125 Lipoprotein Metabolism / Pharm Flashcards
Summary of Lipid Biochemistry
- 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
Lipoprotein general
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
Classification of Lipoproteins (2)
1: Density
2: Electrophoretic mobility
General evolutions of liprprotein species
Lipoprotein Transport:
Four Key Pathways
Three Key Enzymes
- •Exogenous Pathway
- •Endogenous Pathway
- •Reverse Cholesterol Transport
- •Enterohepatic Circulation
•Lipoprotein Lipase (LPL)
- –Insulin deficiency
- –Thyroid deficiency
- Lecithin-cholesterol acyltransferase (LCAT)
- Cholesteryl Ester Transfer Protein (CETP)
Exogenous Lipid Transport Pathway
Gut to Liver
Enterocytes package:
- –Triglycerides
- –Cholesterol
- –Phospholipids
- –ApoA (~28kD)
- –ApoB48 (~250 kD)
Endogenous Lipid Transport Pathway
Nascent VLDL->VLDL->IDL->LDL
Reverse Cholesterol Transport Pathway
Enterohepatic Circulation Pathway
Familial Chylomicronemia Syndrome (Fredrickson Type I Hyperchylomicronemia)
Familial Hypercholesterolemia
(Fredrickson Type II)
Dysbetalipoproteinemia
(Fredrickson Type III)
- 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
Familial Hypertriglyceridemia (Fredrickson Type IV)
How do we measure Cholesterol clinically?
Friedewald Equation
Overview table of lipid lowering therapy
Mech of Statins, Effects, Side Effects
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
Bile Acid Sequestrants:
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
PCSK9 Inhibitors
•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
Ezetimibe
Ezetimibe:
oBlocks Enterocyte NPC1L1 transporter
oInhibits gut uptake of cholesterol
oReasonable as second line LDL lowering
Fibrates
•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
Niacin
- •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
Omega-3 Fatty Acid
•Clinical Use:
–Triglyceride lowering
Approach to treating High LDL-c
Approach to treating Low HDL-c
Approach to treating high TG
General Lipid therapy goals
