B6.086 Prework: Statin Myopathy

Question 1

common drug related myopathies

Answer 1

statins
steroids
alcohol

Question 2

most common defined cause of myalgia and hyperCKemia

Answer 2

statins

used in a widespread fashion

Question 3

mechanism of statins

Answer 3

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

Question 4

net effect of statins

Answer 4

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

Question 5

toxicity of different statins

Answer 5

proportional to their lipophilicity and their dependence on cytochrome P450 (CYP3A4)
generally metabolized in the liver, except pravastatin which is cleared by the kidneys

Question 6

other effects of statins

Answer 6

immunosuppressive
neuroprotective
affect cholesterol metabolism in cell membranes

Question 7

cellular structures that can be damaged by statins

Answer 7

sarcolemma
sarcoplasmic reticulum
mitochondria
severe myonecrosis leading to rhabdomyolysis is unusual (0.1% of patients)

Question 8

effect of statins on CoQ10 (ubiquinone)

Answer 8

inhibit biosynthesis
serum levels of CoQ reduced by 50% in patients taking statins
muscle CoQ levels remain normal in statin myopathy

Question 9

myalgia

Answer 9

muscle discomfort, including muscle aches, soreness, stiffness, tenderness, or cramps with or soon after exercise
normal CK level

Question 10

myopathy

Answer 10

muscle weakness (not due to pain)
with or without elevation in CK

Question 11

myositis

Answer 11

muscle inflammation

Question 12

myonecrosis

Answer 12

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

Question 13

clinical rhabdomyolysis

Answer 13

myonecrosis with myoglobinuria or acute renal failure (increase in serum creatinine of at least 0.5 mg/dL)

Question 14

factors that increase the risk of stain myopathy

Answer 14

drugs that inhibit P450 3A4
concurrent use of a drug or drug class that is independently considered a risk factor for myopathy

Question 15

rug or drug class that is independently considered a risk factor for myopathy

Answer 15

glucocorticoids
cyclosporine
daptomycin
zidovudine
fibrates

Question 16

CYP3A4 drugs

Answer 16

cyclosporine
macrolide antibiotics (erythromycin)
systemic-azole antifungals
HIV/HCV protease inhibitors including ritonavir-boosted regiment
Ca2+ channel blockers

Question 17

grapefruit juice

Answer 17

inhibits intestinal CYP3A4

not much evidence that it increases stain myopathy, but usually cautioned

Question 18

statins metabolized by CYP3A4

Answer 18

simvastatin
lovastatin
atorvastatin (lesser extent)

Question 19

statins metabolized by CYP2C9

Answer 19

fluvastatin

Question 20

statins metabolized by non CYP-450 transformations and affected by fewer interactions

Answer 20

rosuvastatin
pitavastatin
pravastatin

Question 21

symptoms of statin induced myalgia and myopathy

Answer 21

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

Question 22

onset of muscle symptoms of statin myopathy

Answer 22

within weeks to months after the initiation of statin therapy (avg around 6 months)
may occur at any time during treatment

Question 23

treatment of statin myopathy

Answer 23

stop statin (takes around 6 months to stop symptoms)
no other treatment except supportive care for those with rhabdo

Question 24

autoantibodies against HMG-CoA reductase

Answer 24

detected in patients with statin associated necrotizing myopathy

Question 25

what is myotoxicity

Answer 25

direct injury to muscle cell membranes, organelles, or protein - immunopathic processes - secondary systemic effects, such as ischemia and electrolyte disturbances

Question 26

causes of focal myopathy

Answer 26

repeated IM injections snake venoms "needle myopathy" in hospitals

Question 27

characteristic pathological features of focal myopathy

Answer 27

dense focal fibrosis scattered fiber necrosis variable inflammatory infiltration (normal muscle adjacent)

Question 28

features of necrosis and rhabdomyolysis

Answer 28

necrosis, phagocytosis, and fiber regenerations variations in fiber size and an increase in internal nuclei markedly elevated CK levels

Question 29

pathophysiology of statin myopathy

Answer 29

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

Question 30

function of CoQ

Answer 30

participates in electron transport during oxidative phosphorylation

Question 31

enzymes inhibited by statins other than HMG CoA reductase

Answer 31

mevalonate kinase - essential for isoprenylation - causes muscle fiber damage

Question 32

function of isoprenylation

Answer 32

prenylated proteins are vital for optimal function of a number of muscle membrane proteins - lamin A/C - dystroglycans

Question 33

what is statin myositis

Answer 33

statin myopathy that fails to resolve with drug withdrawal | features of inflammatory myopathy

Question 34

features of statin induced necrotizing autoimmune myopathy (NAM)

Answer 34

``` presents without MHC class 1 up regulation principally humorally mediated ```

Question 35

treatment of statin myositis

Answer 35

steroids | immunosuppression

Question 36

treatment of necrotizing myopathy

Answer 36

often protracted | requiring multiple agents including interventions effective against humoral mediators (IVIg)