Anti-hyperlipidemics Flashcards
Dr. Roane
Definition of dyslipidemia
Imbalance of lipids (cholesterol, LDL, HDL, triglycerides) - associated with cardiovascular damage
Diseases of dyslipidemia
Plaque formation in the coronary arteries
in the heart: myocardial infarction
in the brain: stroke
in the liver: hepatic cirrhosis, liver failure
What is Lipoprotein A and its role in plaque formation?
-Lp(a) = LDL containing Protein (a) causes oxidative damage to endothelial cells and promotes fibrin accumulation
-immune cells (monocytes) move to the blood vessel -> uptake of fat droplets -> formation of foam cells -> release of growth factors -> increase of smooth muscle cells and fibroblasts -> narrows the blood vessel
Structure of Lipoproteins
-outside: Phospholipids, Apolipoprotein, free cholesterol
-inside triglycerides, cholesterol esters (cholesterol + fatty acids attached)
How does fat + cholesterol present in the blood after food uptake?
-travels through intestine -> Chylomicrons
-LPL hydrolyses triglycerides and stores free fatty acids in the adipose tissue (or can be used by muscle tissue as an energy source)
-after LPL hydrolysis chylomicron remnants are cleared by the liver (remnant and LDL receptors)
How does the liver secrete fat?
-can be made of carbohydrates
-in the form of VLDL
-LPL hydrolysis triglycerides from VLDL -> to IDL
-IDL can be transported back to the liver
-LPL and HL (hepatic lipase) can convert IDL to LDL
-LDL can be transported back to the liver or to other tissues
How is Cholesterol synthesized?
Liver:
HMG-CoA-Reductase converts Acetyl-Coa to Mevalonic acid -> Cholesterol
What happens to Cholesterol in the liver?
Fuses with Lysosomes containing Triglycerides -> transport to the Golgi apparatus -> formation of Golgi vesicle containing VLDL -> secretion vesicle into the blood, where it get ApoE and ApoC attached
What type of Lipoprotein is rich in Cholesterol?
LDL
What type of Lipoprotein is rich in Triglycerides?
VLDL
Mostly Triglycerides, some cholesterol
Why is HDL considered good Cholesterol?
HDL
Rich in Cholesterol bud deposits it safely
-scavenges lipids and returns them to the liver
Meaning of Atherogenic
promoting plaque formation
Apolipoproteins and Lipoproteins
Apolipoproteins: a protein attached to lipids (ApoE, ApoB, B-100, B-48)
Lipoproteins: apolipoprotein + lipdids
MOA of Statins (HMG-CoA-Reductase inhibitors)
Bind and inhibit HMG-CoA-Reductase
-blocks the synthesis of cholesterol in the hepatocytes
-Prodrugs: Simvastatin, Lovastatin
-long half-life: Atorvastatin, Rosuvastatin, Pravastatin
-many more
Which molecule inhibits the first step of cholesterol synthesis?
-Bempedoic acid
-blocks the formation of Acetyl-CoA
What other effects do Statins have (non-canonical)?
-Inhibit Rho Kinase (ROCK) -> responsible for tissue remodeling
-Resolvin production (involved in the resolution of inflammation)
Resolvins: originate from arachidonic acid -> COX-2 -> prostaglandin like structure (Resolvin)
Which drugs act to accelerate the synthesis of Resolvins?
-Aspirin and Statins
Facilitate COX-2 -> Synthesis of Resolvin
Adverse effects of Statins
-Hepatotoxicity, especially when alcohol is consumed
-Rhabdomyolysis (lysis of muscle cells): muscle pain, dark urine
-variable effects CYPs, so many drug-drug interactions
MOA of Bempedoic acid
-Inhibits ATP Citrate Lyase
-blocks the conversion of Citrate to Acetyl-CoA
-Bempedoic acid binds CoA -> the combi structure blocks Citrate Lyase
Brand name of bempedoic acid
-Nexletol: Bempedoic acid + Ezetimibe
-Prodrug
-AE: muscle spasm, increase in uric acid, disruption in tendon remodeling, Minimal myopathy (BCP)!
MOA of Ezetimibe (Zetia)
-Addon drug
-can be used with Simvastatin (Vytorin)
-inhibits cholesterol absorption from the GI by blocking sterol transporters on the intestinal cells
-stimulates bile salt synthesis, upregulates hepatic LDL receptors, lowers plasma LDL (20-25%)
AE of Ezetimibe (Zetia)
Diarrhea and steatorrhea (fat in the stools, bc it didn’t get absorbed)
Bile acid binding resins
-Cholestyramine, Colestipol, Colesevelam
-water-insoluble polymers
-bind bile acid (many are made of cholesterol) -> excretion in the feces
Result:
-more cholesterol is used for producing bile acids
-liver senses loss of cholesterol -> upregulating hepatic LDL-receptors (for more uptake of LDL which contains cholesterol -> used again to produce bile acid)
as a result, plasma LDL levels go down
Adverse effects Bile acid binding resins
-Constipation, bloating, heartburn -> add fiber to the diet
-decrease in Vitamin K and folic acid absorption
-+/- Cholelithiasis (gallstones formation)
MOA of Niacin (Vitamin B3, nicotinic acid)
-activates adipocytes HC2A receptor -> which lowers the release of fatty acids (would normally travel to the liver and used to produce VLDL)
->as a result there is VLDL secretion by the liver -> Since VLDL is later converted to LDL -> LDL goes down
-increases HDL (MOA unknown)
-decreases Lipoprotein(a) - promotes clotting and fibrin formation in the blood vessels
AE of Niacin
Flushing (tachyphylaxis, goes away quickly) -> can be reduced by taking aspirin before, ramping dosage, slow-release formulation
-Itching, rash
-Insulin resistance may be increased
-GI upset
-Hyperuricemia (too much uric acid in the urine) may worsen gout
Drugs causing an increase in uric acid?
-Bempedoic acid
-Niacin
MOA of Fibrates
-lower VLDL release from the liver -> lower Triglycerides
-Gemfribrosil (Lopid), Fenofibrate
-activate PPARα, transcription factor
upregulates LPL (lipase), apo A-I, apo A-II
PPAR downregulates apo C-III (inhibitor of lipolysis)
fatty acid oxidation (burning fat) goes UP
Triglyceride synthesis goes DOWN (bc less VLDL)
Which drug class has similar side effects as Statins?
Fibrates
-probably should not be given together
PCSK-9 inhibitor
(Pro-protein Convertase Subtilisin/Kexin type 9)
-PCSK-9 naturally downregulates LDL-receptor
-LDL receptors are needed for LDL uptake from the blood into the liver
-inhibition of PCSK-9 with monoclonal antibodies, and siRNA -> binds to the PCSK-mRNA -> initiates its degradation
How does PCSK-9 work?
-outside of the cell: initiates internalization of LDL receptors -> Recycle or Degradation
-inside the cell: facilitates degradation of LDL-receptors
Monoclonal antibodies PCSK-9 inhibitors
-Alirocumab (Praluent)
-Evolocumab (Repatha)
-blocks PCSK-9
siRNA for PCSK-9 inhibition
-Inclisiran (Leqvio)
-the siRNA (drug) binds to ASGPR for endocytosis, in the cell the siRNA is released and loaded into the RISC complex, and the PCSK-9 mRNA binds to the complex and the complementary siRNA (drug) and gets destroyed
-dose: two time per year (expensive)
Brand drug Vytorin
Ezetimibe + Simvastatin
