Anti-Hyperlipidemics Flashcards
What is cholesterol?
-Essential component of cell membranes
-Precursor to sterols and steroids
What are triglycerides?
-Storage form of fuel to support generation of high energy compounds
-Component of structural lipids
What do lipoproteins do?
Lipoproteins transport cholesterol and triglycerides in the blood
What are lipoproteins made of?
-Phospholipid, free cholesterol, and protein making up the surface
-Core made of triglyceride and cholesterol ester
What do apoproteins do?
Critical in regulating transport and metabolism
What does the lipoprotein lipase system do?
Release free fatty acids from lipoproteins
What are the major classes of lipoproteins?
-Chylomicrons
-VLDL
-IDL
-LDL
-HDL
What are chylomicrons?
lipoproteins involved in the transport of dietary lipids from the gut to the liver and adipose tissue
What is VLDL?
Very low density lipoproteins are secreted by the liver into the blood as a source of triglycerides
What is IDL?
Intermediate density lipoproteins - VLDLs when they are depleted of triglyceride
What is LDL?
Low density lipoproteins are the main form of cholesterol in the body
What is HDL?
High density lipoproteins are secreted by the liver and acquire cholesterol from peripheral tissues and atheromas through reverse cholesterol transport
What are the important apolipoproteins?
-ApoA-I
-ApoB-100
-ApoB-48
-ApoE
-APoCII
What are the characteristics of ApoA-I
-Structural in HDL
-Ligand of ABCA1 receptor
-Mediates reverse cholesterol transport
-Produced in the liver and intestine
What are the characteristics of ApoB-100?
-Structural in VLDL, IDL, LDL
-LDL receptor ligand
-Produced in the liver
What are the characteristics of ApoB-48
-Structural in chylomicrons
-Produced in the intestine
What are the characteristics of ApoE?
-Ligand of LDL remnant receptor
-Reverse cholesterol transport with HDL
-Produced in the liver and other tissues
What are the characteristics of ApoCII?
-Found in chylomicrons and LDL
-Binds to lipoprotein lipase to enhance triglyceride hydrolysis
-Found typically in the capillaries where fatty acid transport happens
Where can lipoprotein lipase be found?
In capillaries of fat, cardiac and skeletal muscle
Where can hepatic lipase be found?
Produced in the liver and is key in converting IDL to LDL
Which molecule is key in making cholesterol?
Mevalonate
Which cholesterol synthesis is the major source of cholesterol
De novo synthesis
Which cholesterol synthesis is most critical to total body burden?
Liver synthesis
Which diseases are associated with hyperlipoproteinemia?
-Atherosclerosis
-Premature coronary artery disease
-Stroke
Which diseases are associated with hypertriglyceridemia?
-Pancreatitis
-Xanthomas
-Increased risk of CHD
What is oxidized LDL?
-Modified LDLs
-Stimulates T cells in the intima
-Gets into areas between the endothelium of the blood vessel
How does LDL get into the macrophage?
-LDL gets in through pinocytosis and the LDLR protein
-Oxidized LDL gets in through the SR-A and CD36 proteins
What does the lysosome do in the macrophage?
Breaks down LDL into free cholesterol
What are the two fats of free cholesterol in the macrophage?
-Esterified into cholesterol ester by ACAT1
-Transported out of the macrophage through the HDL mediated proteins ABCA1, SR-BI, or ABCG1
What are the goals of therapy for hyperlipidemia?
-Decrease reabsorption of excreted bile acids
-Increase number of LDL receptors in the liver
-Decrease secretion of VLDL from the liver
-Decrease synthesis of cholesterol
-Increase hydrolysis of lipoprotein triglycerides
-Ultimately the goal is to reduce atherosclerosis
How much of a reduction in the incidence of coronary heart disease is associated with a 10% reduction in cholesterol levels?
~10-30% reduction
Which drug classes are used for high cholesterol?
-Bile acid binding resins
-Inhibitors of cholesterol absorption
-Inhibitors of cholesterol synthesis
-PCSK9 inhibitors
-MTTP inhibitors
Which drug classes are used for high triglycerides?
-Fibrates
-Niacin
-Omega 3 fatty acids
What are the bile acid-binding resins?
