Atherosclerosis 1 + 2

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  • Created by: Sarah
  • Created on: 26-05-19 16:38
what kind of disease is athero?
chronic inflammatory disease
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what are the 3 layers of an artery?
tunica -intima, media and adventitia
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what is the other name for tunica adventitia?
tunica externa
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how many cells thick is the intima usually?
a single cell layer thick layer of endothelial cells
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what is the intima usually called?
the endothelium
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what can happen to the intima in various disease processes?
it can become slightly thickened- becomes more than one cell layer thick
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what is the media?
several layes thick made up of vascular smooth muscle cells
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what does the media give the artery?
its strength and structure
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what is the adventia made up of?
connective tissue mainly collagen
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what is the special blood supply to the adventia called because its too thick to reach the adventitia?
vasa vasorum )small capillaries on the outside wall)
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what separates the 3 layers?
internal and external elastic lamina
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what are the internal and external elastic lamina also called?
lamina
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diseases where inflammation goes wrong?
athero, MS, rhematoid athritis, asthma, too much wound healing is caused by excessive inflammation and scar formation, inflammatory bowel disease
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how is restenosis associated with atherosclerosis?
when we treat atherosclerosis with a physical intervention (stenting) you can get restenosis
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what does atherosclerosis mean in greek?
athero = gruel/paste sclerosis = hardness
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what did athero use to be known as?
hardening of the arteries so arteries getting thicker and stiff
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why do arteries get slightly harder/stiffer if you get athero
build up of cholesterol and calcium which means its stiffer in later stages
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what happens in athero?
you get a build up of plaque that stiffens your artery wall
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what is athero the principle cause of?
heart attacks and strokes, also gangrene
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who described athero as the coat thickening and stopping the movement of blood as a result of absorbing increased nutrients from the blood?
leonardo da vinci
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what is excessively taken up from the blood?
taking up excessive lipids from the blood
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what was athero originally thought to be?
a lipid storage disease- although some lipids are stored in the artery wall its not the cause but we now know it's an inflammatory disease although lipids play a major role
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whats it caused and influenced by?
many different cytokines, growth factors, inflammatory cells = monocytes and macs
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why is athero not really a problem until later stages?
we all have it even in the womb, unless it gets so big that the plaque ruptures that's when its a problem.
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what can plaque rupture lead to?
thrombosis and that will kill you as it causes HA and/or stroke that can lead to death
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what mutlitude of factors can cause atherosclerosis?
smoking, too much alchohol, lifestyle choices eg diet, medical conditions
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how can medical conditions predispose you to atherosclerosis?
they increase the levels of circulating lipids which predispose you to athero
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what else can predispose you to athero
haemodynamics of blood flood- blood is a turbulent flow so it hits bifurcations and side branches which can switch on genes and predispose you to athero
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what is the condition where you develop the disease before you're born?
maternal hypercholestermia- it's rare
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how long does it take to develop athero? who is this different for?
takes decades to develop- only develops really quickly in people that have a homozygous form of dyslipidemia
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why is athero mainly symptomless for the most part?
builds up over decades doesn't occlude or rupture only when it does this get symotoms
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when do you know you've got advanced disease?
when you get symptoms
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when would we go in with a drug treatment to slow athero progression?
when we know someones at risk of developing athero
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regardless of the cause whether its genetic, lifestyle or medical conditions what is athero always a result of?
damage to the endothelium wall- need damage to the endo wall no matter how much lipid you've got if you haven't got damage to the endo wall you won't get an inflammatory reaction and develop athero
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what is the absolute beginning of athero?
damage to the endothelium
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non modifiable risk factors for athero?
gender (male), genetics, age, inflammation, family history of CV disease
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what are the modifiable risk factors for athero )drugs/lifestyle)?
dyslipidaemia, diabetes, hypertension, obesity, smoking/alcohol, stress, physical inactivity
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why are diabetes and dyslipidaemia modifiable risk factors?
