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Flashcards in Pharm: Hyperlipidemia drugs Deck (66):
1

What type of lipid is considered "bad" cholesterol? What about "good" cholesterol?

LDL is bad cholesterol
HDL is good cholesterol

2

Increased LDL is associated with what disease?

Increased LDL is associated with an increased risk of cardiovascular disease

3

Describe the composition of lipoprotein particles

Lipid membrane made of phospholipids and cholesterol
Hydrophobic core containing TGs and cholesterol esters
Apolipoproteins, structural proteins and ligands for particle uptake

4

How does the relative ratio of cholesterol:TG differ between LDL and HDL?

LDL: 60% cholesterol, 25% TG
HDL: 20% cholesterol, 5% TG, 35% phospholipid

5

What is the function of chylomicrons?

Exogenous lipoprotein: Transport of dietary fat, cholesterol and bile acids from intestine to liver

6

What is the function of lipoprotein lipase?

Cleaves off free fatty acids from triglycerides of lipoproteins

7

Describe the endogenous pathway of lipoprotein metabolism

VLDL --> IDL --> LDL
LDL delivers cholesterol to the periphery or back to the liver

8

How does the handling of LDL change in hypercholesterolemia?

LDL levels are too high in hypercholesterolemia
The LDLR-lysosome degradation of LDL cannot keep up with the high LDL levels
LDL is no longer targeted to peripheral cells, which can lead to the development of atherosclerosis

9

Describe the formation of atherosclerosis starting with endothelial injury

Endothelial injury allows LDL to enter vessel wall. LDL is oxidized and then taken up by macrophages, which convert to foam cells that promote SMC migration and proliferation as well as ECM synthesis. Foam cells release debris leading to fatty streak formation.

10

What are the main protective roles of HDL against atherosclerosis?

1) Antioxidant activity: PON1 enzyme
2) Inhibit endothelial adhesion molecules
3) Prevent formation of foam cells
4) Promote reverse cholesterol transport

11

What is reverse cholesterol transport?

Transport of cholesterol from periphery back to the liver where it can be secreted as bile

12

What are the causes of hyperlipidemia?

Genetics: familial genetic disorder
Lifestyle: diet, obesity, alcohol, smoking, age, physical inactivity
Diseases: T2 DM, hypothyroidism
Drugs: antiviral, antipsychotics, corticosteroids, oral contraceptives

13

What levels of LDL and TG are considered "very high"?

LDL > 190 mg/dL
TG > 500 mg/dL

14

High TG levels lead to an increased risk of what disease?

High TGs increase risk of pancreatitis

15

What are the general pharmacological strategies used to treat hyperlipidemia?

Decrease in LDL (Primary targets)
Increase HDL (secondary)
Decrease TG (secondary)

16

What is the treatment for moderate hypercholesterolemia?

Therapeutic lifestyle change is sufficient if there is a low cardiovascular risk

17

What is the treatment for severe hypercholesterolemia?

Drug therapy: reduce LDL using a statin in order to decrease risk of atherosclerosis

18

What are the 4 major classes of drugs that reduce LDL levels?

Statins
Bile acid-binding resins
Cholesterol absorption inhibitors
PCSK9 inhibitors

19

What is the mechanism of action of the statins?

HMG-CoA reductase inhibitors
Competitive inhibition of the rate limiting enzyme of cholesterol biosynthesis. SREBP is activated leading to increased LDLR gene expression, increased LDL clearance

20

What is the effect of statins on concentrations of LDL, HDL, and TGs?

Significant reduction of LDL
Modest increase in HDL
Modest decrease in TGs

21

What is a clinically important difference between Pravastatin and the rest of the statins?

Pravastatin is not metabolized by CYP450, unlike the other statins
Fewer associated adverse events (decreased incidence of rhabdomyolysis)

22

How do baseline LDL levels affect the effectiveness of statins?

Statins are effective at reducing CHD risk irrespective of the initial baseline LDL
-They are the drug of choice for primary and secondary CHD prevention

23

Describe the dose dependence of statins

Decreases in LDL are dose dependent, but there larger doses increase adverse events more than they improve therapeutic effect

24

Describe the adverse events associated with statins

The most serious adverse effects are muscular: rhabdomyolysis, myalgia, myopathy
Others:
-GI disturbances
-Liver enzyme increase
-T2DM

25

What commonly precipitates rhabdomyolysis in patients taking statins?

High statin dose OR drug interaction
Drugs that inhibit CYP3A4 (cyclosporins, macrolides, ketaconazole)

26

What non-drug item can increase the risk of statin adverse events?

Grapefruit juice

27

What transporter is responsible for liver uptake of statins?

OATP2

28

How are statins excreted?

ALL statins are excreted via bile and feces after glucoronidation by UGT1A1/1A3 in the liver

29

What effect do inducers of CYP3A4 have on statin therapy?

Inducers of CYP3A4 reduce plasma concentrations and thus reduce clinical efficacy of statins

30

Describe the drug interaction between gemfibrozil and statins

Gemfibrozil inhibits OATP2 transporter, which decreases statin uptake by the liver. This leads to increased statin concentration in the blood and increased risk of myopathy, rhabdomyolysis
Also inhibits glucoronidation leading to increased systemic levels of statin

31

What are the contraindications for statin therapy?

Pregnancy, nursing mothers and women who may become pregnant
Patients with liver disease

32

What effect do bile acid-binding resins have on LDL, HDL and TGs?

Modest reduction of LDL
No effect on HDL
Small increase in TGs

33

What is the mechanism of action of bile acid-binding resins?

