4. Olah - Dyslipidemias Flashcards
TGs, from where and functions
Trimester of glycerol and fatty acid
Obtained from biosynthesis and diet
Functions: energy source and storage
Lipoproteins function
Activate enzymes, receptors and transporters
What is the rate limiting step in cholesterol synthesis?
HMC-CoA Reductase
Cholesterol Metabolism and Transport
VLDL from hepatic synthesis –> apoproteins allow it to enter capillaries, muscles and fat –> Lipoprotein lipase generate IDL –> Hepatic lipase removes more TGs from IDL creating LDL –> LDL transported to liver and peripheral cells
What is the benefit of HDLs
Anti-atherogenic effects from the role in Reverse Cholesterol Transport
What are HDL’s anti-atherogenic effects?
Hint, there’s 5
- Antioxidant
- Endothelial cell protectant
- Anti-inflammatory
- Anti-platelet and anticoagulant
- Profibrinolytic
What are the 5 main drugs in treatment of dyslipidemia?
- HMG-CoA Reductase Inhibitor
- Ezitimibe
- Bile Acid Sequestrants
- Niacin (Nicotinic Acid)
- PPAR-alpha Activators (Fibrates)
HMG-CoA Reductase Inhibitors are also known as…
Statins
MOA of Statins
Reversible competitive inhibitors of HMG-CoA Reductase - primarily in hepatocytes
What do statins do to lipid profile?
Hint, how are LDL, TGs, and HDL affected
Decrease in LDLs
Decrease in TGs - only if pt has high baseline TG
Increases in HDL - only if pt has low baseline HDL
What are statins other MOA?
Hint, has to do w/ LDL
Since there is a reduction in overall cholesterol, the SREBP pathway senses low LDL levels and synthesizes more LDL receptors. An increase in LDL receptors will lead to an increase in LDL taken into the cell, contributing to a decrease in circulating LDL levels
What is stain “pleiotropy”?
Decrease in cholesterol that is necessary for the anchoring of small G-proteins
What are the benefits of statin pleiotropy?
Hint, there’s 5
- Effects on endothelial cells - increase eNOS, antioxidant effect
- Anti-platelet effect
- Effects on vascular smooth muscle cells
- Inhibit macrophage accumulation
- Increase plaque stability
What is the main side effect of statin therapy?
Myopathy, aka muscle pains
This can lead to myosotis (muscle spasms) or to rhabdomyolysis (breakdown of skeletal muscle)
What can increase the incidence of myopathy associated w/ stains?
(Hint, it’s a certain drug example)
Gemfibrozil competing for the transport into cells
This causes an increase of circulating statins, which can lead to increase toxicity
How does gemfibrozil affect hepatic metabolism of statins?
Hint, there’s 2 ways
- Competes for CYP2C9 metabolism –> increasing circulating statins
- Inhibits glucuronidation of stains - no breakdown of statins, stay out in circulation
What are the 3 proposed mechanism for statin-induced myopathy?
- Effect on membrane integrity
- Effect on small g-proteins, such as Rho and Rac
- Decreased ubiquinone, though to be involved in energy production
What are the two other adverse effects/contraindications of statins besides for myopathy?
- Hepatotoxicity
2. Pregnancy - avoid statins when pregnant
What is Ezitimibe’s MOA?
Inhibits intestinal uptake of cholesterol by blocking the intestinal receptor for dietary cholesterol - NPC1L1 receptor on the luminal side
What is Ezitimibe’s effect on lipoproteins?
Hint, LDL, TGs, and HDL
Decreased LDLs
Slight decrease in TGs
Very little increase in HDL (~1-2%)
What can Ezetimbe be combined w/?
Ezetimbe and statin (simvastatin)
- knocks out each other’s compensatory mechanism
- decreases cholesterol uptake and synthesis
Uses for Ezetimbe
Hint, there’s 3
- Monotherapy to lower LDL
- Combotherapy w/ a statin
- Sitosterolemia - blocks the inappropriate absorption of plant sterol
Clinical toxicity of Ezetimbe
W/ along - similar to placebo
W/ statin - similar to statins
Ezetimbe drug interaction
Avoid concurrent administration w/ bile acid sequestransts
- inhibits the absorption of Ezetimbe
Bile Acid Sequestrants
Examples and MOA
Examples: cholestyramine, colestipol, colesevelam
MOA: interfering w/ enterohepatic recirculation of bile acids
- binds to bile acids and causes them to not be reabsorbed, and are easily excreted out through feces
Bile Acid Sequestrants effect on the lipid profile
Hint, LDL, TG and HDL levels
Decrease in LDLs
Very small INCREASE in TGs when baseline is high
Small increase in HDL (~5%)
Bile Acid Sequestrants Toxicity
No systemic effects
Can cause GI problems
Bile Acid Sequestrants Drug-Drug Interactions and how to avoid interactions
Interfere w/ the absorption of many drugs
Ex. Digoxin, propranolol, etc.