because once you have them you can you modify them with drugs so control diabetes and slow down dyslipidaemia
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what does non-modifiable mean for RFs?
things out of your control that we can't do anything about
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what is the biggest non-modifiable factor?
biggest risk factor we have no control over is age and genetics also big- which links to dyslipidemia you can be genetically predisposed and have a family history of atherosclerosis and heart disease
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if you do have a HA or stroke early in life because of atherosclerosis what does this mean?
you have a genetic link that causes early symptoms
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where does athero mainly form?
bends, branches and bifurcations where the arteries split as you get eddies and tuberlunt flow here which switches on genes that may/may not damage the endotheliu therefore predispose to athero
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when would you be more likely to get it in a straight artery?
when there's something that damages the artery
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what is the atherosclerotic plaque made up of?
necrotic core, CT, cells, lipids, cholesterol and fibrous cap at the top
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what is the fibrous cap made up of?
SM cells and ECM
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what happens to the plaque over time?
it gets bigger and bigger over time it will fully occlude the artery or break off an form a throbus
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why is it a problem that the plaque occludes your artery?
it causes problems with your blood flow- ischemia
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what happens when the plauque ruptures?
breaks apart and substances are exposed to the blood, can get a thrombotic reaction which can kill you or thrombus goes and causes a HA or stroke
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who suggested that athero involves inflammation or a response to injury that requires damage to the endothelium wall? what was this called?
Richard Virchrow
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what was the cause of athero being damage to your endothelial cells called?
response to injury hypothesis
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what is the response to injury hypothesis?
damage to the endothelial wall drives the intitiation of athero
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what is a healthy endotehlium doing?
protective mechanism prevents blood clots by glycocalyx and stops things in the blood interacting with the bv, also produce mediators that are protective against athero formation
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what will the damaged endothelial cells start to express?
inflammatory cytokines
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what do the inflammatory cytokines do?
cause a chemotactic gradient- calls in WBCs, monocytes and macrophages- causes immune cells to migrate to the area and start the inflammatory reaction
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what is the very starting point of developing athero?
endothelial dysfunction
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what causes the chemotactic gradient to attract WBCs, monocytes and inflammatory cells?
endothelial cells expressing cytokine
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what does the chemotactic gradient bringing in monocytes and macs happen by?
the adhesion cascade
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what is the adhesion cascade?
damaged endothelium starts to express GFs and cytokines and macs and monocytes will stick to adhesion molecules revealed by damaged glycocalyx
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how do monocytes/macs move in the adhesion cascade?
they stick and roll along the endothelial wall, slow down and then stop and transmigrate into the vessel wall
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what are the causing the macs/monocytes to bind to the endothelial cells
they're expressing selectins and integrins which macs bind to- adhesion molecules
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what is the other stimulus apart from cytokines?
lipids = LDL
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what do we usually target to slow the progression of athero?
lipids
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how is athero treated in advanced disease?
stenting or angioplasty- intervention
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what is used to slow the progression of athero?
drug treatments
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what plays a major role in athero?
although it's a chronic inflammatory disease we do need lipids in order to develop atherosclerosis. Lipids do play a major role
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what lipid is involved in developing athero?
LDL- low density lipoprotein
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how does LDL get into the vessel wall?
normal lipid transport mechanisms- endogenous pathway, usually deliver cholesterol to the wall anyway
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why is cholesterol delivered to the wall?
cholesterol needed for 1) triglycerides 2) energy metabolism 3) component of CM
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what is the problem in athero of LDL being transferred into the vessel wall?
you have macs and activated endothelial cells there which have built up and are generating free radicals
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what do free radicals do to LDL
free radicals oxidie LDL
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what does oxidised LDL then do?
binds to scavenger receptors on macrophages and gets engulfed by macs
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what does the mac become once its engulfed oxidised LDL?
foam cell- a big cell ful of lipid
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what do foam cells release?
more inflammatiry cytokines which cause a greater chemotactic gradient calls in more mac, oxidise more LDL and create more foam cells
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what kind of cytokines are found in plaques?
