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1

Dyslididemia is a major cause of

increased atherogenic risk and atherosclerosis-associated conditions (IHD, CVD, PVD)

2

lipid lowering is very beneficial for the treatment of

CVD

3

1% reduction in total cholesterol->

2% reduction in CHD events

4

many clinical trials have should that avg dyslipidemic therapy results in

30-40% reduction of fatal/non-fatal CHD events & stroke

5

primary goal of dyslipidemia therapy

reduction of LDL levels

6

comparably important dyslipidemia therapy goals

- elevation in HDL independent of LDL
- reduced CHD events 20-35% in pts with low HDL & avg LDL
- reduction of TGs

7

severe hypertriglyceridemia->

(>1000mg/dL)-> pancreatitis

8

moderate elevation of triglycerides ->

(150-400mg/dL)-> part of metabolic syndrome

9

1% reduction in LDL->

1% reduction in CHD events

10

1% increase in HDL->

3% reduction in CHD events

11

how much cholesterol is biosynthesized in the body daily?

~1000mg

12

cholesterol is important

- synthesis of steroid hormones
- cell membranes
- synthesis of bile acids
- absorption of fats & lipid-soluble vitamins
- transport of fats from liver to tissues

13

statins are

competitive inhibitors of HMG-CoA reductase-> blocks synthesis of cholesterol

14

HMG-CoA

3-hydroxy-3- methylglutaryl coenzyme A

15

statins block the conversion of HMG-CoA to

mevalonate

16

blocked synthesis of cholesterol in the liver leads to

-increased synthesis of LDL receptors in hepatocytes
- increased removal of LDL from blood
- reduction of LDL levels in plasma

17

reduction of LDL levels is

dose dependent

18

TG levels >250mg/dL

-> 35-45% reduction (with max doses)

19

TG levels <250mg/dL

-> up to 25% reduction

20

statins also increase HDL levels by

~7.5%

21

how do statins reduce TG levels

1. blocked synthesis of cholesterol in liver-> increased synthesis of LDL receptors in liver-> increased removal of LDL-precursors (IDL & VLDL) from blood-> reduced TG
2. reduce cholesterol in hepatocytes-> reduced synthesis of VLDL in the liver-> reduced TG

22

main effect of statins

reduction of LDL & improvement of the lipid profile

23

pleiotropic effects of statins

- improvement of endothelial function & enhanced NO production
- down-regulation of AT1 receptor expression
-increased plaque stability by inhibiting vascular SMC proliferation & migration & inhibition of monocyte infiltration into the artery wall

24

pleiotropic effects of statins are independent of

lipid-lowering effects

25

pleiotropic effects of statins are

class specific rather than individual drug specific- effects

26

NO is a potent

vasodilator

27

down regulation of AT1 receptors leads to

- decreased vasocontriction, increase renin & decrease aldosterone

28

statins are being considered for use in

arrhythmias
preoperative prophylaxis
CNS autoimmune disease
epilepsy
sepsis
cancer
inflammatory diseases
thyroid disorders

29

what are the 3 major pleiotropic effects of statins?

- anti-inflammatory effect (reduce C-reactive protein)
- antioxidant effect (inhibit lipoprotein oxidation & peroxidation)
- anti-platelet effect (reduce platelet aggregation)

30

PK of statins

- most have poor bioavailability
- most have large first pass effect
- > 70% of statins & metabolites are excreted by liver & eliminated in feces

31

which statins are prodrugs

lovastatin & simvastatin
- need to be metabolized (non-CYP_

32

which statins are metabolized by CYP3A4

atorvastatin, lovastatin & simvastatin
- watch for drug interaction

33

which statins are not really metabolized by CYP enzymes?

rosuvastatin
pravastatin - not at all
pitavastatin

34

which statins are significantly metabolized by CYP2C9?

fluvastatin

35

which statin has the longest half life

pravastatin

36

inhibitors of CYP3A4

grapefruit juice
clarithromycin, erythromycin, itraconazole, ketoconazole, HIV protease inhibitors

37

inducers of CYP3A4

rifampin
efavirenz

38

inhibitor of CYP2C9

gemfibrozil

39

increased risk of adverse event risk with clarithromycin and

statins NOT metabolized by CYP3A4 (rosuvastatin, pravastatin, or fluvastatin)

40

need for periodic monitoring of liver enzymes when on statins

has been REMOVED in 2012
- elevated liver enzymes resolve spontaneously in most cases
- routine LFT do not detect or prevent statin-induced heptotoxicity

41

myopathy definition

breakdown of muscle fibers

42

myopathy & statins

- major adverse effect, rarely developing to rhabdomylysis
- elevation of creatine-kinase (CK) levels >10 of upper normal limit- indicator of statin-induced rhabdomyolysis

43

cognitive effects of statins

- generally non-serious & reversible, more common >50yo
- impairment is typically reversed upon discontinuation of statin therapy
- is NOT dose-dependent

44

hyperglycemia & statins

- clinical evidence for increased blood glucose & HgbA1C levels
- statin therapy is beneficial in DM

45

thyrotropin (TSH) concentrations & statins

may falsely lower serum TSH levels w/out altering thyroid function

46

the risk of adverse effects with statins is proportional to

plasma statin concentration

47

caution in statin use with:

drug combinations
hepatic/renal dysfunction
perioperative period
advanced age
multisystem disease
small body size

48

most common interaction with statins

gemfibrozil
~38%

49

gemfibrozil

- inhibits uptake of active hydroxyl acid forms of statins into hepatocytes & their glucuronidation-> may double the plasma conc of statins**
- also inhibits CYP2C9(fluvastatin)

