Hyperlipoproteinemia & Antihyperlipedemic Drugs

Question 1

lipoprotein structure (core and surface)

Answer 1

core: non polar - choloesteryl esters and triglycerides
surface: polar monolayer - phospholipids, free cholesterol, proteins

Question 2

cholesterol and choloesteryl ester

Answer 2

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)

Question 3

triglyceride

Answer 3

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

Question 4

apolipoproteins

Answer 4

• 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)

Question 5

classification of cholesterol

Answer 5

1. chylomicrons
   - synthesized in intestine
   - rich in dietary TG
   - short half life (30 mins)
2. VLDL
   - synthesized in liver
   - low protein, rich in TG and cholesterol
3. IDL
4. LDL
   - made from hydrolysis of VLDL and IDL
   - low protein, rich in TG and cholesterol
   - long half life (3 days)
5. 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

Question 6

What is used to measure circulating cholesterol?

Answer 6

APOB100

Question 7

What is atherosclerosis and what is it correlated to?

Answer 7

• occurs due to hardening of arteries due to deposition of plaques
• correlated with high LDL:HDL ratio in plasma

Question 8

What is an atherosclerotic plaque made of?

Answer 8

• 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

Question 9

what is the consequence of atherosclerotic plaques?

Answer 9

• 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)

Question 10

How is a plaque broken up surgically?

Answer 10

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

Question 11

How does high LDL contribute to atherogenesis?

Answer 11

• 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

Question 12

What is the association between lipoprotein half-life and atherogenicity

Answer 12

• 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

Question 13

What is lipoprotein (a)?

Answer 13

• 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

Question 14

What is the correlation between Lp(a) and atherosclerosis?

Answer 14

• 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

Question 15

What is the endogenous cholesterol synthesis and regulation pathway?

Answer 15

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

Question 16

Statin MOA

Answer 16

• 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

Question 17

pharmacological effects of HMg-CoA reductase inhibitors

Answer 17

• deplete sterol pools
• increase LDL uptake
• inhibit Apo B-100 synthesis and assembly into VLDL
• increases plasma HDL and lower TG and total cholesterol

Question 18

Which statins are most effective at lowering LDL levels?

Answer 18

Atorvastatin
- long half life
- requires less dosing

Rosuvastatin
- most potent
- no hepatic metabolism

Question 19

What are statins used for? Combination therapy?

Answer 19

• 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)

Question 20

Statin AEs, contraindications, and DDIs

Answer 20

• 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

Question 21

Statin controversy

Answer 21

• 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

Question 22

Bempedoic acid (drug type, MOA, indication)

Answer 22

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

Question 23

What drugs impair intestinal absorption of cholesterol?

Answer 23

• cholestyramine
• colestipol
• ezetimibe

Question 24

Cholestyramine and Colestipol (drug type, MOA, combinations)

Answer 24

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

Question 25

Cholestyramine and Colestipol AEs

Answer 25

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)

Question 26

Ezetimibe (molecular target and location, MOA, combinations)

Answer 26

- 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

Question 27

Niacin (MOA, use, AEs)

Answer 27

- 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

Question 28

Drugs that impair conversion of plasma lipoproteins

Answer 28

fibric acid derivatives - cleofibrate - fenofibrate - gemfibrozil

Question 29

fibric acid derivatives (names, MOA, effects, AEs)

Answer 29

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!!!!

Question 30

Drugs that increases LDL-R expression

Answer 30

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

Question 31

Evolocumab

Answer 31

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

Question 32

What is the role of PCSK9?

Answer 32

- enzyme ubiquitously expressed - binds to LDL R and internalizes it and increases degradation of bound LDL

Question 33

Inclisiran

Answer 33

- 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

Question 34

Next generation drugs

Answer 34

pelacarsen - antisense oligonucleotide to apo(a) mRNA - decreases [Lp(a)] volanesorsen - antisense oligonucleotide to apoC-III - decreases [TG and chylomicrons] bile acid transport inhibitors

Question 35

controversy of using drugs that alter cholesterol

Answer 35

- 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

Question 36

omega-3 fatty acid ethyl esters

Answer 36

- modified from fish oils with dietary changes - reduce TG levels - potential risk with DDI, unwanted allergies to fish

Question 37

marine derived omega 3 polyunsaturated fatty acids (PUFA)

Answer 37

- 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

Question 38

Naturopathic interventions to lower LDL

Answer 38

- berberine: natural plant sterol that inhibits CYP3A4 - red rice years: manocolin K (natural statin) and phytosterols - mediterranean diet