-Cholestyramine (Queastran)
-Colestipol (Colestid)
What is the mechanism of action of the bile acid-binding resins?
-Inhibit reabsorption of bile acids from the intestine by binding bile acids to form insoluble complex excreted in the feces
-Up-regulates LDL receptors in the liver
-Large molecular weight polymers exchange chloride ions for bile acids
Therapeutic use of bile acid binding resins
-Treatment of primary hypercholesterolemia produces ~20% reduction in LDL cholesterol in 2-4 weeks
-May cause ~5% increase in HDL
-May increase TG
Side effects of bile acid binding resins
-Constipation and bloating
-High fiber diet and water helps
Drugs that interact with bile acid binding resins
-Acetaminophen
-Thiazides
-Warfarin
-Digoxin
-Fibrates
-Ezetimibe
-Oral contraceptive
-Corticosteroids
-Thiazolidinediones
What is the cholesterol absorption inhibitor?
Ezetimibe
What is the mechanism of action of ezetimibe?
Inhibits intestinal absorption of cholesterol from dietary sources and reabsorption of cholesterol excreted in bile (inhibits NPC1L1)
What is the indication for ezetimibe?
The primary clinical effect is to reduce LDL levels (~17%)
-Usually used in combination with statins (may enhance statin action up to 20%)
What are the adverse effects associated with ezetimibe?
-Low incidence of liver/skeletal muscle damage
-Generally well tolerated compared to placebo
What is the common pharmacophore of statins?
Mevalonic acid
Which statins are prodrugs?
Lovastatin and simvastatin
Which statins are not CYP substrates?
Pravastatin and pitavastatin
What is the mechanism of action for statins?
-Competitively inhibit HMG-CoA reductase which is the rate-limiting enzyme in cholesterol biosynthesis
-Up-regulates LDL receptors enabling more LDL to be delivered to the liver, thus reducing plasma cholesterol
What are all of the statin drugs?
-Fluvastatin
-Rosuvastatin
-Atorvastatin
-Lovastatin
-Simvastatin
-Pravastatin
-Pitavastatin
Indications for statin drugs
-Hypercholesterolemia: elevated LDL; elevated LDL with slightly elevated TGs
-Standard practice to initiate therapy immediately after a myocardial infarction, irrespective of lipid levels
Expected results of statins
-20-60% reduction in LDL
-10-33% reduction in TG
-5-10% increase in HDL
Which statins are metabolized by CYP 3A4?
-Lovastatin
-Simvastatin
-Atorvastatin
Which statins are metabolized by CYP 2C9?
-Fluvastatin
-Rosuvastatin
Adverse effects associated with statins
-Rhabdomyolysis (increased incidence when co-administered with cyp inhibitors; may occur with fibrates such as gemfibrozil)
-Hepatotoxicity
-Increased incidence of type 2 diabetes
What is the ATP-Citrate Lyase inhibitor?
Bempedoic acid
How is bempedoic acid taken?
-Orally
-Once daily
-Adjunct to statins
What is ATP-Citrate Lyase?
ACL is an enzyme upstream of HMG-CoA in the cholesterol synthetic pathway
What is bempedoic acid indicated in?
Added to statin therapy in patients with heterozygous familial hypercholesterolemia or established cardiovascular disease
How is bempedoic acid metabolized?
By glucuronidation and excreted via the kidneys
What are some possible side effects that can occur with bempedoic acid?
Hyperuricemia and gout because of the inhibition of OAT2 in renal tubules
What are the PCSK9 inhibitors?
-Alirocumab
-Evolocumab
-Inclisiran
What is PCSK9?
-Proprotein convertase subtilisin kexin type 9 (a serine protease)
-Promotes degradation of LDL receptors in the liver
How are PCSK9 inhibitors taken?
Injected subq every two weeks or once a month for evolocumab
What are PCSK9 inhibitors indicated in?
-Adjunct to diet and maximally tolerated statin therapy in patients with established ASCVD, HeFH, and HoFH
What is the newer PCSK9?
Inclisiran
How does inclisiran work?
It is an siRNA that hybridizes PCSK9 mRNA and directs degradation in hepatocytes to lower LDL cholesterol
When is inclisiran used?
