Statins Flashcards
What are the normal LDL, HDL and TG? Or what do you want them at
LDL <160
HDL >35
TG <200
What controls how much LDL cholesterol is circulating in the blood?
LDL receptors, through up/down receptor regulation
What are the HMG-CoA reductase inhibitors MOA?
Inhibit cholesterol synthesis in the liver, causing the liver to upregulate LDL receptors on the liver, increasing removal of LDL cholesterol in the blood (20-55%), as well as TG
What is the rate limiting step in cholesterol synthesis?
Production of melalonate through MHG-CoA reductase
Summed up, what do statins do?
Decreased LDL cholesterol through upregulation of hepatic LCL receptors, decreased VLDL, IDL, triglycerides
Increases HDL
What did the WOSCOPS discover?
Pravastatin reduced CV events
Independent rate reduction independent of baseline LDL
Event rate reduction did not correlate with pravastatin induced decreases in LDL cholesterol
What are the non lipid effects of statins? Must know
Improved Endothelial function- improved ability to release NO
Anti-inflammatory effects- increased plaque stability
Antioxidant effects-reduced susceptibility of LDL to oxidation
Inhibition of platelet aggregation
Inhibition of cardiac hypertrophic growth
What are the “non lipid” effects due to in statins?
Inhibition of melvolonate leads to inhibition of Isoprenoids, which are biologically active, causing decrease in downstream cellular processes
What is the absorption like in statins?
Poor oral bioavailability due to first pass metabolism
What is the distribution in statins?
Most are highly protein bound once reaching the circulation
What is the metabolism of statins?
Metabolized in the liver, P450 and 3A4 involved
What are the three statins not involved with the CYP system?
Pravastatin, pitavastatin, rosuvastatin
How are most statins eliminated?
Hepatically through bile
What is the main adverse effect of statins?
Skeletal muscle toxicity
Elevation of Creatine phosphokinase
Possibly leading to rhabdo
What can be added with statins to reduce skeletal muscle toxicity?
Gimfibrazil- a fibrate
What is the risk of having lower activity of SLC01B1?
Increasesd risk of skeletal muscle toxicity
What are the other adverse effects of statins?
elevated AST/ALT
Not for pregnancy
Whats the pneumonic for remembering the specific metabolizations of statins?
Lipid lowering Statins Are First line Primary Preventative Rxs
Which statins are metabolized by CYP3A4?
Lovastatin, simvastatin, atorvastatin
What statin is metabolized by CYP2C9?
Fluvastatin
What are the three bile acid sequestrants?
Cholestryamine, colestipol, and colesevela
What is the MOA of bile acid sequestrants?
These meds inhibit reabsorption of bile acid, forcing the liver to upregulate LDL receptors on liver in order to create more bile acid, decreasing plasma levels of LDL
What is also increased in bile acid sequestrants to help produce more bile acid?
HMG-CoA reductase
What rebound effect usually occurs after administration of bile acid sequestrants?
Hypertriclyeridemia, which is usually transient and returns to baseline with continued treatment
What are the pharmacokinetics for BAS?
None. It isn’t absorbed, distributed, metabolized, and gets eliminated in the feces
What are the ADE’s for BAS?
Very little. Relatively safe and inert because they are not absorbed.
Main ADE’s are related to GI discomfort, like bloating, dyspepsia, constipation, or Borborygmi (Rumbly in his tumbly, just gas movement)
What are the drug to drug interactions with BAS?
They reduce absorption of many drugs, so BAS should be administered one hour before or 3-4 hours after the resin
What are the three fibric acid derivatives?
Clofibrate (no longer used), gemfibrozil, and fenofibrate
What are fibric acid derivative MOA?
Fibrates bind to peroxisome proliferator activated receptor alpha (PPARa). which causes stimulation of fatty acid oxidation, increased expression of lipoproteion lipase, increased expression of apoA-I and apoA-II, reduced ecpression of apoC-III
What the main effects fibric acid derivates ultimately cause?
