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CDL301 Cardiovascular Pharmacology Refesher > Lecture 16 Atherosclerosis II > Flashcards

Lecture 16 Atherosclerosis II Flashcards

1
Q

How are lipids transported in the body and why

A

As lipids are hydrophobic they are transported in the body as lipoproteins

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2
Q

Outline the general structure of a lipoprotein

A

Consist of a central core of hydrophobic lipid such as a triglycerides or cholesterol surrounded by a hydrophilic coat of phospholipids free cholesterol and apolipoproteins

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3
Q

How are lipoproteins classified

A

Lipoproteins are classified according to density each has a decreasing amount of core lipid

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4
Q

Recall the different classifications of lipoproteins

A

HDL IDL LDL VLDL and chylomicrons

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5
Q

Below is a table with a list of the different classifications of lipoproteins their diameter and the apolipoproteins contained. Draw a line to match up the lipoprotein with its diameter and constituent apolipoprotein

A

See completed table

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6
Q

What are the three pathways involved in lipid transport and outline the direction of transport

A

Exogenous (dietary) – from food to tissues. Endogenous – from liver to tissues. Reverse cholesterol – cholesterol from tissues to the liver for excretion

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7
Q

Explain the exogenous or dietary lipid transport pathway

A

Ingested lipids are broken down in the stomach to their individual lipid molecules. These lipid molecules are then transported out of the digestive system by the NPC1L1 transporter before they make their way into the lymphatic system. Here they are packaged with ApoB-48 into a nascent chylomicron which then travels through the lymphatic system to the liver where it moves into the blood stream and interacts with HDL. HDL donates ApoC and ApoE to the nascent chylomicron which now forms a mature chylomicron. This mature chylomicron transports itself in the blood stream until it finds adipose tissue which it interacts with via ApoC. This leads to the activation of lipoprotein lipase in the adipose tissue which hydrolyses the chylomicron to release the cholesterol and fatty acids contained in the centre of the molecule. These cholesterols and fatty acids are now accessible by tissue which will then absorb and use the molecule. After being hydrolysed the now remnant chylomicron will continue round the blood stream until it reaches the liver and is taken up by ApoE or ApoB-48 which bind to receptors in the liver. The chylomicron may then further hydrolyse to release cholesterol which may then be either stored oxidised and converted into bile acids or packaged into VLDL.

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8
Q

Explain the endogenous lipid transport pathway

A

In the liver triacylglycerol and cholesterol are assembled with ApoB-100 to form VLDL which then receives ApoC-II and ApoE donated by HDL. VLDL can circulate in the blood stream until ApoC-II activates lipoprotein lipase (LPL) in the tissues leading to the hydrolysis of the VLDL and the release of glycerol and fatty acids these are then absorbed by adipose tissue and muscle. The hydrolysed VLDL is now referred to as IDL which returns to the liver and is further hydrolysed to LDL by hepatic lipase releasing more glycerol and fatty acids. This LDL can then go one of two ways; it can bind to tissues via ApoC and become internalised before being hydrolysed in lysosomes to release yet more cholesterol. Alternatively LDL binds to the LDLR in the liver via ApoB-100 and is removed from the circulation

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9
Q

Explain the reverse cholesterol transport pathway

A

The reverse cholesterol pathway removes cholesterol from peripheral tissues and returns it to the liver. ApoA1 on the HDL molecule binds to transport proteins ABC-A1 or ABC-G1 that are found on macrophages/foam cells in the atherosclerotic lesion and adsorbs cholesterol. HDL can then transport cholesterol to liver via either the indirect pathway or the direct pathway. In the indirect pathway cholesterol esters are transferred to VLDL and LDL particles via cholesterol ester transport protein (CETP). LDL then binds to LDLR in the liver and is taken up. Alternatively in the direct pathway ApoA1 from HDL binds the SRB1 receptor in the liver and cholesterol is transferred. HDL is then free to recirculate back to collect more cholesterol. Cholesterol in liver is processed and secreted in bile or transported to intestine via ABC-G5/G8 for excretion

