atherosclerosis and lipid lowering drugs Flashcards
what is atherosclerosis
characterised by chronic inflammation of the blood vessel walls
leads to vessel narrowing, occlusion and distal ischaemia (e.g infarction and stroke)
what are hallmarks of atherosclerosis
activation of leukocytes and platelets
vascular smooth muscle hypertrophy
modification and deposition of lipid
what are sequence of events that lead to atherosclerosis
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
what are the cytoprotective mediators
nitric oxide (NO), prostacyclin and endothelium derived hyperpolarising factor
how do the cytoprotective mediators act
they inhibit activation of leukocytes and platelets, prevent vascular smooth muscle proliferation, they are vasodilators and promote regeneration of damaged/lost endothelium
what are functions of cholesterol
integral component in synthesis of steroid hormones, structural importance in cell wall, fat soluble vitamin synthesis
how are lipids transported in plasma
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)
what type of lipoproteins are there
high density lipoprotein, low density lipoprotein, very low density lipoprotein and chylomicrons
what is function of high density lipoprotein
transports cholesterol from periphery to liver for removal and steroidogenic organs
(good cholesterol)
what is function of low density lipoprotein
transports cholesterol from liver to cells that require it
bad cholesterol
what causes hyperlipidaemias
metabolic disorders that alter lipid transport to give primary (genetically determined) or secondary (resulting from other disease such as diabetes) hyperlipidaemias
what are the types of lipidaemias and how do they happen
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
what effects do the different types of hyperlipidaemias have on lipoproteins and how are they treated
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
what is the aim of drug treatment of hyperlipidaemias
aimed at achieving: dietary modification, lowering LDL, increasing HDL, sequestering cholesterol and bile acids, preventing cholesterol absorption and facilitating LDL breakdown
how are statins used in treatment of hyperlipidaemias, what are side effects,
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
how are bile acid binding resins used?
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
how are fibrates used in treatment of hyperlipidaemias, what are side effects
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
how is niacin used to treat hyperlipidaemias, what are side effects, how are they used
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
what is mechanism and effects of ezetimibe, how is it used
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
what are risk factors that increase chance of atherosclerosis
smoking, diabetes, hypertension, hyperlipidaemias
why are low cholesterol diets not usually useful in atherosclerosis
high blood cholesterol is usually hereditery
what are function and mechanism of PCSK9 inhibitors in treatment of hyperlipidaemias
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
