Lipid Disorders and Drugs Flashcards
What are lipoproteins and what determines their density
The lipoproteins are the transporters of cholesterol and triacylglycerols (TAG) in circulation that allow the very hydrophobic lipids to travel in the hydrophilic blood.
The density of the lipoprotein is determined by the TAG: protein ratio; the greater the TAG content, the larger the lipoprotein and the lower the density.
What are chylomicrons
deliver lipids from the intestinal absorption of food to two recipients, our body tissues and the liver
Tagged wuth ApoB-48
Why are ApoCII and ApoE important
ApoCII activates lipoprotein lipase in vascular endothelium, hydrolyzing TG to free fatty acids that diffuse into tissue for energy. ApoCII is shed, and the chylomicron remnant is “supposed to be” absorbed into the liver, which is facilitated by ApoE. This is important, as chylomicrons build up when ApoE is defective.
Function of VLDL
deliver lipids from the liver to the tissues and ultimately becomes LDL. This LDL can either be absorbed back into the liver, or can enter vascular wall macrophages to cause artherosclerosis.
Pathway of VLDL to LDL
What is the role of lipoprotein lipase?
Hydrolyze triglycerides in low-density lipids to free fatty acids that can diffuse into tissues for use as an energy substrate.
What apolipoprotein is required to activate lipoprotein lipase?
ApoCII, which is present in chylomicrons created when fat is absorbed from the intestines, as well as VLDL aka “the liver’s chylomicron”
What is the main function of ApoB?
To mark LDL for uptake by the liver, where it is metabolized, or for uptake by vascular wall macrophages, where it becomes oxidized LDL and contributes to artherosclerosis
What is the only way cholesterol can come out of cells
ApoA-1 is released from the liver and cruises around looking for excess cholesterol it can collect from cells. This is the only way cholesterol can come back out of cholesterol in the dangerous macrophages above.
ApoA-1 knows to target macrophages with excess cholesterol, which carry the ABCA-1 transporter. The purpose of this transporter is bringing free cholesterol out of the macrophage and giving it to ApoA-1 to create HDL3.
What is LCAT
LCAT (lecithin cholesterol acyltransferase) enzyme esterifies the free cholesterol so it can get into the middle of the HDL3 where it’s supposed to be.
Three fates of HDL2
HDL2 can go back to the liver and be recycled back into HDL3 so it can go back out and scavenge more cholesterol from macrophages
Or it can exchange lipids with the less dense and pro-artherogenic lipoproteins by giving them cholesterol and taking back TG. The protein that does this carrying and switching in a 1:1 ratio is called CETP (cholesterol ester transfer protein.) If it does this, the TG get hydrolyzed via hepatic lipase and the HDL2 recycles back into HDL 3 again so it can accept more cholesterol from macrophages.
OR, it can just be catabolized by the liver!
Which lipoproteins are anti-arthrogenic and arthrogenic
HDL is also the only lipoprotein that is anti-artherogenic!!! “ AKA The good cholesterol”
LDL, VLDL, and TG are all artherogenic as they function to bring cholesterol into tissues!! ApoB is required for this process.
Functions of Lipoprtein lipase, LDL receptor, and ApoE
Lipoprotein lipase (LPL): removes triglycerides from chylomicrons. ApoCII is required to activate it, so if there is a problem with ApoC-II, then it will look just like a problem with LPL.
LDL receptor: allows liver to collect LDL from blood for metabolism
ApoE: allows liver to remove chylomicron remnants
What is type 1 hyeprlipidemia
Marked increase in serum triglycerides, in the thousands!
Defect in lipoprotein lipase, so triglycerides are not hydrolyzed from chylomicrons or VLDL effectively for tissue use.
How does type 1 hyeprlipidemia present and what is TX
Present with: eruptive xanthomas, acute pancreatitis!
