Hmg Coa Reductase Inhibitor

From Anvita Health Wiki

Contents 1 More Specific Terms 2 Epidemiology 3 Indications 4 Contraindications 5 Dosage 6 Dosage-adjustment-in-renal-failure 7 Pharmacokinetics 8 Monitor 9 Adverse-effects 10 Drug-interactions 11 Laboratory 12 Mechanism-of-action 13 Notes 14 More General Terms 15 Additional Terms 16 References

More Specific Terms

• atorvastatin (Lipitor)
• cerivastatin; rivastatin (Baycol, Lipobay)
• fluvastatin (Lescol)
• lovastatin (Mevacor, Altocor, monacolin-K, Altoprev)
• mevastatin
• pitavastatin; nisvastatin; itavastatin (Livalo)
• pravastatin (Pravachol)
• rosuvastatin (Crestor)
• simvastatin (Zocor)

Epidemiology

• 25% of people > 45 years of age are on a statin [99]

Indications

• treatment of hypercholesterolemia*

• may be coadministered with ezetimibe; effects on LDL cholesterol additive, but clinical benefit does not correlate
• may not be useful in patients > 80 year of age [45]

• peripheral vascular disease [30]
• treatment of proteinuria in conjunction with ACE inhibitors
• may attenuate risk associated with elevated CRP

• after acute myocardial infarction [3]
• in prevention of myocardial infarction [6]
• unstable angina [15,36]
• even in those patients with low LDL cholesterol* [17]
• serum CRP does NOT predict response to statins [82]

• may or may not benefit elderly with heart failure [45,46,71]
• may prevent sepsis in elderly with atherosclerosis [44]
• may provide benefit for osteoporosis [2,40]

• may diminish risk of fractures [42]

• may diminish risk of macular degeneration [8,40]
• may diminish risk of glaucoma [40] & cataracts [50]
• may diminish inflammatory-associated demyelination in multiple sclerosis [23]
• might be associated with reduction in cancer risk [55-57]

• may diminish risk of prostate cancer & colon cancer [39]
• no reduction in cancer risk [43]

• may reduce mortality from ischemic stroke [48]

• may diminish risk of stroke in women > 55 years of age
• may reduce all-cause mortality in women [56]

• may diminish perioperative mortality [52]
• rosuvastatin & other statins may reduce risk of venous thromboembolism [66]
• cardiovascular risk reduction [67,75,76] {4-year}

• all-cause mortality 0.6% (secondary prevention)
• # needed to treat to prevent 1 death = 48 [76]
• major coronary events 1.3%
• ischemic stroke 0.4%
• no mortality benefit for primary prevention [76]

• may diminish risk of mortality associated with pneumonia [83]

• * cardiovascular benefits may be independent of LDL cholesterol [10], or total cholesterol [19,27]; target for statin therapy may be non-HDL cholesterol [98]

Contraindications

• probably does not diminish risk of dementia (see Statins & the risk of dementia ..) [4,40]
• may not benefit patients > 80 years of age [45]
• does not lower risk of infection [87]

Dosage

• QD or QOD dosing may be equivalent [21]
• most of benefit obtained at usual starting dose [26]

Dosage-adjustment-in-renal-failure

• not required for atorvastatin, fluvastatin [12]

Pharmacokinetics

• most statins are metabolized by cyt P450 3A4, except

• pravastatin is isomerized to inactive metabolite
• rosuvastatin ( Crestor) & fluvastatin ( Lescol) are metabolized by cyt P450 2C9

• lovastatin bioavailability increased by food

• others may be taken without food [12]

• most statins cross the blood brain barrier

• the CNS has its own cholesterol metabolism
• pravastatin does not penetrate the blood brain barrier [54]

Monitor

• liver function tests no longer routinely indicated [80,97,100]

• check LFTs prior to initiation of statin
• check LFTs again only if symptomatic
• slight difference in recommendations for each statin [74]
• discontinue if serum ALT or serum AST > 3x upper limit of normal
• increased liver function tests (< 10-fold normal) NOT associated with increased risk of hepatotoxicity [33]

• creatine kinase [20]

• baseline levels on ALL patients
• recheck patients who develop myalgias or brown urine
• discontinue if 10x upper limit of normal
• monitor elevated levels < 10x normal weekly
• routine monitoring NOT recommended
  

• monitor with HMG CoA reductase inhibitors (statins)

Adverse-effects

• myopathy [49]

• increase in creatine kinase (mild to rhabdomyolysis)
• myopathy may occur with normal serum creatine kinase [22]
• risk factors [88]

• older age
• female gender
• renal insufficiency
• coadministration of fibrates, niacin, macrolides
• hypothyroidism
• alcoholism

• genetic variants in SLCO1B1 gene may predispose to statin myopathy [58]
• uncertain benefit of CoQ supplements [31,53]
• symptoms usually subside within a month or two after stopping the statin, but they sometimes persist longer [70]

