Antihyperlipidemics:

Question 1

Cholesterol

Answer 1

• not water soluble; transported by phospholipids
• Component of cell membrane
  
  • increases fluidity
• Precursor for:
  
  • bile acids
  • steroid hormones
• Liver
  
  • main source of circulating cholesterol
  • synthesized from acetyl-CoA
• Skin/GUT
  
  • produce cholesterol
• Total Cholesterol levels
  
  • correlate w/dietary satruated fat intake, not dietary cholesterol

Question 2

Triglycerides:

Answer 2

• Not water soluble
• Esterified fatty acids:
• FA
  
  • important source of energy for:
    
    • muscles
    • liver
    • heart
• Triglycerides:
  
  • all cell synthesize
  • stored in adipose tissue

Question 3

Rate limiting step for cholesterol synthesis:

Answer 3

• Enzyme: HMG-CoA Reductase
  
  • inhibits:
    
    • Insulin (natural regulator)
  • Stimulates:
    
    • Glucagon (natural)
    • statins
    • cholesterol
• Acetyl-CoA–> Mevalonic acid

Question 4

Lipid level guidelines:

Answer 4

• Total cholesterol:
  
  • Desirable: <200
  • Borderline high: 200-240:
    
    • High risk of HD
  • High: >240:
    
    • Very high risk of HD
• HDL
  
  • Desirable (high): >60
  • Acceptable: 40-60
  • undesirable: <40
• LDL:
  
  • Optimal: <100
  • Near optimal: 100-130
  • Borderline high: 130-160
  • High: 160-190
  • Very High: >190
• Triglycerides:
  
  • Normal: <150
  • Borderline high: 150-200
  • High: 200-500
  • Very high: >500

Question 5

Statins:

Answer 5

• # 1 approach to reduce LDL
• Atorvastatin-best
• Rosuvastatin
• Simvastatin
• Positive Outcomes:
  
  • reduce LDL chol by >50% (& total chol)
  • reduces secondary CVD events
  • Increase HDL by 5-10% except:
    
    • Rosavastatin-10-15%
    • Pitvastatin-10-25%
      
      • decreases ApoC-III expression
  • High level of evidence support safety
• MOA: HMG-CoA Reductase Inhibitors/ Reductase Inhibitors
  
  • decrease endogneous chol synthesis
  • homologous w/HMG-CoA
  • Decrease Chol levels reduce VDL production, thus LDL formation
  • bc Chol negative feedbackon LDL receptor expression
    
    • LDLR expression increases
    • causing a clearance of LDL and chylomicron remnants
• Negative outcomes:
  
  • Simvastatin 80mg
    
    • myalgia and rhabdomyolysis

Question 6

Bile acid-binding resins or sequestrants:

Answer 6

• Cholestyramine-only one that reduces CVD events by 20%
• Colesevelam
• Colestipol
• Positive outcomes:
  
  • Modest LDL lowering effect compared to statins
  • Statin + Bile acid resin=synergistic effect
    
    • Familial hypercholesterolemia
  • Fibrate + Bile acid resins
    
    • familial combined hyperlipidemia if they can’t tolerate niacin or statins
• MOA:
  
  • High molecular weight polymers bind bile acids in the intestes and excreted in the stool instead of cycled back to liver
  • LDL expression increases, bc bile acid not absorbed from gut, liver needs choesterol, so uses LDL to compensate
• Negative outcomes:
  
  • reduced absorption of some drugs and vitamins
  • main side effects:
    
    • constipation
    • gas
  • May increase Tryglycerides; so avoid in patients with High TGs

Question 7

Cholesterol absorption inhibitor:

Answer 7

• # 2 choice
• Ezetinibe (Zetia)
• Positive outcomes:
  
  • Ezetinibe:
    
    • modest LDL lowering effect
    • marginal effect on HDL and Triglycerides
      
      • more selective than Binding acid resins and Statins
  • Ezetinibe + simvastatin(vytorin)
    
    • synergistic effect
    • increased LDL lowering effect
    • homozygous familial hypercholerolemia
• MOA: same as Biding acid resins
  
  • prevent chol from binding to NPC1L1R, so chol remains in the liver
• Negative outcomes:
  
  • well tolerated
  • unknown effect on CHD and mortality

Question 8

Fibrates:

Answer 8

• -fib-
• Fibric acid derivatives
  
  • Fenofibrate
  • Gemfibrozil
• Positive Outcomes
  
  • effective primary prevention for CVD especially in type 2 diabetics pts
  • Increase HDL, Decrease TGs
• MOA:
  
  • peroxisome proliferator-activated receptor alpha agonists (PPARa)–>binds PPRE/target genes
  • Increase LDL particle size
  • increase HDL:
    
    • increase A-I and AII
  • Increase reverse cholesterol transport
    
    • ABCA1 and ABCG1
  • decrease TGs
    
    • decrease C-III
    • increase LPL
  • Decrease inflammation-benefit for CHD
• Negative outcomes:
  
  • side effects:
    
    • GI
    • rhabdomyolysis (statins also)
  • Combos to avoid:
    
    • Fibrates/stains
    • Fibrates/niacin
  • can be coupled with bile-sequestering resins if seperated by 2 hours
    
    • bc they bind to resins

Question 9

Niacin:

Answer 9

• Positive:
  
  • reduced LDL mildly
  • most effective at reducing TGs and increasing HDL
  • 1st agent to prevent CHD and death
• MOA:
  
  • inhibitss adipose tissue lipolysis
  • decreases the formation of VLDL
  • causes a reduction in TGs and LDL
• Negative outcomes:
  
  • Side effects: Control with NSAIDS(aspirin)
    
    • intense vasodilatin
    • flushing
    • feeling of warmth
    • tingling
    • pruritus
      
      • reduce adherence to treatment
      • controlled with NSAIDS-aspiriin
  • hepatotoxiticity
  • GI distress and aggrevate peptic ulcers

Question 10

PCSK9 inhibitors

Answer 10

• -cumab
• Alivocumab
• evolocumab
• Increase LDL clearance; prescribed when statins don’t work
• MOA: Increase LDL clearance
  
  • Normaly: LDL+PCSK9 binds to the LDL receptor, gets internalized and degraded by endosome
  • PCSK9=neutralizing antibodies
    
    • PCSK9 inhibitor inhibits PCSK9 from binding to LDL receptor
    • LDL receptor+LDL internalized
    • LDL receptor is receycled, not degraded
  • Increases uptake of LDL

Question 11

Drugs used for cardiogenic shock

Answer 11

• Vasopressors/inotropic agents
• PDE inhibitors
• Vasodilators
• Analgesics
• Diuretics

Question 12

Mipomerson

Answer 12

• antisense oligonucleotide inhibit ApoB-100 mRNA
• Decrease levels of VLDL-
• leads to decreased formation of LDL

Question 13

Lomitapide

Answer 13

• inhibits MTTP
• inhibit formation of VLDL