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Year 5 Path Chemical Pathology > Year 2: Atherosclerosis+ Lipid lowering drugs > Flashcards

Year 2: Atherosclerosis+ Lipid lowering drugs Flashcards

1
Q

Explain the role of endothelial dysfunction in the formation of atherosclerotic plaques

A
  1. Increased endothelial permeability
  2. Upregulation of endothelial adhesion molecules
  3. Leukocyte adhesion
  4. Migration of leukocytes into the artery wall

Initiation of Fatty Streak formation

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2
Q

Explain the formation of fatty streaks in Atherosclerosis

A
  1. Foam cells formation and accumulation in the intima
  2. Causing drivin of inflammation and triggers the initiation of other effects
    • Adherence and entry of leukocytes
    • migration of SM cells
    • Platelet aggregation
    • T-cell activation
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3
Q

Explain the development from a fatty streak to an atherosclerotic plaque

A
  1. Foam cells die and dissolve –> bulit up of necrotic core
  2. Causes an macrophage accumulation
  3. Formation of a protective fibrous cap by Vascular smooth muscles cell
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4
Q

What is the role of Remnant lipids and Atherosclerosis

A

Remnant lipids are associated with the inflammatory compound of Atherosclerosis

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5
Q

What are remnant lipids?

A

Remanants are break down products of cyclomicrons , composed of VLDL and IDL (very high in cholesterole)

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6
Q

Explain the role of LDL in the formation of Atherosclerosis

A

Formation of Atherosclerosis is highly associated with LDL levels but LDL levels do not cause the inflammatory component of Atherogenesis

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7
Q

What are the diffferences between a stable and an unstable atherosclerotic plaque?

A
  • Unstable plaque have a thin fibrous cap and can easily rupture –>
  • Rupture can be triggured by increased BP or inflammation
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8
Q

What does a 10% increase in LDL levels mean in regards to the risk of developing CHD?

A

•10% increase results in a 20% increase
in CHD risk

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9
Q

Which factors can influence the negative effects of LDL on CHD and atherosclerosis?

A

Risk factors like:

  • low HDL cholesterol
  • smoking
  • hypertension
  • diabetes

Can make the risk for CHD (with high LDL) a lot worse

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10
Q

Explain the role of HDL in CHD and atherosclerosis

A
  • HDL cholesterol has a protective effect for risk of atherosclerosis and CHD
  • The lower the HDL cholesterol level, the higher the risk for atherosclerosis and CHD
  • HDL cholesterol tends to be low when triglycerides are high
  • HDL cholesterol is lowered by smoking, obesity and physical inactivity
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11
Q

What are statins?

What is their drug target?

A

inhibitors of HMG CoA reductase (enzyme involved in the rate-limiting step of cholesterole synthesis)

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12
Q

Explain the MOA of statins

A

Statins competitevely inhibit the HMG-CoA reductase (enzyme in the rate limiting step of cholesterole synthesis)

–> reduce cholesterole synthesis in the liver leading to

  1. Hepatic upregulation of LDL receptors
  2. increasing binding and removal of LDL cholesterol and LDL precursors from the plasma

Resulting in:

  • Decreased LDL
  • Increased HDL
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13
Q

What are the main side effect in the use of statins?

A

General (common): headache and gastrointestinal symptoms (e.g., constipation, diarrhea, flatulence)

Rarer:

  • increase in Liver-function test
  • myopathy
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14
Q

Explain the effects of the use of Statins on the lipid profile

A

Generally: Statins lower LDL and triglycerides, increase HDL

  • different statins are differently effective
  • But in all statins : Rule of 6: double the dose but only 6% reduction in LDL
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15
Q

Explain the effects of statins on CHD and aterostclerosis

A

They overall: decrease the risks of CHD and atherosclerosis via

  • lipid-lowering effects
  • Plyothropic effects (not related to lipid profile)
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16
Q

What are the pylotrophic effects of statins?

A

The effects they get which are not related to improvement of the lipid profile

  • Decrease platelet aggregation
  • have a thrombolytic effect
  • increase plaque stability
  • decrease inflammation
  • decrease vasoconstriction
17
Q

What are fibrates?

When would you use them?

A

A type of lipid lowering drugs

–> used as second line-treatment in dyslipidaemia

18
Q

Explain the MOA of fibrates

A

Activatethe peroxisome proliferator-activated receptor alpha (PPAR–α) →

↑ lipoprotein lipase activity →

↓ LDL, ↑ HDL, ↓↓↓ triglyceride

19
Q

Explain the clinical use of Nicotinic acid (Nicatin, VIt B3)

A

As an additional treatment with statins

(thought it has lipid lowering effects, no clinical significant effects could be proven yet)

20
Q

Explain the MOA of Nocotinic Acid (Niactin, VIt B3)

A

inhibits lipolysis and fatty acid release in adipose tissue, decreases hepatic VLDL synthesis → ↓ triglyceride and LDL synthesis, ↑ HDL

21
Q

What are the effects of Niactine on clinical outcome

A

Though it does increase lipid profile, it is not does not decrease the risk of vascular events

  • –> use needs to be reconsidered
22
Q

What is Ezetimibe?

What is its clinical use?

A

It is a lipid-lowering agent

  • used as an addition to statins
  • outcomes are there but not too significant
23
Q

Explain the MOA of Ezetimibe

A

selective inhibition of cholesterol reabsorption at the brush border of enterocytes (cholesterol transporter NPC1L1) → ↓ LDL

24
Q

What is Proprotein convertase subtilisin/ kexin type 9? (PCSK9)

What happens to it in the treatment of statins?

A

It is an inhibitor of LDL receptor

  • In the treatment of statins: though receptors are upregulated: PCSK9 is also upregulated and limits the effects of statins
25
Q

Explain the use of PCSK9 inhibitors and its limitations

A

Normally as an add on to statins to get a more effective reduction in dyslipidaemia

  • but: Expensive (4000ppy)
  • Maybe: use in familiar hypercholesteraemia
  • Might be available as drug
26
Q

Explain the MOA of PCSK9 inhibitors

A

Inhibits the LDL receptor degradation by PCSK9

27
Q

What type of lipid-lowering drugs are there?

What is the MOA?

A
  1. Bile acid sequestians
    • low adherence due to side effects like bloating
  2. Cholesterole absorbance inhibitors (Ezetimibe)
  3. HMG-reductase inhibitors (Statins)
  4. Fibrates
  5. Nicotinic acid (Niactin)
  6. PCSK9-inhibitors
28
Q

Summarise lipoprotein metabolism

A

Uptake of fats by cyclomycrons and transported to the liver

  • Synthesis of LIVer–> LDL, IDL and VLDL by heptic lipase
  • VLDL are sent out to the blood stream and lipoprotein lipase removes triglycerides from the core and replaces them with Cholesterol
  • VLDL is converted into
    • LDL (majoity)
    • IDL (directly removed from circulation, very atherogenic)
  • LDL in circulation or excreted in bile

Year 5 Path Chemical Pathology (24 decks)

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