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Torcetrapib Withdrawn: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
25
Q
PKC pathway of PTH increasing phosphate excretion by kidney
A
- Npt2a is a Na/Pi transporter
- NHERF-1 is an adaptor protein that tethers PTH1R to Npt2a
- Enhances endocytosis, decreases Pi reabsorption
26
Q
PKC AND PKA pathway of PTH increasing osteoclasts
A
- Increase in RANKL and CSF
- Decrease in decoy receptor osteoprotegerin
- Osteoclasts # increases and are more active
- PKA→Transcription factor and increased gene expression→activation
- PKC→Proliferation
27
Q
Why is vitamin D called a hormone?
A
- Synthetic cells
- Specific receptors
- Activation/inactivation
- Feedback regulation
- Disease syndrome
- Circulates bound to carrier protein
28
Q
Different vitamers of vitamin D
A
- Have different potencies
- >10,000 fold differences in potencies
29
Q
How does vitamin D work at the molecular level?
A
- RXR heterodimer transcription factor
- A/B Recruits co-repressors or co-activator depending on whether or not ligand is bound
30
Q
Gene Targets for VitD
A
- TRPV6
- Calcium channel
- PMCA1
- ATP dependent Ca pump
- CaBP
- Allow transport of otherwise toxic Ca across cell
- NCX1
- Na/Ca coexchanger
31
Q
Treatment of Hypo-function of VitD
A
- Vitamin D2-ergocholeciferol
- Vitamin D3-cholecalciferol
- Activated analogs
- 25-hydroxy (calcifediol)
- 1,25-dihydroxy (calcitrol)
- Paricalcitol-partial agonist of Ca++ with greater PTH release
32
Q
Genetic Rickets
A
- Type 1: Hydroxylase
- Type 2: Receptor
33
Q
Therapeutic Consideration
A
- Rickets: D3
- Vit Resistant Rickets: 1-OH-D3
- Renal Rickets: D3 or 1-OH-D3
- Dialysis Patients: 1-OH-D3
- Rapid acting: 1-OH-D3
- Safest: D3
34
Q
Mechanisms for Ca++ regulation of PTH secretion
A
- Ca bind to Gq receptor
- PLC→IP3→release of calcium from ER
- PLA2 is the turned on and inhibits PTH secretion
- VitD binds to VDR, TF, reduces PTH synthesis
35
Q
Cinacalcet
A
- Allosteric site on extracellular-CR is target for cinacalcet (sensipar)
- Acts as a calcium sensitizer, making the cell more receptive to calcium
- Reduces PTH in renal disease
- Renal failue→high phosphate→low calcium→high PTH→uncontrolled VitD/Ca absorption
36
Q
Bisphosphonates
A
- Analogs of pyrophosphate
- Inhibit osteoclast activity
- Best to give before too much bone loss has occurred
- Nitrogen containing and inhibit FPP synthase
- Long term use associated with arrhythmias and heart disease
- Prevent prenylation of regulation proteins
- Disrupted ruffled membrane in osteoclast
- Loss of survival signals
37
Q
Zoledronate
A
- Once annual dose
- Goes into bone and stays there a long time
38
Q
Denosumab
A
- Monoclonal Ab against RANKL (osteoclast)
- Osteoclastogenesis is controlled by stromal osteoblastic cells via expression RANKL and OPG
- Osteoblasts produce OPG that bind to RANKL and inhibit
- RANKL normally bind to RANK on osteoclast and activate it
39
Q
Romosozumab
A
- Monoclonal Ab against sclerotsin (osteoblast)
- Sclerotsin produced by osteocyte and has antianabolic effects on bone formation
40
Q
Odanacatib
A
- Inhibitor of cathepsin k (osteoclast)
- Lysosomal protesase that degrades collagen
41
Q
Saracatanib
A
- Inhibitor of Src kinase (osteoclast)
42
Q
Teriparatide
A
- Intermittent therapy
- Get more osteoblast
43
Q
Treatments for Type 1 Diabetes
A
- Immunosuppressive therapy: have to be on for life
- Insulin
- Control acidosis or else it will kill you
- Control blood sugar
- Glycosylate B100, not taken back into liver and goes to foam cells
- Extend healthy life span
- Problems: different glucose load, sensitiveness, and needs
44
Q
Insulins
A
- Aspart, lispro, gulisin: ultra short
- Semilente: short
- NPH, lente: intermediate
- Glargine, determir: long
- Inhaled (exubera) creates less antibodies and could replace lispro/semilente
45
Q
What pathways does insulin alter?
