Hyperlipoproteinemia & Antihyperlipedemic Drugs Flashcards
lipoprotein structure (core and surface)
core: non polar - choloesteryl esters and triglycerides
surface: polar monolayer - phospholipids, free cholesterol, proteins
cholesterol and choloesteryl ester
cholesterol: less lipophilic, on surface
choloesteryl ester: more lipophilic, in the core
- precursor of steroid hormones and bile acid
- essential cell membrane constituent
- endogenous synthesis in liver and from diet (animals)
triglyceride
location: core
storage: adipose tissue
source: dietary fat absorbed from intestine (animal and plant) and endogenous synthesis in liver and adipose tissue
metabolism: by lipoprotein lipase on endothelial cell surface into glycerol and FFAs
apolipoproteins
- protein constituent of lipoprotein that provides structure
- acts as ligand: binds to cellular lipoprotein Rs which results in internalization (ApoB 100 binds to LDL R)
- acts as a cofactor for enzymes in lipoprotein metabolism (ApoC II activates lipoprotein lipase LPL, ApoC III inhibits it)
classification of cholesterol
- chylomicrons
- synthesized in intestine
- rich in dietary TG
- short half life (30 mins) - VLDL
- synthesized in liver
- low protein, rich in TG and cholesterol - IDL
- LDL
- made from hydrolysis of VLDL and IDL
- low protein, rich in TG and cholesterol
- long half life (3 days) - HDL
- synthesized in liver and intestine
- high protein, low TG and cholesterol
- reverse cholesterol transport to liver to process cholesterol to bile salts so they can be excreted instead
What is used to measure circulating cholesterol?
APOB100
What is atherosclerosis and what is it correlated to?
- occurs due to hardening of arteries due to deposition of plaques
- correlated with high LDL:HDL ratio in plasma
What is an atherosclerotic plaque made of?
- thrombus (fibrous cap)
- core of foam cells, extracellular lipids and necrotic cellular debris
- foam cells are damaged macrophages that damage the intima of BVs –> causes inflammation –> more damage –> clot
what is the consequence of atherosclerotic plaques?
- results in narrowed BV lumen
- can reduce blood flow to tissue –> infarct
- if it breaks off –> embolus –> infarct (if goes to lungs - pulmonary embolism, if goes to heart - myocardial infarction)
How is a plaque broken up surgically?
angioplasty + stent
- narrow wire put through femoral artery and a balloon is blown up that breaks it up
- if it is not broken up enough a stent can be put in - tube so that blood can go through
How does high LDL contribute to atherogenesis?
- high plasma levels of (oxidized) LDL
- LDL infiltration into intima
- along with macrophages form foam cells which cause cell necrosis due to injurious substances, foam cells can’t be bind to LDL R so they can’t be taken up by the liver
- it also contributes to endothelial dysfunction which increases permiability to LDL and also causes platelet aggregation
- adherence of platelets leads to thrombosis and (along with platelet derived growth factor) cell proliferation
What is the association between lipoprotein half-life and atherogenicity
- the longer the half life the more the LP is modified and interacted with macrophages causing foam cell formation
- chylomicrons have the shortest half life (5-30 min) and are the least atherogenic
- VLDL (12 hrs), IDL (1-2 days), LDL (3 days) are increasing atherogenic
- HDL is anti atherogenic and facilitates transfer of cholesterol from periphery back to the liver
What is lipoprotein (a)?
- composed of LDL particle with Apo A covalently bound to Apo B-100 so it can’t be taken up as easily by LDL R
- will circulate for longer and is not as controlled because it can’t bind to LDL R well
- larger and denser than LDL
- plasma levels are genetically determined and variable
- specific protein with high risk for CVD
What is the correlation between Lp(a) and atherosclerosis?
- correlated between plasma Lp(a) levels and atherosclerosis risk
- competitively inhibits tissue plasminogen activator (it converts plasminogen to plasmin which leads to lysis of fibrin, if it is not lysed it will be converted to fibrinogen and lead to a clot)
- promotes thrombus formation because clots are not broken down as readily, which is atherogenic
What is the endogenous cholesterol synthesis and regulation pathway?
synthesis
- acetyl-CoA is converted to HMg-CoA
- HMg-CoA is converted to mevalonic acid by HMg-CoA reductase (rate limiting step)
- mevalonic acid is converted to cholesterol
regulation
- hepatic cholesterol exerts feedback inhibition on HMg-CoA reductase
- hepatic cholesterol inhibits synthesis and expression of LDL receptor to lower metabolic removal of LDL from periphery
- the more the liver makes the less it takes up
Statin MOA
- they are HMg-CoA reductase inhibitors
- statins are structural analogs of HMg-CoA
- acts through competitive inhibition to decrease cholesterol
- depletes sterol pools as less cholesterol increases reductase activity which resets of cholesterol homeostatis
- less cholesterol leads to higher LDL R synthesis and expression which increases LDL uptake form periphery and lowers plasma LDL
pharmacological effects of HMg-CoA reductase inhibitors
- deplete sterol pools
- increase LDL uptake
- inhibit Apo B-100 synthesis and assembly into VLDL
- increases plasma HDL and lower TG and total cholesterol
Which statins are most effective at lowering LDL levels?
Atorvastatin
- long half life
- requires less dosing
Rosuvastatin
- most potent
- no hepatic metabolism
What are statins used for? Combination therapy?
