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MVST1B MODA > Cardio Renal L8 > Flashcards

Cardio Renal L8 Flashcards

1
Q

Atherosclerosis is a disease affecting the ..

A

Atherosclerosis is a disease affecting the arterial blood vessel.

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2
Q

what is an atheroma?

A

the atheroma is the accumulation of a soft, flaky, yellowish material at the centre of large plaques, composed of macrophages nearest the lumen of the artery. The process is progressive and the effects cumulative. The changes can progress to more complex lesions with underlying areas of cholesterol crystals, and also calcification in more advanced stages.

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3
Q

atheroma leads to ______

A

stenosis

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4
Q

stenosis is bad - and can lead to?

A

The atheroma leads to stenosis and compromises the arterial supply, and can produce ischaemia: Angina

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5
Q

what is part of the atheroma breaks off?

A

Parts of the atheromatous tissue can break off, or can form a good substrate for clot formation

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6
Q
A
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7
Q

Chronic under-perfusion of the myocardium may lead to….

A

Chronic under-perfusion of the myocardium may lead to congestive heart failure

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8
Q

If the conductive tissue of the myocardium is subject to either ischaemia or infarction this can lead to….

A

If the conductive tissue of the myocardium is subject to either ischaemia or infarction this can lead to dysrhythmias

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9
Q

what is angina?

A

‘Angina’ is the normal abbreviation for angina pectoris.

This is the commonest manifestation (and often the first sign) of ischaemic heart disease which is itself a consequence of inadequate blood flow to the myocardium through the coronary circulation.

This is usually as a result of atherosclerosis.

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10
Q

It is therefore a good idea to try to prevent the development of atherosclerosis in vulnerable individuals. This can be achieved using …… which drugs?

A

It is therefore a good idea to try to prevent the development of atherosclerosis in vulnerable individuals. This can be achieved using hypolipidaemic drugs.

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11
Q

T or F

atherosclerosis is a form of arteriosclerosis.

A

T

atherosclerosis is a form of arteriosclerosis.

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12
Q

Cholesterol is transported in the blood in ______,

A

Cholesterol is transported in the blood in lipoproteins,

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13
Q

excessive ………………….. especially predispose to atheroma

A

excessive low-density lipoproteins (LDL) especially predispose to atheroma

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14
Q

Lipoproteins are composed of:

A

Cholesterol, intercalated in a phospholipid membrane together with cholesteryl esters

Apolipoproteins associated with the lipid particle

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15
Q
A
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16
Q

difference between LDL and HDL?

A
  • Different lipoproteins have different apolipoproteins
  • LDL has apolipoprotein B (ApoB)
  • High-density lipoproteins (HDL) have (mainly) ApoA-type proteins
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17
Q

is HDL good>

A

HDL seem to be protective against atheroma development

Reduce the ratio of LDL to HDL

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18
Q

the liver uses a relatively large amount of cholesterol to synthesise bile salts.

where does the cholestrol come from?

A

the liver uses a relatively large amount of cholesterol to synthesise bile salts.

The cholesterol can either be synthesised in the liver de novo, or can be taken up from the blood.

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19
Q

how is LDL taken up by liver cels?

A

There are LDL receptors on the hepatocyte plasma membrane that help achieve this. LDL binds to the receptors and the LDL-receptor complex enters the cell by ‘receptor-mediated endocytosis’.

20
Q

describe the enterohepatic circulation)

A
21
Q

describe the synthetic pathway for cholesterol

A
22
Q

describe statins

A

‘Statins’ such as atorvastatin and simvastatin inhibit HMG-CoA reductase (hydroxymethylglutaryl-coenzyme A reductase), the rate-limiting enzyme for cholesterol synthesis .

If HMG CoA reductase is blocked, the liver has to take up more LDL from the blood (to keep the cholesterol pool for the enterohepatic circulation topped-up).

The liver does this by synthesising more LDL receptors, which leads to a reduction in blood LDL levels, and so less predisposition to atheroma formation.

23
Q

describe statins mechanism of action?

A

The SREBP/SCAP pathway

final 2 points:

  • SREBPs contain two transmembrane domains and are normally anchored in the endoplasmic reticulum
  • A further protein, called SREBP cleavage activating protein (SCAP) acts as a chaperone protein and it transports the precursor SREBPs from the endoplasmic reticulum to the Golgi
  • At the Golgi, two proteases, site 1 and site 2 protease (S1P and S2P) sequentially cleave the SREBPs
  • These cleavages must occur in the proper order. The first cleavage, by S1P, separates the SREBPs into two halves, both of which remain membrane- bound
  • After the two halves of the SREBP have separated, S2P cleaves the remaining NH2-terminalfragment
  • This liberates the mature SREBP proteins from the membrane and allows them to enter the nucleus, bind to the sterol response elements of target genes and activate LDL receptor gene transcription
24
Q

describe the pleiotropic effects of statins

A

improvement of endothelial function, enhancement of the stability of atherosclerotic plaques, a decrease in oxidative stress and inflammation and inhibition of thrombus formation. Furthermore, statins seem to have beneficial extrahepatic effects on the immune system, CNS and bone - and probably more

25
Q

should you cehcl the notes ofr statins mechanism of action?

