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YAY ALMOST DONE > Hyperlipoproteinemia & Antihyperlipedemic Drugs > Flashcards

Hyperlipoproteinemia & Antihyperlipedemic Drugs Flashcards

1
Q

lipoprotein structure (core and surface)

A

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

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2
Q

cholesterol and choloesteryl ester

A

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)
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3
Q

triglyceride

A

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

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4
Q

apolipoproteins

A
  • 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)
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5
Q

classification of cholesterol

A
  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
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6
Q

What is used to measure circulating cholesterol?

A

APOB100

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7
Q

What is atherosclerosis and what is it correlated to?

A
  • occurs due to hardening of arteries due to deposition of plaques
  • correlated with high LDL:HDL ratio in plasma
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8
Q

What is an atherosclerotic plaque made of?

A
  • 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
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9
Q

what is the consequence of atherosclerotic plaques?

A
  • 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)
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10
Q

How is a plaque broken up surgically?

A

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

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11
Q

How does high LDL contribute to atherogenesis?

A
  • 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
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12
Q

What is the association between lipoprotein half-life and atherogenicity

A
  • 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
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13
Q

What is lipoprotein (a)?

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
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14
Q

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

A
  • 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
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15
Q

What is the endogenous cholesterol synthesis and regulation pathway?

A

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

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16
Q

Statin MOA

A
  • 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
17
Q

pharmacological effects of HMg-CoA reductase inhibitors

A
  • deplete sterol pools
  • increase LDL uptake
  • inhibit Apo B-100 synthesis and assembly into VLDL
  • increases plasma HDL and lower TG and total cholesterol
18
Q

Which statins are most effective at lowering LDL levels?

A

Atorvastatin
- long half life
- requires less dosing

Rosuvastatin
- most potent
- no hepatic metabolism

19
Q

What are statins used for? Combination therapy?

A
  • 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)
20
Q

Statin AEs, contraindications, and DDIs

A
  • 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
21
Q

Statin controversy

A
  • 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

22
Q

Bempedoic acid (drug type, MOA, indication)

A

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

23
Q

What drugs impair intestinal absorption of cholesterol?

A
  • cholestyramine
  • colestipol
  • ezetimibe
24
Q

Cholestyramine and Colestipol (drug type, MOA, combinations)

A

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

25
Q

Cholestyramine and Colestipol AEs

A

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)

26
Q

Ezetimibe (molecular target and location, MOA, combinations)

A
  • 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
27
Q

Niacin (MOA, use, AEs)

A
  • 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
28
Q

Drugs that impair conversion of plasma lipoproteins

A

fibric acid derivatives
- cleofibrate
- fenofibrate
- gemfibrozil

29
Q

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

A

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!!!!

30
Q

Drugs that increases LDL-R expression

A

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
31
Q

Evolocumab

A

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

32
Q

What is the role of PCSK9?

A
  • enzyme ubiquitously expressed
  • binds to LDL R and internalizes it and increases degradation of bound LDL
33
Q

Inclisiran

A
  • 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
34
Q

Next generation drugs

A

pelacarsen
- antisense oligonucleotide to apo(a) mRNA
- decreases [Lp(a)]

volanesorsen
- antisense oligonucleotide to apoC-III
- decreases [TG and chylomicrons]
bile acid transport inhibitors

35
Q

controversy of using drugs that alter cholesterol

A
  • 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
36
Q

omega-3 fatty acid ethyl esters

A
  • modified from fish oils with dietary changes
  • reduce TG levels
  • potential risk with DDI, unwanted allergies to fish
37
Q

marine derived omega 3 polyunsaturated fatty acids (PUFA)

A
  • 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
38
Q

Naturopathic interventions to lower LDL

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

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