Term
| Rate limiting step of cholesterol synthesis |
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Definition
| HMG-CoA reductase (Hydroxy-Methyl-Glutaryl CoA reductase: HMG CoA to Mevalonate) |
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Term
| Lipophilic statins mode of action, effect, examples |
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Definition
| Diffuse freely through cell membrane of hepatocytes, inhibit HMG-CoA reductase, which reduces cholesterol in cell, which triggers the sterol sensing domain of ER to move to Golgi where SREBP (sterol regulating element binding protein) is freed. This activates genes for LDL receptors that increase LDL/cholesterol re-uptake from blood vessels, ex: lovastatin, simvastatin, fluvastatin, atorvastatin |
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Term
| Pleiotropic effects of statins |
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Definition
| Helps to treat osteoporosis, cancer, Alzheimer's Disease and Multiple sclerosis |
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Term
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Definition
| When isoprenoids (intermediate product of cholesterol syntheses down stream of HMG CoA and mevalonate) bind to G-proteins like Rho/Ras, they are brought to cell membrane and activated. Statins reduce isoprenoid and thus G-protein activation. |
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Term
| Formation of atherosclerotic plaque mechanism |
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Definition
| Diabetes, high cholesterol and high bp damage endothelium of vessel, lipids leak in and are oxidized attracting monocytes that invade endothelium (sub-epithelium) and become macrophages that grow and become foam cells. Smooth muscle cells also proliferate further narrowing lumen, plaque breaks open, clot forms, clot released into blood stream. |
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Term
| How do statins prevent endothelial dysfunction? |
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Definition
| Statins reduce monocyte adherence to endothelium, reduce MMP (matrix metaloproteases) used by macrophages to move through endothelium (increasing plaque stability), increase collagen (increasing plaque stability), decrease Rho/Ras prenylation and activity (which decreases smooth muscle cell proliferation and stenosis), blocks production of mevalonate which usually inhibits production of NO. Increased NO dilates vessel. |
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Term
| Action of statins on osteoclasts |
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Definition
| Statins block formation of isoprenoids Geranylgeranyl PP and Farnesyl PP (also blocked by N-containing bisphosphonates), which prenylate Rho protein that promotes ruffled border of osteoclasts, which is necessary for bone breakdown. |
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Term
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Definition
| Lovastatin, simvastatin, pravastatin (from fungus) |
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Term
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Definition
| Atorvastatin (Lipitor), fluvastatin, rosuvastatin...cerivastatin removed from market due to drug interaction with fibrates |
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Term
| Hydrophilic statins mode of action, effect, examples, advantages over lipophilic statins?? |
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Definition
| Move through OATs (organic acid transporters) of membrane of hepatocytes, inhibit HMG-CoA reductase, which reduces cholesterol in cell, which triggers the sterol sensing domain of ER to move to Golgi where SREBP (sterol regulating element binding protein) is freed. This activates genes for LDL receptors that increase LDL/cholesterol re-uptake from blood vessels, ex: pravastatin, rosuvastatin; higher FPE, lower bioavailability, can't diffuse into other cells |
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Term
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Definition
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Term
| Statin not metabolized by CYP450 enzyme? CYP450 enzyme that metabolizes most statins? Statins metabolized by 2C9? Excretion? |
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Definition
| Pravastatin; CYP450 3A4 (beware of inhibitors like grapefruit juice and cimetidine); Fluvostatin and Rosuvastatin by 2C9. Excreted through feces. |
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Term
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Definition
| Natural, hydrophilic statin, not metabolized by CYP450 enzyme, with only 50% protein binding (bad, frees to move throughout body) but uses liver specific OAT, so cancels possible negative effect. |
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Term
| Statins with long half lifes (>3 hr) |
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Definition
| Atorvastatin and Rosuvastatin (greatest effect on HDL-cholesterol and TGs too) |
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Term
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Definition
| Decreased LDL-cholesterol (Also smaller decrease in TG and small increase in HDL-cholesterol especially atorvastatin and rosuvastatin) |
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Term
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Definition
| hepatotoxicity (dose-related elevated serum transaminases in minority of users), rhabdomyotoxicity (myalgia -> myopathy with elevated CK [creatin phosphokinase] levels -> rhabdomyolysis with myoglobinemia [clogs glomerulus] & myoglobinuria [tea-colored]); increases K = hyperkalemia and cardiac arrhythmias |
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Term
| Risk factors for statin-induced myotoxicity |
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Definition
| -dose, use of other CYP450 (3A4 & 2C9) metabolized drugs, use of other drugs that produce myotoxicity like fibrates, theoretically lipophilic statins are worse |
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Term
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Definition
| Pregnancy (FDA category X), active chronic liver disease |
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