Lipid Lowering Meds Flashcards
dyslipidemic drug classes
- HMG CoA reductase inhibitors (“statins” & bempedoic acid
- cholesterol absorption inhibitor (ezetimibe)
- PCSK9 inhibitors (monoclonal anibodies & siRNA)
- niacin
- fibrates/fibric acid derivatives
- omega 3 fatty acid derivatives
- bile acid binding resins (BABR)
citrate pathway to cholesterol synthesis within hepatocyte (important steps)
- ATP citrate lyase catalyzes conversion of citrate → acetyl-CoA
- acetyl-CoA → HMG Co-A
- HMG CoA REDUCTASE catalyzes conversion of HMG Co-A → mevalonic acid
- mevalonic acid → cholesterol
HMG CoA reductase inhibitors (statins) - MOA
*block HMG CoA reductase (one of the rate-limiting enzymes in the cholesterol synthesis pathway; normally converts HMG CoA to mevalonic acid)
*reversible inhibition
*results in decreased total cholesterol levels & increased LDL receptor expression
*main effect: LOWERS LDL
bempedoic acid - MOA
*blocks ATP citrate lyase (enzyme in the cholesterol synthesis pathway; normally converts citrate to acetyl-CoA)
*reversible inhibition
*results in decreased total cholesterol levels & increased LDL receptor expression (dose-dependent fashion)
HMG CoA reductase inhibitors - examples
*simvastatin
*ATORVASTATIN
*pravastatin
*ROSUVASTATIN
HMG CoA reductase inhibitors - ADEs
*headache
*fatigue
*N/V/D
*MUSCLE ACHES & PAINS (myopathies, myalgias, myositis)
*increased LFTs
*rhabdomyolysis
atorvastatin - MOA & metabolism
*HMG CoA reductase inhibitor → decreased total cholesterol & increased LDL receptor expression
*main effect: LOWERS LDL
*hepatic metabolism (CYP3A4 minor)
rosuvastatin - MOA & metabolism
*HMG CoA reductase inhibitor → decreased total cholesterol & increased LDL receptor expression
*main effect: LOWERS LDL
*hepatic metabolism (mixed enzymes [2C9]) & some renal
pravastatin - MOA & metabolism
*HMG CoA reductase inhibitor → decreased total cholesterol & increased LDL receptor expression
*main effect: LOWERS LDL
*hepatic GLUCURONIDATION (& some renal) metabolism
statin metabolism
*CYP3A = lovastatin, simvastatin, ATORVASTATIN (highest risk of drug interactions)
*CYP2C9 = fluvastatin, pitavastatin
*other enzymes/renal = pravastatin
*ROSUVASTATIN = CYP2C9/other enzymes/renal
dose-dependent effects of statins on LDL levels
*lower doses of statins result in a baseline reduction of LDL; increasing doses of statins results in a dose-dependent reduction of LDL
*2 high-intensity statins (cause the most marked reduction of LDL) = atorvastatin & rosuvastatin
*high doses of high intensity statins result in decreased triglycerides
*rule of 7: if you double the dose of the statin, you do NOT double the reduction of LDL levels (decrease it by about 7-8 mg/dL)
unintended benefits/consequences of statins
*mild increases in HDL
*decreased triglycerides if using high doses of high-intensity statins (atorvastatin, rosuvastatin)
*anti-inflammatory
*plaque stabilization or regression
*increased blood sugar
*dementia risk?
