Lect 3- Pharm of Dyslipidemia

Question 1

Dyslipidemia definition

Answer 1

includes hypercholesterolemia/ TGemia and low levels of HDL-C
major cause of increased atherogenic risk and atherosclerosis-assoc conditions
takes time to develop atherosclerotic plaques

Question 2

atherosclerotic plaques can lead to ___

Answer 2

ischemic heart disease (IHD)
cerebrovascular disease (CVD)
peripheral vascular disease (PVD)

Question 3

lipid lowering therapy in CVD

Answer 3

30-40% reduction of fatal/non-fatal CHD events and stroke (since dyslipidemia is a risk factor for CVD)

Question 4

what is the primary treatment goal for dyslipidemia?

Answer 4

reduction of LDL-C levels

Question 5

what are the other comparably important goals of dyslipidemia treatment?

Answer 5

• elevation of HDL-C (independent of LDL-C levels)

* reduction of TG levels (b/c high TG levels can cause acute pancreatitis)

Question 6

where and how much of cholesterol is synthesized daily?

Answer 6

about 1 g synthesized in the liver daily

Question 7

synthesis of cholesterol

Answer 7

• Starts with Acetyl CoA → HMG-CoA → mevalonic acid → cholesterol
○ HMGCoA reductase is rate limiting step!

Question 8

why is cholesterol important in the human body?

Answer 8

• biosynthesis of steroid hormones
• part of cell membranes
• biosynthesis of bile acids
• absorption of dietary fats and lipid-soluble vitamins from GI tract
• transport of fats from liver to tissues

Question 9

when does serum cholesterol need to be decreased?

Answer 9

when it exceeds normal amounts!!
• Will be bad if we completely deplete our body of cholesterol
○ Want to maintain normal levels (not completely get rid of it)

Question 10

MOA of statins

Answer 10

competitively inhibit HMG-CoA reductase (rate limiting step of chol biosynthesis)
• Structurally very similar to HMG CoA (Can fool the reductase and bind to it and shut down its function → will not convert HMGCoA into mevalonic acid) → increased synthesis of LDL receptors in hepatocytes → increased removal of LDL from blood → reduction of LDL-C levels in plasma

Question 11

which statins are prodrugs?

Answer 11

lovastatin and simvastatin (closed ring system that has to be opened up)
HOWEVER they are INACTIVATED by CYP3A4 enzyme

Question 12

reduction of LDL-C levels in statins

Answer 12

dose dependent
• If you give a low dose, reduce little
• High dose, reduce LDL a lot

Question 13

Statins’ effect on TG levels

Answer 13

reduced chol in hepatocytes → reduced synthesis of VLDL in liver → reduction of TG levels that is dependent on initial levels of TGs

• *TG levels >250= 35-45% reduction (with max dose)
• *TG levels <250= up to 25% reduction

Question 14

Statins’ effect on HDL-C levels

Answer 14

increase HDL-C by approx 7.5%

Question 15

pleiotropic effects

Answer 15

other potential benefits that are independent from primary effect

Question 16

pleiotropic effects of statins

Answer 16

• improvement of endothelial function and enhanced prod of NO
• down-regulation of AT1 receptor upon chronic use
• increased plaque stability (inhibit smooth muscle cell migration and monocyte infiltration)
• anti-inflammatory effect (reduction of C-reactive protein)
• antioxidant effect (inhibition of lipoprotein oxidation)
• anti-plt effect (reduce plt aggregation)

Question 17

which statins are metabolized by CYP3A4?

Answer 17

atorvastatin, lovastatin, simvastatin
(Lovastatin and simvastatin do not need CYP to be metabolized to active form (there’s a diff enzyme that converts the prodrug to active form) but they are INACTIVATED by CYP3A4)

Question 18

what’s special about pravastatin?

Answer 18

non-CYP metabolizing drug so you don’t have to worry about as many drug interactions
pretty long half-life compared to all other statins

Question 19

what CYP metabolizes fluvastatin?

Answer 19

CYP2C9

Question 20

What drugs are common inhibitors of CYP3A4?

Answer 20

clarithromycin, erythromycin, itraconazole, ketoconazole, grapefruit juice, HIV protease inhibitors
*will see more free drug in serum

Question 21

What drugs are common inducers of CYP3A4?

Answer 21

rifampin, efavirenz

*will see less free drug in serum

Question 22

What drug inhibits CYP2C9?

Answer 22

GEMFIBROZIL!

so watch out in using with fluvastatin

Question 23

what are the adverse effects of statins?

Answer 23

hepatotoxicity, myopathy/ rhabdomyolysis, cognitive effects, hyperglycemia, falsely lower the serum TSH levels

Question 24

hepatotox in statins

Answer 24

need for routine monitoring of liver enzymes has been removed due to insufficient evidence

Question 25

myopathy in statins

Answer 25

elevation of creatinine-kinase (CK) levels >10X of upper normal limit

Question 26

rhabdomyolysis

Answer 26

myopathy that progresses to breakdown of muscles

Question 27

cognitive effects of statins

Answer 27

generally non-serious and reversible with D/C memory loss, confusion, etc more common in >50 yo pts NOT dose dependent

Question 28

hyperglycemia in statins

Answer 28

clinical evidence for increased blood glucose but statin therapy is beneficial in diabetic pts for CV events Need to do better at managing glucose levels in DM pts but overall statins are beneficial

Question 29

risk of adverse effects with statins

Answer 29

proportional to plasma statin concentration | so caution with: drug combos, hep/renal dys, perioperative period, elderly, multisystem disease, small body size

Question 30

what is the most common interaction with statins?