-Used as an adjunct to statins in HeFH and ASCVD
Side effects of inclisiran
-Injection site reactions
-Arthralgia
What is juxtapid?
Small molecule microsomal TG transfer protein inhibitor
What does juxtapid do?
Inhibits assembly of Apo B containing lipoproteins in the liver (VLDL production) and intestine (chylomicron production)
How is juxtapid given?
-Orally
-Daily, with increases in dose every two weeks
What is juxtapid indicated in?
Adjunct to other treatments for patients with homozygous familial hypercholesterolemia - LDLR mutation
What is a warning associated with juxtapid?
High risk of liver damage - restricted prescription program
What is mipomersen?
Phosphorothioate anti-sense oligonucleotide inhibitor of Apo B100 (liver)
What does mipomersen do?
Hydrolizes Apo B100 mRNA in the liver and promotes degradation
How is mipomersen taken?
Injected SQ once/week
What is mipomersen indicated in?
indicated as adjunct to other treatments for patients with homozygous familial hypercholesterolemia
What is a risk associated with mipomersen?
High risk of liver damage - restricted prescription program hepatic steatosis
What does evinacumab-dgnb do?
Increases lipoprotein lipase and endothelial lipase activity by preventing ANGPTL3 mediated inhibition. Lowers LDL-cholesterol
How is evinacumab-dgnb given?
IV infusion once per month
What does evinacumab-dgnb indicated for?
Homozygous familial hypercholesterolemia
What are the fibrates?
Gemfibrozil and fenofibrate
What do fibrates target?
Peroxisome proliferator-activated receptor-alpha activatrors
What are fibrates derived from?
Branched carboxylic acid know as fibric acid
What is the difference between gemfibrozil and fenofibrate?
Fenofibrate must undergo bioactivation to fenofibric acid
Expected results of fibric acid derivatives
-Reduce serum LDL by 6-20%
-Reduce serum TGs by 35-53%
-Elevate HDL 15-30%
Therapeutic indications for fibric acid derivatives
-Hypertriglyceridemia in which VLDL predominate
-Second line drug for mixed hyperlipidemia
Side effects associated with fibric acid derivatives
-Gallstones
-Rhabdomyolysis (Use with caution with statins)
What drug can interact with fibric acid derivatives?
Warfarin
What is the mechanism of action of niacin?
-Reduce serum triglycerides
-Increases lipase activity to increase clearance of VLDL
-Decreases hepatic VLDL production
-May significantly reduce serum LDL and TG
-Usually increases HDL levels
What tissues does niacin target?
-Adipose tissue
-Liver
-Macrophages
How does niacin effect adipose tissue?
Inhibits TG lipolysis by hormone-sensitive lipase decreasing FS transport to liver via activation of GPR109A
How does niacin effect liver tissue?
-Inhibits fatty acid synthesis and esterification reducing TG export via VLDL
-Reduces clearance of apoA-I but not CEs increasing HDL levels and reverse transport
How does niacin effect macrophages?
Increases expression of CD36 and ABCA1 decreasing CE content via HDL-mediated reverse transport
Indications for niacin
-Effective for mixed hyperlipidemias
-Hypertriglyceridemia with risk of pancreatitis (decreases TG 25-30%)
-Effective drug for raising HDL levels (15-35%)
-Used in combination with resin drugs to treat severe cases of hyperlipidemia; also combined with statins
Adverse effects associated with niacin
-Marked vasodilation (cutaneous flushing), itching, tingling of upper body and headache may occur with initial dosing - prostaglandins mediate these
-Hepatotoxicity - sustained release preparations
What are the omega-3-fatty acid ethyl esters?
-Lovaza, Omtryg (EPA + DHA)
-Vascepa (EPA only)
Mechanism of action of omega-3-fatty acid ethyl esters
-Reduce synthesis of triglycerides in the liver: omega-3 fatty acids are poor substrates for enzymes responsible for TG synthesis
-Inhibits esterification of other fatty acids
Indications of omega-3-fatty acids
-Lipid lowering diet is initiated before Lovaza is started
-Severe hypertriglyceridemia >500 mg/dl
Adverse effects of omega-3-fatty acids
-Can increase LDL-C levels (only the combo products)
-Combined with statins to lower LDL-C levels