A

ya

26
Q

what is PCSK9?

A

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a circulating enzyme, produced by the liver, that is involved in LDL receptor turnover. When PCSK9 interacts with the LDL receptor it stimulates receptor internalisation and degradation and hence leads to fewer receptors being available at the plasma membrane to bind and allow the cell to take up LDL-cholesterol.

27
Q

how does PSCK9 work?

(picture)

A
28
Q

give some examples of PCSK9 inhibitors

A

Evolocumab and alirocumab are monoclonal antibodies, that target and inhibit PCSK9.

29
Q

Under conditions of PCSK9 inhibition……

A

Under conditions of PCSK9 inhibition there is a larger pool of LDL receptors available to bind LDL and then to be internalised and recycled.

30
Q

how are Evolocumab and alirocumab administered?

A

injection

31
Q

Evolocumab and alirocumab price?

A

very expensive - so regulated clinica luse in NHS atm

32
Q

Evolocumab and alirocumab - when would they be prescribed?

A

Primary hypercholesterolaemia or mixed dyslipidaemia in patients who have not responded adequately to other appropriate measures (in combination with a statin, or with a statin and other lipid-lowering therapies, or with other lipid-lowering therapies or alone if a statin contra-indicated or not tolerated)

33
Q

what si Bezafibrate

A

Bezafibrate is one of several fibric acid derivatives which lower VLDL and, to a lesser extent, LDL.

It stimulates lipoprotein lipase, releasing triglycerides from VLDL and chylomicrons.

The lipid can then be taken up and stored in fat or metabolised in skeletal muscle.

Its action has been found recently to hinge upon mechanisms of HDL processing.

34
Q

how is HDL protective ?

short answer

A

a process called ‘reverse cholesterol transport’.

35
Q
A
36
Q

long - describe reverse cholesterol transport

A
  • Cholesterol can be removed from peripheral tissues (including atheromatous tissues) and returned to the liver, transported in HDL, for excretion in bile
  • Cholesterol from non-hepatic peripheral tissues is transferred to HDL by the ATP-binding cassette transporter ABCA1
  • ApoA-I acts as an acceptor and the phospholipid component of HDL acts as a sink for the mobilised cholesterol
  • The cholesterol is converted (for transport in the HDL) to cholesteryl esters by the action of the enzyme lecithin cholesterol acyltransferase (LCAT)
  • Cholesteryl esters can be transferred to other lipoproteins (including LDL) that can be taken up by the liver by the LDL receptor
  • The receptor-SR-B1 (‘Scavenger Receptor-B1’) present on liver cells’ plasma membranes mediates most of the livers uptake of cholesteryl from HDL.
  • Once in the liver, the cholesteryl esters are converted to cholesterol and enter the general pool
    *
37
Q

The rate-limiting mechanism of HDL formation is ….

A

The rate-limiting mechanism of HDL formation is the removal of phospholipids and cholesterol by apoproteins or by HDL from peripheral cells and tissues

38
Q

Studies in patients with Tangier disease - who have extremely low HDL levels - showed that ______ controls this rate-limiting step in cellular phospholipid and cholesterol efflux

A
39
Q

difficult info:

A
40
Q

It is now clear that one of the ways in which fibrates work is by activating ____.

A

It is now clear that one of the ways in which fibrates work is by activating PPARs.

41
Q

Drugs involved in the Enterohepatic Circulation:

give 4

A
  1. Colestyramine
  2. Ezetimibe
  3. Nicotinic acid
  4. Fish oil
42
Q

Colestyramine - how does it lower cholesterol (LDL levels)

A

Colestyramine is an anion exchange resin.

It prevents reuptake of bile acids from the intestine. This causes an increase in cholesterol metabolism to synthesise bile acids in the liver.

43
Q

how does Ezetimibe work?

A
  • new drug
  • inhibits intestinal absorbtion of cholesterol
  • mechanism of action involves binding NPC1L1 on the brush border
  • NPC1L1 mediates sterol transport across the brush border of intestinal epithelial cells and is also present in the liver where it helps in the reabsorption of cholesterol from bile
  • it circulates enterohepatically - efficient
44
Q

Nicotinic acid - how can it lower LDL cholesterol?

A

Nicotinic acid inhibits liver triglyceride production and VLDL secretion when used in very large doses.

It increases levels of t-PA

45
Q

how can fish oil lower LDL?

A

Fish oil reduces hypertriglyceridaemia by an unknown mechanism and use of fish oil reduces pancreatitis due to hypertriglyceridaemia.

The increased amounts of highly unsaturated fatty acids in fish oil reduces risk of thrombosis.

The eicosapentaenoic acid they contain substitutes for arachidonic acid in production of prostaglandins and thromboxanes.

Eicosapentaenoic acid produces PGI3 instead of PGI2 in endothelial cells, without a great change in antithrombotic activity but the TXA3 produced in platelets is much less effective than TXA2 at causing platelet aggregation.

Maceral, herring - good for you

46
Q

fat

A

mamba

MVST1B MODA (22 decks)

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