bempedoic acid - metabolism
*hepatic glucuronidation (lower risk of drug interactions)
bempedoic acid - ADEs
*tendon rupture
*hyperuricemia/gout
*increased serum creatinine/BUN
*anemia (decreased Hb)
*increased LFTs
ezetimibe - drug class & MOA
*cholesterol absorption inhibitor
*MOA: inhibits cholesterol absorption at the brush border of the small intestine
*mildly lowers LDL
ezetimibe - metabolism, ADEs, uses
*hepatic metabolism
*ADEs: N/V/D
*mainly used as an add-on therapy to a statin to achieve additional LDL reduction or in statin intolerance
PCSK9 inhibitors - examples
- monoclonal antibodies = alirocumab, evolocumab
- small interfering RNA (siRNA) = inclisiran
PCSK9 inhibitors (monoclonal antibodies) - MOA
*normally, PCSK9 binds to LDL receptors to prevent them from being recycled to the cell surface (resulting in decreased LDL receptors)
*monoclonal antibodies against PCSK9 allows for an INCREASE IN LDL RECEPTOR RECYCLING TO THE CELL SURFACE, so there are more receptors available to bind LDL (causing DRAMATIC LDL REDUCTION)
alirocumab - drug class, MOA
*PCSK9 inhibitor (monoclonal antibody)
*inhibition of PCSK9 → increased LDL receptors on the cell surface → marked LDL reduction
evolocumab - drug class, MOA
*PCSK9 inhibitor (monoclonal antibody)
*inhibition of PCSK9 → increased LDL receptors on the cell surface → marked LDL reduction
PCSK9 inhibitors (monoclonal antibodies) - metabolism, ADEs
*reticulo-endothelial system metabolism
*ADEs: injection site reactions, flu-like symptoms, myalgias, increased LFTs
inclisiran - drug class, MOA
*indirect PCSK9 inhibitor (siRNA)
*MOA: binds to ASPGR receptor & endocytosed → endosome is degraded, releasing siRNA → siRNA loaded into RISC complex → complex binds to PCSK9 mRNA and destroys it
*result: increased LDL receptors at the cell surface → marked LDL reduction
inclirisan - metabolism, ADEs
*metabolism: catalytic breakdown of mRNA for PCSK9 production
*ADEs: injection site reactions, flu-like symptoms, arthralgias, anti-drug antibodies
niacin - MOA & uses
*unclear; decreases synthesis and secretion of VLDL by the liver
*RAISES HDL (best drug to raise HDL), lowers LDL, lowers TG
*place in therapy:
-mixed hyperlipidemia
-combination therapy
-hypertriglyceridemia
niacin - ADEs
*dyspepsia
*FLUSHING
*itching
*urticaria
*increased LFTs
*use with caution in PUD and diabetes
niacin - metabolism
*hepatic conjugation (drug interactions: simvastatin, gemfibrozil)
fibrates (fibric acid derivatives) - examples
*gemfibrozil
*fenofibrate
fibrates (fibric acid derivatives) - MOA
*increase lipoprotein lipase activity (LPL)
*increase catabolism of VLDL
*variable effects on LDL, moderate rise in HDL, significant reduction of triglycerides
*BEST DRUG TO LOWER TRIGLYCERIDES
fibrates (fibric acid derivatives) - ADEs
*myalgias
*increased LFTs
*N/V/D
fibrates (fibric acid derivatives) - metabolism
*gemfibrozil: hepatic (drug interactions with lovastatin, simvastatin, and niacin)
*fenofibrate: hepatic (lower risk of drug interactions)
gemfibrozil - drug class, MOA
*class: fibrates (fibric acid derivatives)
*MOA: increase LPL activity & VLDL catabolism → REDUCTION OF TRIGLYCERIDES primarily
fenofibrate - drug class, MOA
*class: fibrates (fibric acid derivatives)
*MOA: increase LPL activity & VLDL catabolism → REDUCTION OF TRIGLYCERIDES primarily
omega 3 fatty acid derivatives - MOA
*decrease VLDL-TG synthesis and increase TG clearance (decrease lipogenesis, increase LPL)
*DECREASE TRIGLYCERIDES; increase HDL
omega 3 fatty acid derivatives - examples
*icosapentaenoic/docosahexenoic acids
*icosapent ethyl
omega 3 fatty acid derivatives - ADEs
*icosapentaenoic/docosahexenoic acids: taste disturbances, dyspepsia, increased risk of developing atrial fibrillation, increased risk of bleeding
*icosapent ethyl: peripheral edema, gout, increased risk of developing atrial fibrillation, increased risk of edema
bile acid binding resins (BABR) - examples
*cholestyramine
*colestipol
*colesevalm
bile acid binding resins (BABR) - MOA
*binds bile acids in the GI tract
*upregulation of LDL receptors
*lowers LDL, +/- HDL, raises triglycerides
bile acid binding resins (BABR) - uses
*mild to moderate LDL elevation
*combination therapy
bile acid binding resins (BABR) - ADEs
*N/V/D
*dyspepsia
*increased triglycerides
drugs to use to significantly reduce total cholesterol & LDL
- statins (high intensity - atorvastatin, rosuvastatin)
- PCSK9 inhibitors (alirocumab, evolocumab)
*second line: bempedoic acid, ezetimibe, BABRs, niacin
drugs used to significantly reduce triglycerides
- statins (high intensity - atorvastatin, rosuvastatin)
2nd line: fibrates, omega 3’s, niacin
drugs used to raise HDL levels
- NIACIN
2nd line: statins, omega 3’s