IL-1 IL-6, IL-8, IFN-Y, TGF-B
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what happens to SMCs in athero?
they begin to divide and secrete ECM particles- they penetrate into the intima from the meida where they join other SMCs in forming a fibrous cap over the lipid core
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what can activated macs secrete?
free radicals, cytokines and matrix proteases
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what do the matrix proteases do?
they degrade the fibrous cap and make it susceptible to rupture
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what happens when we slow the progression with drugs?
lipids can leave, WBCs can die and that leaves a thickened fibrous cap, leaves a stable and asymptomatic plaque
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how do macs become activates?
T lymphocytes send signals to them or activate them by contact
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what is the first stage of atherosclerosis development?
fatty streak formation
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what happens in your fatty streak formation?
macs/monocytes are called in by chemotactic gradient of cytokines from activated endothelium, macs + endo release free radicals oxidise LDL, ox-LDL engulfed by macs become foam cells- foam cells are the fatty streak
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is fatty streak formation symptomatic?
no asymptomatic
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what are leukocytes?
various WBCs- macs, monocytes and T lymphocytes
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what is the second stage of atherosclerosis development?
intermediate lesions
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what happens in the intermediate lesions stage?
where foam cells and fatty streak start to become bigger as Vascular SMCs start t become involve, get pools of EC lipid and cholesterol because foam cell will apoptose and release free floating cholesterol crystals (LDL broken down)
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what do you have in your intermediate lesion?
foam cells and free floating cholesterol crystals, t lympocytes and sometime small aggregation of platelets but small lesion asymptomatic
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what way does the plaque usually start to form?
usually pushes wall outwards but starts to enroach on the lumen when it gets really big has no where else to go so grows into lumen and blocks it
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why will a lot of atheroscleoris stop at the intermediate stage?
because we have a protective mechanism = reverse cholesterol transport pathway
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what does the reverse cholesterol transport pathway do?
removes lipids from the vessel wall using HDL
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what does HDL do?
can interact with the foam cells within the vessel wall and collect cholesterol from the fam cells and lipid from the artery wall
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what is there a balance of?
cholesterol going into the wall by LDL and cholesterol being taken out of the wall by HDL so there's not enough around to progress the lesion
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what is the 3rd stage of athero progression?
fibrous plaques or advanced lesions
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when does the intermediate lesion usually become an advanced lesion?
added risk factors- smoke bad diet, no exercise, diabetes- have an imbalance and develop a larger lesion
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what does HDL contian that allow it to interact with foam cells and collect cholesterol?
apo-A1 particles
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where does mature HDL travel back to once its collected hte cholesterol?
the liver to release the cholesterol where its processed and excreted
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what happens in the advanced lesion stage?
cytokines release by cells cause SMC proliferation and deposition of CT - fibrous cap is formed overlying a lipid-rich core
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what is the cap made up of?
ECM proteins- collagen (Strength) and elastin (flexibility)
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what does the lipid core in the advanced lesion contain?
necrotic and apoptotic debris, SMCs, foam cells, macs and T-lymphocytes
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what problems do the advanced lesions cause?
impede blood flow and prone to rupture
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what happens to start forming the fibrous cap in the advanced lesion?
SM cells from media proliferate and move into intima and ECM deposited collagen and elastin
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when will you start to get sympotms?
advanced lesion- if plaque starts to impede blood flow will get angina as lesion progresses
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what is the cycle of vascular inflammation & LDL that results in the formation of a necrotic core?
