Atherosclerosis 2 Flashcards
What are lipoproteins?
Lipids are transported around the body in lipoproteins
core of hydrophobic lipid surrounded by hydrophilic coat
largest: chylo-microns
VLDL
IDL
LDL
smallest: HDL
classified by which apolipoproteins they contain
What are they 3 lipoprotein transport pathways?
Exogenous- dietary
Endogenous- synthesized in liver
Reverse cholesterol pathway- from tissues to liver
Basic steps of endogenous pathway
intestines into lymph system via NPC1L1
lipid + apolipoprotein B-48= nascent chylomicron
into liver- then bloodstream
HDL donates apolipoproteins C2 & E= mature chylomicron
reaches target -activates LPL via ApoC
release of glycerol and fatty acids - absorbed by tissue
chylomicron remnants taken up in the liver
Where do ApoC and ApoE bind?
ApoC can only bind to receptors found on adipose tissue
ApoE can only bind to receptors on hepatocytes
Basic steps of the endogenous pathway
in liver- triacylglycerol and cholesterol are assembled with apolipoprotein B-100 to form VLDL
nascent VLDL in blood- HDL donates alp C2 and E- mature VLDL
ALP C2 activates LPL- the release of fatty acids and glycerol - absorbed by adipose tissue and muscle
hydrolyzed VLDL= IDL
IDL returns to liver- further hydrolyzed- into LDLS
LDLs bind to receptors on target tissues- and are endocytosed
Basic steps on reverse cholesterol pathway
ApoA1 of HDL binds to transport proteins ABC-A1 or ABC-G1 on foam cells
release of cholesterol from foam cells
HDL:
interacts with VLDL/IDL- transfers cholesterol to them via CETP
ApoA1 binds to SRB1 receptors on the liver- cholesterol returned to liver
What is dyslipidaemia, what are the 2 main types
Abnormal amounts of lipid in the blood- predispose you to atherosclerosis
- Primary- genetics and diet, mainly genetics- depends on what gene has been mutated- often polygenic
- Secondary- too much lipid in the blood due to underlying condition: diabetes, alcoholism, renal failure of taking sets of drugs affecting lipid levels
What is the Frederickson classification
The classification system of primary dyslipidemia
classified according to which lipoprotein particle is abnormal
higher the ldl, and the lower the hdl= higher the risk of IHD
What is FH?
Familial hypercholesterolemia
Genetic disorder causing very high LDL levels in the blood and early CVD
Most have a mutaton in either:
-LDLR gene
-Apolipoprotein B- part of the LDL that binds to the LDLR
Heterozygous= likely to have premature CVD- 30/40- treatment: statins, bile acid sequestrants, lipid lowering agents
Homozygous= severe CVD in childhood
treatment: generally dont respond to medical treatment- new PCSK9 inhibitors seem to be having an effect
Drugs we use to treat dyslipidemia/ atherosclerosis
Statins
inhibitors of cholesterol absorption
PCSK9 inhibitors
fibrates
What are statins and what do they do
HMG-CoA reductase inhibitors
inhibit the enzyme- reduce cholesterol synthesis
decrease in cholesterol synthesis: causes increased production of LDLRs
increased clearance of LDLs from the plasma
*decrease plasma LDLs
Examples of statins
Simvastatin
Lovastatin
Pravastatin
Atorvastatin
Why do statins have pleiotropic effects?
Inhibition of the mevalonate pathway
products of the mevalonate pathway involved in lipidation- lots of important membrane-bound enzymes are modified in this way
inhibition of this pathway= affects lots of processes
*improved endothelial function
When are statins used in clinic?
Primary prevention of arterial disease in at risk patients
Secondary prevention of MI and stroke in patients who have symptomatic atherosclerotic disease
-Atorvastatin reduces serum cholesterol in patients with homozygous FH
-in severe drug-resistant dyslipidemia- statin treatment is combined with other drugs
NOT USED IN PREGNANCY
Statins adverse effects
muscle pain gastrointestinal disturbance increased concentrations of liver enzymes in blood insomnia rash
What are fibrates- examples of them
Fibrates activate PPAR receptors (especially alpha)
PPAR receptors= intracellular receptors that modulate fat and carb metabolism and adipose tissue differentiation
activating PPARs induces the transcription of genes that facilitate lipid metabolism
-bezefibrate
-ciprofibrate
- gemfibrozil
not often used in clinic anymore
What are the effects of fibrates?
markedly reduce circulating VLDL modest decrease in LDL modest increase in HDL rarely used due to side effects only used when: statins or ezetimibe are not tolerated can be combined with other lipid-lowering agents in patients with severe resistant dyslipidemia
Fibrates adverse effects
risk of kidney failure gall stones mil stomach upset myopathy statin and fibrate+ increased risk of muscle damage
What is ezetimibe?
Inhibitor of cholesterol absorption
blocks intestinal absorption of cholesterol by clocking a transport protein (NPC1L1)
high potency- usually combined with a statin- can lower LDL by 25%
Whats the pharmacology of ezetimibe and what are its advs and disadvs?
Pharmacology: oral drug, extensively metabolized, slow half life and elimination
Advs: doesn’t interact with other drugs, 1 pill a day
Disadvs: expensive, given to people who cant tolerate statins, or as a supplementary to statins in patients with severe dyslipidemia, can enter into breastmilk
-mild diarrhea
abdominal pain
headache
rash
What are resins?
Inhibitors of cholesterol absorption
first cholesterol-lowering drug to be used clinically
remains in the intestinal tract - binds bile acids- prevents their absorption into the bloodstream
Why aren’t resins used much anymore?
Due to their intolerance- significant side effects:
severe bloating, constipation or diarrhoea, interacts with other medications
What are sterols/ stanols?
Inhibitors of cholesterol absorption
structurally similar to cholesterol- incorporated into mixed micelles- replace cholesterol
body takes up sterols and packages it into the chylomicron
less cholesterol absorbed into the blood stream
competition between cholesterol and sterols
*sterols may also be increasing the speed at which cholesterol is expelled from the body
What is evolocumab/ repatha? When it used?
Human monoclonal antibody
inhibitor of PCSK9
PCSK9 binds to LDLR= complex internalizes = receptor undergoes lysosomal degradation
evolocumab inhibits this- allows LDL to bind to LDLR and be cleared from the plasma
lowers circulating LDL levels :)
Used specifically for:
-supplementary to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous FH/ clinical CVD
-supplement to diet and other LDL lowering therapies for the treatment of patients with homozygous FH
Disadvantages of evolocumab?
expensive subcutaneous injection adverse effects: upper respiratory tract infection back pain injection site reaction