Should administer 1 hour before or 4-6 hours after bile acid sequestrant
Niacin and its MOA (multiple)
Niacin - a vitamin B complex
MOA:
- to decrease TG and LDL: in adipose to decrease TG lipolysis and enhance activity of hepatic LPL
- to increase HDL: increase plasma levels of ApoA-1 (building block of HLD)
How does Niacin affect the lipid profile?
Hint, LDL, TGs and HDL affected?
WIDESPREAD BENEFIT!
Significant decrease in LDL
Significant decrease in TGs
Significant increase in HDL - the best agent for this
Niacin and toxicity
Hint, there’s 5
- Flushing - typically initial therapy or immediate release
- Hepatotoxicity - usually from sustained release
- Hyperglycemia - caution w/ diabetics
- Increased uric acid - caution w/ gout
- Dyspepsia - upset stomach
PPAR-alpha activators (Fibrates, Fibric acid derivatives)
Examples and how it acts
Examples: Clofibrate, Gemfibrozil, Fenofibrate
How it acts: nuclear receptor/transcription factor, will promote the oxidation of free fatty acids –> leading to decreased FFAs for production of TGs –> decreased TGs
PPAR-alpha activators MOA
Hint, there’s 2
- Promote oxidation of FFA –> upregulate FFA into cell –> primes and modifies FFA –> upregulates enzymes to prove oxidation
- Increase expression and/or activity of lipoprotein lipase –> increase the metabolism of TGs
PPAR-alpha Activators effect on the lipid profile
Hint, LDL, TGs and HDL
Major: decrease ~50% of TGs if baseline is over 400 mg/dL
Decrease VLDL
Might see increase LDL
Might increase HDL
PPAR-alpha activators and their non-lipid anti-atherogenic effects
(Hint, there’s 4)
- Macrophage increasing cholesterol efflux for HLD particles
- Anti-inflammatory effects
- Protective endothelial effects
- Vascular smooth muscle - inhibit proliferation and migration
PPAR-alpha activators toxicity
GI upset
Not used in pregnancy
PPAR-alpha activators and drug-drug interactions
- Statins! - increased incidence of myopathy
2. Potentiates effects of warfarin
What are the not so common dyslipidemic agents?
Hint, there’s 4
- Omega-3 Fatty Acids (aka fish oils)
- Lomitapide
- Mipomersen
- PCSK-9 inhibitors
What are the two main agents in Omega-3 fatty acids?
- Omega-3 fatty acid ethyl esters (EPA and DHA)
2. Icosapent Ethyl (EPA only)
Uses of omega-3 fatty acids
Reduction of TGs
Variable effects on LDL and HDL
Proposed MOA of omega-3 fatty acids
Reduced hepatic synthesis of TGs, increase in oxidation, and increase lipoprotein lipases activity
May also be anti-inflammatory
Toxicity of omega-3 fatty acids
Burping and fishy after tastes
Small incidence of bone pain, and joint pain
Lomitapide and its use
For reduction of LDL in combo w/ diet and stains in pts w/ familial hypercholesterolemia
MOA of Lomitapide
Inhibits microsomal transfer protein - inhibits the synthesis of chylomicrons and VLDL
Toxicity of Lomitapide
Hepatotoxicity
Mipomersen and its use
For combo therapy w/ statins and diet to reduce LDL in pts w/ homozygous familial hypercholesterolemia
MOA of Mipomersen
Antisense oligonucleotide against ApoB100 - decreases production of ApoB100 - decreased LDL cholesterol
Toxicity of Mipomersen
Hint, there’s 3
- Pain at injection site
- Flu-like symptoms
- Liver toxicity
PCSK-9 Inhibitor and MOA
Alirocumab, Evolocumab
Inhibits the normal breakdown process of LDL receptors. Leads to more LDL receptors on the cell membrane, more LDL can go into cell, leading to decreased LDL out in circulation
PCSK-9 Inhibitors on the lipid profile
Hint, LDL, TGs, and HLD
W/ or w/o statin therapy - significant decrease in LDL ~60-70%
Decrease in TGs
Cholesterol, where is it from and what’s its function
Synthesized in the liver and though died
Functions: membrane constituent, steroid precursor, and bile acid formation