1) LDL enters wall 2) macs enter engulf ox-LDL become foam cells 3) LDL lysed cholesterol crystals released 4) crystals in foam cells induce apoptosis 5) EC lipid pool in bv wall 5) further attration of macs
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what forms the lipid core?
foam cells apoptosing and release free cholesterol
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what have you got a cycle of?
foam cells release more inflammatory mediators- bring in more macs and LDL entering- cycle of foam cells recruiting more foam cells and apoptosis contributing to the plawue
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what is the 4th stage in the progression of athero?
plaque rupture
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how does athero kill you?
plaque rupture or erosion
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what happens in plaque rupture?
the cap is being resorbed and deposited constantly so cells grow and divide but if many macs release metalloproteinase - degrade cap
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where are metalloproteinases released from?
activated macrophages
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what can happen once the plaque has ruptured
you can get thrombus and occlusion, heart attack stroke and death
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what does the fibrous cap need to be maintained
to be resorbed and redeposited
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what stabilises the plaque?
VSMCs and matrix proteins
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what are drugs targetting?
slowing progression of athero to prevent plaque rupture- very effective at preveting plaque rupture and reducing num of deaths from HA+strokes
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what is another way to degrade the plaque?
plaque erosion
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what is plaque erosion?
like wearing away from the top surface sandpapering
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difference between plaque erosion and rupture?
Plaque rupture- lipid core, fibrous cap, thrombus is made of a lot of RBCs but plaque erosion is white thrombus = involves platelets (not RBCs)
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what is plaque erosion thought to be?
endothelial cells are being wiped off or sloughed off metalloproteinases take away bonds between endo and underlying layer so expose lower layer to platelets cause thrombus
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what do drug treatments do?
prevent the progression of athero reaching the point where its symptomatic- keeping lesion small
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when might be given treatment (drugs)?
to prevent another HA or if you have big risk factors
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why do lipids need to be packaged to be transported in the blood?
lipids are hydrophobic water hating so cholestrol and triglycerides need to packaged with a lipoprotein particle
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what is the structure of these lipoprotein particles?
cholesterol on the inside in the centre then the coating made of apolipoproteins, some cholestrol and lipids
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what are lipoprotein particles classified by?
density (Size) and what lipoprotein particle they contain
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size of lipoproteins from small to big?
HDL = smallest, LDL, intermediate LDL, very low density LDL (vLDL) = biggest then chylomicron
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what apoprotein does LDL, IDL, vLDL contain?
apoB-100
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what apoprotein does HDL contain?
apoA1 and apoA2
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what are the biggest lipoproteins we have travelling round the body?
chylomicrons
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what apoprotein do chylomicrons contain?
apo-48
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What do all the apoprotein particles have?
apoE and apoC
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3 different pathways of lipoprotein transport?
1) endogenous pathway (liver to tissues) 2) exogenous pathway (lipids from diet) 3) reverse cholesterol pathway (take from tissues to liver to be excreted)
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where does the exogenous pathway transport lipids to?
from our food to tissues
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describe exogenous pathway?
food -> digestive lipids in intestines, cholesterol gets into lymph system through NPC1L1 , in lymph its packaged with apoB-48 into a nascent chylomicron
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why is it a nascent chylomicron?
it hasn't got apoB or apoC yet so it can't bind to tissues
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where does the nascent chylomicron go?
travels through lymph system and ends up in circulation where it interacts with HDL, HDL donates apoC and ApoE
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When does the nascent chylomicron become activated?
when HDL donates ApoC and ApoE
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what happens to the mature chylomicron?
it will flow around the body until it comes into contact with and interacts with target tissues
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what will the target tissues have associated with them?
apolipoprotein lipase
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what activates the apolipoprotein lipase on the target tissue?
apoC on the chylomicron
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What happens when apoC on the chylomicron activates apolipoprotein lipase on the target tissue?
hydrolyses the chylomicron to release cholesterol from within it and then cholesterol used for energy etc
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what happens to what's left of the chylomicron?
it will eventually end up back in the liver where it binds to apoE or apoB48 recs on the liver and the cholesterol left will be taken up by the liver
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what happens to that cholesterol taken up by the liver?
it's excreted or oxidised to bile acids or converted to VLDL and enters the endogenous transport pathway
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how are digested lipids taken across the small intestine into the lymphatic vessels?