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10
Q

What is meant by the term dyslipidaemia

A

An abnormal amount of lipids in the blood

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11
Q

Most dyslipidaemias are what kind

A

Hyperlipidaemias where there is an elevation of blood lipids

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12
Q

Dyslipidaemias can be primary or secondary how do they differ

A

Primary dyslipidaemia is a combination of diet and genetics and is usually polygenic. Secondary dyslipidaemia on the other hand is a consequence of other conditions such as diabetes alcoholism chronic renal failure liver disease and administration of drugs. These secondary dyslipidaemias are treated where possible by correcting the underlying cause

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13
Q

What is the Frederickson classification of dyslipidaemias

A

The Frederickson classification classifies primary dyslipidaemias into 6 phenotypes based on which lipoprotein particle is abnormal.

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14
Q

The higher the LDL and the lower the HDL the higher the risk of atherosclerosis and IHD T or F

A

T

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15
Q

Quite a few of primary dyslipidaemias don’t really influence atherosclerosis as they are affecting different lipoproteins T or F

A

T

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16
Q

Which is the main classification of dyslipidaemia relevant to atherosclerosis

A

Type II dyslipidaemia increases the risk of atherosclerosis as it significantly increases LDL levels in the blood. This dyslipidaemia is also known as familial hypercholesterolaemia

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17
Q

What is familial hypercholesterolaemia

A

A genetic disorder causing very high LDL levels in the blood and early cardiovascular disease

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18
Q

Patients which familial hypercholesterolaemia usually have mutations in which genes

A

LDLR or ApoB

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19
Q

Although most mutations are in LDLR or ApoB most FH is thought to be polygenic T or F

A

T

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20
Q

Most FH patients are homozygous for mutations in the LDLR gene T or F

A

F – they are heterozygous and this occurs in 1:500 people

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21
Q

How is FH treated in heterozygous patients

A

Normally treated with statins bile acid sequestrants or other lipid lowering agents that lower cholesterol levels

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22
Q

How do the symptoms of FH differ in homozygotes

A

Patients homozygous for the LDLR mutation can have severe CVD in childhood. These patients often do not respond to medical therapy and may require other treatments

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23
Q

How is FH treated in homozygous patients

A

LDL apheresis (removal of LDL from the blood) and occasionally liver transplantation

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24
Q

What is the incidence of homozygous FH

A

1 in 1 million

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25
Q

What is the overall treatment strategy in dyslipidaemia and atherosclerosis

A

Drug therapy aimed at reducing levels of LDL combined with dietary changes

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26
Q

What are the main classes of drugs available for the treatment of atherosclerosis

A

Statins fibrates cholesterol absorption inhibitors and PSCK9 inhibitors

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27
Q

What is the most commonly used treatment of dyslipidaemias

A

Statins

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28
Q

How do statins act

A

Statins act by inhibiting the conversion of HMG-CoA to mevalonic acid. HMG-CoA reductase is a rate-limiting enzyme in cholesterol synthesis hence you can regulate cholesterol levels by targeting HMG-CoA reductase

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29
Q

List some of the specific reversible competitive statins

A

Simvastatin lovastatin and pravastatin

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30
Q

List some of the longer-lasting statins

A

Atorvastatin rosuvastatin

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31
Q

Outline how the active statin drug is formed

A

All statins require converting to an active metabolite in the liver before they can exert their effects. Most statins are subject to extensive pre-systemic metabolism via cytochrome P450 pathway with pravastatin requiring processing by the glucuronidation pathway

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32
Q

When are short acting statins given and why

A

Short-acting statins are given orally at night to reduce peak cholesterol synthesis in the early morning after they have been converted to an active metabolite

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33
Q

Statins are efficiently absorbed and extracted by their site of action in the liver T or F

A

T

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34
Q

How does inhibiting HMG-CoA reductase in the liver lead to a decrease in blood LDL when using statins

A

In response to decreased cholesterol synthesis in the liver it responds by upregulating the LDLR in order to uptake more cholesterol from the blood. This upregulation of LDLR increases the LDL clearance from the blood plasma which then in turn acts to lower blood LDL and decrease the atherosclerosis.