50

main statins

atorvastatin
lovastatin
simvastatin
pravastatin
pitavastatin
fluvastatin
rosuvastatin

51

main ADE

hepatotoxicity
myopathy
cognitive effects
decreased TSH levels

52

bile acid sequestrants (resins)

cholestyramine
colestipol
colesevlam

53

bile acid sequestrants are not absorbed

from the intestines

54

cholesterol is the precursor of

bile acids

55

bile acid sequestrants can reduce LDL

up to 25%

56

what is usually second line if statin monotherapy is not sufficient?

bile acid sequestrants

57

what can be used in 11-20 yo patients?

bile acid sequestrants

58

bile acid sequestrant MOA

- resins are highly + and bind - bile acids. being large, they are NOT absorbed in the intestines & are eliminated in feces-> increase hepatic synthesis of bile-acids (cholesterol is used!)-> decreased hepatic cholesterol-> increased LDL receptors & clearance of LDL-> reduced plasma LDL

59

effects of resins on lipid profile

- reduce LDL (max red. in 1-2 wks)
- reduce cholesterol content in the liver stimulates its biosynthesis by up-regulating HMG-CoA reductase, so combining with statins is very beneficial
- HYPER-TG: bc of altered bile acid production
- elevated HDL by 4-5%

60

ADE of resins

hyper-triglyceridemia
- can interfere with absorption of other drug: sterols (digitalis), acidic drugs, fat-soluble vitamins
- may cause constipation (bulky)

61

niacin is a

B vitamin & is a precursor of nicotinamide adenine dinucleotide (NAD) & NAD-P

62

niacin is the best agent for

increasing HDL (up to 30-40%) in 4-7 days

63

niacin effect on LDL & TGs

dec. LDL 20-30%
dec. TG 35-45%

64

niacin MOA

- niacin + specific receptors in adipocytes->reduction of cAMP
- decreased lipolysis of TG
- decreased transport of FFA to liver
- decreased hepatic TG synthesis
- decreased production of VLDL & reduction of LDL
- elevation of HDL levels in the result of reduced hepatic clearance of apaA-I

65

niacin PK

- complete absorption
- at LOW doses: metabolized into nicotinuric acid & excreted in urin
- HIGH doses: greater amount excreted unchanged

66

Niacin ADE

flushing & associated pruritis
dyspepsia
hepatotoxicity- elevated AST/ALT & hyperglycemia
insulin resistance
- elevated urinc acid->gout

67

sign of niacin toxicity

50% or more reduction of LDL

68

fibric acid derivatives

clofibrate
gemfibrozil
fenofibrate

69

fibric acid derivatives are

PPAR (peroxisome proliferator-activated receptor) alpha agonists

70

fibric acid derivatives MOA

- increase FA oxidation
- increase lipoprotein lipase synthesis->increase clearance of TG rich lipoproteins
- decr. expression/synthesis of apoC-III-> incr. clearance of VLDL
- -> reduced TGs
- incr expression/synthesis of apoA-I & II-> elevation of HDL

71

effects of fibric acids on lipid profile

- mild hyperTG (<400mg/dL): up to 50% decr in TG, ~15% inc in HDL, LDL unchaged
- marked hyperTG (400-1000mg/dL): ~50% TG reduction, 10-30% LDL INCREASE

72

fibrates are DOC for treating

sever hypertriglyceridemia & chylomicronemia syndrome
- usually used as second choice if statin therapy is not sufficient

73

where are PPAR alpha found

abundant in liver and brown adipose cells

74

fibrate PK

- take with food
- strong protein binding

75

fibrate main ADE

- GI
- rash, myalgia, fatigue, HA, sexual impotency, anemia
- increased lithogenicity of bile

76

caution in combining fibrates with

- oral anticoagulants- decreased albumin binging-> higher circulating dose of oral anticoagulants
- statins w/ gemfibrozil: decr hepatic uptake-> higher circulating statins

77

ezetimibe is a

dietary cholesterol uptake inhibitor

78

ezetimibe inhibits cholesterol absorption in

the small intestines (inhibits its transport) by 54%

79

MOA of ezetimibe

- decr. cholesterol absorption in SI-> decr chylomicron formation-> incr LDL receptors-> incr clearance of LDL

80

ezetimibe effect on lipids

- 15-20% LDL reduction
- 5% TG reduction
- 1-2% HDL increase

81

ezetimibe PK

- water INSOLUBLE
- do not admin with bile acid sequestrants

82

main ADE of ezetimibe

rare allergic rxns

83

omega-3 acid ethyl esters

lovaza
vascepa

84

lovaza

aka omacor
- mix of omega 3 acid ethyl esters, mostly EPA & DHA

85

vascepa

icosapent
- contains EPA

86

omega 3 acid ethyl esters are used in adjunct to

diet to reduce TG
- NOT combined with statins

87

omega 3 acid ethyl esters MOA

- not well understood
- inhibition of acyl CoA: 1,2- diacylglycerol acyltransferase
- inc mito & peroxisomal beta- oxidation of lipids in liver cells
- decr. lipogenisis in liver
- incr plasma lipoprotein activity

88

omega 3 is mainly used for the treatment of

hyperTG (>500mg/dL)

89

lovaza vs vascepa

- lovaza incr LDL
-vascepa decr LDL

90

fish oil

- large doses (1-4g)
- fish burps
- risks: mercury & other heavy metals, hypomania/mania

91

novel drug target for dyslipidemic therapy

targeting PCSK9
- induces degradation of LDL receptor