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Pharm Test 4 > Hypolipidemic Agents 1&2 > Flashcards

Hypolipidemic Agents 1&2 Flashcards

1
Q

What is hyperlipoproteinemia?

A

Occurs when the blood triacylglyceraol (TAG or triglycerides) or cholesterol in lipoproteins exceeds normal

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2
Q

Elevated lipoprotein accelerates development of the three types of atherosclerosis, they are?

A

Peripheral vascular disease
Ischemic cardiovascular disease
Coronary heart disease (CHD or myocardial infarction)

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3
Q

What accounts for a half of adult deaths in the U.S. each year?

A

Atherosclerosis

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4
Q

When does risk begin for hyperlipoproteinemia?

A

Risk begins at levels of cholesterol previously considered normal

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5
Q

What is the pathology of atherosclerosis?

A

Monocytes migrate to the endothelial cells of the artery wall where macrophages engulf LDL (low density lipoprotein) and are transformed into foam cells that are cholesterol esters and form plaques on the artery wall

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6
Q

What is the implication of drug therapy on decreasing CHD?

A

Hypolipidemic drug therapy has decreased CHD mortality continuously as more drugs are approved.
Mostly due to statins

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7
Q

What is the suggestion surrounding statins?

A

Statins can prevent cardiac events in patients with cholesterol levels thought to be normal

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8
Q

What are the two pathways of lipoprotein synthesis?

A

Exogenous and endogenous

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9
Q

What is the exogenous pathway?

A

Dietary lipids (triglycerols, cholesterol, and cholesterol esters) are packaged into chylomicrons in the intestinal mucosal cells. The chylomicrons then travel through the lymphatic system to reach the general circulation where they deliver their lipids to peripheral tissues

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10
Q

What is the endogenous pathway?

A

The liver synthesizes fatty acids and cholesterol from dietary glucose and uses these in addition to lipids taken up from the blood to produce Very Low Density Lipoproteins (VLDL). These VLDL deliver lipids to peripheral tissues and become Intermediate Density Lipoproteins (IDL) and Low Density Lipoproteins (LDL).

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11
Q

Where does cholesterol synthesis occur

A

In all cells

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12
Q

What does the synthesis of 1 cholesterol molecule require?”

A

180 ATPs making it energetically expensive

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13
Q

What is the pathway for degradation of cholesterol?

A

There is no pathway for degradation of cholesterol

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14
Q

How is cholesterol removed?

A

Cholesterol is removed by hepatic conversion to bile acids leading to excretion in feces; however some secreted bile acids are recovered by enterohepatic cycling

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15
Q

Where are the carbon atoms of cholesterol derived?

A

All the carbon atoms of cholesterol are derived from the acetate of Acetyl-CoA

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16
Q

What do statins inhibit?

A

HMG-CoA Reductase

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17
Q

What does isopentenyl- pyrophosphate turn into in the cholesterol synthesis pathway?

A

Vitamin E, Ubiquinone (Q10), prenylated proteins

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18
Q

What is cholesterol vitally important for?

A

Cell membrane stability

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19
Q

Where is VLDL synthesized?

A

Only in the liver

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20
Q

Where is HDL synthesized?

A

Only in the liver

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21
Q

Where are chylomicrons secreted?

A

In the intestines

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22
Q

Which lipoprotein in the largest?

A

Chylomicrons ( they have the highest percentage TAG)

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23
Q

What are chylomicrons secreted by?

A

The intestine

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24
Q

Where are chylomicrons secreted?

A

Into the lymphatic system

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25
Q

Chylomicrons deliver what

A

Lipids to the muscles and adipose tissue

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26
Q

What do chylomicron remnants bind to?

A

Remnant receptors

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27
Q

What is the second largest lipoprotein?

A

VLDL

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28
Q

What is VLDL secreted by?

A

Secreted by the liver directly into the blood

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29
Q

What does VLDL deliver?

A

Lipids to the muscle and adipose tissue

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30
Q

What is the end product of VLDL?

A

VLDL ends up as LDL which binds to LDL receptors on the liver

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31
Q

Chylomicron Remnant Receptor

A

Part of the LDL receptor family

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32
Q

LDL receptor

A

Not a transporter

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33
Q

Microsomes Triglyceride Transfer Protein (MTTP)

A

Transfers hepatic TG from cytosol into the endoplasmic reticulum for packaging into VLDL particles

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34
Q

Scavenger Receptor 1B

A

A channel to allow HDL lipids into the liver

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35
Q

PCSK9

A

Proprotein Convertase Subtilisin/Kevin type 9 binds to LDL receptors

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36
Q

Cholesterol Ester Transfer Protein

A

Exchanges lipids (HDL-LDL)

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37
Q

Hepatic Lipase

A

Metabolizes triglycerides for hepatic import

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38
Q

Why does the liver need cholesterol?

A

To make bile acids to process fats

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39
Q

The liver synthesizes

A

A lipoprotein known as High Density Lipoprotein (HDL)

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40
Q

What is Reverse Cholesterol Transport?