NPC1L1 transport protein
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what can ApoC bind to?
recs on adipose tissue
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what can apoE bind to?
recs on hepatocytes
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what takes up chylomicron remnants into the liver?
ApoE, ApoB48
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what happens to the remaining cholesterol (4 things)?
cholesterol is stored, secreted in bile, oxidised into bile acids or converted into vLDL
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what apolipoproteins does the endogenous pathway involve?
LDL, IDL and vLDL
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what happens in the endogenous pathway?
cholesterol and triglycerides synthesised by the liver will be transported to tissues
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what do the particles like vLDL and LDL contain?
ApoB-100
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what is the apoliproteins when they are released into the bloodstream?
nascent
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how do they become active?
in the same way as chylomicrons- interact with HDL to receive apoC and apoE
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what happens to the vLDL, IDL or LDL particle once its become active?
continues in bloodstream, reaches target tissue apoC on particles interact with lipoprotein lipase on LDL and vLDL and wil be hydrolysed to release cholesterol to the tissue
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enzyme that breaks down vLDL/LDL/chylomicrons?
lipoprotein lipase
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what happens to the vLDL once its hydrolysed?
will shrink into IDL
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what does IDL then do?
1) travels back to liver can interact by apoE with LDL rec and be hydrolysed by fatty lipase 2) continue circulating hit tissues where apoC on IDL interacts gets hydrolysed into LDL
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what does LDL then do?
goes around circulation hits tissue apoC interacts with lipoprotein lipase and releases cholesterol
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what causes the problem for athero? what pathway?
LDL causes the problem by the endogenous transport pathway
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what is the other option for LDL?
can go back to liver and via apo-100 binds to LDL rec and can be removed from circulation (vLDL +IDL also do this)
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what apoprotein does HDL have?
apoA1 and apoA2
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what does apo-A1 on HDL bind to?
transport proteins AB-A1 or AB-G1 in macs and foam cells
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what will apo-A1 on HDL binding to AB-A1 or AB-G1 on macs/foam cells do?
take up cholesterol from them into the HDL- HDL absorbs cholesterol from foam cells via Apo-A1
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what is the 2 ways HDL transports cholesterol back to the liver?
directly and indirectly
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how does HDL directly transport cholesterol back to the liver?
goes to the liver nad via ApoA1 (which was reacting with macs) will bind to SRB1 rec on liver and transfer cholesterol into liver where it will be processed, HDL recirculates collects more cholesterol
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how does HDL indirectly transport cholesterol back to the liver?
HDL interacts with a VLDL or LDL paricle in the circulation and tranfer cholesterol to them
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what protein does HDL use to transfer cholesterol to vLDL and LDL?
ester transport protein
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why is the indirect pathway nbad?
LDL is circulating collects cholesterol goes back to tissue and undo all the work HDL has done releases cholesterol back into tissues
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endogenous transport takes cholesterol from where to where?
liver to tissues or can eventually end up back in liver (LDL apoB-100 binds LDL rec on liver)
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do the lipoprotein transport pathways interact?
yes all work together
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what is the disease called where you have an abnormal amount of lipid in the blood that predisposes you to athero?
dyslipidemia
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what are most dyslipidemias?
hyperlipidemias
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what are the 2 forms of dyslipidemia?
primary and secondary
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what form of dyslipidemia is where you have too much lipid circulating in your blood due to something else?
secondary dyslipidemia because you've got too much lipid circulating in your blood as a result of an underlying condition
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what can these underlying conditions be?
diabetes that's not controlled, alcholic, renal failure, drugs that affect your lipid levels and cause too much circulating lipids
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how is secondary dyslipidemia treated?
its caused by something else so you treat the underlying condition eg get diabetes under control
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what is the genetic cause of dyslipidemia?
primary dyslipidemia
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what drives dyslipidemia?
combo of diet and genetics but its genetics that's driving it
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what classification is used to classify dyslipidemia?
