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PT 1 > L 38, 39 Drugs Used to Treat Hyperlipidemia > Flashcards

L 38, 39 Drugs Used to Treat Hyperlipidemia Flashcards

1
Q

What is hyperlipidemia?

A

Abnormal/elevated levels of cholesterol/triglycerides in the blood

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2
Q

What is atherosclerosis?

A

The build-up of lipids, cells, and other compounds in the artery wall. This leads to hardening of the artery and narrowing of the lumen, increasing the risk of plaque rupture and clot formation.

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3
Q

Triglycerides play a role in hyperlipidemia development and ___ development.

A

Pancreatitis

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4
Q

What are lipoproteins?

A

Carrier molecules for the transport of cholesterol and triglyceride in the blood

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5
Q

How do lipoprotein particles differ?

A

Size, lipid content, associated apolipoproteins

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6
Q

What are the 3 major components of lipoproteins?

A
  1. Lipid membrane (phospholipids and cholesterol)
  2. Hydrophobic core (triglycerides and cholesterol esters)
  3. Apolipoproteins
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7
Q

Compare the cholesterol composition of LDL and HDL.

A

LDL: 60%
HDL: 20%

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8
Q

LDL makes up ___% of total plasma cholesterol.

A

65-75

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9
Q

Discuss exogenous lipoprotein metabolism.

A

Dietary fat and cholesterol are ingested. 50% is excreted; 50% is absorbed via the intestinal epithelium. Chylomicrons are formed when these combine with apolipoproteins. Chylomicrons enter the bloodstream, where lipoprotein lipases are cleaved to FFA. FFA is stored or used in adipose/muscle tissue. Chylomicron remnants are degraded into cholesterol in the liver.

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10
Q

Discuss endogenous lipoprotein metabolism.

A

Cholesterol from the liver combines with triglycerides to form VLDLs. These enter the blood and are converted via LPL to FFA which are also stored. VLDLs become IDLs and LDLs. LDL goes to peripheral tissue where it is used to make steroids and cell membranes.

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11
Q

Discuss the role of LDLs in the development of atherosclerosis.

A
  1. Endothelial injury/dysfunction allows entry of LDL into the intima
  2. LDLs are oxidized to form OxLDLs. These activate the endothelium.
  3. Monocytes migrate to the activated endothelium and extravasate.
  4. Macrophages take up OxLDL and form foam cells. These secrete proteases and growth factors that promote SMC migration and proliferation.
  5. SMC migration, ECM synthesis, and necrotic foam cell apoptosis/release of cholesterol contribute to the formation of a fatty streak/plaque.
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12
Q

What are the 4 major roles of HDL in the prevention of atherosclerosis?

A
  1. Inhibit the oxidation of LDL
  2. Inhibit expression of adhesion molecules on the endothelium
  3. Inhibit formation of foam cells
  4. Promote reverse cholesterol transport
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13
Q

How do HDLs inhibit the oxidation of LDLs?

A

Paraoxonase enzyme (PON1)

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14
Q

What is reverse cholesterol transport?

A

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

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15
Q

In addition to genetics, what are some of the lifestyle factors that can lead to hyperlipidemia?

A

High fat/carb diet, obesity, alcohol consumption, smoking, increasing age, physical inactivity

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16
Q

What are some diseases that can lead to hyperlipidemia?

A

T2DM, hypothyroidism, nephrotic syndrome, hypopituitarism, anorexia nervosa

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17
Q

What are some drugs that can lead to hyperlipidemia?

A

Antiviral proteases, antipsychotics, corticosteroids, oral contraceptives

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18
Q

What are the optimal/desirable levels of total cholesterol, LDL, HDL, and triglyceride?

A

Total: < 200 mg/dL
LDL: < 100 mg/dL
HDL: >40 (men), >50 (women)
Triglyceride: < 150 mg/dL

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19
Q

What are considered very high levels of LDL and triglyceride?

A

LDL: > 190 mg/dL
Triglyceride: > 500 mg/dL

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20
Q

What specific drugs can be used to target increased LDL?

