Quiz #4 Material Flashcards
1
Q
How high should your HDL be and how low should your LDL be?
A
- Every institution will have their own numbers
- Ratios and risk factors are more important than actual values
2
Q
Cholesterol Treatments: Overview
A
- Diet: Always an adjunct, calories count
- Nicotinic Acid: Decreases lipolysis, increases HDL, cheap, flushing (aspirin)
- CETP Inhibitors: May greatly increase HDL (unsafe?)
- Statins: Inhibit cholesterol synthesis
- Bile Resins: Physically remove cholesterol
- Fibric Acids: Inhibit VLDL synthesis, increase HDL
- Sterols, ezetimibe: Decrease absorption
- PCSK9 inhibitors: Target LDL receptor recycling
- VLDL Packaging inhibitors: Target VLDL particle synthesis and release
- Probucol: Antioxidant
3
Q
Nicotinic Acid (Niacin)
A
- MOA: inhibits lipolysis
- Decreased delivery of free fatty acid to liver
- Decreased TG synthesis and hence VLDL
- Raises HDL and lowers LDL, VLDL
- Reduces LDL by 10-20%
- Reduces TG by 30+%
- Increases HDL by 20-35%
- Side effects in >50%
- Flushing treated with aspirin
- Delayed release formulation
- Antiinsulinemic, hyperuricemic
- CHEAP!
- New orphan receptor, GRP109A/HM74b, couples to Gi
4
Q
Mechanisms of change in lipid metabolism induced by nicotinic acid
A
- Activate receptor GRP109A→Gi mediated inhibition of adenylyl cyclase
- Decreases PKA, which decreases FFA
- Less substrate for TAG and subsequently VLDL/LDL synthesis
- Unknown interaction with CETP that raises HDL?
5
Q
Inhibitors of Cholesterol Ester Transport Protein (CETP)
A
- Dalcetrapib, Torcetrapib, Anacetrapib
- Dalcetrapib: disulfide bond with CETP
- Torcetrapib: stabilize association of CETP with its lipoprotein substrate, creating a nonfunctional complex
- HDL-C levels were increased by 30-106%
6
Q
CETP Mediates Transfer of Cholesterol between HDL and LDL
A
- Makes hydrophobic tunnel so cholesterol can transfer between HDL and LDL
- Blockage of CETP causes net higher HDL lipid
7
Q
Torcetrapib Withdrawn:
A
- 60% increase in deaths
- Increase in aldosterone might be the culprit
8
Q
Summary of Agents that Raise HDL
A
- Niacin: effect on HDL but little to no effect on decreasing overall rate of cardiovascular events
- Dalcetrapib: lack of efficacy and small increase in deaths
- Evacetrapib: lack of efficacy
- Anatrapib: still in trials
- What form of HDL needs to be raised and how do we do it?
9
Q
Biological Effect of Fibrates
A
- Reduces TG better than most other
- Fenofibrate might be safer than gemfibrozil with a statin
- Clofibrate: first fibrate administered as an ester, increased mortality
- Gemfibrozil: ligand for PPARa
- Combo with niacin or statin can cause severe muscle inflammation
- Decreases VLDL and TG, modest increase in HDL
10
Q
Fibrates bind to the RXR heterodimer transcription factor family
A
- Activates PPARa (Transcription factor)
- Stimulation of fatty acid oxidation, increased LPL, decreased apo CIII
11
Q
Cholesterol Biosynthesis Inhibitors
A
- Statin have high affinity for HMG CoA reductase
- HMG CoA→Mevalonate
- Cholesterol normally binds to HMG CoA reductase in feedback inhibition
- Also inhibit protein prenylation and Co-Q as well
- Side effects
- Have the greatest effect on CHD/MI than any other agent
- Takes several years for effects to show
12
Q
Bile Acid Binding Agents
A
- Colestipol, Cholestyramine, HMPC
13
Q
Bile /cholesterol recycling
A
- Liver cholesterol→bile salts→gallbladder→small intestine→ileum back to liver
- 95% per day are recycled via the portal system
- 0.2g/day are excreted
14
Q
Cholestyramine
A
- Not absorbed into blood stream
- Low toxicity
- Anion exchange resin
15
Q
LDL Receptor/Cholesterol Feedback
A
- LDL receptor are taken up by coated pit and chewed up by lysosome to make cholesterol
- High cholesterol inhibits LDL receptors being made
- In resins, cholesterol is being syphoned off into bile, so more LDL receptors are made
16
Q
Ezetimbe
A
- Inhibit dietary cholesterol uptake
- Recycled enterohepatically; long half life
- Reduces LDL ~15%; increases HDL ~2%
- Most effective when packaged with a statin
- Questions about efficacy
- Statin can do more than a 3% reduction, so is Zetia actually redcing?
17
Q
PCSK9
A
- Binds the LDL receptor targeting it for degradation
- Monoclonal antibodies
- Repatha (evolocumab), Praulent (alirocumab)
- Both tested in clinical trials with statins
- Too early for long term data on efficacy, particularly with death as an endpoint
18
Q
Lomitapide
A
- Inhibit microsomal transfer protein (MTP) that is necessary for VLDL and chylomicron synthesis
- For homozygous familial hypercholesterolemia
- Used with other agents
19
Q
Mipomersen
A
- For homozygous familial hypercholesterolemia
- Antisense oligonucleotide inhibitor of apoB synthesis
- Decreases VLDL and chylomicron
- Used with other agents
20
Q
Probucol
A
- Acts as an antioxidant
- Less oxidation of LDL receptor, more taken up and recycled
- Oxidized LDL can be taken up by foam cell macrophage
- Protect against atherosclerosis and therefore decrease death
21
Q
Sites of Calcium Regulation
A
- Bone, kidney, intestine
- Calcium flux in body regulated at 200mg/day regardless of intake
- Goal is 1.2 mM free serum Calcium
22
Q
Common cause of parathyroid disease
A
- Iatrogenic
- “Doctor induced”
- Trying to remove the thyroid glands and fuck up the parathyroid
23
Q
How does PTH increase blood calcium?
A
- Increase calcium absorption in gut
- Decreases calcium loss from kidney
- Increases phosphate loss from kidney
- Stimulates 1-hydroxylase in kidney (VitD activation)
- Increases bone reabsorption
- Increases osteoclast to osteoblast ratio in bone
- PKA and PKC pathways are activated by PTHR
24
Q
PKA pathway of PTH in increasing calcium reabsorption in kidney
A
- Increases cAMP/PKA
- Increases # transporter on luminal side
- PKA activity increases Ca++ pump on serosal side
- Increased activity of Ca/Na cotransporter on serosal side