Bind to negatively charged bile acids to prevent small intestinal reabsorption, thus leading to excretion of bile acids via feces.
Increased bile acid production --> decrease cholesterol levels
LDLR is upregulated leading to increased LDL clearance

34

What is the mechanism for bile acid resins increasing TG levels?

bile acids normally suppress endogenous TG synthesis, so the resins decrease bile acid levels leading to increased TG synthesis

35

Describe the clinical use of bile acid resins

Not typically used when statin therapy is an option, but are used in combination for aggressive reduciton of LDL.
Statins are contraindicated in children, and women who are lactating/pregnant, so bile acid resins are a useful statin alternative

36

What are the adverse effects associated with bile acid resins?

Very few side effects because they are not absorbed or metabolized (remain in GI tract)
- GI disturbances
- Impaired absorption of fat soluble vitamins

37

What drugs interact with bile acid resins?

Many. Do not give drugs at same time as resins (Stagger doses to avoid interactions)

38

What are the contraindications for bile acid resins?

Type III dysbetalipoproteinemia
Raised TGs (risk for pancreatitis)

39

What are the bile acid binding resin drug names?

Cholestryramaine
Colestipol
Colesevelam

40

What is the only cholesterol absorption inhibitor drug?

Ezetimibe

41

What is the mechanism of action of ezetimibe?

Inhibits NPC1L1 (protein for uptake of dietary and biliary cholesterol in small intestine)
Reduces VLDL and LDL production and increases LDLR

42

What effect does ezetimibe have on TG levels?

Ezetimibe does not raise TG levels (unlike bile acid resins)

43

Describe the therapeutic uses of ezetimibe

Used to lower LDL in hypercholesterolemia
Used in combination with statin to decrease LDL using a lower dose of statin (decrease side effects)

44

What adverse events are associated with ezetimibe?

Flatulence and diarrhea

45

What role does PCSK9 play in hypercholesterolemia?

PCSK9 is a secreted enzyme responsible for controlling the levels of LDLR expressed on liver cells. Binds to LDLR, triggers internalization and degradation of LDLR

46

Describe the effect of gain of function and loss of function mutations in the PCSK9 gene

Gain of function: high LDL levels, increased risk for CVD
Loss of function: low LDL levels, decreased risk for CVD

47

What are the PCSK9 inhibitor drug names?

Alirocumab
Evolocumab

48

What is the mechanism of action of PCSK9 inhibitors?

PCSK9 inhibitors are human antibodies that are specific for the PCSK9 protein. They bind PCSK9 and prevent its interaction with LDLR.
Result: increased expression of LDLR

49

Do PCSK9 inhibitors work if statins are also being used?

Yes. They decrease serum LDL even in the presence of maximally tolerated statin drugs.

50

What are the new drugs developed for the treatment of homozygous familial hypercholesterolemia?

Lomitapide and Mipomersen

51

What is the mechanism of action of lomitapide?

Inhibition of MTP enzyme, preventing the formation of chylomicrons by enterocytes and VLDLs by hepatocytes

52

What is the mechanism of action of mipomersen?

This oligonucleotide reduces the expression of apoB leading to reduced production of VLDLs by hypatocytes

53

Elevated triglycerides are an independent risk factor for what diseases?

Atherosclerosis
Cardiovascular disease
Pancreatitis (at very high TG levels >500mg/dL)

54

How are HDL levels associated with TG levels?

Elevated TGs are associated with decreased HDL (good cholesterol)

55

What are the drugs that treat hypertriglyceridemia?

Niacin
Fibrates (gemfibrozil, fenofibrate)

56

What effect does niacin have on TGs, LDLs and HDLs?

Reduce TGs
moderately reduce LDLs
moderately increase HDLs (most effective drug to raise HDL)

57

What are the therapeutic uses of niacin?

Lower plasma cholesterol and TG
Used in patients with familial combined hyperlipidemia and familial dysbetalipoproteinemia

58

Describe the mechanism of action of niacin

COMPLEX
-decreases release of FFAs, decreasing FA synthesis
-increases HDL via increased apoA1
-decreased macrophage recruitment to lesions
-decreased thrombosis risk by decreasing Lp(a)
-decreased VLDL production, increased clearance

59

What is Lp(a) and how are Lp(a) levels related to risk of atherosclerosis?

Lp(a) is a lipoprotein that prevents thrombolysis (competitive inhibition of thrombolysis pathway)
Decreased levels are associated with decreased risk for atherosclerosis

60

What are the major adverse effects associated with niacin?

Skin flushing, itching
Inhibited uric acid secretion can cause gout
Can exacerbate peptic ulcer disease

61

How do fibrates affect levels of TG, LDL, HDL?

Large reduction in TG
Mild reduction in LDL
Mild increase in HDL

62

What is the mechanism of action of the fibrates?

Ligands for the PPAR-alpha transcription factor
Promotes expression of genes involved with lipoprotein structure, function and metabolism

63

What adverse events are associated with fibrates?

Gallstones
Myopathy, Rhabdomyolysis

64

Describe the drug interactions with fibrates

Strong protein binders, can displace other albumin bound drugs leading to increased concentrations of other drugs in unbound, active form

Major rxn between gemfibrozil and statins (fenofibrate does not affect statin levels)

65

What are the contraindications for fibrate usage?

Pregnant/lactating women
Hepatic dysfunction (drug is hepatotoxic)
Renal dysfunction (drug renally excreted)
Gall bladder disease

66

What is the clinical effect of omega-3 fatty acids?

Lowers TG levels, increases HDL, may increase LDL