A
  1. Statins
  2. Bile acid-resins
  3. Cholesterol absorption inhibitors
  4. PCSK9 inhibitors
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21
Q

What specific drugs can be used to increase HDL/inhibit triglycerides?

A
  1. Niacin

2. Fibrates

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22
Q

How should moderate hypercholesterolemia with low cardiovascular risk be treated?

A

Therapeutic lifestyle change (dietary reduction of cholesterol intake, exercise/weight reduction)

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23
Q

How should severe hypercholesterolemia and/or high cardiovascular risk be treated?

A

Drug therapy to reduce LDL and reduce risk of atherosclerosis

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24
Q

What are the effects of statins?

A
  1. Significant reduction in LDL (20-60%)
  2. Modest reduction in triglycerides (10-20%)
  3. Modest increase in HDL (5-10%)
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25
Q

True or false - statins are effective at reducing CHD risk irrespective of initial baseline LDL.

A

True

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26
Q

What are the indications of statins?

A
  1. Patients with elevated LDL
  2. Secondary prevention (preventing a second event in an individual with a prior history of CHD)
  3. Primary prevention (preventing a first CHD event in an individual with a high 10 year risk of develop CVD)
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27
Q

Maximal statin doses lead to a ___% decrease in 10 year CVD risk.

A

20-30

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28
Q

What is the MOA of statins?

A

Statins are analogues of HMG-CoA, a substrate of HMG-coA reductase (rate limiting enzyme in cholesterol biosynthesis). They competitively inhibit HMG-CoA reductase and thus inhibit endogenous cholesterol synthesis. Reduced hepatic cholesterol synthesis triggers a signaling pathway that induces activation of SREBP TF. This increases expression of the LDL receptor gene, which increases clearance of serum LDL.

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29
Q

What are additional activities of statins that contribute to their anti-atherogenic effects?

A
  1. Inhibit adhesion molecule expression on the endothelium
  2. Inhibit adhesion of monocytes to the endothelium
  3. Inhibit monocyte proliferation and migration
  4. Inhibit oxidation of LDLs (decrease foam cell formation)
  5. Inhibit SMC proliferation
  6. Inhibit inflammatory responses
  7. Stabilize the endothelium (decrease risk of plaque rupture)
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30
Q

What happens when you double the statin dose?

A

5-6% further decrease in LDL + significant increase in the potential for adverse effects

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31
Q

What are the major adverse effects of statins?

A
  1. Some GI disturbances
  2. Increase in liver enzymes (rare)
  3. T2DM (small increased risk)
  4. Myalgia (pain) and myopathy (weakness)
  5. Rhabdomyolysis (rare but serious)
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32
Q

What is rhabdomyolysis?

A

Muscle inflammation and disintegration; statins damage muscles, which break down and release myoglobulin. Kidney damage and failure can occur.

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33
Q

Rhabdomyolysis caused by statins is associated with an inactivating polymorphism in the ___.

A

Statin hepatic anion transporter (decreases hepatic uptake and increases serum concentration)

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34
Q

Fewer muscle adverse effects have been observed with which statin?

A

Pravastatin

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35
Q

Where are statins absorbed?

A

Intestine (30-85%)

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36
Q

Which three statins are metabolized by CYP3A4 in the intestines?

A

Lovastatin, Simvastatin, Atorvastatin

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37
Q

How are statins transported into the liver?

A

Organic Anion Transporter 2 (OATP2)

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38
Q

Where and how are statins metabolized?

A

Liver; all are glucuronidated by glucuronyl transferase enzymes (UGT1A1/1A3), which facilitates further metabolism and excretion; they are variably metabolized by CYP450.

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39
Q

How are statins excreted?

A

Bile and feces

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40
Q

Which CYP450 enzymes metabolize which statins?

A

CYP3A4: Lova, Simva, Atorva
CYP2C9: Fluva
CYP2C19: Rosuva
None: Prava

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41
Q

Drugs that inhibit CYP450 enzymes will ___ the concentration of specific statins, leading to increased risk of adverse effects.

