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Cardio > Anti-hyperlipidemics > Flashcards

Anti-hyperlipidemics Flashcards

Dr. Roane

1
Q

Definition of dyslipidemia

A

Imbalance of lipids (cholesterol, LDL, HDL, triglycerides) - associated with cardiovascular damage

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2
Q

Diseases of dyslipidemia

A

Plaque formation in the coronary arteries
in the heart: myocardial infarction
in the brain: stroke
in the liver: hepatic cirrhosis, liver failure

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3
Q

What is Lipoprotein A and its role in plaque formation?

A

-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

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4
Q

Structure of Lipoproteins

A

-outside: Phospholipids, Apolipoprotein, free cholesterol

-inside triglycerides, cholesterol esters (cholesterol + fatty acids attached)

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5
Q

How does fat + cholesterol present in the blood after food uptake?

A

-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)

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6
Q

How does the liver secrete fat?

A

-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

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7
Q

How is Cholesterol synthesized?

A

Liver:
HMG-CoA-Reductase converts Acetyl-Coa to Mevalonic acid -> Cholesterol

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8
Q

What happens to Cholesterol in the liver?

A

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

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9
Q

What type of Lipoprotein is rich in Cholesterol?

A

LDL

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10
Q

What type of Lipoprotein is rich in Triglycerides?

A

VLDL

Mostly Triglycerides, some cholesterol

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11
Q

Why is HDL considered good Cholesterol?

A

HDL
Rich in Cholesterol bud deposits it safely
-scavenges lipids and returns them to the liver

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12
Q

Meaning of Atherogenic

A

promoting plaque formation

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13
Q

Apolipoproteins and Lipoproteins

A

Apolipoproteins: a protein attached to lipids (ApoE, ApoB, B-100, B-48)

Lipoproteins: apolipoprotein + lipdids

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14
Q

MOA of Statins (HMG-CoA-Reductase inhibitors)

A

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

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15
Q

Which molecule inhibits the first step of cholesterol synthesis?

A

-Bempedoic acid
-blocks the formation of Acetyl-CoA

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16
Q

What other effects do Statins have (non-canonical)?

A

-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)

17
Q

Which drugs act to accelerate the synthesis of Resolvins?

A

-Aspirin and Statins

Facilitate COX-2 -> Synthesis of Resolvin

18
Q

Adverse effects of Statins

A

-Hepatotoxicity, especially when alcohol is consumed
-Rhabdomyolysis (lysis of muscle cells): muscle pain, dark urine

-variable effects CYPs, so many drug-drug interactions

19
Q

MOA of Bempedoic acid

A

-Inhibits ATP Citrate Lyase
-blocks the conversion of Citrate to Acetyl-CoA
-Bempedoic acid binds CoA -> the combi structure blocks Citrate Lyase

20
Q

Brand name of bempedoic acid

A

-Nexletol: Bempedoic acid + Ezetimibe
-Prodrug
-AE: muscle spasm, increase in uric acid, disruption in tendon remodeling, Minimal myopathy (BCP)!

21
Q

MOA of Ezetimibe (Zetia)

A

-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%)

22
Q

AE of Ezetimibe (Zetia)

A

Diarrhea and steatorrhea (fat in the stools, bc it didn’t get absorbed)

23
Q

Bile acid binding resins

A

-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

24
Q

Adverse effects Bile acid binding resins

A

-Constipation, bloating, heartburn -> add fiber to the diet
-decrease in Vitamin K and folic acid absorption
-+/- Cholelithiasis (gallstones formation)

25
Q

MOA of Niacin (Vitamin B3, nicotinic acid)

A

-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

26
Q

AE of Niacin

A

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

27
Q

Drugs causing an increase in uric acid?

A

-Bempedoic acid
-Niacin

28
Q

MOA of Fibrates

A

-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)

29
Q

Which drug class has similar side effects as Statins?

A

Fibrates
-probably should not be given together

30
Q

PCSK-9 inhibitor

A

(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

31
Q

How does PCSK-9 work?

A

-outside of the cell: initiates internalization of LDL receptors -> Recycle or Degradation

-inside the cell: facilitates degradation of LDL-receptors

32
Q

Monoclonal antibodies PCSK-9 inhibitors

A

-Alirocumab (Praluent)
-Evolocumab (Repatha)

-blocks PCSK-9

33
Q

siRNA for PCSK-9 inhibition

A

-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)

34
Q

Brand drug Vytorin

A

Ezetimibe + Simvastatin

Cardio (27 decks)

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