Anti-Hyperlipidemic Drugs Flashcards
Major lipids
cholesterol: essential component of cell membranes; precursor to sterols and steroids
triglyceride: storage form of fuel to support generation of high energy compounds; component of structural lipids
both are transported in blood in macromolecular aggregates known as lipoproteins
Know the relative size, composition, and physiological function of the major classes of lipoproteins
lipids form lipoproteins to help them move around the body
lipoproteins transport cholesterol & triglycerides in blood; spherical particles with phospholipid, free cholesterol & protein making up surface; core made up of triglyceride & cholesterol ester; apoproteins on surface are critical in regulating transport & metabolism; lipoprotein lipase system releases free FAs from lipoproteins
major classes of lipoproteins: chylomicrons, VLDL, IDL, LDL, HDL
classes based on density, composition, and electrophoretic mobility
Chylomicrons
involved in transport of dietary lipids from gut to liver and adipose tissue
dumped into lymphatic system and makes its way through the body
VLDL - very low density lipoprotein
secreted by liver into blood as a source of triglycerides
IDL - intermediate density lipoprotein
triglyceride-depleted VLDLs
LDL - low density lipoprotein
main cholesterol form in blood
HDL - high density lipoprotein
secreted by liver and acquire cholesterol from peripheral tissue and atheromas (reverse cholesterol transport)
bring cholesterol from peripheral tissues and back into liver
Lipoproteins sizes
bigger they are –> less dense they are
biggest: chylomicron –> VLDL –> LDL –> HDL
Lipoproteins compositions
chylomicrons: mostly triglycerides
VLDL: mostly triglycerides, more cholesterol too
LDL: more cholesterol relative to TGs
HDL: mostly protein
Important apolipoproteins
ApoA-I
ApoB-100
ApoB-48
ApoE
ApoCII
ApoA-I
structural in HDL; ligand of ABCA1 receptor mediates reverse cholesterol transport produced in liver and intestine
ApoB-100
structural in VLDL, IDL, LDL; LDL receptor ligand produced in liver
ApoB-48
structural in chylomicrons produced in intestine
ApoE
ligand for LDL remnant receptor reverse cholesterol transport with HDL; produced in liver and other tissues; helps get cholesterol back into the liver
ApoCII
found in chylomicrons, VLDL; binds to lipoprotein lipase to enhance TG hydrolysis
Know the exogenous and endogenous pathways for lipid absorption and transport
LDL-lipoprotein lipase: in capillaries of fat, cardiac & skeletal muscle
HL-hepatic lipase: produced in liver, key in converting IDL to LDL
CETP-cholesterol ester transfer protain: more cholesterol esters from HDLs into IDLs in exchange for trigylcerides
Endogenous pathway
liver secretes VLDL –> IDL –> LDL –> cholesterol distributed throughout the body
Exogenous pathway
dietary fat + cholesterol –> intestine –> chylomicrons –> chylomicron remnants –> liver
Know the role of the LDL receptor in lipid metabolism, and factors that regulate LDL receptor levels
LDL goes in through LDL receptors –> lipoproteins taken into lysosome
mLDL goes in through CD36 or SR-A –> lipoproteins taken into lysosome
fate 1: cholesterol is esterified, now have long chain FA (storage form)
fate 2: free cholesterol effluxed, HDL stimulates this
CEH = cholesterol ester hydrolase, hydrolyzes cholesterol ester back to free cholesterol
Understand the central role of the liver in cholesterol synthesis and lipid distribution
De novo synthesis is the major source of cholesterol
liver synthesis is most critical to total body burden
mevalonate is the key building block for cholesterol
Lipoprotein disorders
detected by measuring lipid in serum after a 10 hr fast
ratio of total cholesterol to HDL-cholesterol is key in assessing risk of CVD
ratio > 4.5 is associated with increased risk of CVD
ratio of </= 3.5 is desirable, ratio of < 3 is optimal
Give the diseases that are associated with hyperlipoproteinemia and hypertryglyceridemia
hyperlipoproteinemia: atherosclerosis - excess accumulation of cholesterol in vascular smooth muscle, premature coronary artery disease, neurologic disease - stroke
hypertriglyceridemia: pancreatitis, xanthomas, increased risk of CHD
Atherosclerosis
fatty streak - initial stage, leads to accumulated plaques, reduces blood flow
LDL receptors are present on endothelial cells
monocyte squeezes in b/w endothelium, gets into intima –> oxidized (modified) LDL gets into initma and stimulates T cell sectretion –> T cells secrease # of pro-inflammatory cytokines with chemotactic effect on monocytes –> causes differentiation of monocytes into macrophages –> macrophage starts to take up LDL –> store as cholesterol esters –> forms foam cells –> cell dies
Know the strategies for controlling hyperlipidemias and give the molecular targets, mechanism of action, and major side-effects for: statins, bile acid sequestrants, ezetimibe, bempedoic acid fibrates, niacin, omega-3 fatty acids
goals of therapy: prevent formation of atherosclerotic plaques; decrease reabsorption of excreted bile acid; decrease secretion of VLDL from liver; decrease synthesis of cholesterol; increase hydrolysis of lipoprotein triglycerides
each 10% reduction in cholesterol levels is associated with 10-30% reduction in incidence of coronary heart disease
Drugs mainly for high cholesterol
bile acid binding resins