A
- Activates a downstream signaling cascade that had pleiotropic effects on:
- Liver, muscle, fat
46
Q
Mechanism of action for insulin ~’95
A
- Insulin to tyrosine kinase
- Phosphorylation of receptor and of IRS-1
- GRB2 binds to IRS-1 and Sos to GRB2 couples insulin signal to Ras
- Sos promotes dissociation of GDP from Ras; GTP binds and Sos dissociates
- Active Ras then causes MAP kinase cascade
47
Q
Insulin Receptor Tyrosine phosphorylation initiates several regulatory cascades
A
- Glucose transport
- Cell proliferation; MAP kinase pathway
- Major Insulin Action Route
- PIK3 pathway
48
Q
Mechanism of Action of Sulfonylureas
A
- Glucose stimulation requires Ca++ and K+
- ATP inhibits K channel causes depolarization
- Depolarization stimulates voltage sensitive Ca++ channel in beta cell
- Increased Ca++ stimulates secretion in any secretory cell
- Sulfonylureas mimic ATP
- Megaglitinides inhibit K channels at same and different sites
49
Q
Glucagon
A
- Increases blood sugar by stimulating gluconeogenesis and glycogenolysis in liver and muscle
- Increases cAMP and PKA
50
Q
GLP-1
A
- Decreases blood sugar by stimulating insulin secretion and protecting beta cells
- Increase cAMP and PKA
- Inhibits gastric acid and increases satiety
- Can’t be drug because protein that is subject to proteolysis
51
Q
Glucagon and GLP-1 Formation
A
Both from proglucagon with alternate processing
52
Q
GLP-1 agonists
A
- Exendin
- From Gila Monster venom
- Longer half life than GLP-1
- DPP-4 resistant
- Major issue: immune response because of different amino acids
53
Q
Gliptins
A
- DPP-4 inhibitors
- Increase GLP-1 by slowing down it’s degradation
- Orally active
- May decrease loss of beta cells
54
Q
Alpha-Glucosidase Inhibitors
A
- Acarbose
- Delays carbohydrate absorption by decreasing conversion of complex carb to glucose
- Lowers post meal blood glucose levels
- Doesn’t stress pancreas
- SE: diarrhea, abdominal pain, gas
55
Q
Insulin Sensitizers
A
- Biguanides: Metformin
- Suppress glucose formation
- Thiazolidinediones
- Alter transcription of key gluconeogenic enzymes
- Rozglitazone
56
Q
Metformin MOA
A
- Inhibits mitochondrial complex 1 and increases AMP/ATP ratio
- Activates AMPK, an energy sensing kinase
- Decreases glucose production
- KO of AMPK and LKB1 has little effect on metformin activity…other MOAs
57
Q
Metformin: Acting through cAMP as well as AMP?
A
- Inhibits mitochondrial complex 1 and increases AMP/ATP ratio
- Inhibits AC to decrease cAMP/PKA
- Reduces effects of glucagon
- Inhibits PKB1 so that F26BP not made
- Decreases G6P and F6P
58
Q
Thiazolidinediones
A
- Pioglitazone (Actos)
- Rosaglitazone (Avandia)
- Insulin sensitizer, were once a mainstay in treatment
- Liver toxicity (troglitazone), stroke, heart failure (Avandia), bladder cancer (Actos)
59
Q
Glitazone MOA
A
- Bind to RXR heterodimer TF
- Bind and activate PPAR alpha/gamma
- Alter key levels of enzymes involved in energy utilization and storage
- Increase HDL, lower VLDL-TG
- Increase insulin sensitivity, increase beta cell function
60
Q
SGLT2 Inhibitors MOA
A
- Increase renal excretion of glucose
- Canagliflozin and Dapagliflozin
- Na/K gradient drives glucose reabsorption
- Low sodium inside cell drive the co-transport of sodium and glucose back into cell
- Not as effective as other agents, but have few SE