Treat with fibrates, which have the most activity to decrease triglycerides by activating what lipoprotein lipase does exist/function
What is type 2 hyperlipidemia
Most common familial hyperlipidemia, varied inheritance, can have AR or AD type pedigree
Type 2a = elevated LDL and total chol
Type 2b = elevated LDL, total cholesterol, also elevated TG
Marked increase in serum LDL, usually 350-1,000, some may have some elevation in TG and total cholesterol too but the LDL is what is most impressive
Due to defect in LDL receptor (most common and testable defect) so liver can’t take up LDL
Type 2 hyperlipidemia presentation and Tx
Presents with? Premature CAD or tendon xanthomas, Very high LDL +/- TG elevation on lipid screen
Treat with? Statins or PCSK9 inhibitors if statins fail
Major increased risk for cardiovascular disease!
What is type 3 hyperlipidemia
Elevated TG and LDL in the low 200-300’s
Defect in ApoE is the most testable thing about this, chylo and VLDL remnants can’t be taken up by the liver because of defective ApoE, so remnants build up
Type 3 hyperlipidemia presentation and Tx
Presents with palmar xanthomas (yellow lakes of lipid in the palm creases), xanthelasma, eruptive large xanthomas of elows and knees
Increased cardiovascular risk!
Treat with statins and fibrates
What is type 4 hyeprlipidemia
Elevated triglycerides, not nearly as dramatic as Type 1, like >150
Very common, 1:50 or 1:100 incidence, autosomal dominant
Marked increase in VLDL, which has to be tested for separately (not on a standard lipid panel), cause unknown
Type 4 hyeprlipidemia presentation
Presents with pancreatitis like Type 1, but no skin findings
Cardiac risk unclear
Secondary causes of hyperlipidemia
“Western” diet, Physical inactivity, Obesity aka “The “Unholy Trinity”
Non-insulin-dependent diabetes mellitus (when uncontrolled), metabolic syndrome, Polycystic ovarian syndrome: obesity with glucose intolerance to frank diabetes symptoms and elevated A1C
Hypothyroidism: hoarse voice, cold intolerance, dry skin, fatigue, menstrual irregularities
Cholestatic liver disease (e.g., primary biliary cirrhosis) becase the normal enterohepatic cycling doesn’t work
Nephrotic syndrome, due to loss of regulatory lipoproteins in urine
Drugs (e.g., corticosteroids, protease inhibitors for HIV, immunosuppressants)
Which diets are suggested to treat hyperlipidemia
vegan diets (since cholesterol is only animal-derived products) and the mediterranean diet (although with lower fat intake recommended than the true mediterranean diet.)
Best targets of lipid therapy
- DECREASE TG, LDL, VLDL (pro-artherogenic)
- INCREASE HDL (anti-artherogenic)
Statins examples and MOA
Lovastatin, pravastatin, suvastatin, atorvastatin, simvastatin
Inhibits HMG-CoA reductase step in cholesterol synthesis, the rate limiting step prior to the export from the liver
Statins adverse effects
Elevation in hepatic transaminases, usually dose dependent and reverses with stopping the drug
Myalgias (muscle pain and soreness) which is a frequently reported symptom; patients reporting muscle soreness should have a serum creatine phosphokinase (CPK) level checked to make sure they don’t have:
True myositis or rhabdomyolysis, with elevations of serum creatine phosphokinase (CPK) above normal is rare, but a notable and dangerous side effect. The risk of this is increased with interactions with certain drugs viCYP450-3A4.
Major drug interactions: protease inhibitors, cyclosporine, antifungal azoles, verapamil and amiodarone
What changes in a serum lipid profile will likely occur in patients started on a statin drug?
Decrease in LDL, the pro-artherogenic cholesterol that can go into vessel macrophages and contribute to artherosclerosis.
Bile acid resins examples and MOA
cholestyramine, cholestipol
Block intestinal reabsorption of bile acids, liver uses LDL cholesterol up to make more
Bind and drag bile acids from the terminal ileum lumen out with stool, decreasing enterohepatic bile acid recycling.
This creates a lack of feedback inhibition on the transcriptional regulation of bile acid production, keeping the liver pumping out bile acids (made from cholesterol) and also upregulating the liver’s removal of LDL and VLDL to keep hepatic cholesterol supplies sufficient to meet the demand
Liver uses cholesterol to make more bile acids.