A

Increase

42
Q

What are some CYP3A4 inhibitors?

A
  1. Cyclosporin and tacrolimus
  2. Clarithro/erythromycin
  3. Diltiazem and verapamil
  4. Amiodarone
  5. Itraconazole and ketoconazole
  6. Ritonavir, indinavir, and nelfinavir
  7. Warfarin
  8. Large quantities of grapefruit judice
43
Q

What are some CYP2C9 inhibitors?

A

Ketoconazole, itraconazole, metronidazole, sulfinpyrazone

44
Q

Inducers of CYP3A4 can ___ concentrations of Lovastatin, Simvastatin, and Atorvastatin, reducing clinical efficacy.

A

Reduce

45
Q

What are some inducers of CYP3A4?

A

Phenytoin, barbiturates, rifampin, thiazolidnediones

46
Q

What is the statin of choice when drug interactions are a concern?

A

Pravastatin

47
Q

What is strongly associated with an increased risk of statin-induced myopathy and rhabodmyolysis and why?

A

Gemfibrozil; inhibits OAT2P transporter-mediated uptake of statins, doubling bioavailability and inhibits glucuronidation of statins, increasing systemic levels of ALL statins.

48
Q

What are the contraindications for statins?

A
  1. Pregnancy, nursing mothers, and women who may become pregnant
  2. Patients with liver disease
49
Q

Statins are classified as category X - why?

A

Concern that statin inhibition of cholesterol synthesis may adversely affect the fetus/newborn

50
Q

Why is pravastatin safer in patients with liver disease?

A

It is eliminated both hepatically and renally rather than just hepatically.

51
Q

Why do some argue for earlier, more aggressive statin therapy?

A

Typical patients are prescribed a statin in their 40’s/50’s. At this point, the patient has probably experienced years of LDL-induced arterial damage.

52
Q

What are the three bile acid-binding resins?

A
  1. Cholestyramine
  2. Colestipol
  3. Colesevelam
53
Q

What is the primary clinical effect of bile acid-binding resins?

A

Modest reduction in LDL (10-25%)

54
Q

What is the MOA of bile acid-binding resins?

A

Resins are cationic polymers that bind to negatively charged bile acids and prevent their reabsorption in the small intestine, increasing excretion. Decreased bile acid resorption causes increased bile acid synthesis in the liver, resulting in the a decrease in hepatic cholesterol. This also triggers upregulation of LDL-R and increased clearance.

55
Q

Decreased bile acid resorption upregulates ___, the rate limiting enzyme in bile acid synthesis, resulting in increased conversion of cholesterol to bile acids.

A

Cholesterol 7-alpha-hydroxylase

56
Q

What is the effect of bile acid resins on triglcyeride levels?

A

Normally, bile acids suppress endogenous triglyceride synthesis; resins increase triglyceride levels

57
Q

When would resins be used in combination with statins?

A

To aggressively reduced LDL if statin is not sufficient (additive) and/or to allow use of lower statin does to avoid adverse effects

58
Q

When would resins be used instead of statins?

A

Patients for whom statins are not effective or contraindicated

59
Q

What are the adverse effects of resins?

A

Generally very few, as they are not absorbed or metabolized; some GI disturbances. At high concentrations cholestyramine and colestipol (NOT colesevelam) impair absorption of fat soluble vitamins (ADEK)

60
Q

Which 2 resins interfere with the absorption of other drugs?

A

Cholestyramine and colestipol

61
Q

When are resins contraindicated?

A

Type III Dysbetalipoproteinemia and raised triglycerides

62
Q

What is the primary effect of ezetimibe?

A

Reduces LDL (18%), minimal effect on HDL and triglycerides

63
Q

What is the MOA of ezetimibe?

A

Inhibits Niemann-Pick C1-like protein (NPC1L1), which is involved in the absorption of biliary and dietary chosterol in the SI; this reduced absorption decreases delivery of cholesterol to the liver, reducing VLDL/LDL production and increasing LDL-R

64
Q

What are the clinical uses of ezetimibe?