Fredrickson classification
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what does how dangerous dyslipidemia is and whether it'll cause athero?
what genes are mutated
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what is type 2 dyslipidemia?
familial hypercholesterolemia (FH)
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what causes FH or type 2 dyslipidemia?
a defect in the LDL receptor on the liver or the ApoB-100 lipoprotein- which both affect LDL uptake from the blood
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what does FH or type 2 dyslipidemia give you?
a very high risk of athero
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what is the chance of developing athero if you have a heterozygous FH mutation?
1 in 500
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when does the risk increase?
when you've got a homozygous mutation in the genes
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what are you likely to have in your family if you have a family history of heart attacks at an early age?
FH
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what is mutated in FH?
LDL rec on liver or ApoB100- that makes up LDL and binds to rec
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what is the effect of both of these mtuations?
either way it stops LDL binding to the LDL rec on the liver and LDL uptake from the circulation- reduced ability to uptake LDL
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is FH homzygous or heterozygous?
can be either
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if you're heterozygous FH when are you likely to get premature CVD>
30 to 40 and having a heart attack at 50 in extreme cases
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if you're homozygous and have a defect in both your alleles what will you get?
severe CV disease- will develop CVD in childhood but very rare
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what are most of the drug treatments based on?
heterozygous people- 1 in 500 large proportion of population
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which FH do we treat with drugs?
heterozygous FH
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what is ezetimibe?
cholesterol absorption inhibitor
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what drugs are used to treat heterozygous FH 3 main ones + extra?
1) statins 2) inhibitors of cholesterol absorption (ezetimibe) 3) PCSK9 inhibitors 4) Fibrates
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homozygous FH generally doesn't respond to medical tratment but what drug has shown some effect on homo FH?
PCSK9 inhibitors
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what are statins know as? why?
HMG-coA reductase inhibitors = as they inhibit HMG-CoA reductase
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what do statins target?
the rate limiting step of cholesterol synthesis in the liver
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what is the bit of the melvanoate pathway statins inhibit?
HMG-CoA -> mervasionic acid via HMG-CoA reductase
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what does the liver normally do if we have a lot of cholesterol circulating round the body?
turn off HMG-CoA reductase enzyme to switch off cholesterol synthesis
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what happens in dyslipidemia?
this switch off mechanism is faulty as the liver can't detect the circulating cholesterol levels as it can't take up LDL so body fooled into thinking we need to make more cholesterol
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what are the differences between different types of statins
some are specific reversible and short acting, some are long acting
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what are most FH thought to be monogenic or polygenic?
polygenic
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how is homo FH treated if it doesn't respond to the drugs?
LDL apheresis (removal of LDL in a similar method to dialysis) and occasionally liver transplant
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examples of statins that are specific, reversible competitive?
simvastatin, lovastatin, pravastatin
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example of long lasting statins?
Atrovastatin and Rosuvasatin
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when are short acting statins given?
orally at night to reduce peak cholesterol synthesis early in the morning
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where are statins absorbed and extracted?
by the liver
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what pathways metabolise statins? where?
cytochrome P450 (liver) and glucuronidation pathway (intestines)
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what is mevalonic acid (which HMG-CoA turns into) then converted into?
cholesterol
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when do statins become active?
they're all taken orally and then activated once they've been metabolised in the liver by cytochrome P450 or glucuronidation pathway)
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why might some statins be better than others?
because they have different metabolism pathways
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what would you do if you're given a statin and it doesn't work very well or you get side effects?
give a different statin to see if it works better and its all to do with how it's processed in the liver
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statins mechanism of action?
switch off cholesterol syn -> don't make cholesterol in liver -> liver needs cholesterol to make bile acids -> uptakes more cholesterol from the blood by making+expressing more LDL recs -> increase LDL uptake liver -> less in circulation for plaque
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what did simvastatin against a placebo show?
that using a statin does prolong your lige
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what are pleiotropic effects?
