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Flashcards in Drugs for Lipoprotein issues Deck (57):

Relationship between LDL-C levels and relative risk for CHD

-data suggests that for every 30mg/dL change in LDL-C, the RR of CHD is changed in proportion by about 30%


All adults of what age should have a fasting lipid screen? What 4 things should it include?

->20 -TGs, total cholesterol, HDL cholesterol. LDL cholesterol (usually calculated)


Evolution of lipid management guidelines

-increasing aggressiveness of cholesterol-lowering therapy and now analyze lipid panel more thoroughly


Primary and secondary goals of lipid therapy

-primary therapeutic target is a reduction in LDL cholesterol to an appropriate level -decreasing TGs and non-HDL (if elevated) or raising HDL (if reduced) are secondary goals


LDL-Cholesterol Goals


Classification of fasting plasma TG levels

normal <150

Borderline High: 150-200


Very high 500


Non-HDL cholesterol represents all ______ lipid particles. How is it calculated and what is the target?

-atherogenic: VLDL, VLDL remnant, IDL, LDL, dense LDL -Non-HDL: total cholesterol- HDL -target is 30 mg/dL higher than LDL-C target


Definition of low HDL-C

-<50 in premenopausal women; <40 in men


Therapeutic Lifestyle Changes (TLC) for lipid disorders

-diet management -aerobic exercise -weight loss -avoidance/moderation in alcohol intake


2 main categories of drugs used in the rx of lipid disorders

-reduced LDL-C -treat TG-HDL axis (tend to be inversely related)


3 classes of drugs used to reduce LDL-C

-HMG CoA reductase inhibitors (statins) -Cholesterol absorption inhbitors (CAI; ezetimibe) -Bile acid sequestrants (BAS)


Why target HMG CoA reductase?

-rate limiting step in cholesterol formation


6 HMG CoA Reductase Inhibitors

1. lovastatin (mevacor) 2. Simvastatin (Zocor) 3. Pravastatin (Pravachol) 4. Atorvastatin (Lipitor) 5. Fluvastatin (lescol) 6. Rosuvastatin (crestor)


Statins mechanism of action

-have an appendage that mimics HMG CoA that is recognized as a pseudosubstrate. -binding of the drug inhibits binding of the true substrate -Competitive inhibitor (reversible) but the inhibitors have >> affinity for the enzyme


How does statins cause reduction in LDL-C?

-LDLRs on hepatic cells are regulated by intracellular levels of cholesterol. -so blocking cholesterol synthesis causes an increase in LDLR and uptake from the blood, decreasing LDL levels!! Main mechanism! -HMG CoA Reductase expression is also increased.


The Rule of 6%

-in general, each doubling of statin dose produces approximately a 6% decrease in LDL-C, but biggest decrease in first dose! -ex: atorvastatin 10/80 dose is 37% reduction at 10, 43% at 20, 49% at 40 and 55% at 80.


The more you reduce a patient's LDL, the more you reduce event rate. However, even if LDL is below 50, some will still have risk of recurrent events. What does this tell us?

-LDL is not the only picture; we need to treat beyond LDL reduction -22% reduction per 40 mg/dL lower LDL-C


_______ are the first line therapy for LDL-C reduction



Adverse effects of statins

1. elevated hepatic transaminases 2. muscle-related adverse effects!! most important reason for discontinuation! Myalgias, myopathy, rhabdomyolysis


Myalgia vs myopathy vs rhabdomyolysis

1. myalgia: msucle ache or weakness without CK elevation 2. muscle symptoms with increased CK levels > 10 ULN^2 3. Rhabdomyolysis: muscle sxs with marked CK elevation (>10) and with creatinine elevation (usually with brown urine and urinary myoglobin)


Factors that increase risk of statin-induced myopathy

1. pt characteristics: age, female gender, frailty/low body weight, renal insufficiency, hepatic dysfunction, hypothyroidism, diet (grapefruit juice), polypharmacy 2. statin properties: high systemic exposure, lipophilicity, high bioavailability, limited protein binding, potential for drug-drug interactions metabolized by CYP3A4


When do doctors use cholesterol absorption inhibitors or bile acid sequestrants?

-when statin intolerant pt or need further LDL


The small intestine plays a role in cholesterol balance. Where does the cholesterol come from?

-25% diet -75% biliary ~50% absorbed


Plasma cholesterol levels depend on balance of ______ and _______.

-cholesterol production and intestinal absorption



-cholesterol absorption inhibitor -localizes and acts at the brush border of the small intestine, where it inhibits the absorption of cholesterol by binding to and inhibiting the cholesterol transporter NPC1L1


Why are CAIs such a good idea?