A
  1. 2nd most prescribed after statins to lower LDL, often in combination with statins
  2. Reduce LDL-Cin patients with primary hypercholesterolemia
65
Q

What are the adverse effects of ezetimibe?

A

Generally well tolerated, some flatulence and diarrhea

66
Q

Mutations in ___ are responsible for a small number of patients with familial hyperlipidemia.

A

PCKS9 (proprotein convertase subtilisin/kexin type 9)

67
Q

What happens in a gain of function mutation of PCKS9 and how is it inherited?

A

Autosomal dominant; serum LDL >350 mg/dL, increased risk of CVD and death < 50 years

68
Q

What happens in a loss of function mutation of PCKS9?

A

40% decrease in LDL levels, 88% reduction in CVD risk

69
Q

What does PCSK9 do?

A

It is a secreted enzyme produced by the liver and other cell types. It binds to the LDLR at the surface and is internalized with the receptor and LDLs. It prevents LDL-R recycling back to the membrane, targeting it for degradation.

70
Q

What are the two inhibitors of PCSK9?

A

Alirocumab and evolocumab

71
Q

What is the MOA of PCSK9 inhibitors?

A

Bind PCSK9, prevent it binding to the LDLR, which prevents the targeting of LDLR to the lysosome, promoting enhanced LDL clearance

72
Q

True or false - alirocumab promotes a decrease in serum LDL even in the presence of maximally tolerated statins.

A

True

73
Q

What are the indications of anti-PCSK9 antibodies?

A

Heterozygous FH patients with very high LDL levels and patients that have not achieved LDL goals with maximally tolerated doses of statins

74
Q

What are the clinical effects of anti-PCKS9?

A

Reduction of LDL (~70%), reduction of Lp(A) (~18-36%), and ~50% reduction in CVD risk

75
Q

What is lomitapide?

A

Inhibitor of microsomal triglyceride transfer protein (MTP), which is required for the assembly of chylomicrons and VLDL; this leads to reduced LDL levels

76
Q

What is mipomersen?

A

Antisense oligonucleotide specific for apoB48 and apoB100, reducing expression of these proteins. This results in reduced production of chylomicrons and VLDLs, leading to lower levels of LDLs.

77
Q

Why are elevated serum triglycerides problematic?

A
  1. Independent risk factor for atherosclerosis and CVD
  2. Risk factor for pancreatitis
  3. . Associated with decreased HDL
78
Q

How should hypertriglyceridemia be treated when levels are borderline high (150-199 mg/dL)?

A

Lifestyle change (low fat diet, exercise, cessation of smoking/alcohol)

79
Q

How should hypertriglyceridemia be treated when levels are very high (>500 mg/dL)?

A

Initial goal: prevent pancreatitis by lowering triglyceride with niacin or a fibrate; then address LDL-C goals when triglycerides are <500 mg/dL

80
Q

What is the clinical effect of niacin (nicotinic acid/vitamin B3)?

A

Reduction in triglycerides (30-80%)
Reduction in LDLs (10-20%)
Reduction in HDLs (10-30%)

81
Q

___ is the most effective drug at raising HDLs.

A

Niacin

82
Q

What are the therapeutic uses of niacin?

A
  1. Lower cholesterol and triglycerides (treatment of familial combined hyperlipidemias)
  2. Increasing HDL levels
  3. History of MI, prevention of re-infarctions, cerebrovascular events, and overall mortality
  4. Combined with statin or resin
83
Q

What is the MOA of niacin?

A
  1. Agonist for Gi-coupled GPCR in adipose tissue; this inhibits cAMP-induced lipolysis, which reduces FFA release, leading to less triglyceride synthesis
  2. Inhibits DGAT2, the rate limiting enzyme in hepatic triglyceride synthesis
  3. Reduces hepatic expression of apoCIII, leading to increased LPL activity and increased VLDL breakdown
  4. Increases half life of apoAI, the major lipoprotein in HDLs, increasing concentration of serum HDLs
  5. Inhibits macrophage recruitment to atherosclerotic lesions via activation of GPR109A
  6. Reduces levels of Lp(a) lipoprotein, which normally inhibits tPa/uPa to block the formation of plasmin from plasminogen
84
Q

What are the adverse effects of niacin?

