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Pharmacology > Atherosclerosis, lipoproteins and lipid-lowering drugs > Flashcards

Atherosclerosis, lipoproteins and lipid-lowering drugs Flashcards

1
Q

What is endothelial dysfunction in atherosclerosis characterised by?

A

A series of early changes that precede lesion formation.
Changes include greater permeability of the endothelium, up-regulation of leukocyte and endothelial adhesion molecules, and migration of leukocytes into the artery wall.

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2
Q

What is the earliest recognisable lesion of atherosclerosis?

A

Fatty streak formation

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3
Q

What is fatty streak formation caused by?

A

Aggregation of lipid-rich foam cells, derived from macrophages and T-lymphocytes, within the intima (innermost part of artery wall).

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4
Q

What is the series of steps in fatty streak formation in atherosclerosis?

A 
Smooth muscle cell migration
T-cell activation
Adherence and entry of leukocytes
Foam cell formation
Platelet adherence and aggregation
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5
Q

What does development of an atherosclerotic plaque indicate?

A

Advanced stage in the atherosclerotic process.

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6
Q

What does development of an atherosclerotic plaque result from?

A

Death and rupture of the lipid-laden foam cells in the fatty streak.

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7
Q

What is the role of the fibrous cap?

A

Crucial component of the mature atherosclerotic plaque as it separates the highly thrombogenic lipid-rich core from circulating platelets and other coagulation factors.
Protective.

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8
Q

What results in the formation of a fibrous cap over the lipid core?

A

Migration of vascular smooth muscle cells to the intimacy

Laying down of collagen fibres

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9
Q

What are stable atherosclerotic plaques characterised by?

A

Necrotic lipid core covered by a thick vascular smooth muscle-rich fibrous cap.

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10
Q

What is involved in the exogenous pathway of lipid metabolism?

A

Absorption of fats from the diet.

Transport and utilisation of dietary fats.

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11
Q

Where is dietary fat broken down, and into what?

A

In the GI tract, into cholesterol, fatty acids and mono- and diglycerides.

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12
Q

What are water-soluble micelles formed from?

A

Products of dietary fat breakdown (cholesterol, fatty acids and mono- and diglycerides) and bile acids.

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13
Q

What is the role of water-soluble micelles in the exogenous pathway of lipid metabolism?

A

Carry the lipid to absorptive sites in the duodenum.

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14
Q

What happens following absorption of triglycerides and cholesterol in the duodenum?

A

Chylomicrons are formed, which enter the bloodstream via intestinal lymphatics and the thoracic duct.

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15
Q

What happens to chylomicrons when they enter plasma?

A

Hydrolysed by lipoprotein lipase, releasing the triglyceride core, free fatty acids and mono- and diglycerides for energy production or storage

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16
Q

What happens to the residual chylomicron after hydrolysis?

A

Undergoes further delipidation, resulting in the formation of chylomicron remnants.

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17
Q

What happens to chylomicron remnants?

A

Taken up by a number of tissues.
In the liver they undergo lysosomal degradation, and are either used for remanufacture into new lipoproteins, production of cell membranes, or excretion as bile salts.

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18
Q

What is the role of VLDL in the endogenous pathway of lipid metabolism?

A

Transports triglycerides (together with cholesterol, cholesterol ester and other lipoprotein particles) from the liver to the rest of the body via the bloodstream.

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19
Q

What happens to VLDL in the bloodstream?

A

It undergoes delipidation with lipoprotein lipase, in a similar way to chylomicrons. Triglycerides are removed from the core and exchanged for cholesterol esters, principally from HDL.

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20
Q

What is the main enzyme used in the lipolysis of large VLDL particles?

A

Lipoprotein lipase

21
Q

What is most VLDL transformed into in the endogenous pathway of lipid metabolism?

A

LDL

22
Q

What are larger VLDL particles converted to?

A

They are lipolysed to IDL, which is then removed from the plasma directly.

23
Q

What is the role of hepatic lipase?

A

Reacts with small VLDL and IDL particles in the endogenous pathway of lipid metabolism.

24
Q

What is the role of the enterohepatic circulation in the endogenous pathway of lipid metabolism?

