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Cardio Exam 2 > Lect 3- Pharm of Dyslipidemia > Flashcards

Lect 3- Pharm of Dyslipidemia Flashcards

1
Q

Dyslipidemia definition

A

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

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2
Q

atherosclerotic plaques can lead to ___

A

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

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3
Q

lipid lowering therapy in CVD

A

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

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4
Q

what is the primary treatment goal for dyslipidemia?

A

reduction of LDL-C levels

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5
Q

what are the other comparably important goals of dyslipidemia treatment?

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

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

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6
Q

where and how much of cholesterol is synthesized daily?

A

about 1 g synthesized in the liver daily

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7
Q

synthesis of cholesterol

A

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

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8
Q

why is cholesterol important in the human body?

A
  • 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
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9
Q

when does serum cholesterol need to be decreased?

A

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)

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10
Q

MOA of statins

A

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

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11
Q

which statins are prodrugs?

A

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

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12
Q

reduction of LDL-C levels in statins

A

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

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13
Q

Statins’ effect on TG levels

A

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
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14
Q

Statins’ effect on HDL-C levels

A

increase HDL-C by approx 7.5%

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15
Q

pleiotropic effects

A

other potential benefits that are independent from primary effect

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16
Q

pleiotropic effects of statins

A
  • 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)
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17
Q

which statins are metabolized by CYP3A4?

A

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)

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18
Q

what’s special about pravastatin?

A

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

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19
Q

what CYP metabolizes fluvastatin?

A

CYP2C9

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20
Q

What drugs are common inhibitors of CYP3A4?

A

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

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21
Q

What drugs are common inducers of CYP3A4?

A

rifampin, efavirenz

*will see less free drug in serum

22
Q

What drug inhibits CYP2C9?

A

GEMFIBROZIL!

so watch out in using with fluvastatin

23
Q

what are the adverse effects of statins?

A

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

24
Q

hepatotox in statins

A

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

25
Q

myopathy in statins

A

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

26
Q

rhabdomyolysis

A

myopathy that progresses to breakdown of muscles

27
Q

cognitive effects of statins

A

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

28
Q

hyperglycemia in statins

A

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

29
Q

risk of adverse effects with statins

A

proportional to plasma statin concentration

so caution with: drug combos, hep/renal dys, perioperative period, elderly, multisystem disease, small body size

30
Q

what is the most common interaction with statins?

A

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

31
Q

why was cerivastatin withdrawn from the market?

A

higher reports of rhabdomyolysis

32
Q

bile acid sequestrants (resins)

A

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

33
Q

MOA of bile-acid sequestrants

A

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

34
Q

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

A

1-2 weeks

Takes time for liver to realized it is being depleted of bile acids

35
Q

effects of bile-acid resins on lipid profile

A

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

36
Q

adverse effects of bile acid resins

A

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

37
Q

niacin (nicotinic acid)

A

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

38
Q

niacin MOA

A

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

39
Q

adverse effects of niacin

A
  • 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
40
Q

fibric acid derivatives: PPARa agonists

A 
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
41
Q

PPARa

A

peroxisome proliferator-activated receptor alpha

42
Q

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

A

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

43
Q

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

A

50% TG reduction

LDL= 10-30% increase

44
Q

caution combo of PPARa agonists and ___

A

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

45
Q

ezetimibe

A

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

46
Q

MOA of ezetimibe

A

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

47
Q

omega-3-acid ethyl esters

A

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

48
Q

omega-3-acid ethyl esters main use

A

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

49
Q

fish oil

A

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

50
Q

targeting PCSK9

A

• 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

Cardio Exam 2 (7 decks)

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