Reduced triglycerides, LDL may go up or down
Mainly just effective for hypertriglyceridemia
What are the pharmacokinetics to know about fibrates (fibric acid derivatives)? ADME
Well absorbed orally, especially on an empty stomach
Highly protein bound, but well distributed
Metabolized by phase II Glucoronidation
Eliminated in the urine
What are fibrates ADE’s?
N/V, SKELETAL MUSCLE MYOPATHY
What medication class should not be administered with fibrates?
Statins
What are DHA or EPA?
Omega-3 fatty acids-fish oil
What is fish oil MOA?
Same as fibrate. Activation of PPAR-a Reduces triglycerides (IN THEORY)
What are ADE’s of fish oil?
GI-bad taste/regurgitation, GI upset
Allergic reactions
Purity concerns-trace metals like mercury
What is the MOA of Niacin?
Multiple
Inhibits the lipolysis of triglycerides, reducing the transport of free fatty acids to the liver
In the liver, reduces triglyceride synthesis, as well as LDL levels
Enhances LPL, promoting clearance of chylomicrons and VLDL triglycerides
What are the ADE’s of Niacin?
Facial flushing on first dose d/t prostoglandin mediated vasodilation, lasts about 1-2 weeks
GI- Dypepsia, n/v, diarrhea
Hepatotoxicity-Elevated LFT’s, fulminate hepatic necrosis
Insulin resistance-hyperglycemia
Increased uric acid levels-gout
Teratogenicity- Birth defects
What is the given cholesterol uptake inhibitor?
Ezetimibe
What is ezetimide MOA?
Inhibits the cholesterol transport protein (NPC1L1) in the membrane of jejunal enterocytes, which reduces cholesterol absorption by 54%, inhibits absorption of plant sterols from dietary source
What is the bodies compensatory response to ezetimide alone?
Liver increasing LDL receptor expression and cholesterol synthesis.
Which stains can inhibit
Should ezetimide be used alone?
No, used with statins
What is important to know about ezetimides ADME?
Just that it is restricted to the enterohepatic system, eliminated in the feces mainly
What is ezetimides ADE?
Very little, not sure if its safe in pregnancy
What is PCSK9?
Bind to LDL receptors, causing degredation, leading to decreased LDL uptake (more LDL levels in blood)
Genetic mutation
What are the PCSK9 inhibitors to know?
Alirocumab and evolocumab
What is the MOA of PCSK9 inhibitors?
Binds to PCSK9 and inactivates it
What are the two specific used for PCSK9 inhibitors?
Patients with familial hypercholesterolemia
Those who cannot tolerate statins
What is the one major downside to PSCK9 inhibitors?
Must be injected SQ every two weeks
What are the ADE’s of PSCK9 inhibitors?
Nasopharyngitis, Upper RTI, injection site reactions, allergic reactions, COGNITIVE IMPAIREMENT (r/t decreased cholesterol)
What is the MOA of Antsense Oligonucleotide?
Hybridizes with the mRNA, forming a complex, leading to degradation by RNAses
What is the antisense oligonucleotide?
Mipomersen
What is the downside to administration of mipomersen?
It is injected sq every week
What are the ADE’s for mipomersen?
Flu like symptoms
Injection site reactions
HEPATOTOXICITY BBW
Elevated LFTs, hepatic steatosis, contraindicated with drinkers of alcohol
What is Lopitamide?
MTTP inhibitors
What is lopitamides MOA?
Inhibits the microsomal triglyceride transfer protein which is used for chylomicron and VLDL assembly and sedcretion, so ultimately decreases LDL
What is Lopitamides BBW?
Liver toxicity
What is bempedoic acid?
An ATP Citrate Lyase Inhibitor
What is Bempedoic acids MOA?
Inhibits ATP citrase Lyase, which is what synthesizes acetyl CoA from citrate, leading to increased LDL receptors and decreased LDL plasma levels
What is Bempedoic acids ADEs?
Elevated uric acid levels