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35
Q

Statins reduce plasma LDL as well as reducing plasma triglyceride and increasing HDL levels T or F

A

T

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36
Q

Why do statins often have pleiotropic effects

A

Products of the mevalonate pathway are involved with lipidation of target proteins. For example lipid fatty groups serve as anchors to localise the proteins in organelles. In addition several important membrane-bound enzymes (e.g. eNOS) are modified by lipidation. Hence by inhibiting the mevalonate pathway statins also affect lipidation

37
Q

Give some examples of the pleiotropic effects of statin use

A

Improved endothelial function reduced vascular inflammation reduced platelet aggregability increased neo-vascularisation of ischaemic tissue increased circulating endothelial progenitor cells stabilization of atherosclerotic plaques antithrombotic actions enhanced fibrinolysis

38
Q

What are some of the negative pleiotropic effects of statin use

A

Inhibition of germ cell migration during development (contraindicated in pregnancy) immune suppression

39
Q

What is the primary use of statins in the clinic

A

For the prevention of arterial disease in at risk patients. These are patients with elevated serum cholesterol concentration and/or with other risk factors of atherosclerosis

40
Q

What is the secondary use of statins in the clinic

A

For the prevention of MI and stroke in patients who have symptomatic atherosclerotic disease

41
Q

What can be done in patients with severe statin-resistant dyslipidaemia

A

Statins are usually combined with another lipid-lowering drug

42
Q

Why are statins contraindicated in pregnancy

A

HMG-CoA reductase guides migrating primordial germ cells and hence inhibiting it causes embryopathy

43
Q

What are the potential adverse effects of statin usage

A

Muscle pain GI disturbance raised concentrations of liver enzymes in the plasma insomnia rash angio-oedema skeletal muscle damage (myositis and rhabdomyolysis)

44
Q

Which patients are more at risk of skeletal muscle damage such as myositis and rhabdomyolysis

A

Patients who are on high doses of statins or who have a low lean body mass or uncorrected hypothyroidism. Similarly patients with SNPs in the SCLO1B1 gene have a higher risk of skeletal muscle adverse drug reactions

45
Q

Why are statins still used despite the adverse reactions that they can cause

A

In high risk patients the side effects are negligible compared to the benefit in cutting the chances of heart disease

46
Q

What disease can statins increase the risk of by around 1% especially in women

A

Diabetes

47
Q

What is the controversy surrounding some of the key findings around statin use

A

Some of the key findings on statins effectiveness and side effects comes from industry-funded studies and not all of the raw data has been made available for all researchers to see. In addition industry and non-industry publications often show different results both in effectiveness and side effects of statin use

48
Q

What controversy exists around the use of statins alongside lifestyle changes

A

No statin drug has ever been compared with lifestyle interventions for the prevention of cardiovascular disease and as such there may be an interaction between medication and lifestyle. In addition statin users have been shown to consume more calories gain weight and exercise less which would negate cardiovascular benefits

49
Q

Fibrates/fibric acid derivatives are another class of drugs used to treat dyslipidaemias. Give some examples of these drugs

A

Bezafibrate ciprofibrate gemfibrozil fenofibrate clofibrate

50
Q

What is the mechanism of action of fibrates

A

Fibrates activate the peroxisome proliferator-activated receptors (PPAR) especially PPARα. PPARs are intracellular receptors that modulate carbohydrate and fat metabolism as well as adipose tissue differentiation. Activating PPARs induces the transcription of a number of genes that facilitate lipid metabolism such as LPL ApoA1 and ApoA2 that hence lower circulating lipid levels

51
Q

How are fibrates metabolised

A

Fibrates are metabolised by the enzyme cytochrome P450 3A4 (CYP3A4) that is mainly found in the liver and intestine. CYP3A4 oxidises small foreign inorganic molecules (xenobiotics) such as toxins or drugs so that they can be removed from the body

