Anti-hyperlipidemic drugs (Hockerman) Flashcards
Relative size, composition, physiological function of major classes of lipoproteins
Major classes of lipoproteins listed largest to smallest
* Chylomicrons
* Very Low-Density Lipoproteins (VLDL)
* Intermediate Density Lipoproteins (IDL)
* Low Density Lipoprotein (LDL)
* High Density Lipoprotein (HDL)
General Function/Info
* Transport cholesterol & triglycerides in blood
* Apoproteins on surface regulate transport & metabolism
Composition & physiological function of chylomicrons
- Primarily triglycerides, very little cholesterol, phospholipid and protein
- transports dietary lipids from gut to liver & adipose tissue
Composition & physiological function of VLDL
- Triglycerides, cholesterol, phospholipids, and protein
- Secreted by liver into blood as a source of triglycerides
Composition & physiological function of IDL
- Triglyceride-depleted VLDLs
- Intermediate stage in lipoprotein metabolism, can be further processed into LDL
Composition & physiological function of LDL
- Mainly cholesterol, very little triglycerides, phospholipids, and protein
- Main cholesterol form in blood; delivers cholesterol to cells
Composition & physiological function of HDL
- High protein content, intermediate cholesterol & phospholipids, very little triglyceride
- “Clean up” mechanism; secreted by liver, picks up cholesterol from peripheral tissues and atheromas, returns to liver for cholesterol to be excreted
Exogenous pathway for lipid absorption and transport
- Dietary fat enters the small intestine.
- Bile acids and pancreatic lipases break down triglycerides into fatty acids.
- Fatty acids are then re-synthesized into triglycerides within the enterocytes.
- Triglycerides, along with other lipids, form chylomicrons.
- Chylomicrons enter the bloodstream.
- Lipoprotein lipase (LPL) breaks down chylomicron triglycerides.
- Fatty acids are released and travel to adipose tissue.
- Fatty acids are taken up by adipose tissue and stored as triglycerides.
Basically: TG is synthesized and stored in adipocytes when body has excess energy (after meal) and is then broken down when the body needs energy (between meals, during physical activity)
Endogenous pathways for lipid absorption and transport
- VLDL is synthesized in the liver using both de novo lipogenesis (creation of fatty acids from non-lipid precursors within the liver) and the uptake of fatty acids from the bloodstream.
- VLDL is released into the bloodstream from the liver.
- In the bloodstream, VLDL undergoes lipolysis, facilitated by lipoprotein lipase (LPL) located in peripheral tissues. This process results in the conversion of VLDL to Intermediate-Density Lipoproteins (IDL).
- IDL can undergo further metabolism in the bloodstream. Triglycerides are removed from IDL, transforming it into Low-Density Lipoproteins (LDL).
- LDL carries cholesterol to various tissues in the body, where it can be utilized for cellular functions.
Role of LDL receptor in lipid metabolism, and factors that regulate LDL receptor levels
Role of LDL receptor:
* LDL binds to LDL receptors located on the surface of cells, particularly in the liver.
* The LDL receptor-LDL complex is internalized into the cell through endocytosis.
* Within the cell, LDL is processed, releasing cholesterol for cellular needs.
Factors that regulate LDL receptor levels:
* High intracellular cholesterol levels suppress the synthesis of LDL receptors (to prevent excessive cholesterol uptake)
* Low intracellular cholesterol levels stimulate the synthesis of LDL receptors.
Central role of the liver in cholesterol synthesis and lipid distribution
Cholesterol synthesis:
* de novo cholesterol synthesis from acetyl-CoA
* Cholesterol synthesized by liver is incorporated into VLDL
Lipid distribution:
* VLDL transports triglycerides to peripheral tissues
* VLDL –> IDL –> LDL
* LDL carries cholesterol to various tissues for cellular needs
Diseases that are associated w/ hyperlipoproteinemia and hypertriglyceridemia
Hyperlipoproteinemia diseases:
* Atherosclerosis (excess accumulation of cholesterol in vascular smooth muscle)
* Can lead to premature coronary artery disease (CAD) & stroke
Hypertriglyceridemia diseases:
* Pancreatitis
* Xanthomas
* Increased risk of coronary heart disease (CHD)
recognize molecular structures or statins and indicate which statins are prodrugs
Prodrugs: lovastatin & simvastatin
recognize molecular structure of fibrates and indicate which fibrate is a prodrug
Prodrug: fenofibrate
strategies for controlling hyperlipidemias and molecular targets
Goals of therapy
* decrease reabsorption of excreted bile acids (bile acid sequestrants)
* decrease secretion of VLDL from liver AKA lipoprotein catabolism (fibrates, niacin, omega 3 fatty acid)
* decrease synthesis of cholesterol (statins)
* increase hydrolysis of lipoprotein triglycerides/lower TG (fibrates)
MOA & major side effects for: statins
HMG-CoA Reductase Inhibitors “Statins”
* fluvastatin, rosuvastatin, atorvastatin, lovastatin, simvastatin, pravastatin, pitavastatin
MOA:
* competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis
* upregulate LDL receptors (stimulate synthesis), so LDL delivered to liver and plasma cholesterol is reduced
HMG-CoA reductase function:
Acetyl-CoA –> HMG-CoA reductase –> mevalonic acid –> cholesterol
Side Effects:
* rhabdomyolysis (myopathy) –> dose related; monitor serum creatinine phosphokinase (CPK)
* hepatotoxicity –> monitor serum transaminase activity
* increased incidence of T2D
MOA & major side effects for:
bile acid sequestrants
Bile Acid-Binding Resins
* cholestyramine (Queastran) & colestipol (colestid)
MOA:
* inhibit reabsorption of bile acids from intestine by binding bile acids to form insoluble complex excreted in feces
* upregulate LDL receptors in liver
Side Effects:
* constipation
* bloating
* high fiber diet & water helps
Block bile acid in stomach from being absorbed in blood. After binding the bile acids, the complex is excreted in feces. Cholesterol is then taken up to be used to form bile acids which lowers cholesterol levels.
