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Phcol 401 > Quiz #4 Material > Flashcards

Quiz #4 Material Flashcards

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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
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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
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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
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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?
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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%
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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
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7
Q

Torcetrapib Withdrawn:

A
  • 60% increase in deaths
  • Increase in aldosterone might be the culprit
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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?
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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
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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
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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
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12
Q

Bile Acid Binding Agents

A
  • Colestipol, Cholestyramine, HMPC
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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
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14
Q

Cholestyramine

A
  • Not absorbed into blood stream
  • Low toxicity
  • Anion exchange resin
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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
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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?
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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
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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
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19
Q

Mipomersen

A
  • For homozygous familial hypercholesterolemia
  • Antisense oligonucleotide inhibitor of apoB synthesis
  • Decreases VLDL and chylomicron
  • Used with other agents
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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
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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
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22
Q

Common cause of parathyroid disease

A
  • Iatrogenic
    • “Doctor induced”
  • Trying to remove the thyroid glands and fuck up the parathyroid
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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
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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
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25
PKC pathway of PTH increasing phosphate excretion by kidney
* Npt2a is a Na/Pi transporter * NHERF-1 is an adaptor protein that tethers PTH1R to Npt2a * Enhances endocytosis, decreases Pi reabsorption
26
PKC AND PKA pathway of PTH increasing osteoclasts
* 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
Why is vitamin D called a hormone?
* Synthetic cells * Specific receptors * Activation/inactivation * Feedback regulation * Disease syndrome * Circulates bound to carrier protein
28
Different vitamers of vitamin D
* Have different potencies * \>10,000 fold differences in potencies
29
How does vitamin D work at the molecular level?
* RXR heterodimer transcription factor * A/B Recruits co-repressors or co-activator depending on whether or not ligand is bound
30
Gene Targets for VitD
* TRPV6 * Calcium channel * PMCA1 * ATP dependent Ca pump * CaBP * Allow transport of otherwise toxic Ca across cell * NCX1 * Na/Ca coexchanger
31
Treatment of Hypo-function of VitD
* 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
Genetic Rickets
* Type 1: Hydroxylase * Type 2: Receptor
33
Therapeutic Consideration
* 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
Mechanisms for Ca++ regulation of PTH secretion
* 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
Cinacalcet
* 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
Bisphosphonates
* 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
Zoledronate
* Once annual dose * Goes into bone and stays there a long time
38
Denosumab
* 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
Romosozumab
* Monoclonal Ab against sclerotsin (osteoblast) * Sclerotsin produced by osteocyte and has antianabolic effects on bone formation
40
Odanacatib
* Inhibitor of cathepsin k (osteoclast) * Lysosomal protesase that degrades collagen
41
Saracatanib
* Inhibitor of Src kinase (osteoclast)
42
Teriparatide
* Intermittent therapy * Get more osteoblast
43
Treatments for Type 1 Diabetes
* 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
Insulins
* Aspart, lispro, gulisin: ultra short * Semilente: short * NPH, lente: intermediate * Glargine, determir: long * Inhaled (exubera) creates less antibodies and could replace lispro/semilente
45
What pathways does insulin alter?
* Activates a downstream signaling cascade that had pleiotropic effects on: * Liver, muscle, fat
46
Mechanism of action for insulin ~’95
* 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
Insulin Receptor Tyrosine phosphorylation initiates several regulatory cascades
* Glucose transport * Cell proliferation; MAP kinase pathway * Major Insulin Action Route * PIK3 pathway
48
Mechanism of Action of Sulfonylureas
* 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
Glucagon
* Increases blood sugar by stimulating gluconeogenesis and glycogenolysis in liver and muscle * Increases cAMP and PKA
50
GLP-1
* 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
Glucagon and GLP-1 Formation
Both from proglucagon with alternate processing
52
GLP-1 agonists
* Exendin * From Gila Monster venom * Longer half life than GLP-1 * DPP-4 resistant * Major issue: immune response because of different amino acids
53
Gliptins
* DPP-4 inhibitors * Increase GLP-1 by slowing down it’s degradation * Orally active * May decrease loss of beta cells
54
Alpha-Glucosidase Inhibitors
* 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
Insulin Sensitizers
* Biguanides: Metformin * Suppress glucose formation * Thiazolidinediones * Alter transcription of key gluconeogenic enzymes * Rozglitazone
56
Metformin MOA
* 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
Metformin: Acting through cAMP as well as AMP?
* 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
Thiazolidinediones
* Pioglitazone (Actos) * Rosaglitazone (Avandia) * Insulin sensitizer, were once a mainstay in treatment * Liver toxicity (troglitazone), stroke, heart failure (Avandia), bladder cancer (Actos)
59
Glitazone MOA
* 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
SGLT2 Inhibitors MOA
* 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

Phcol 401 (10 decks)

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