52
Q

What are the effects of fibrates of levels of circulating lipoproteins

A

Fibrates markedly reduce circulating VLDL and therefore decrease triglyceride levels. They result in a 10% decrease in LDL and a 10% increase in HDL

53
Q

Fibrates are rarely used in the clinic today T or F

A

T – due to their adverse effects

54
Q

When are fibrates only really used

A

If patients cannot tolerate statins or ezetimibe or in combination with other lipid lowering drugs in patients who have drug resistance dyslipidaemia

55
Q

Fibrates have not been shown to improve survival but they do reduce the numbers of non-fatal MI T or F

A

T

56
Q

What are the adverse effects of fibrates

A

Mild stomach upset and myopathy. Clofibrate specifically increases risk for gallstones as it increases the cholesterol content of bile. Hence it is only given to patients that have had gall bladder removed. In addition combination of a statin and a fibrate increases the risk of muscle damage (rhabdomyolysis) which can lead to kidney failure

57
Q

What are the two main contraindications of fibrate usage and why

A

Fibrates should not be taken by patients with advanced kidney disease due to the increased risk of rhabdomyolysis and impaired drug elimination. In addition they should not be taken by alcoholics because of the risk of severe muscle inflammation and injury

58
Q

Which drug is an example of an inhibitor of cholesterol absorption

A

Ezetimibe

59
Q

How do inhibitors of cholesterol absorption act

A

Ezetimibe blocks the intestinal absorption of cholesterol by blocking the NPC1L1 transport protein in the brush border of enterocytes

60
Q

What is significant about the off-target effects of ezetimibe in inhibiting the uptake of other compounds by the enterocytes

A

Ezetimibe does not affect the absorption of fat-soluble vitamins triglycerides or bile acids

61
Q

What can be said about the potency of ezetimibe in inhibiting cholesterol absorption

A

It has a high potency as 10mg/day reduces LDL cholesterol by 17-19%

62
Q

How is ezetimibe used in the clinic

A

It is often given in combination with a statin resulting in a 25% decrease in LDL. One example is where ezetimibe is given in a single tablet in combination with simvastatin (INEGY)

63
Q

Give an overview of ezetimibe pharmacokinetics

A

Ezetimibe is orally administered and absorbed into intestinal epithelial cells localising to the brush border (presumed site of action). The drug is extensively (>80%) metabolised to an active metabolite and enterohepatic recycling results in slow elimination

64
Q

What is the approximate half-life of ezetimibe

A

22 hours

65
Q

What are the advantages of ezetimibe

A

Very low potential for interactions with other medications convenient to take a single 10mg tablet once a day side effects are few

66
Q

What are the disadvantages of ezetimibe

A

It is quite expensive

67
Q

What is the major contraindication of ezetimibe

A

It is contraindicated in women who are breastfeeding due to its ability to enter the milk

68
Q

What are the main side effects of ezetimibe

A

Mild diarrhoea abdominal pain headache rash angio-oedema

69
Q

Outline the typical patient profile who would receive ezetimibe

A

Given to patients who experience side effects from high-dose statins in order to decrease the dose of the statin to one that is tolerable. It is also given as a supplementary treatment to statins in patients with severe dyslipidaemia

70
Q

Resins were the first oral cholesterol lowering drug to be used clinically what are the main examples

A

Colestyramine colestipol colesevelam

71
Q

How do resins act in the treatment of hypercholesterolaemia

A

They inhibit cholesterol absorption by sequestering bile acids. This prevents the bile acid absorption into blood stream. The liver compensates to decreased bile acid absorption by increasing the metabolism of endogenous cholesterol into bile acids. It also increases expression of LDL receptors leading to increased clearance of LDL from the blood. This hence leads to a subsequent decrease in the concentration of LDL in plasma

72
Q

What are the downsides of resins

A

Severe side effects including bloating constipation diarrhoea nausea. In addition the tablets are bulky and unpalatable making them difficult to take. Finally they also interfere with the absorption of fat-soluble vitamins and a wide range of drugs (digoxin diuretics warfarin thyroid hormones beta blockers calcium channel blockers)

73
Q

Due to their interference with other drugs and food resins must be taken at specific times when is this

