Flashcards in Lipid Disorders Deck (43):
Cholesterol is primarily derived from what?
What is atherosclerosis?
- abnormal deposition of cholesterol in the arteries
VLDL's are the endogenous forms of ____
- primarily chylomicrons, VLDLs as well
- increase pancreatitis
What are some of the other key factors in deposition on artery walls?
- genetic factors
What is the LDL involvement in the generation of atherosclerosis?
- LDL's make their way inside the artery, and from here are able to produce oxidizing products (are able to oxidize)
- from here, they cannot move out of the artery, have to stay here inside the artery
- they send out signals to attract monocytes into the intima
- monocytes are transformed into macrophages and are very efficient into taking up LDL
- increase in the level of foam cells, where cholesterol can be taken up- these foam cells developing a core that allows plaques to form on the artery wall, and these plaques can get so big that they can cause blockage
What is the action of HDL?
- takes cholesterol from the peripheral circulation and takes them back into the proteins that of to the liver
- allows the cholesterol from being excreted into the bile from the liver
- HDL cannot cause the build up of the plaque- it can go into the lymphatic vessels because it is so small, but because LDL is so big it cannot move from inside the arteries to the lymph vessels
What would be recommend to a patient that has no risk factors and has only slightly elevated cholesterol?
- no medication intervention , do NOT give drugs
What are the potential sites to decrease cholesterol?
1. decreasing GI uptake
- decreasing dietary intake
- decreasing reabsorption of bile acids
- decreasing reabsorption of cholesterol
2. decreasing LDL levels
- decreasing VLDL
- increasing LDL receptors
3. decreasing endogenous cholesterol synthesis
What are the non-pharmacological treatment options for lowering cholesterol?
- can increase dietary fibre
- adding in omega 3 fatty acids- will use a reduction in LDL cholesterol levels
What are HMG-CoA reductase inhibitors also known as?
Statins are known as the first choice for most patients with a risk for what?
coronary heart disease
What do statins do?
- decrease LDL levels
- also decrease triglyceride levels
- patients with a coronary artery disease - decreased cardiac morbidity, mortality, reduced incidence of stroke
- benefits seen with initial high or normal cholesterol
What is the mechanism of statins?
- inhibit HMG-CoA reductase, the rate limiting step of cholesterol synthesis
- compensatory increase in LDL receptors
- best if given in the evening- diurnal pattern of cholesterol synthesis
What are the adverse effects of statins?
- well tolerate but contraindicated in pregnancy
- myalgia, muscle weakness
- may increase with cyclosporin, fibrates or niacin
- monitor creatine kinase levels
- increase in plasma aminotransferase >3x in ,2% (symptomatic hepatitis is rare)
- first pass metabolism- CYP3A4 (avoid inhibitors like grapefruits with some statins)
- renal dysfunciton, behavioural and cognitive, diabetes, neuropathy
What is the effect that grapefruit will have on the availability of stains in the body?
there is an INHIBITION of the enzyme (CYP3A4) that metabolizes statins, causing an increase in the amount go medication that is in the body
- the concentration of the statin is increased
Which statins in particular are affected by grapefruit juice?
- atorvastatin and simvastatin
Ezetimibe belongs to what class?
cholesterol absorption inhibitors
Ezetimibe causes inhibition of both ___ and ____ cholesterol absorption
dietary and biliary
(work at the intestinal brush border)
What is the specific protein that ezetimibe works on?
- it inhibits a cholesterol transport protein that is known as NPC1L1
Ezetimibe lowers cholesterol by _____ when used alone, but you can get reflex increase in cholesterol ____
What is the one dangerous part of potentially combining ezetimibe with a statin?
possible greater elevations of transaminases compared to just using statins alone (does allow a lower dose of statin to be used however)
What are the adverse effects associated with using ezetimibe?
- myalgia, hepatitis, rhabdomyolysis, acute pancreatitis
What are the examines of bile acid binding resins?