inhibitors of cholesterol absorption
inhibitors of cholesterol synthesis
PCSK9 inhibitors
MTTP inhibitors
Drugs mainly for high triglycerides
fibrates
niacin
omega-3 fatty acids
Strategies for controlling hyperlipidemia
statins - inhibit HMG CoA reductase
fibrates, niacin, omega-3 FAs - lipoprotein catabolism
bile acid sequestrants - inhibit reabsorption of cholesterol
ezetimibe - inhibits diet cholesterol
Bile acid-binding resins
MOA: inhibits reabsorption of bile acids from intestine by binding bile acids to form insoluble complex excreted in feces; exchanging bile acid for chloride; want to interfere with the recycling and make the liver use more cholesterol to make bile acids, get more cholesterol, bring LDLs back into liver and prevent going into peripheral tissues
up-regulate LDL receptors in liver when liver’s running low on cholesterol
ex: cholestyramine and colestipol - polymers with (+) charge, exchange counterion chloride) for bile acids
cholesterol oxidized by CYP450s to cholic acid - negatively charges, will bind to the (+) charged resins
Bile acid binding resins SEs
constipation and bloating
Bile acid binding resins drug interactions
acetaminophen, thiazides, warfarin, digoxin, fibrates, ezetimibe, oral contraceptive, corticosteroids, thiazolidinediones
Ezetimibe
cholesterol absorption inhibitor; inhibits intestinal absorption of phyosterols and cholesterol
MOA: inhibits intestinal absorption of cholesterol from dietary sources and reabsorption of cholesterol excreted in bile (inhibits NPC1L1 - Neimann-Pick C1-like 1, ezetimibe binds to this transporter)
NPC1L1 - cholesterol transporter
expressed on apical surface of enterocytes in small intestine
cholesterol activates sterile sensing domain (SSD) which stimulates endocytosis, brings in cholesterol that’s bound in the membrane around the transporter
ezetimibe blocks this transporter
Ezetimibe SEs
low incidence of liver/skeletal muscle damage
Recognize the molecular structure of statins and indicate which statins are prodrugs
HMG-CoA reductase inhibitors - “statins” statins are derivatives of mevalonic acid
lovastatin and simvastatin are prodrugs
HMG-CoA reductase inhibitors
MOA: competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis
up-regulate LDL receptors enabling more LDL delivered to liver, thus reducing plasma cholesterol
prevent conversion of HMG-CoA to mevalonic acid
Mechanism for upregulation of hepatic LDL receptors by statins
reducing synthesis of cholesterol in the liver, causes the liver to react, allows it to take more LDL up from plasma
SREBP - sterol regulatory element binding protein has 2 domains - regulatory and basic helix loop helix domain; this complex stays when sterols are present; SCAP - SREBP cleavage activating protein keeps it in the ER when a lot of sterols are around
when sterols depleted by inhibiting HMG-CoA reductase –> site one protease (S1P) cleaves SREBP, site two protease cleaves bHLH from transmembrane domain –> complex translates to golgi apparatus –> goes to nucleus to activate transcription –> transcription + production of LDLr –> incrase hepatic LDL uptake
HMG-CoA reductase inhibitors metabolism
CYP3A4: lovastatin, simvastatin and atorvastatin - tend to accumulate in presence of drugs that inhibit or compete for CYP 3A4: macrolide antibiotics, cyclosporine, ketoconazole, grapefruit juice
CYP 2C9: fluvastatin, rosuvastatin - inhibitors may increase plasma levels: cimetidine, metronidazole, amiodarone
sulfation: pravastatin, most excreted unchanged
pitavastatin excreted unchanged in bile, undergoes enterohepatic recirculation
HMG-CoA reductase inhibitors SEs
skeletal muscle effects: rhabdomyolysis with renal dysfunction secondary to myoglobinuria, monitor creatine phosphokinase; increased incidence when co-adm with CYP inhibitors, gemfibrozil
hepatotoxicity - monitor serum transaminase activity
increased incidence of T2DM
ATP-citrate lyase inhibitor
bempedoic acid (nexletol)
adjunct to statins
inhibits OAT2 in renal tubules - inhibits secretion of uric acid
Bempedoic acid SEs
hyperuricemia and gout
Drugs used to lower serum cholesterol in pts with homozygous familial hypercholesterolemia
LDL-r function is severely reduced in this condition
lomitapide
mipomersen
angiopoietin-like protein 3
Recognize the molecular structure of fibrates and indicate which fibrate is a prodrug
fibric acid derivatives: peroxisome proliferator-activated receptor-alpha activators (PPARalpha)
fenofibrate must undergo bioactivation to fenofibric acid
gemfibrozil
Fibrates
bind to PPAR-alpha and regulate gene transcription along with the retinoic acid receptor (RXR) to reduce triglyceride levels
Fibrates SEs
gallstones (cholelithiasis)
skeletal muscle effects - rhabdomyolysis
drug interaction: potentiate the effects of warfarin
Niacin MOA
reduces serum triglycerides
blocks the mobilization of FFAs from adipose tissue, so less FFAs are taken to the liverm less TG synthesis, less VLDL export, decrease LDL, increase HDL
increases lipase activity to increase clearance of VLDL –> decreases hepatic VLDL production –> may significantly reduce serum LDL and TG –> increases HDL levels
niacin inhibits a hormone-sensitive lipase in adipose tissue which reduces the breakdown of triglycerides to free fatty acids, and the transport of free fatty acids to the liver.