• memory impairment is the 2nd most common complaint [14,54]

• reversible cognitive impairment [97]

• may increase incidence of postoperative delirium [61]
• hepatotoxicity (rare) [20,29,80]

• increased serum transaminases 3-10 fold 1.4% [40]
• increased liver function tests (> 10-fold) 1% [29,33,40]
• statins reduce cardiovascular events in patients with moderately abnormal liver function tests [[[Liver_Function_Test | LFTs]]]
• statins more beneficial in patients with abnormal LFTs than with normal LFTs [77]
• patients with abnormal LFTs who receive statins tend to have improvements in LFTs [77,80]
• no particular statin is more or less likely to cause LFT abnormalities [80]

• peripheral neuropathy (< 0.1%/year) [16]

• no evidence that CoQ supplements help [18]
• may take 3-12 months for neuropathy to improve after discontinuing statin [18]

• statin use may increase risk of pneumonia [69]
• increased risk of intracranial hemorrhage, independent of LDL [81]
• statins may increase risk of type 2 diabetes

• atorvastatin & rosuvastatin (evidence-base)
• risk may be dose-related [84]

• NO evidence of increased cancer risk within 10 years [37]
  
• drug adverse effects of HMG CoA reductase inhibitors

Drug-interactions

• inhibitors of cyt P450 3A4 inhibit metabolism of statins

• simvastatin ( Zocor), lovastatin ( Mevacor) > atorvastatin ( Lipitor)
• pravastatin ( Pravachol), rosuvastatin ( Crestor), fluvastatin ( Lescol) are safe to use with cyt P450 3A4 inhibitors
• pravastatin allegedly has least interaction [68]
• cyt P450 3A4 inhibitors that may interact with statins

• antibiotics:

• erythromycin, clarithromycin, telithromycin, isoniazid
• azithromycin ok

• antifugals:

• itraconazole, ketoconazole
• terbinafine ok

• Ca+2 channel blockers: diltiazem, nifedipine, verapamil
• antiretrovirals: delavirdine, efavirenz, indinavir, ritonavir, saquinavir
• others, see cyt P450 3A4

• increased risk of myopathy when statin is combined with:

• fibrates, cyclosporine, niacin
• use fenofibrate rather than gemfibrozil with statin [68]
• fluvastatin my be safest to use with cyclosporine [68]

• statin drug interaction summaries [47,68,72]
  
• drug interaction(s) of statins with antiviral protease inhibitors
• drug interaction(s) of statins with fibrates

Laboratory

• serum C-reactive protein does not predict response to statins [82]

Mechanism-of-action

• inhibition of HMG CoA reductase

• inhibition to cholesterol biosynthesis

• response to lipid-lowering effects dependent on genotype: apo E2 > apo E3 > apo E4

• also inhibits biosynthesis of isopentenyl pyrophosphate derivatives, including:

• ubiquinone CoQ
• dolichol phosphate
• prenyl proteins

• inhibition of HMG CoA reductase in the liver stimulates LDL-receptors, which results in an increased clearance of LDL from the bloodstream & a decrease in blood cholesterol & LSL cholesterol levels

• enhancement of osteoblast activity [2]
• anti-inflammatory properties

• reduction of plasma levels of C-reactive protein [7]
• lowers mortality associated with sepsis [11]

• Gram negative bacteria
• Staphylococcus aureus

• improves renal tubule function; reduces proteinuria [20]

• reduction in autoimmunity [24]

• reduction in MHC class II molecules
• increased production of Th2 cells
• decreased production of Th1 cells

• enhancement of nitric oxide synthase activity [9]
• inhibition of endothelin-1 [9]
• anti- platelet effects [13]
• inhibits proliferation of endothelial cells

• effects observed at somewhat higher level than achieved with clinical dose

• may have antithrombotic effects & fibrinolytic effects & may enhance the activity of other fibrinolytic agents [81]
• reduces risk of myocardial infarction & stroke in diabetics regardless of cholesterol levels [28]
• continuation of prescribed statin therapy lowers risk for all-cause mortality among patients with & without coronary heart disease ( mean age, 58 years; 51% female) [64]
• pravastatin does not lower blood pressure; it is not likely that other statin do either [73]
• high doses of rosuvastatin & atorvastatin result in similar atherosclerosis regression, despite greater reductions in LDL cholesterol with rosuvastatin [86]
  

• * benefits in elderly (see PROSPER study, [44])
• benefits shown in meta-analysis [41]
• benefits in elderly with coronary artery disease > 80 years [93]
• no reduction in mortality after MI in the elderly (> 80) [45]

Notes

• for comparison of different satins (see [80])

More General Terms

• enzyme inhibitor
• anti-hyperlipidemic agent

Additional Terms

• cholesterol biosynthesis
• hydroxymethylglutaryl [HMG] CoA reductase (HMGCR)
• statin clinical trials
• statin therapy in children
• Statins & the risk of dementia

References

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HMG CoA reductase inhibitor (statin)