- cholestyramine (Questran), colestipol (Colestid), colesevelum
What are tile acid binding resins useful for?
- useful in mild to moderate elevated LDL levels
- effective with statins or nicotinic acid in high LDL levels
Are bile acid binding resins absorbed by the gut?
- no, they are not (they are anion exchange resins)
What is the mechanism of action of bile acid binding resins?
- binds bile acids in the intestinal lumen - prevents reabsorption (normally 95% reabsorbed)
- to produce new bile acids, the liver must do what?
-> take up cholesterol (increase LDL receptors and/or synthesize de novo cholesterol)
What are the most common adverse effects associated with bile acid binding resins?
- may increase LDL levels
- decrease absorption of fat soluble vitamins (vitamin K deficiency is a problem)
- nausea, constipation and bloating
- unpleasant taste and texture
- absorption of drugs is altered (positive, negative and neutral) eg. digitalis, thiazides, warfarin and aspirin
Why is ezetimibe beneficial to use with a statin?
- additively lower the level of cholesterol
- ezetimibe decreases cholesterol uptake in the gut, but compensatory increase in cholesterol synthesis in the liver
- HMG-CoA reductase inhibitors blocks the increased synthesis in the liver
What are some of the reasons that there is such a failure to achieve the LDL target concentrations?
- poor adherence to the treatment
- high baseline LDL-concentrations
- high cholesterol diet
- high cholesterol absorption
- variable statin release
- inability to tolerate (higher dose) statins
What are the newest therapies used to lower lipids?
- targeting the LDL receptor for degradation
- inject human monoclonal antibodies to PCSK9 to increase LDL receptors on the liver
- known as evolocumab
What is the role o PCSK9 in the regulation of LDL receptor expression
- LDL particle binds to the LDL receptor in the absence of the PCSKp complex
- LDL receptor recirculates back to the surface
- more LDL receptor on the surface of the liver which will allow the liver to pull in more of the LDL and metabolize it
- this receptor is primarily found on the liver, BUT you can still see muscle weakness with this therapy
What are the potential sites to decrease triglycerides?
- decrease dietary triglycerides
- increase lipoprotein lipase activity
- decrease VLDL secretion from the liver
What is the non-pharmacological approach in decreasing lipids?
- decreasing dietary TG's
- increasing dietary fibre - increasing soluble and insoluble fibre
What are the other uses of dietary fibre?
- increases bulk of the stool
- good for constipation
- decreases colonic cancer
In fenofibrate and gemfibrozil (fibrates) the incidence of death from coronary heart disease, non-fatal MI and stroke was decreased, but what was NOT altered?
- LDL levels were unaltered
Vibrates may ____ triglycerides and may _____ HDL
What is the mechanism of fibrate action?
- increased VLDL clearance (increase lipoprotein lipase activity)
- decreased VLDL secretion
What are the adverse effects of fibrates?
- flu-like: muscle cramps, tenderness, stiff, weak
-- increased myopathy when combined with statins
- avoid in hepatic or renal dysfunction
- may potentiate oral anticoagulants and hypoglycaemia agents
- increases cyclosporine clearance - transplant rejection?
- use with caution if increased risk of biliary tract disease (women, obese patients, First Nation)
Generally describe niacin?
- water soluble vitamin B3 (nicotinic acid) - NOT nicotinamide
- low dose can increase HDL levels (most effective)
- higher dose - decreases VLDL levels - decreases triglycerides and may therefore may decrease LDL levels
What effect does niacin have on men with a previous MI?
- decreases the incidence of a non-fatal MI and at 9 years a decreases mortality rate
What is the mechanism that nicotinic acid has action at?
- decreased hepatic VLDL production - activated Niacin receptors in adipocytes -> decrease in cAMP -> decreases TG hydrolysis -> less fatty acid in circulation to be taken up by the liver and converted to TG and then secreted as VLDL
- increased VLDL clearance (increase lipoprotein lipase activity)
- effective at decreasing triglycerides and increasing high density lipoproteins