the reduction in transport of free fatty acids from fat to liver decreases hepatic triglyceride synthesis
the reduction in hepatic triglyceride synthesis inhibits VLDL secretion from hepatocytes, which in turn decreases the production of LDL.
Niacin targets
adipose tissue: inhibits TG lipolysis by hormone-sensitive lipase - decreasing FA transport to liver via activation of GPR109A
liver: inhibits FA synthesis and esterification reducing TG export via VLDL - reduces clearance of ApoA-I but not CEs, increasing HDL levels and reverse transport
macrophages: increases expression of CD36 and ABCA1, decreasing CE content via HDL-mediated reverse transport
Niacin SEs
marked vasodilation (flushing), itching, tingling of upper body and headache - prostaglandins mediate these, treat with aspirin or ibuprofen
hepatotoxicity
Omega-3 fatty acid ethyl esters
nutrients
combo of ethyl esters of omega-3 fatty acids
lovaza, omtryg, vascepa
MOA: reduce serum triglycerides; reduce synthesis of triglyceride in liver: omega-3 FAs are poor substrates for enzymes responsible for TG synthesis; inhibit esterification of other FAs
Omega-3 FAs SEs
can increase LDLc levels, not EPA-ethyl ester alone
combined with statins to reduce LDLc level
Eicosapentaenoic acid (an omega-3 FA)
TXA3- less potent in stimulating platelet aggregation than TXA2; PGI3 - equipotent in ihibiting platelet aggregation than PGI2
low incidence of atherosclerotic disease with a tendency to bleed
inhibiting platelet aggregation that would normally be mediated by TXA2, still maintaining good prostacyclin activity even if you incorporate this FA into the synthetic pathway
Explain the mechanism of action of angiopoietin-like protein 3 inhibitors
reduce LDL levels independently of LDLrs - mechanism does not require LDL-R
evinacumab (evkeeza): monoclonal antibody
increases lipoprotein lipase and endothelial lipase activity by preventing ANGPTL3 mediated inhibition, this binding interferes with the ANGPTL3 ability to inhibit activity of LPL and EL; lowers LDLc
evinacumab allows greater breakdown by LPL and EL, by allowing greater breakdown of TGs by these lipases from the VLDL, the IDL that results is more likely to be cleared by the remnant receptor as an IDL than to be processed to an LDL (reduce conversion of IDL to LDL)
Explain the mechanism of action of mipomerson and lomitapide, and their primary toxicities
lomitapide and mipomerson - inhibits apo B lipoprotein synthesis
Lomitapide
juxtapid
small molecule microsomal TG transfer protein (MTTP) inhibitor
inhibits assembly of Apo B containing lipoproteins in liver + intestine - interferes with assembly of both VLDL and chylomicrons
high risk of liver damage
Lomitapide MOA
mechanism does not require LDL-R
MTTP inhibitors inhibit VLDL assembly and reduce VLDL secretion into bloodstream from liver
small molecule inhibits microsomal triglyceride transport protein (MTTP); also works in the intestines - interferes with packaging of chylomicrons affect ability to absorb lipophilic compounds
Mipomersen
kynamro
phosphorothioate anti-sense oligonucleotide inhibitor of Apo B100, more specific to ApoB100, greater effect on VLDL export
hybridizes Apo B100 mRNA in liver and promotes degradation
binds to Apo B100 mRNA and causes it to be destroyed; duplex mRNA w/ oligo, mRNA will be degraded –> degrading Apo B100 mRNA reduces Apo B100 protein, reduce VLDL export
VLDL are processed LDL, so reducing VLDL export will reduce these serum LDL cholesterol as well
phosphorothioate has an added sulfur instead of oxygen, decreases ability of nucleases to degrade this oligo
high risk of liver damage
Explain the mechanism of action of the PCSK9 inhibitors
augment the clearance of LDL cholesterol
PCSK9 - proprotein convertase subtilisin kexin type 9 (serine protease) - promotes degradation of LDL receptors in liver
MOA: controls level of LDLr on surface of hepatocytes –> binds to LDLr and marks it for internalization + degradation; develop antibody against PCSK9 that will bind this soluble enzyme, prevent it from binding LDLr allowing recycling of receptor when internalized
alirocumab and evolocumab are human IgG Abs against PCSK9 - increase LDLr # and reduce serum LDLc levels
inclisiran: siRNA hybridizes PCSK9 mRNA and directs degradation of PCSK9 mRNA in hepatocytes, lowers LDLc
PCSK9 inhibitors SEs
injection site rxn
arthralgia
