Anti-hyperlipidemic Drugs Flashcards
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
Lipoproteins transport
cholesterol and triglycerides in the blood
Describe the structure of lipoproteins
spherical particles with phospholipid, free cholesterol and protein making up surface; core made up of triglyceride and cholesterol ester
Apoproteins on surface of lipoproteins are critical in
regulating transport and metabolism
Lipoprotein lipase system
release free fatty acids from lipoproteins
Chylomicrons
involved in transport of dietary lipids from gut to liver and adipose tissue
VLDL
secreted by liver into blood as a source of triglycerides
IDL
triglyceride-depleted VLDLs
LDL
main transport form in blood
HDL
secreted by liver and acquire cholesterol from peripheral tissues and atheromas (reverse cholesterol transport)
ApoA-1
structural in HDL; ligand of ABCA1 receptor; mediates reverse cholesterol transport; produced in liver and intestine
ApoB-100
structural in VLDL
ApoB-48
structural in chylomicrons; produced in intestine
ApoE
ligand for LDL receptor remnant receptor; reverse cholesterol transport with HDL; produced in liver and other tissues
ApoCIII
found in chylomicrons, VLDL, HDL > LDL; inhibits LPL and interferes with ApoB and ApoE binding to hepatic receptors
LPL-Lipoprotein lipase
in capillaries of fat, cardiac and skeletal muscle
LCAT
lethicin-cholesterol acyltransferase
CETP
cholesterol ester transfer protein
Hyperlipoproteinemia is related to
atherosclerosis; premature coronary artery disease; neurologic disease
Hypertriglyceridemia is related to
pancreatitis; xanthomas; increased risk of CHD
Goals of hyperlipidemia drug therapy
decrease reabsorption of excreted bile acids; decrease secretion of VLDL from liver; decrease synthesis of cholesterol; increase hydrolysis of lipoprotein triglycerides
Drugs mainly for high cholesterol
HMG-CoA reductase inhibitors
Bile acid binding resins
Inhibitors of cholesterol absorption
Drugs mainly for high triglycerides
Fibrates
Niacin
Omega 3 fatty acids
Ezetimibe (Zetia)
cholesterol absorption inhibitor; inhibits intestinal absorption of cholesterol from dietary sources and reabsorption of cholesterol excreted in bile (inhibits NPC1L1)
Indication for Ezetimibe
primary clinical effect is reduction of LDL levels; usually used in combination with statins
Adverse effects of Ezetimibe
low incidence of liver/skeletal muscle damage; generally well tolerated
HMG-CoA reductase inhibitor/Statins
Fluvastatin (Lescol), Rosuvastatin (Crestor), Atorvastatin (Lipitor); Lovastatin (Mevacor), Simvastatin (Zocor), Pravastatin (Pravachol)
MOA of statins
competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis
Indications for HMG-CoA reductase inhibitors
hypercholesterolemia: elevated LDL; elevated LDL with slightly elevated TGs
standard to initiate therapy immediately after MI, irrespective of lipid levels
Dosing of Lovastatin
should be taken with evening meal to facilitate absorption
Dosing of Rosuvastatin, Atorvastatin, and Pravachol
taken as a single dose any time of the day
Dosing of Fluvastatin XL
can be taken as a single dose any time of the day
Metabolism of Lovastatin, Simvastatin and Atorvastatin
CYP3A4; tends to accumulate in presence of drugs that inhibit or compete for CYP 3A4 (macrolide antibiotics, cyclosporine, ketoconazole; grapefruit juice)
Prodrug statins
Lovastatin and Simvastatin
Metabolism of Fluvastatin and Rosuvastatin
inhibitors may increase plasma levels: cimetidine, metronidazole and amiodarone
Metabolism of Pravastatin
sulfation
Adverse effects of HMG-CoA reductase inhibitors
Rhabdomyolysis with renal dysfunction secondary to myoglobinuria; dose related phenomenon; monitor serum creatinine phosphokinase; increased incidence when co-administered with CYP inhibitors; may occur with gemfibrozil
Hepatotoxicity: monitor serum transaminase activity
Juxtapid (Lomitapide)
inhibits assembly of ApoB containing lipoproteins in liver and intestine; interferes with the ability to absorb dietary lipids and fat-soluble vitamins
Indications for Juxtapid
indicated as adjunct to other treatments for patients with homozygous familial hypercholesterolemia - LDLR mutation
Mipomersen (Kynamro)
phosphorothioate anti-sense oligonucleotide inhibitor of apoB 100; hybridizes Apo B100 mRNA in liver and promotes degradation
Indications for Mipomersen
indicated as adjunct to other treatments for patients with homozygous familial hypercholesterolemia
Fibrates bind to
PPAR-alpha and regulted gene transcription along with the retinoic acid receptor (RXR)
Therapeutic indications for fibric acid derivates
hypertriglyceridemia in which VLDL predominate; second line drug for mixed hyperlipidemia
Side effects of fibric acid derivatives
gallstones; skeletal muscle effects - rhabdomyolysis
Lovaza
combination of ethyl esters of omega-3-fatty acid
Lovaza MOA
reduce synthesis of triglyceride in liver: omega-3 fatty acids are poor substrates for enzymes responsible for TG synthesis; inhibit esterification of other fatty acids
Therapeutic indications for omega-3 fatty acids
lipid lowering diet is initiated before Lovaza therapy is started; severe hypertriglyceridemia >500 mg/dl
MOA of Niacin
reduces 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 does Niacin do in adipose tissue?
inhibits TG lipolysis by hormone-sensitive lipase; decreaseing FA transport to liver; via activation of GPR109A
What does Niacin do in the liver?
inhibits FA synthesis and esterification; reducing TG export via VLDL;
reduces clearance of apoA-1 but no CEs; increases HDL levels and reverse transport
What does Niacin do to macrophages?
increases expression of CD36 and ABCA1; decreasing CE content via HDL0mediated reverse transport
Indications for Niacin
effective for mixed hyperlipidemias; effective drug for raising HDL levels; used in combo with resin drugs to treat severe cases of hyperlipidemia; also combined with statins
Adverse effects of Niacin
marked vasodilation (cutaneous flushing), itching, tingling of upper body and headache may occur with initial dosing - prostaglandins mediate these (treat with aspirin or ibuprofen) hepatotoxicity
