYP3A4)
generally metabolized in the liver, except pravastatin which is cleared by the kidneys
other effects of statins
immunosuppressive
neuroprotective
affect cholesterol metabolism in cell membranes
cellular structures that can be damaged by statins
sarcolemma
sarcoplasmic reticulum
mitochondria
severe myonecrosis leading to rhabdomyolysis is unusual (0.1% of patients)
effect of statins on CoQ10 (ubiquinone)
inhibit biosynthesis
serum levels of CoQ reduced by 50% in patients taking statins
muscle CoQ levels remain normal in statin myopathy
myalgia
muscle discomfort, including muscle aches, soreness, stiffness, tenderness, or cramps with or soon after exercise
normal CK level
myopathy
muscle weakness (not due to pain) with or without elevation in CK
myositis
muscle inflammation
myonecrosis
elevation in muscle enzymes compared to either baseline CK levels (when not on statin therapy) or the upper limit of normal that had been adjusted for age, race and sex
clinical rhabdomyolysis
myonecrosis with myoglobinuria or acute renal failure (increase in serum creatinine of at least 0.5 mg/dL)
factors that increase the risk of stain myopathy
drugs that inhibit P450 3A4 concurrent use of a drug or drug class that is independently considered a risk factor for myopathy
rug or drug class that is independently considered a risk factor for myopathy
glucocorticoids cyclosporine daptomycin zidovudine fibrates
CYP3A4 drugs
cyclosporine macrolide antibiotics (erythromycin) systemic-azole antifungals HIV/HCV protease inhibitors including ritonavir-boosted regiment Ca2+ channel blockers
grapefruit juice
inhibits intestinal CYP3A4
not much evidence that it increases stain myopathy, but usually cautioned
statins metabolized by CYP3A4
simvastatin
lovastatin
atorvastatin (lesser extent)
statins metabolized by CYP2C9
fluvastatin
statins metabolized by non CYP-450 transformations and affected by fewer interactions
rosuvastatin
pitavastatin
pravastatin
symptoms of statin induced myalgia and myopathy
proximal, symmetric muscle weakness and/or soreness
muscle tenderness
functional impairment such as difficulty raising the arms above the head, arising from a seated position, or climbing stairs
onset of muscle symptoms of statin myopathy
within weeks to months after the initiation of statin therapy (avg around 6 months)
may occur at any time during treatment
treatment of statin myopathy
stop statin (takes around 6 months to stop symptoms) no other treatment except supportive care for those with rhabdo
autoantibodies against HMG-CoA reductase
detected in patients with statin associated necrotizing myopathy
what is myotoxicity
direct injury to muscle cell membranes, organelles, or protein
- immunopathic processes
- secondary systemic effects, such as ischemia and electrolyte disturbances
causes of focal myopathy
repeated IM injections
snake venoms
“needle myopathy” in hospitals
characteristic pathological features of focal myopathy
dense focal fibrosis
scattered fiber necrosis
variable inflammatory infiltration
(normal muscle adjacent)
features of necrosis and rhabdomyolysis
necrosis, phagocytosis, and fiber regenerations
variations in fiber size and an increase in internal nuclei
markedly elevated CK levels
pathophysiology of statin myopathy
sarcolemmal damage allows an influx of Ca2+
-cycles of fiber necrosis
experimental studies:
-accumulation of subsarcolemmal autophagic lysosomes
-degeneration of mitochondria and the sarcoplasmic reticulum
-marked necrosis and regeneration with macrophage infiltration
function of CoQ
participates in electron transport during oxidative phosphorylation
enzymes inhibited by statins other than HMG CoA reductase
mevalonate kinase
- essential for isoprenylation
- causes muscle fiber damage
function of isoprenylation
prenylated proteins are vital for optimal function of a number of muscle membrane proteins
- lamin A/C
- dystroglycans
what is statin myositis
statin myopathy that fails to resolve with drug withdrawal
features of inflammatory myopathy
features of statin induced necrotizing autoimmune myopathy (NAM)
presents without MHC class 1 up regulation principally humorally mediated
treatment of statin myositis
steroids
immunosuppression
treatment of necrotizing myopathy
often protracted
requiring multiple agents including interventions effective against humoral mediators (IVIg)
