Atherosclerosis (Concepts) Flashcards

1
Q

Why do hypolipidaemic drugs aid in preventing atherosclerosis?

A

Reduces circulating levels of LDL which is pro-atherosclerotic (and possibly increase amount of HDL which is anti-atherosclerotic)

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2
Q

How are LDLs taken into cells?

A

Receptor-mediated endocytosis (via LDL receptors)

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3
Q

What is the process of reverse cholesterol transport?

A
  1. Cholesterol from peripheral tissues (including foam cells in atheromas) is transferred into HDLs by ATP-binding cassette transporter ABCA1.
  2. Within HDLs, cholesterol is converted to cholesteryl esters by lechitin cholesterol acyltransferase (LCAT) and is stored in the core.
  3. At the liver, SR-B1 (scavenger receptor B1) is responsible for uptake of HDLs.
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4
Q

What is the rate-limiting step in HDL synthesis?

A

Transport of cholesterol into HDL by ABCA1 (expression indirectly regulated by LXR)

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5
Q

What is the enterohepatic circulation?

A
  1. Cholesterol is used in the synthesis of bile salts, which is secreted from the liver and ultimately ends up in the duodenum where it is used to emulsify fat.
  2. Majority of bile reabsorbed in the small intestine and is returned to the liver via the hepatic portal vein.
  3. Some bile is lost in faeces. In order to make up for the lost bile, the liver needs to synthesis more from cholesterol.
  4. Cholesterol can be synthesised de novo in the liver or taken up from blood in form of LDLs.
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6
Q

What is the mechanism of action of statins?

A
  1. Competitive inhibition of HMG-CoA reductase (conversion of HMG-CoA to mevalonate in cholesterol synthesis, rate-limiting step) in hepatocytes.
  2. ↓ [Cholesterol] in hepatocytes.
  3. Stimulation of LDL uptake via SREBP/SCAP pathway.
  4. Shift in source of cholesterol of hepatocytes for bile synthesis from de novo synthesis to LDLs in bloodstream.
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7
Q

What is the SREBP/SCAP pathway of LDL uptake?

A
  1. SREBP (SRE binding protein) binds to SCAP (SERBP cleavage activating protein), which act as chaperone for SREBP from the ER to golgi apparatus.
  2. When intracellular [sterol] is high, SCAP undergoes inhibitory conformational change that prevents activation of SREBP.
  3. However, when [sterol] is low, SCAP activates SREBP, making it susceptible to cleavage. S1P (Site 1 protease) in the golgi cleaves the SREBP into 2 halves, excising the half with regulatory (reg) domain.
  4. S2P (Site 2 protease) then cuts the remaining N-terminus half at a site within transmembrane domain, releasing the bHLH-Zip domain (mature SREBP).
  5. bHLH leaves golgi and enters the nucleus, where it binds onto SRE (sterol response element) of the LDL receptor gene and activates transcription.
  6. Increased LDL receptor expression results increased uptake of LDLs from the blood.
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8
Q

What are the clinical uses of statins?

A

Given to patients with:

  1. Increased risk of cardiovascular disease due to high blood cholesterol
  2. Existing cardiovascular disease (to prevent MI)
  3. History of coronary artery disease (angina, MI)
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9
Q

What are the side-effects of statins?

A

Minor:

  1. Muscle pain (myalgia)
  2. Rash
  3. Insomnia
  4. GI disturbances

Major:

  1. Skeletal muscle damage (rhabdomyolysis)
  2. Angio-oedema
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10
Q

What are the pleiotrophic effects of statins?

A
  1. Improvement in endothelial function
  2. Enhancement of stability of atherosclerotic plaque
  3. Decreased oxidative stress/inflammation
  4. Inhibition of thrombosis
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11
Q

What are the mechanisms of actions of fibrates?

A
  1. Agonist of PPARα, nuclear receptor that upregulates expression of lipoprotein lipase. This increases breakdown of LDLs and increases uptake by hepatocytes, muscle and adipocytes.
  2. Activation of PPARα & PPARγ → ↑LXR transcription → ↑ABCA1 expression → ↑HDL synthesis and reverse cholesterol transport.
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12
Q

What is the mechanism of action of bile absorption inhibitors (bile acid-binding resins)?

A
  1. These drugs physically sequester bile acids and prevent them from being absorbed in the small intestine, causing them to be lost in faeces.
  2. This forces the liver to synthesise more from cholesterol, thus increasing cholesterol uptake in blood.
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13
Q

What are the problems with bile absorption inhibitors?

A
  1. Fatty diarrhoea
  2. Interference in absorption of fat-soluble vitamins
  3. Does not incresse plasma HDL levels
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14
Q

What is the mechanism of action of cholesterol absorption inhibitors?

A
  1. Inhibition of sterol transporter NPC1L1 in brush border of enterocytes.
  2. Highly efficient as it is circulated enterohepatically and so can repeatedly inhibit intestinal cholesterol absorption.
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15
Q

What is the clinical use of cholesterol absorption inhibitors?

A

Used in conjunction with other hipolipidaemic drugs such as statins.

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16
Q

What is the mechanism of nicotinic acids?

A
  1. May act through GPCR HM74A
  2. Inhibits hepatic VLDL secretion
  3. Causes ↓[LDL] and ↑[HDL]
  4. ↑ t-PA
17
Q

What is are the mechanisms of action of fish oil derivaties?

A
  1. Reducing hypertriglyceridaemia via unknown mechanism.
  2. Reduces thrombosis due to containing large amounts of unsaturated fatty acids.
  3. Contains eicosapentaenoic acid, which acts as substitute for arachidonic acid and has 2 anti-clotting effects:
    - Switches prostaglandin production in endothelial cells from PGI2 to PGI3 with little effects on antithrombotic activity.
    - Switches thromboxane production in platelets from TXA2 to TXA3, which is less efficient in causing platelet aggregation
18
Q

What is Tangier disease?

A

Mutation in ABCA1 gene causes severely low levels of HDL, resulting in abnormal cholesterol deposition in peripheral tissues.