effects aside our main aim
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why do statins have pleiotropic effects?
because they target the mevalonate pathway which is a lipidation pathway, melvanoate used in lipidation involved in anchoring enzymes/recs to cells/organelles
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positive pleiotropic effects of statins?
improve endothelial function, reduced vascular inflammation, reduced platelet aggregrability (Reduce thrombus risk), stabilisation of athero plaque, immune supression
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why can't statins be taken when your pregnant?
because they inhibit germ cell migration during development = affect developing fetus
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what is lipidation that the mevalonate pathway are involved in?
lipidation = add hydrophobic groups to anchor proteins to organelles/cells
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whats an example of an important membrane bound enzyme that undergoes lipidation?
NO synthase
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what is the commonest drug to target athero?
statins- given if you've got a high athero risk eg dsylipidemia
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when else are statins given?
if you've had a MI or a stroke reduce chances of reoccuring
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adverse effects of statins?
muscle pain ,GI disturbance, raised concs of liver enzymes in plasmam insomnia, rash, angioedema, skeletal muscle damage (Rare and dose related- common in patients with lean body mass or uncorrected hypothyroidism)
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why was NICE guidance to prescribing statins controversial?
proposed to prescribe statins to people with lower levels of circulating cholesterol so people who weren't at signifcant risk were given statins- if at low risk 99% see no benefit of statins so side effects aren't worth it for 1% reduced HA
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why is it worth taking statins if you have dyslipidemia?
you're at high risk of having a HA so risk and lifesaving outweighs the side effects
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what has been shown recently about the side effects?
side effects might not be real- people given a statin but it was a placebo experienced the same side effects as people on statins so nocebo effect- unsure is SEs are real
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what is this effect of expecting symptoms getting them called?
nocebo effect
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why is it controversial that research into side effects were done by drug companies?
drug companies want to make profit so don't publish really adverse effects- GPs report higher side effects than research show
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what drug for athero is rarely used these days?
fibrates
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what do fibrates do?
activate the PPAR receptor (peroxisome prolfierator activator rec)
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what do PPAR recs do so why is fibrates activating them good?
switch on genes involved in lipoprotein metabolism- if you take a fibrate switch on lipid metabolism genes increase metabolism and decrease circulating LDL
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how are fibrates metabolised?
by CYP enzymes in liver- same as statins
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how are fibrates taken?
oral drug
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what do fibrates do?
markedly reduce your circulating vLDL levels so decrease your triglyceride/cholesterol levels, decrease LDL and modest increase in HDL
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why are fibrates rarely used in clinical practice?
because of their side effects
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when are fibrates used?
when ezetimibe or statins aren't tolerated by patients
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adverse effects of fibrates?
risk of developing kidney failure, gall stones, stomach upset, muscle damage
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what does ezetimibe do?
its an inhibitor of cholesterol absorption so it blocks the NPC1L transport protein in the intestines = reduces chylomicron production
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what does this mean?
you can't get as much cholesterol out of your diet, less chylomicrons circulating round the body, chylomicrons can't release cholesterol to tissues or be absobed into endogenous pathway
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what is ezetimibe usually combined with? why?
a statin- ezetimibe can reduce circulating levels by 20% combined with a statin 25%
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how do you take ezetimibe? why can you take one a day?
orally- can take one pill a day as they have a slow half life
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advantages of ezetimibe?
doesn't interact with other medicine (may be older if given statins other complications), convenient- one tablet a day
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disadvantage of ezetimibe?
still expensive
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when is ezetimibe usually given?
in combo with statins or to people who can't tolerate a high dose of statins so it will supplement statins
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what is the issue with babies and ezetimibe?
in animal studies ezetimibe shown to enter milk so can't breastfeed
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side effects of ezetimibe?
mild diarrhoea, abdominal pain, headache, rash, angioedema
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what's another inhibitor of cholesterol absorption?
resins
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what was the first cholesterol absorption inhibitor to be used clinically?
resins- oral drugs
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what statin lowers serum cholesterol levels in patients with homo FH?
atorvastatin
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examples of fibrates?
bezafibrae, ciprofibrate
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what do PPA receptors do?
modulate carbohydrate and fat metabolism and adipose tissue differentation- if you activate PPAR turn on genes to metabolise liporportiens
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fibrates have been shown to improve what? what do they not imporve?
reduce the number of non-fatal MI but do not improve survival
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when should fibrates not be taken?
patients with advances kidney disease or by alcholics
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what is the single tablet combining simvastatin and ezetimibe?
