atherosclerosis and lipid lowering drugs

Question 1

what is atherosclerosis

Answer 1

characterised by chronic inflammation of the blood vessel walls

leads to vessel narrowing, occlusion and distal ischaemia (e.g infarction and stroke)

Question 2

what are hallmarks of atherosclerosis

Answer 2

activation of leukocytes and platelets

vascular smooth muscle hypertrophy

modification and deposition of lipid

Question 3

what are sequence of events that lead to atherosclerosis

Answer 3

starts with endothelial dysfunction and loss of cytoprotective mediators

macrophages are activated and adhere to endothelium

production of reactive oxygen species by macrophages leads to low density lipoprotein oxidation and further damage to endothelium

the modified low density lipoprotein is not cleared from plasma so macrophages take up modified LDL and migrate to foam cells in the vessel wall

platelets are also activated and so adhere to the endothelium

macrophages and platelets release cytokines, growth factors and reactive oxygen species to cause further damage, hyperplasia and attract additional cells

Question 4

what are the cytoprotective mediators

Answer 4

nitric oxide (NO), prostacyclin and endothelium derived hyperpolarising factor

Question 5

how do the cytoprotective mediators act

Answer 5

they inhibit activation of leukocytes and platelets, prevent vascular smooth muscle proliferation, they are vasodilators and promote regeneration of damaged/lost endothelium

Question 6

what are functions of cholesterol

Answer 6

integral component in synthesis of steroid hormones, structural importance in cell wall, fat soluble vitamin synthesis

Question 7

how are lipids transported in plasma

Answer 7

in plasma lipids transported as macromolecular complexes with protein called lipoproteins (fatty acids transported on albumin)

lipoproteins have lipid core (triglyceride and cholesterol ester) and coat of phospholipid, free cholesterol and protein (apoprotein)

Question 8

what type of lipoproteins are there

Answer 8

high density lipoprotein, low density lipoprotein, very low density lipoprotein and chylomicrons

Question 9

what is function of high density lipoprotein

Answer 9

transports cholesterol from periphery to liver for removal and steroidogenic organs

(good cholesterol)

Question 10

what is function of low density lipoprotein

Answer 10

transports cholesterol from liver to cells that require it

bad cholesterol

Question 11

what causes hyperlipidaemias

Answer 11

metabolic disorders that alter lipid transport to give primary (genetically determined) or secondary (resulting from other disease such as diabetes) hyperlipidaemias

Question 12

what are the types of lipidaemias and how do they happen

Answer 12

type1/ familial hyperlipoproteinaemia: due to decreased lipoprotein lipase

type 2a/familial hyperocholesterolaemia: due to LDLR deficiency (low density lipoprotein receptors)

type 2b/ combined hyperlipidaemia: due to deficiency of LDLRs and increase in apolipoprotein B

type 3: apolipoprotein E deficiency

type 4: increased very low density lipoprotein production and clearance

type 5: same as 4

Question 13

what effects do the different types of hyperlipidaemias have on lipoproteins and how are they treated

Answer 13

type 1: causes increased number of chylomicrons, is treated with controlled diet

type 2a: causes increase in low density lipoprotein, is treated with sequestrates, statins and niacin

type 2b: causes increase in low density lipoprotein, very low density lipoprotein and triglycerides, is treated with statins, niacin and fibrates

type 3: causes increase in low density lipoproteins, is treated with fibrates

type 4: causes increase in very low density lipoproteins, is treated with fibrates and niacin

type 5: causes increase in very low density lipoproteins and chylomicrons, is treated with niacin and fibrates

Question 14

what is the aim of drug treatment of hyperlipidaemias

Answer 14

aimed at achieving: dietary modification, lowering LDL, increasing HDL, sequestering cholesterol and bile acids, preventing cholesterol absorption and facilitating LDL breakdown

Question 15

how are statins used in treatment of hyperlipidaemias, what are side effects,

Answer 15

HMG Co-A reductase is rate limiting step in cholesterol synthesis

statins are HMG Co-A reductase inhibitors, preventing HMG Co-A conversion to mevalonate in pathway to cholesterol

reduction of hepatic cholesterol synthesis leads to increased synthesis of LDL receptor so that LDL clearance is increased

clinical evidence they benefit atherogenic cardiac disease and increase the life expectancy for those with it

side effects: may impair liver function other than cholesterol synthesis, can cause inflammatory reaction in skeletal muscle

Question 16

how are bile acid binding resins used?

Answer 16

they are anion exchanging resins, they are not water soluble and are inert to digestive enzymes

they are not absorbed from the gut, they bind bile acids and prevent entero-hepatic recirculation (they sequester bile acids)

reduced cholesterol absorption and increase in metabolism of endogenous cholesterol to form bile acids

Question 17

how are fibrates used in treatment of hyperlipidaemias, what are side effects

Answer 17

they are PPARalpha agonists

they primarily decrease serum triglycerides

increase fatty acid oxidation in muscle and liver, increase lipoprotein catabolism (activate lipoprotein lipase)

causing decrease in VLDL and LDL (to a lesser extent) and increase in HDL

most used in type 3 4 and 5 hyperlipidaemias

like statins that can cause inflammatory reaction in skeletal muscle

Question 18

how is niacin used to treat hyperlipidaemias, what are side effects, how are they used

Answer 18

primary effect is to reduce fatty acid mobilisation from periphery and reduce hepatic (V)LDL synthesis

drug with largest impact on HDL,
only agent that lowers lipoprotein A (LDL+ ApoA)

usually empolyed in combination with fibres, resin or statins

avoids side effects of higher doses due to prostaglandin release

Question 19

what is mechanism and effects of ezetimibe, how is it used

Answer 19

prevent absorption of cholesterol from diet

reduces serum LDL, cholesterol, triglycerides and increases HDL

effective in mild/moderate hypercholesterolaemia as monotherapy of if more sever used in combination with statins

Question 20

what are risk factors that increase chance of atherosclerosis

Answer 20

smoking, diabetes, hypertension, hyperlipidaemias

Question 21

why are low cholesterol diets not usually useful in atherosclerosis

Answer 21

high blood cholesterol is usually hereditery

Question 22

what are function and mechanism of PCSK9 inhibitors in treatment of hyperlipidaemias

Answer 22

RNAi therapies that inhibit PCSK9 synthesis in liver cells are being developed

PCSK9 directs endocytosed LDLRs to be degraded meaning that few LDLRs are recycled, meaning fewer LDLRs

PCSK9 inhibitors cause increased number of LDLRs

studies have shown it greatly reduces levels of LDLC more so than ezetimibe