A

1h after or 4-6h before any other medication

74
Q

Resins are often used in the clinic to lower cholesterol and treat dyslipidaemias T or F

A

F – due to intolerance issues

75
Q

Why are stanols not prescribed to treat hypercholesterolaemia

A

They are generally found in the diet as they are isolated from wood pulp and used to make margarines or yoghurts

76
Q

How do stanols and sterols act to lower cholesterol

A

Stanols and sterols are structurally similar to cholesterol and as such they are often incorporated into chylomicrons replacing the cholesterol. This results in less cholesterol (40-45%) being absorbed into the bloodstream. Less absorption means a reduced serum total and LDL cholesterol concentrations

77
Q

What is the hypothesised mechanism of action of sterols and stanols on ABCG5/ABCG8

A

Stanols/sterols may also activate the ABCG5/ABCG8 heterodimer transporter within enterocytes. This increases movement of cholesterol from enterocytes back into the intestinal lumen to be excreted

78
Q

Niacin nicotinic acid or vitamin B3 is also a cholesterol lowering drug. How does this compound act

A

Niacin is converted to nicotinamide which inhibits hepatic VLDL secretion. It therefore causes a decrease in circulating triglyceride a decrease in LDL and an increase in HDL

79
Q

What is significant about the dose of niacin required to lower blood cholesterol

A

You need high levels (3g/day) of niacin to improve cholesterol

80
Q

What is the hypothesised mechanism of action of niacin

A

The mechanism of action is poorly understood but it is thought to be initiated by an effect on lipolysis via an orphan GPCR known as HM74A present in adipocyte membranes

81
Q

What are the adverse effects of niacin use

A

Flushing palpitations itching/redness of face arms and chest headaches and gastrointestinal disturbance. Large doses of niacin can also be toxic to the liver

82
Q

Why is niacin almost never used clinically

A

The HSP2-THRIVE trial found that niacin along with a statin does not improve cardiovascular outcome but does increase serious adverse effects

83
Q

Repatha or evolocumab is a drug recently introduced into the clinic to treat hypercholesterolaemia. What is this drug and what does it target

A

Repatha is a human monoclonal antibody against the proprotein convertase subtilisin/Kexin type 9 (PCSK9). PCSK9 is a natural negative regulator of low density lipoprotein receptor (LDLR). It binds LDLR and the complex internalises before the LDLR receptor undergoes lysosomal degradation

84
Q

What is the mechanism of action of evolocumab

A

Evolocumab binds to PCSK9 and prevents circulating PCSK9 from binding to LDLR. This in turn acts to prevent PCSK9-mediated LDLR degradation and hence LDL is then free to bind LDLR. Upon binding to LDLR the complex then internalizes and releases its LDL before the LDLR then recycles back to the liver cell surface. Hence PCSK9 inhibitors effectively increase the number of LDLRs available to clear LDL from the blood which in turn acts to lower circulating LDL levels

85
Q

What does this graph tell us about the efficacy of evolocumab in lowering LDL levels

A

The graph shows that when given in combination with a statin PCSK9 inhibitors have an enhanced effect on reducing circulating LDL levels when compared with statin alone and when a statin/ezetimibe combination is given

86
Q

How is evolocumab/repatha given

A

Repatha is supplied as an injection for subcutaneous administration. The recommended dosage is either 140 mg every 2 weeks or 420 mg once monthly

87
Q

What are the specific indications for repatha

A

Adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical CVD who require additional lowering of LDL-C. Or adjunct to diet and other LDL-lowering therapies (e.g. statins ezetimibe LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C

88
Q

How is Repatha given to patients with homozygous FH

A

Monthly dosages followed by monitoring of LDL-C levels every 4 to 8 weeks

89
Q

What are the adverse effects of Repatha

A

Nasopharyngitis upper respiratory tract infection influenza back pain injection site reactions (erythema pain bruising) and hypersensitivity reactions (rash eczema erythema urticaria)

CDL301 Cardiovascular Pharmacology Refesher (17 decks)

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