Cardio Renal L8

Question 1

Atherosclerosis is a disease affecting the ..

Answer 1

Atherosclerosis is a disease affecting the arterial blood vessel.

Question 2

what is an atheroma?

Answer 2

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.

Question 3

atheroma leads to ______

Answer 3

stenosis

Question 4

stenosis is bad - and can lead to?

Answer 4

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

Question 5

what is part of the atheroma breaks off?

Answer 5

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

Question 6

Answer 6

Question 7

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

Answer 7

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

Question 8

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

Answer 8

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

Question 9

what is angina?

Answer 9

‘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.

Question 10

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

Answer 10

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

Question 11

T or F

atherosclerosis is a form of arteriosclerosis.

Answer 11

T

atherosclerosis is a form of arteriosclerosis.

Question 12

Cholesterol is transported in the blood in ______,

Answer 12

Cholesterol is transported in the blood in lipoproteins,

Question 13

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

Answer 13

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

Question 14

Lipoproteins are composed of:

Answer 14

Cholesterol, intercalated in a phospholipid membrane together with cholesteryl esters

Apolipoproteins associated with the lipid particle

Question 15

Answer 15

Question 16

difference between LDL and HDL?

Answer 16

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

Question 17

is HDL good>

Answer 17

HDL seem to be protective against atheroma development

Reduce the ratio of LDL to HDL

Question 18

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

where does the cholestrol come from?

Answer 18

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.

Question 19

how is LDL taken up by liver cels?

Answer 19

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’.

Question 20

describe the enterohepatic circulation)

Answer 20

Question 21

describe the synthetic pathway for cholesterol

Answer 21

Question 22

describe statins

Answer 22

‘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.

Question 23

describe statins mechanism of action?

Answer 23

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

Question 24

describe the pleiotropic effects of statins

Answer 24

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

Question 25

should you cehcl the notes ofr statins mechanism of action?

Answer 25

ya

Question 26

what is PCSK9?

Answer 26

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.

Question 27

how does PSCK9 work? | (picture)

Answer 27

Question 28

give some examples of PCSK9 inhibitors

Answer 28

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

Question 29

Under conditions of PCSK9 inhibition......

Answer 29

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

Question 30

how are Evolocumab and alirocumab administered?

Answer 30

injection

Question 31

Evolocumab and alirocumab price?

Answer 31

very expensive - so regulated clinica luse in NHS atm

Question 32

Evolocumab and alirocumab - when would they be prescribed?

Answer 32

**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)

Question 33

what si Bezafibrate

Answer 33

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.

Question 34

how is HDL protective ? short answer

Answer 34

a process called ‘reverse cholesterol transport’.

Question 35

Answer 35

Question 36

long - describe reverse cholesterol transport

Answer 36

* 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 *

Question 37

The rate-limiting mechanism of HDL formation is ....

Answer 37

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

Question 38

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

Question 39

difficult info:

Answer 39

Question 40

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

Answer 40

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

Question 41

Drugs involved in the Enterohepatic Circulation: give 4

Answer 41

1. Colestyramine 2. Ezetimibe 3. Nicotinic acid 4. Fish oil

Question 42

Colestyramine - how does it lower cholesterol (LDL levels)

Answer 42

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.

Question 43

how does Ezetimibe work?

Answer 43

* 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

Question 44

Nicotinic acid - how can it lower LDL cholesterol?

Answer 44

Nicotinic acid inhibits liver triglyceride production and VLDL secretion when used in very large doses. It increases levels of t-PA

Question 45

how can fish oil lower LDL?

Answer 45

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

Question 46

fat

Answer 46

mamba