lecture 3 Flashcards
1
Q
Dyslididemia is a major cause of
A
increased atherogenic risk and atherosclerosis-associated conditions (IHD, CVD, PVD)
2
Q
lipid lowering is very beneficial for the treatment of
A
CVD
3
Q
1% reduction in total cholesterol->
A
2% reduction in CHD events
4
Q
many clinical trials have should that avg dyslipidemic therapy results in
A
30-40% reduction of fatal/non-fatal CHD events & stroke
5
Q
primary goal of dyslipidemia therapy
A
reduction of LDL levels
6
Q
comparably important dyslipidemia therapy goals
A
- elevation in HDL independent of LDL
- reduced CHD events 20-35% in pts with low HDL & avg LDL
- reduction of TGs
7
Q
severe hypertriglyceridemia->
A
(>1000mg/dL)-> pancreatitis
8
Q
moderate elevation of triglycerides ->
A
(150-400mg/dL)-> part of metabolic syndrome
9
Q
1% reduction in LDL->
A
1% reduction in CHD events
10
Q
1% increase in HDL->
A
3% reduction in CHD events
11
Q
how much cholesterol is biosynthesized in the body daily?
A
~1000mg
12
Q
cholesterol is important
A
- synthesis of steroid hormones
- cell membranes
- synthesis of bile acids
- absorption of fats & lipid-soluble vitamins
- transport of fats from liver to tissues
13
Q
statins are
A
competitive inhibitors of HMG-CoA reductase-> blocks synthesis of cholesterol
14
Q
HMG-CoA
A
3-hydroxy-3- methylglutaryl coenzyme A
15
Q
statins block the conversion of HMG-CoA to
A
mevalonate
16
Q
blocked synthesis of cholesterol in the liver leads to
A
- increased synthesis of LDL receptors in hepatocytes
- increased removal of LDL from blood
- reduction of LDL levels in plasma
17
Q
reduction of LDL levels is
A
dose dependent
18
Q
TG levels >250mg/dL
A
-> 35-45% reduction (with max doses)
19
Q
TG levels <250mg/dL
A
-> up to 25% reduction
20
Q
statins also increase HDL levels by
A
~7.5%
21
Q
how do statins reduce TG levels
A
- blocked synthesis of cholesterol in liver-> increased synthesis of LDL receptors in liver-> increased removal of LDL-precursors (IDL & VLDL) from blood-> reduced TG
- reduce cholesterol in hepatocytes-> reduced synthesis of VLDL in the liver-> reduced TG
22
Q
main effect of statins
A
reduction of LDL & improvement of the lipid profile
23
Q
pleiotropic effects of statins
A
- 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
Q
pleiotropic effects of statins are independent of
A
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
