4. Olah - Dyslipidemias Flashcards by Julie Amos

TGs, from where and functions

Trimester of glycerol and fatty acid
Obtained from biosynthesis and diet
Functions: energy source and storage

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Lipoproteins function

Activate enzymes, receptors and transporters

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What is the rate limiting step in cholesterol synthesis?

HMC-CoA Reductase

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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

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What is the benefit of HDLs

Anti-atherogenic effects from the role in Reverse Cholesterol Transport

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What are HDL’s anti-atherogenic effects?

Hint, there’s 5

Antioxidant
Endothelial cell protectant
Anti-inflammatory
Anti-platelet and anticoagulant
Profibrinolytic

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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)

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HMG-CoA Reductase Inhibitors are also known as…

Statins

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MOA of Statins

Reversible competitive inhibitors of HMG-CoA Reductase - primarily in hepatocytes

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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

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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

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What is stain “pleiotropy”?

Decrease in cholesterol that is necessary for the anchoring of small G-proteins

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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

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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)

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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

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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

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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

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What are the two other adverse effects/contraindications of statins besides for myopathy?

Hepatotoxicity

2. Pregnancy - avoid statins when pregnant

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What is Ezitimibe’s MOA?

Inhibits intestinal uptake of cholesterol by blocking the intestinal receptor for dietary cholesterol - NPC1L1 receptor on the luminal side

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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%)

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What can Ezetimbe be combined w/?

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Ezetimbe and statin (simvastatin)

knocks out each other’s compensatory mechanism
decreases cholesterol uptake and synthesis

Uses for Ezetimbe

Hint, there’s 3

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Monotherapy to lower LDL
Combotherapy w/ a statin
Sitosterolemia - blocks the inappropriate absorption of plant sterol

Clinical toxicity of Ezetimbe

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W/ along - similar to placebo

W/ statin - similar to statins

Ezetimbe drug interaction

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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

1. Flushing - typically initial therapy or immediate release 2. Hepatotoxicity - usually from sustained release 3. Hyperglycemia - caution w/ diabetics 4. Increased uric acid - caution w/ gout 5. 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

1. Promote oxidation of FFA --> upregulate FFA into cell --> primes and modifies FFA --> upregulates enzymes to prove oxidation 2. 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)

1. Macrophage increasing cholesterol efflux for HLD particles 2. Anti-inflammatory effects 3. Protective endothelial effects 4. Vascular smooth muscle - inhibit proliferation and migration

PPAR-alpha activators toxicity

GI upset | Not used in pregnancy

PPAR-alpha activators and drug-drug interactions

1. Statins! - increased incidence of myopathy | 2. Potentiates effects of warfarin

What are the not so common dyslipidemic agents? | Hint, there's 4

1. Omega-3 Fatty Acids (aka fish oils) 2. Lomitapide 3. Mipomersen 4. PCSK-9 inhibitors

What are the two main agents in Omega-3 fatty acids?

1. 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

1. Pain at injection site 2. Flu-like symptoms 3. 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

4. Olah - Dyslipidemias Flashcards

(51 cards)