A

Provides a route for excretion of cholesterol and bile acids.

25
Q

What is a feature of IDL?

A

Highly atherogenic.

26
Q

What is the product of the metabolic cascade in the endogenous pathway of lipid metabolism?

A

LDL, which exists in the plasma in a number of sub-fractions: LDL I-IV.

27
Q

What are the most atherogenic particles?

A

Small dense LDL particles

28
Q

What happens to small dense LDL particles in the endogenous pathway of lipid metabolism?

A

Absorbed by macrophages within the arterial wall to form lipid-rich foam cells, the initial stage in the pathogenesis of atherosclerotic plaques.

29
Q

Why is cholesterol eliminated from the body intact?

A

Cannot be broken down within the body.

30
Q

What is the role of HDL in reverse cholesterol transport?

A

Cholesterol is transported via HDL from the peripheral tissues to be excreted by the liver.
HDL begins as a lipid-deficient precursor which transforms into lipid-rich lipoprotein. In this form it transfers cholesterol either directly to the liver or to other circulating lipoproteins to be transported to the liver for elimination.
HDL is a protective factor against the development of atherosclerosis.

31
Q

What are elevated levels of LDL cholesterol associated with?

A

Ischaemic heart disease and atherosclerosis (without a major inflammatory component).

32
Q

What is an inflammatory component of atherosclerosis driven by?

A

Elevated remnant cholesterol levels

33
Q

What are vulnerable atherosclerotic plaques characterised by?

A

Thin fibrous cap
Core rich in lipid and macrophages
Less evidence of smooth muscle proliferation
Vulnerable plaques are prone to rupture and ulceration, followed by rapid development of thrombi.

34
Q

Where does a plaque rupture usually occur?

A

At sites of thinning, particularly at the shoulder area of the plaque.
Associated with regions with relatively few smooth muscle cells but abundant macrophages and T-cells.

35
Q

What is plaque rupture associated with?

A

Greater influx and activation of macrophages

Release of matrix metalloproteinases involved with the breakdown of collagen

36
Q

What risk factors is LDL cholesterol modified by?

A

Low HDL cholesterol
Smoking
Hypertension
Diabetes

37
Q

What percentage increase in CHD risk would a 10% increase in LDL cholesterol result in?

A

20%

38
Q

What is a lower HDL cholesterol level associated with?

A

Higher risk of atherosclerosis and CHD

39
Q

What is HDL lowered by?

A

Smoking
Obesity
Physical inactivity

40
Q

List lipid-lowering therapies.

A 
Bile acid sequestrants (resins)
Nicotinic acid and its derivatives
Fibrates (e.g. gemfibrozil)
Statins (inhibit HMG CoA reductase)
Ezetimibe
41
Q

What are the first-line drugs in the treatment of dyslipidaemias?

A

Statins

42
Q

What do bile acid sequestrants do?

A 
Lower cholesterol (potent)
Compliance is a problem (taste and texture)
Adverse events: GI bloating, nausea, constipation
43
Q

What does nicotinic acid do?

A

Increases HDL cholesterol levels
B-complex vitamin
Indicated for all dyslipidaemias except congenital lipoprotein lipase deficiency
Adverse events: flushing, skin problems, GI distress, liver toxicity, hyperglycaemia, hyperuricaemia

44
Q

What do fibrates do?

A

Lower triglycerides-effect for patients with type III hyperlipoproteinaemia
Moderately successful in reducing LDL cholesterol in most patients

45
Q

What do statins do?

A

Lower LDL cholesterol

Good tolerability profile

46
Q

What is the mechanism of action of statins?

A

Inhibit HMG-CoA reductase (rate-limiting step of cholesterol formation, usually responsible for 2/3 of body cholesterol).
Hepatocytes up-regulate and increase the number of LDL receptors in response, increasing binding and removal of LDL cholesterol and LDL precursors from the plasma.
Increase in HDL levels.

47
Q

What is the mechanism of action of fibrates?

A

Activation of PPAR (peroxisome proliferator activated receptors) alpha receptors.

48
Q

What does ezetimibe do?

A

Inhibits cholesterol absorption.

Absorbed then activated as glucuronide.

Pharmacology (21 decks)

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