- all hyperlipoproteinemias except for homozygous LDL-R deficiency
- act synergistically with cholestyramine and colestipol
- used in combination with ezetimibe, niacin, and amlodipine (Ca+ chanel blocker)
Statin AEs, contraindications, and DDIs
- myositis and rhabdomyolysis (SAMS), dose dependent muscle pain and inflammation, main reason for non compliance
- elevated liver transaminase levels in 1-2% patients, dose dependent
- contraindicated in pregnancy, HMg-CoA reductase and cholesterol important in fetal development
- P450 inhibitors can increase statin concentration
Statin controversy
- said to be useful in decreasing C-reactive protein and MI in females, melavonic acid pathway inhibition, decreasing ROS, cancer, inflammation, etc
- increase risk of diabetes, muscle injury
recent evidence has indicated
- benefits outweigh the risk of T2DM de novo in individuals
- high dose statin is associated with hepatoxcity risk
Bempedoic acid (drug type, MOA, indication)
drug type: HMg-CoA reductase inhibitor
MOA: prodrug –> ATP citrate lyase inhibitor (upstream of HMg-CoAR) –> inhibition prevents endogenous cholesterol synthesis –> increases LDL R expression
- used for familial hyperlipoproteinemias and as add on for patients that one drug is not enough for
What drugs impair intestinal absorption of cholesterol?
- cholestyramine
- colestipol
- ezetimibe
Cholestyramine and Colestipol (drug type, MOA, combinations)
drug type: cationic resins that bind bile acids
MOA: prevents bile acid absorption from intestine and increase bile acid excretion –> compensatory bile acid production from cholesterol in liver –> increases HMg-CoA reductase activity –> decreases cholesterol –> increases LDL R –> less circulating LDL, more HDL
combination: synergistic effects and increased efficacy with HMg-CoA reductase inhibitors
Cholestyramine and Colestipol AEs
impair intestinal absorption of other drugs
- fat soluble molecules and vitamins
- due to affinity for acidic compounds, may need to adjust timing of other drugs
steatorrhea
- excess fat in stool, weight loss, diarrhea
- due to impaired absorption of dietary fat (which we want)
Ezetimibe (molecular target and location, MOA, combinations)
- acts on NPC1L transported at the brush border of small intestine
- MOA: blocks absorption of dietary and biliary cholesterol –> reduce intracellular cholesterol and LDL
- used in monotherapy or usually with statins –> synergistic, both doses can be reduced, acting on endogenous and exogenous synthesis
Niacin (MOA, use, AEs)
- MOA not well defined
- only lipid lowering drug that lowers Lp(a) levels
- can be given with bile acid binding resins to increase clinical effects
- given to patients with elevated Lp(a)
- inexpensive and effective
- can be given OTC or RX –> needs monitoring especially OTC –> OTC niacin not regulated so there are variable amounts
- unwanted effects stop it from being first line
- flushing, hyperglycemia (even diabetes), serious liver dysfunction, GI upset/bleeding
Drugs that impair conversion of plasma lipoproteins
fibric acid derivatives
- cleofibrate
- fenofibrate
- gemfibrozil
fibric acid derivatives (names, MOA, effects, AEs)
names: cleofibrate, fenofibrate, gemfibrozil
MOA: stimulate PPARa –> increases transcription of genes to increase expression of proteins involved in lipid metabolism
effects:
- increased LPL syntehsis –> increases VLDL conversion to IDL and LDL –> intially increasesLDL but then dereases due to VLDL depletion
- decreased apoC III expression (inhibits LPL)
- increases FFA oxidation and decrease FFA synthesis
- increases HDL levels
- antithrombitic effects –> inhibibts coagulation and enhances fibrinolysis –> reduce CV disease risk
AE: cholelithiais –> gallstones
- not used with statins!!!!
Drugs that increases LDL-R expression
PCSK9 inhibitors
- evolocumab
- inclisiran
- vaccination against PCK9 (VLP trigger IgG removal)
- berberine inhibits PCSK9 gene transcription (natural compound)
- CRISPR Cas9 inhibits by editing on top of statins
Evolocumab
MOA: inhibits PCSK9 –> increases recycling of LDL R –> increases expression –> increased removal of circulating LDL
used on top of ongoing therapy, usually statins
used in patients with
- high risk of CV but still have high LDL levels
- statin intolerance
- familial hypocholesteremia
What is the role of PCSK9?
- enzyme ubiquitously expressed
- binds to LDL R and internalizes it and increases degradation of bound LDL
Inclisiran
- siRNA targeting PCSK9 –> cleaves PCSK9 mRNA to reduce expression –> less degredation of LDL R
- administered sc d1, 90, 180 ad eveyr 6 months
- 50% LDL reduction vs placebo
Next generation drugs
pelacarsen
- antisense oligonucleotide to apo(a) mRNA
- decreases [Lp(a)]
volanesorsen
- antisense oligonucleotide to apoC-III
- decreases [TG and chylomicrons]
bile acid transport inhibitors
controversy of using drugs that alter cholesterol
- worry that decreasing cholesterol will affect systems and organs in the body that need it
- but cholesterol is the #1 modifiable risk for CVD and hyperlipoproteinemia then it should be used
omega-3 fatty acid ethyl esters
- modified from fish oils with dietary changes
- reduce TG levels
- potential risk with DDI, unwanted allergies to fish
marine derived omega 3 polyunsaturated fatty acids (PUFA)
- omega 3 fish oil of fatty acids
- used in large doses to reduce high blood TG levels via increasing TG clearance
- potential risk with DDI, unwanted allergies to fish
Naturopathic interventions to lower LDL
- berberine: natural plant sterol that inhibits CYP3A4
- red rice years: manocolin K (natural statin) and phytosterols
- mediterranean diet