MOA & major side effects for: ezetimibe
Cholesterol Absorption Inhibitor
MOA:
* inhibits intestinal absorption of cholesterol from dietary sources & inhibits NPC1L1 which prevents the reabsorption of cholesterol excreted in bile
NPC1L1 function:
* NPC1L1 is expressed on cell surface of enterocytes and binds with cholesterol where cholesterol then enters the enterocyte and is packaged into chylomicrons which transports it into the bloodstream; inhibition of NPC1L1 prevents cholesterol from entering enterocyte, so it sits in intestinal lumen and is then excreted in feces
Side Effects:
* none, generally well-tolerated
MOA & major side effects for: bempedoic acid
used as adjunct to statins
ATP-Citrate Lyase Inhibitor (ACL)
* bempedoic acid (nexletol)
MOA:
* inhibits ACL, an enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway
* increases expression of LDL receptors
Indications:
* heterozygous familial hypercholesterolemia (HeFH)
* ASCVD
Side Effects:
* hyperuricemia
* gout
MOA & major side effects for: fibrates
used mainly for high TG
Fibric Acid Derivatives
* clofibrate, gemfibrozil, fenofibrate, ciprofibrate, bezafibrate
MOA:
* binds to PPAR-α and regulates gene transcription
* reduces LDL, TG
* Increases HDL
Indications:
* hypertriglyceridemia in which VLDL predominate
* second line for mixed hyperlipidemia
Side Effects: (usually minor)
* gallstones
* rhabdomyolysis (use w/ caution w/ statins)
MOA & major side effects for: niacin
used mainly for high TG
MOA:
* decreases VLDL, LDL, and TG
* increases HDL
Indications:
* mixed hyperlipidemias/severe cases
Side Effects:
* vasodilation (cutaneous flushing)
* itching
* tingling of upper body & headache w/ initial dosing (treat w/ aspirin or ibuprofen)
* hepatotoxicity (SR preparations)
MOA & major side effects for: omega-3 fatty acids
used mainly for high TG
- Lovaza & Omtryg (EPA + DHA); Vascepa (EPA)
- May increase LDL by 4-49%
MOA:
* reduces synthesis of triglyceride in liver
* inhibit esterification of other fatty acids
Indications:
* severe hypertriglyceridemia (>500 mg/dl)
Side Effects:
* can increase LDL-C levels (except meds that only contain EPA, like Vascepa)
MOA of PCSK9 inhibitors
used as adjunct to statins
Proprotein Convertase Substilisin Kexin Type 9
* alirocumab, evolocumab
MOA:
* promotes degradation of LDL receptors in liver
Indications:
* adjunct to diet & max tolerated statin therapy in pts w/ ASCVD, HeFH, or HoFH
Side Effects:
* injection site reaction
* arthralgia (joint stiffness)
MOA of angiopoietin-like protein 3 inhibitors
- Evinacumab-dgnb
MOA:
* Increases LPL and EL activity by preventing ANGPTL3 mediated inhibition
* Lowers LDL-C
Indication:
* HoFH
MOA of mipomersone and primary toxicity
MOA:
* oligonucleotide inhibitor of Apo B100
* hybridizes Apo B100 mRNA in liver and promotes degradation
Indications:
* adjunct to other treatments for pts w/ HoFH (LDLR mutation)
Primary Toxicity:
* high risk of liver damage (restricted Rx program)
MOA of lomitapide and primary toxicity
MOA:
* binds to and inhibits MTTP which prevents the assembly of Apo B containing lipoproteins in liver and intestine
* this interferes with chylomicron and VLDL production
Indications:
* adjunct to other treatments for pts w/ HoFH (LDLR mutation)
Primary Toxicity:
* high risk of liver damage (restricted Rx program)
