125 Lipoprotein Metabolism / Pharm

Question 1

Summary of Lipid Biochemistry

Answer 1

• Lipids are Heterogenous; Insoluble in Water
• There are 4 Main Classes of Lipids:

–Fatty Acids

–Triglycerides

–Phospholipids

–Cholesterol; Cholesteryl Ester

• Amphipathic Nature à Complex Structures
• Cholesterol Metabolism:

–HMG CoA Reductase is the RLS of Cholesterol Biosynthesis

–Cholesterol is the Precursor for Bile Acid Synthesis

Question 2

Lipoprotein general

Answer 2

Structure

• Apolipoproteins
• Amphipathic surface
• Hydrophobic core

Purpose

• Deliver Fats as FUEL
• Cholesterol transport
• Phospholipid transport
• Other Roles in the Body?

Roles

• Cofactors for enzymes and receptors, conferring specificity
• Structural scaffolds

Question 3

Classification of Lipoproteins (2)

Answer 3

1: Density
2: Electrophoretic mobility

Question 4

General evolutions of liprprotein species

Answer 4

Question 5

Lipoprotein Transport:
Four Key Pathways

Three Key Enzymes

Answer 5

1. •Exogenous Pathway
2. •Endogenous Pathway
3. •Reverse Cholesterol Transport
4. •Enterohepatic Circulation

•Lipoprotein Lipase (LPL)

• –Insulin deficiency
• –Thyroid deficiency
• Lecithin-cholesterol acyltransferase (LCAT)
• Cholesteryl Ester Transfer Protein (CETP)

Question 6

Exogenous Lipid Transport Pathway

Answer 6

Gut to Liver

Enterocytes package:

• –Triglycerides
• –Cholesterol
• –Phospholipids
• –ApoA (~28kD)
• –ApoB48 (~250 kD)

Question 7

Endogenous Lipid Transport Pathway

Answer 7

Nascent VLDL->VLDL->IDL->LDL

Question 8

Reverse Cholesterol Transport Pathway

Answer 8

Question 9

Enterohepatic Circulation Pathway

Answer 9

Question 10

Familial Chylomicronemia Syndrome (Fredrickson Type I Hyperchylomicronemia)

Answer 10

Question 11

Familial Hypercholesterolemia

(Fredrickson Type II)

Answer 11

Question 12

Dysbetalipoproteinemia

(Fredrickson Type III)

Answer 12

• Defect in ApoE2 synthesis (ApoE isoform)
• ApoE then less able to bind lipoprotein receptors
• E2/E2 (normal is E3/E3) + Second hit e.g. hypothyroidism
• Accumulation IDL à Increased atherosclerotic risk
• Presentation: adulthood – HL, xanthomas, premature CVD

Question 13

Familial Hypertriglyceridemia (Fredrickson Type IV)

Answer 13

Question 14

How do we measure Cholesterol clinically?

Answer 14

Question 15

Friedewald Equation

Answer 15

Question 16

Overview table of lipid lowering therapy

Answer 16

Question 17

Mech of Statins, Effects, Side Effects

Answer 17

Effects

• •Reduce LDL cholesterol levels by 20-60%
• •Atorvastatin, Rosuvastatin: High potency statins
• •Relative risk reduction 20-22% consistently across subgroups
• •Absolute risk reduction depends on event rate

Side Effect: Hepatotoxicity

• •Up to 3x upper limit of normal for AST, ALT is acceptable (transaminases, markers of liver function/inflammation)
• •Rare side effect
• •Generally reversible

Side Effect: Myopathy

• •Often involves proximal leg or arm muscles
• •Significant myositis (elevated creatine kinase) < 0.5%
• •Myalgias more common
• •Rhabdomyolysis is very rare
• •Potentiated by drugs inhibiting CYP450-3A4
• •Drugs that don’t depend on 3A4 - pravastatin, rosuvastatin, fluvastatin potentially better tolerated

Statin interactions:

• •Cytochrome P450:
  
  • –3A4: atorvastatin, simvastatin, lovastatin
  • –2C9: fluvastatin; less so rosuvastatin
• –NONE: pravastatin
• •Cyclosporine increases toxicity of all statins
• •Grapefruit juice interferes with intestinal CYP-450

Question 18

Bile Acid Sequestrants:

Answer 18

Bile Acid Sequestrants:

• oBind Bile Acids in the gut
• oPrevents reuptake of the Bile Acids
• oStimulates more de-novo liver synthesis
• of Bile Acids
• oTherefore Reduces Cholesterol in the Liver
• oIncreases LDLRs
• oTherefore decreases Serum Cholesterol
• oGood choice as second line lipid lowering agent

Question 19

PCSK9 Inhibitors

Answer 19

•Major actions

–Lowers LDL-C ~50% on top of high intensity statin

• Route: Intravenous injection every 2-4 weeks
• Side effects: myalgias, delerium, dementia
• Clinical Use:

–Further LDL reduction in Familial Hypercholesterolemia patients

–Further use awaiting outcomes trial; likely also cost reduction

Question 20

Ezetimibe

Answer 20

Ezetimibe:

oBlocks Enterocyte NPC1L1 transporter

oInhibits gut uptake of cholesterol

oReasonable as second line LDL lowering

Question 21

Fibrates

Answer 21

•Major actions

• –Lower LDL-C 5–20% (with normal TG)
• –May raise LDL-C (with high TG)
• –Lower TG 20–50%
• –Raise HDL-C 10–20%
• Side effects: dyspepsia, gallstones, myopathy
• Contraindications: Severe renal or hepatic disease
• Clinical Use: Lowering triglycerides

Question 22

Niacin

Answer 22

• •Major actions
  
  • –Lowers LDL-C 5–25% (with normal TG)
  • –Lowers TG 20–50%
  • –Raises HDL-C 15–35%
• •Side effects: flushing, GI distress, hyperuricemia, hepatotoxicity, hyperglycemia
• •Contraindications: liver disease, severe gout, peptic ulcer disease
• •Clinical Use:
  
  • –Lowering TG
  • –Likely no clinical benefit on top of statin for LDL

Question 23

Omega-3 Fatty Acid

Answer 23

•Clinical Use:

–Triglyceride lowering

Question 24

Approach to treating High LDL-c

Answer 24

Question 25

Approach to treating Low HDL-c

Answer 25

Question 26

Approach to treating high TG

Answer 26

Question 27

General Lipid therapy goals

Answer 27