INEGY
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pharmacology of ezetimibe?
oral, absorbed into intestinal epithelial cells, localises to brush border, extensively metabolised to activae metabolite, enterhepatic recycling results in slow elimination = long half life one tablet a day
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when is ezetimibe given?
patients who experience side effects from high dose statins to reduce dose, supplementary treatment to statins in patient with severe dyslipidemia
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example of resin?
colestipol
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where do resins remain and what do they bind?
resins remain in the intestinal tract and bind bile acids to prevent their absorption into blood stream
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how does resins work?
liver compensates for not taking up bile acids by increasing metabolism of endogenous cholesterol into bile acids so need to increase cholesterol uptake by increasing expr of LDL recs so reduce conc of LDL in blood
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why are resins rarely used?
due to intolerance and they need to be taken 1hr after or several hours before other medication
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side effects of resins?
bloating, constipation, diarrhoea, nausea, intefere with absoprtion of fat soluble things like vitamins/digoxin/diuretics/warfarmin/b blockers/ca channel blockers
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final inhibitor of cholesterol absorption thats natural?
plant sterols/stanols
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where are plant sterols found?
found in margaines or yoghurts
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what do these plant sterols do?
they are similar in structure to cholesterol so instead of packaging cholesterol into chylomicrons packages plant sterol and body thinks its transporting cholesterol, competition so not taking up as much cholesterol
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as well as reducing amount of cholesterol being taken up what else do plant sterols do?
may be increasing the speed of excreting cholesterols from body- thought it might activate transport proteins on the liver to increase cholesterol excretion
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how are PCSK9 inhibitors taken? why?
they are injected- IV it's a monoclonal antibody
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examples of PCSK9 inhibitors?
Evolocumba or Rapatha
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what does PCSK9 stand for?
proprotein convertase subtilisin/kexin type 9
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what does PCSK9 naturally do in the body?
PCSK9 binds to the LDL rec on the liver, complex will be internalised and degraded by the lysosomes, so removing LDL recs from liver surface and allowing LDL to circulate
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how does PCSK9 inhibitors work?
antibody that binds to PCSK9 so it can't bind to the LDL rec and leaves the LDL rec free to bind LDL, mops up PCSK9, more recs present remove LDL from circulation
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what happens with a PCSK9 inhibitor when LDL binds to the LDL rec?
once LDL is bound to LDL rec will go into the liver and instead of being degraded by lysosomes LDL rec recycles back to the surface where it can bind more LDL
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so by inhibiting PCSK9 what is the overall effect?
increasing uptake of LDL from the blood = reduce circulating LDL levels
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what was better a statin, statin+ezetimibe or PCSK9 inhibitor + statin?
PCSK9 inhibitor and statin has a even greater reduction of circulating cholesterol in the blood
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if PCSK9 is really highly effective why is it not used that much?
because it's highly expensive and subcutaneous injection given every 2 weeks or once a month
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what is repetha (PCSK9 inhibitor) specifically indicated for?
used alongside statins these days, shown postivity with homo FH
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adverse effects of Reptha
inflammation at injection site, back pain, upper respiratory tract infection like influenza and especially if you have a hypersensitivy reaction need to discontinue treatment
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what pathway do resins affect?
endogenous and exogenous pathway
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what pathway do fibrates affect?
endogenous pathway
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exetimibe and statins affect which pathway?
endogenous pathway
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