-they not only block uptake, but by doing so, decrease hepatic cholesterol stores which results in upregulation of LDLRs to remove even more from the blood -work especially well with statins which will block the body's response to CAIs to just make more Cholesterol


Efficacy of Ezetimibe

-reduces LDL-C by 18-20% as monotherapy or in combo with a statin -minimal effects on TG or HDL-C -not yet shown to reduce CV events


Primary indication for ezetimibe and adverse effects

-indications: add to statin therapy to achieve LDL-C goal, statin intolerant patients -adverse: elevated transaminases


Bile Acid Sequestrants aka resins mechanism of action

-they are large MW, insoluble anion exchange resins -bind bile acids in intestine to prevent their recycling -causes liver to use more cholesterol to make more bile salts!


3 types of BAS

-cholestyramine -colestipol -colesevelam


Efficacy of BAS

-reduced LDL-C by 15-25% as monotherapy or in combo with statin -minimal effects on HDL-C; can raise TG levels -shown in 1 trial to reduce MI


Primary indications for BAS

-add to statin therapy to achieve LDL goal -statin intolerant pts


Adverse effects of BAS

-not absorbed systemicaly and therefore lack toxicity -can result in constipation, bloating, flatulance, heartburn, nausea -can interfere with absorption of other drugs -can raise TG levels


Hepatic influence of all 3 classes of LDL lowering meds

-all cause an increase in intrahepatic cholesterol and therefore an increase in LDLR to remove more from blood -they all converge on the hepatic LDL R


What do you do for patients who cannot achieve LDL-C goals with existing drug therapies?

-LDL apheresis


Potential approach of therapy with PCSK9

-inhibition of PCSK9 could lower LDL-C and CHD by keeping more LDLR present -antibodies, small mlcs?


ApoB target

-antisense oligonucleotide to ApoB to reduce hepatic VLDL secretion for patients who lack LDLR -like being homozygous FH


MTP target

-MTP inhibition: MTP loads TG onto ApoB to form VLDL -would reduce VLDL secretion small mlc inhibitor: Lomitapide


Potential issues of ApoB and MTP targets

-fatty liver since no way to export TGs


How are TGs and HDL-C metabolism closely linked?

-HDL takes TGs from VLDL and gives CE via CETP enzyme -tend to be inversely related


3 classes of drugs meant to treat the TG-HDL axis

-fibrates: fibric acid derivatives -Omega 3 fatty acids (fish oils) -Nicotinic acid (niacin)--not used much any more


3 examples of fibrates

-clofibrate -gemfibrozil -fenofibrate


Fibrates mechanism of action

-activate the nuclear receptor PPARa in liver and peripheral tissues to affect multiple aspects of lipid metabolism


Effects of fibrates

-increase ApoA and ABCA1 to increase HDL -decrease ApoC to decrease VLDL -increase VLDL clearance -decrease LDL particles -increase LPL activity


Fibrates efficacy

-decrease TG levels 20-50% -increase HDL 5-20% -mixed results on CV outcomes, but maybe good for those with elevated TG levels


Primary Indications for fibrates

-severe hypertriglyceridemia (>500) to prevent pancreatitis -adjunct to statis in pts with persistently elevated TG and to possibly reduce CV risk


Fibrates adverse effects

-typically well tolerated -increase liver transaminases infrequently -may cause myalgia/myopathy esp if used with statins -may potentiate action of oral anticoagulants -statin blood levels increase with gemfibrozil


Omega 3 fatty acids (fish oils)

-EPA and DHA are primary ones -decrease TG 30-50% in those with hyperTG and raise HDL by 10% -indicated for use an adjunct to diet for reducing very high levels of TG >500


Nicotinic acid (niacin)

-aka vitamin B3 -efficacious hypolipidemic agent at high dosage, much higher than whats needed as vitamin


Niacin MOA

-acts on adipose to reduce FFA release and flux to liver so TGs cannot be assembled or formed into VLDL -keep FFA out of blood and lower VLDL production and therefore LDL too -CETP helps transfer and makes more HDL


Niacin efficacy

-increase HDL -decrease TG -decrease LDL -decrease Lpa


Niacin adverse effects

-flushing in 88% taking extended-release niacin -hyperuricemia (gout) made worse -hepatotoxicity at high doses -hypophosphatemia and reduced platelets = rare


Contraindications of niacin

-relatively contraindicated in pts with T2DM bc may exacerbate insulin resistance


Role of CETP and what if deficient in it?

-transfer cholesterol out of HDL -markedly increase HDL levels if deficient


Effect of drugs used to inhibit CETP

-some were bad others increased HDL by 130%!!! and decreased LDL by 40%!!! -but effect of rising HDL hasnt been shown to decrease a patient's CV risk


HDL flux hypothesis

-promoting cholesterol efflux and reverse cholesterol transport (from macrophages in plaques) will reduce CV events -not sure if it works


Lipid management in high-risk patients

-1. target LDL <70 or lower with high dose statin and combinations as needed. Non HDL is secondary target 2. if HDL is low, do lifestyle intervention, enroll in trials of new HDL therapies