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exam 5 > Anti-hyperlipidemic drugs (Hockerman) > Flashcards

Anti-hyperlipidemic drugs (Hockerman) Flashcards

1
Q

Relative size, composition, physiological function of major classes of lipoproteins

A

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

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2
Q

Composition & physiological function of chylomicrons

A
  • Primarily triglycerides, very little cholesterol, phospholipid and protein
  • transports dietary lipids from gut to liver & adipose tissue
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3
Q

Composition & physiological function of VLDL

A
  • Triglycerides, cholesterol, phospholipids, and protein
  • Secreted by liver into blood as a source of triglycerides
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4
Q

Composition & physiological function of IDL

A
  • Triglyceride-depleted VLDLs
  • Intermediate stage in lipoprotein metabolism, can be further processed into LDL
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5
Q

Composition & physiological function of LDL

A
  • Mainly cholesterol, very little triglycerides, phospholipids, and protein
  • Main cholesterol form in blood; delivers cholesterol to cells
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6
Q

Composition & physiological function of HDL

A
  • 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
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7
Q

Exogenous pathway for lipid absorption and transport

A
  • 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)

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8
Q

Endogenous pathways for lipid absorption and transport

A
  • 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.
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9
Q

Role of LDL receptor in lipid metabolism, and factors that regulate LDL receptor levels

A

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.

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10
Q

Central role of the liver in cholesterol synthesis and lipid distribution

A

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

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11
Q

Diseases that are associated w/ hyperlipoproteinemia and hypertriglyceridemia

A

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)

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12
Q

recognize molecular structures or statins and indicate which statins are prodrugs

A

Prodrugs: lovastatin & simvastatin

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13
Q

recognize molecular structure of fibrates and indicate which fibrate is a prodrug

A

Prodrug: fenofibrate

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14
Q

strategies for controlling hyperlipidemias and molecular targets

A

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)

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15
Q

MOA & major side effects for: statins

A

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

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16
Q

MOA & major side effects for:
bile acid sequestrants

A

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.

17
Q

MOA & major side effects for: ezetimibe

A

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

18
Q

MOA & major side effects for: bempedoic acid

used as adjunct to statins

A

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

19
Q

MOA & major side effects for: fibrates

used mainly for high TG

A

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)

20
Q

MOA & major side effects for: niacin

used mainly for high TG

A

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)

21
Q

MOA & major side effects for: omega-3 fatty acids

used mainly for high TG

A
  • 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)

22
Q

MOA of PCSK9 inhibitors

used as adjunct to statins

A

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)

23
Q

MOA of angiopoietin-like protein 3 inhibitors

A
  • Evinacumab-dgnb

MOA:
* Increases LPL and EL activity by preventing ANGPTL3 mediated inhibition
* Lowers LDL-C

Indication:
* HoFH

24
Q

MOA of mipomersone and primary toxicity

A

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)

25
Q

MOA of lomitapide and primary toxicity

A

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)

exam 5 (5 decks)

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