A
  1. GI distress, nausea, abdominal pain
  2. Skin flushing and itching (pruritis)
  3. Gout (inhibition of tubular secretion of uric acid)
  4. Exacerbate peptic ulcer disease
  5. Modest hyperglycemia in T2DM
  6. Hepatic toxicity (rare)
85
Q

How can the skin flushing/itching AE of niacin be treated?

A

NSAID (as the effect is mediated by prostaglandins)

86
Q

When is niacin contraindicated?

A
  1. Peptic ulcer disease
  2. History of gout
  3. Caution in diabetes
  4. Caution in patients with impaired liver function
87
Q

What are the two fibrates?

A

Fenofbirate and gemfibrozil

88
Q

What are the clinical effects of fibrates?

A

Reduction in triglycerides (40-60%)
Mild reduction in LDL (10-20%)
Increase in HDL (10-20% increase)

89
Q

What is the MOA of fibrates?

A

Act as ligands for the nuclear hormone TF PPAR-alpha. This promotes expression of genes involved in lipoprotein structure, function, and metabolism.

90
Q

PPAR-alpha activation increases apoA1, AII synthesis in hepatocytes - what is the downstream effect?

A

Increased plasma LDL (these are the HDL lipoproteins)

91
Q

PPAR-alpha activation decreases apoCIII synthesis in hepatocytes - what are the downstream effects?

A

ApoCIII is an inhibitor of LPL. Decreasing its synthesis increases LPL expression in muscle. This leads to FFA uptake in muscle, fatty acid oxidation, and increased peripheral VLDL clearance. Plasma triglycerides decrease.

92
Q

PPAR-alpha activation increases hepatic expression of genes involved in fatty acid transport/metabolism - what are the downstream effects?

A

Increased fatty acid oxidation in hepatocytes, decreased hepatic triglyceride synthesis, decreased VLDL secretion, and decreased plasma triglycerides

93
Q

What are the indications of fibrates?

A
  1. Hypertriglyceridemia with low HDL (treatment of choice for familial dysbetalipoproteinemia and Type III hyperlipoproteinemia)
  2. Patients w/high triglyercides
  3. Long-term usage to reduce coronary events, stroke, and transient ischemia events
94
Q

What are the adverse effects of fibrates?

A
  1. Generally well tolerated - mild GI
  2. Increased predisposition to gallstones
  3. Myopathy and rhabdomyolysis leading to acute renal failure (rare)
  4. Hepatitis
95
Q

Why do fibrates increase predisposition to gallstones?

A

They inhibit expression of cholesterol 7-alpha-hydroxylase, decreasing bile acid production. This increases secretion of free cholesterol, which can lead to gallstones.

96
Q

Which fibrate more commonly leads to rhabdomyolysis?

A

Gemfibrozil (especially when given with a high dose of statin)

97
Q

Both gemfibrozil and fenofibrate are strong protein binders - how does this affect other drugs?

A

Can displace other protein-bound drugs from albumin, resulting in increased concentrations - anti-coagulants (warfarin), sulfonylureas

98
Q

When are fibrates contraindicated?

A
  1. Pregnancy/lactating women or women who may become pregnant
  2. Patients with severe hepatic dysfunction
  3. Patients with severe renal dysfunction
  4. Patients with pre-existing gallbladder disease
99
Q

What is the clinical effect of fish oils?

A

Lower serum TG levels by ~30-50%
Minor increase in HDL
Increase LDL in some

100
Q

What is the therapeutic use of fish oils?

A

Adjunct to diet in the treatment of hypertriglyceridemia in individuals with triglyceride levels >500 mg/dL

101
Q

What is the apparent MOA of fish oils?

A

Inhibition of genes involved in hepatic triglyceride synthesis; may also possess anti-inflammatory actions via GPCR expressed on macrophages

PT 1 (34 decks)

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