What change in the serum lipid profile is expected with the use of bile acid binding resins?
Decrease in LDL
Bile acid resins adverse effects
It’s like pooping styrofoam beads, which causes “GI distress,” and the beads can absorb other drugs and ADEK vitamins
Ezetimibe MOA
prevents absorption of cholesterol from food in intestine by blocking NPC1L1-mediated enterocyte absorption of cholesterol.
What is the primary change expected on the lipid panel when a patient is given ezetimibe?
Decrease in LDL
Fibrates examples and MOA
clofibrate, fenofibrate, gemfibrozil
Increase lipoprotein lipase activity, increasing clearance of triglycerides and mildly increasing synthesis of HDL.
In addition, fibrates activate peroxisome proliferator-activated receptors (PPARs), leading to an increase in HDL-C associated apolipoprotein AI and AII production
Fibric acid derivatives (fibrates) enhance lipoprotein lipase activity and hepatic bile secretion and reduce hepatic triglyceride production
Fibrates indication
This is the drug of choice for hypertriglyceridemia as their effect to lower triglycerides is the most marked of all lipid lowering agents.
They are indicated for Type 1 hyperlipidemia with its very very high triglycerides
They are not particularly effective at lowering LDL and are not used for this purpose.
Fibrates adverse effects
Myopathy, gallstones, warfarin tox
What are the expected effects of fibrate drugs on the lipid profile?
Decrease triglycerides and increase HDL!
Niacin (B3) MOA
Inhibits hormone-sensitive lipase, reducing VLDL synthesis
Decreases lipolysis by inhibition of hormone-sensitive lipase, which decreases the free fatty acids in the blood
Results in decreased triglyceride synthesis and decreased serum TG
Since the major TG carriers are (artherogenic) LDL and VLDL, these bad lipids also DECREASE.
Niacin adverse affects
FLUSHING of the face and feeling hot in the head and face due to stimulation of prostaglandins by the niacin. This can be decreased by taking with their daily aspirin dose or another NSAID or taking it at night, and eventually gets better, but patients need to be counseled about that at the time of prescribing.
Niacin can also cause gout flares, so gout is a contraindication, and hyperglycemia, so uncontrolled diabetes is a contraindication. There is no increased benefit in cardiovascular endpoints with this drug when added to statin therapy.
What is the expected result on the lipid profile when a patient is treated with niacin?
Increased HDL, the anti-arthrogenic “good cholesterol” that carries out revers transport (more than any other drug) and decreased LDL and VLDL
PCSK9 inhibitors (Proprotein convertase Subtilisin-like Kexin type 9) examples and MOA
alirocumab and evolocumab
These drugs prevent the LDL receptor breakdown that results from feedback inhibition, resulting in the liver removing more LDL from the bloodstream.
PCSK9 is a cofactor in the serum that normally binds to the LDL receptor and leads to degradation of the LDL receptor.
Less LDL receptors on hepatocytes means more circulating LDL = BAD.
When you inhibit PCSK9, LDL receptors last longer on the surface of the hepatocyte, and so they remove more circulating LDL from the blood.
PCKS9 inhibitors administration and benefit
It is given as an injection 1 to 2 times per month leads to 60% reduction in LDL (on top of statin reduction) . THIS IS AN AMAZING AMOUNT OF REDUCTION, guys. This is the only drug that shows a clear additional decrease in cardiovascular endpoints beyond that seen with statin therapy.
PCSK9 inhibitors adverse effects
Myalgias, delirium, dementia
Tx for familial hyperlipidemias
A. Diet and Exercise for everyone!
B. Elevated chylomicrons and thus TG (FH type I) - Diet management with an extremely low fat diet and fibrates
C. For elevated LDL and total cholesterol (FH type IIa) - all agents except fibrates and niacin. Statins are first choice.
D. For elevated LDL cholesterol and TG (FH type IIb) - same as above, except now that TAG is also a problem, we can also add fibrates and niacin!
E. For elevated VLDL, TG (Type IV) - treat the underlying metabolic disorder if present, and fibrates again!