Answer 30

with gemfibrozil gem inhibits uptake of active hydroxy acid forms of statins into hepatocytes & their glucuronidation --> may double the plasma conc of statins gem also inhibits CYP2C9

Question 31

why was cerivastatin withdrawn from the market?

Answer 31

higher reports of rhabdomyolysis

Question 32

bile acid sequestrants (resins)

Answer 32

cholestyramine, colestipol, colesevelam prob the safest as they are not absorbed in the intestine can be used in kids

Question 33

MOA of bile-acid sequestrants

Answer 33

chol is the precursor of bile acids!! → (+) charged resins bind to (-) charged bile acids → become large macromolecules → cannot be absorbed in the intestines → increased elimination of bile acids → increased hepatic synthesis of bile acids → decreased hepatic chol → increase LDL-R and increased clearance of LDL → reduction of plasma LDL

Question 34

when will you see reduction in LDL-C levels with bile acid sequestrants?

Answer 34

1-2 weeks | Takes time for liver to realized it is being depleted of bile acids

Question 35

effects of bile-acid resins on lipid profile

Answer 35

reduction in chol content in liver will make the liver try to increase biosynthesis of cholesterol as a compensatory mechanism so it is effective to use these drugs in combo with statins hyperTGemia (b/c of altered bile-acid prod) elevation of HDL-C levels

Question 36

adverse effects of bile acid resins

Answer 36

hyperTGemia can interfere with absorption of other drugs (sterols, acidic drugs, fat-soluble vitamins) constipation (since they are bulky drugs)

Question 37

niacin (nicotinic acid)

Answer 37

one of the oldest drugs for dyslipidemia treatment **best agent for increasing HDLs B-vitamins= precursors of NAD and NADP ONLY NIACIN IN MUCH HIGHER CONCENTRATION HAS LIPID LOWERING EFFECT

Question 38

niacin MOA

Answer 38

niacin binds to specific receptors in the adipocytes → reduction of cAMP → decreased lipolysis of TGs → decreased transport of FAs to liver → decreased hepatic TG synthesis → decreased prod of VLDL & reduction of LDL levels → elevation of HDL levels b/c of reduced hepatic clearance of ApoA-1

Question 39

adverse effects of niacin

Answer 39

* flushing and assoc pruritus * dyspepsia * *hepatotoxicity= 50% or more reduction of LDL-C is a sign of niacin toxicity! * insulin resistance (caution in diabetic pts) * *elevation of uric acid levels → reactivation of gout

Question 40

fibric acid derivatives: PPARa agonists

Answer 40

``` clofibrate, gemfibrozil, fenofibrate reduction of TG levels elevation of HDL-C levels drugs of choice for treating severe hyperTGemia and chylomicronemia syndrome LOOK AT MOA ON SLIDE ```

Question 41

PPARa

Answer 41

peroxisome proliferator-activated receptor alpha

Question 42

PPARa agonists effect on lipid profile if TG's <400

Answer 42

up to 50% decrease in TG approx 15% increase in HDL-C LDL unchanged/ decreased

Question 43

PPARa agonists effect on lipid profile if TG's 400-1000

Answer 43

50% TG reduction | LDL= 10-30% increase

Question 44

caution combo of PPARa agonists and ___

Answer 44

oral anticoagulants: decreased binding to albumin= higher circ doses of anticoags statins w/ gemfibrozil

Question 45

ezetimibe

Answer 45

dietary chol uptake inhibitor= inhibits chol absorption in the small intestine → stimulates synthesis of chol in liver (as compensatory mech) does not affect intestinal TG absorption

Question 46

MOA of ezetimibe

Answer 46

reduction of intestinal chol absorption → decreased chylomicron formation → increased expression of LDL receptors in hepatocytes → increased clearance of LDL-C → 15-20% LDL reduction, 5% TG reduction, 1-2% HDL-C increase

Question 47

omega-3-acid ethyl esters

Answer 47

Lovaza/ Omacor= mix of omega-3-acid ethyl esters, mostly EPA and DHA Vascepa (icosapent)= EPA Fish oil

Question 48

omega-3-acid ethyl esters main use

Answer 48

treatment of hyperTGemia (>500) not combined with statins **evidence that Lovaza can increase LDL-C levels whereas Vascepa can decrease LDL-C levels

Question 49

fish oil

Answer 49

large daily quantities needed side effects= fish burps risks= mercury & other heavy metals, hypomania/mania!

Question 50

targeting PCSK9

Answer 50

• Protein that binds to LDL receptors and the receptor is sequestered and degraded ○ Once that happens a new LDL receptor must be made from scratch ○ So we want to keep this drug away so we will have greater number of LDL receptors to effectively clear away LDL