A

After HDL particles are secreted into the blood by the liver they travel to the peripheral tissues and pick up cholesterol. Cholesterol then esters to bring HDL back to the liver to be metabolized

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41
Q

What is “bad cholesterol”?

A

LDL particles that become trapped in the blood vessels to produce atherosclerosis

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42
Q

Normal cholesterol values

A

Total cholesterol < 200mg/dl
Triglycerides < 150 mg/dl
HDL >60 mg/dl
LDL <100 mg/dl
Total/HDL ratio <4

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43
Q

Borderline Risk of ASCVD values

A

Total cholesterol 200-239 mg/dl
Triglycerides 150-199 mg/dl
HDL 40-50 mg/dl (men); 50-59 mg/dl (women)
LDL 100-190 mg/dl
Total/HDL ratio 4-6

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44
Q

High Risk of ASCVD values

A

Total cholesterol >240mg/dl
Triglycerides >200 mg/dl
HDL <40 mg/dl (men); <50mg/dl (women)
LDL >190 mg/dl
Total/HDL ratio >6

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45
Q

Major risk factors exclusive of LDL Cholesterol

A

-Cigarette smoking
-Hypertension (BP >140/90 mmHg) or patient on antihypertensive medication
-Low HDL cholesterol (<40mg/dl; >60 is neg.)
-Family history of CHD (male <55, female <65
-Age (men >45 years; women >55 years)

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46
Q

What are genetic causes of increased LDL?

A

Familial Hypercholesterolemia
Familial Combined Hyperlipidemia
Polygenic Hypercholesterolemia

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47
Q

Familial Hypercholesterolemia (FH)

A

-Homo and Heterozygous
-Defect in or lack of functional LDL receptor (LDL receptor gene mutation)
-Excessive accumulation of LDL ( decreased clearance)

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48
Q

Familial Combined Hyperlipidemia

A

-Excessive production of VLDL by the liver
-Increased levels of both cholesterol & TAG

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49
Q

Polygenic Hypercholesterolemia

A

-largest number if patients
-abnormal LDL (doesn’t bind to receptors)
-increased sensitivity to saturated fat and cholesterol
-other, unknown causes

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50
Q

Secondary causes if Hyperlipidemia

A

Diabetes, hypothyroidism, obstructive liver disease, chronic renal failure, drugs that increase LDL-C and decrease HDL-C (progestins, anabolic steroids and corticosteroids)

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51
Q

What encompasses metabolic syndrome?

A

Abdominal obesity, elevated TAG, low HDL-C, high blood pressure, high fasting glucose

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52
Q

What is the treatment for metabolic syndrome?

A

Lose weight; treat lipid abnormalities

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53
Q

What do dietary principles do for treating LDL?

A

-1st line treatment for hyperlipidemia
- Effective in lowering mild elevations of LDL-C
- Saturated fat and cholesterol suppress expression of LDL receptors
-replace saturated fat with:
-monounsaturated fat (olive oil)
-polyunsaturated fat (most vegetable oils)
-carbohydrate (complex)
-no replacement (weight reduction diet)
-obesity and caloric excess lower HDL
-exercise raises HDL
-diets should be tried for 6 months

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54
Q

What is the responsibility of bile?

A

Helps to emulsify fats and fat soluble vitamins thereby aiding absorption

55
Q

Where is bile produced?

A

Yellow-green bile is produced by hepatocytes and stored in the gallbladder

56
Q

What controls bile acid synthesis?

A

Bile acid synthesis is controlled by the first enzyme in the pathway, hepatic cholesterol 7 alpha-hydroxylase (CYP7A1)

57
Q

What is the composition of bile?

A

Bile contains bile salts, cholesterol, phospholipids, and bile pigments (bilirubin and biliverdin)

58
Q

What makes enterohepatic cycling possible?

A

Ileal bile acid transporter (S1c10a2)

59
Q

What is cholesterol degradation?

A

Cholesterol is converted to bile acids, but the the bile acids can be reabsorbed int he lower part of the small intestine and converted back to cholesterol or re-utilized in the liver

60
Q

What is the method of action of hypolipidemic agents (“the fibrates”)?

A

Activation of transcription factor PPAR alpha to increase fatty acid oxidation; activates lipoprotein lipase

61
Q

What is clofibrate?

A

P-chloroPHenoxyIsoButyRATE
*first drug in the FIBRATE class and is no longer available in the US (not very effective in lowering cholesterol and “unexplained” deaths in clinical trials)

62
Q

The Fibrates are

A

The oldest hypolipidemic drugs (developed from study of sick farm workers in France exposed to insecticide)

63
Q

Which fibrates are useful for lowering VLDL?

A

Gemfibrozil (Lopid) and Fenofibrate (Tricor)
*decrease TAG better than cholesterol

64
Q

Which fibrate is useful for raising HDL?

A

Gemfibrozil

65
Q

What increases the absorption of fibrates?

A

Food

66
Q

What are the side effects of Fibrates?

A

They can cause myopathy, myositis, and rhabdomyolysis, but much less than statins

67
Q

What are fibrates contraindicated in?

A

Colelithiasis

68
Q

When should fibrates be used?

A

When statins are contraindicated or when statins are not tolerated by the patient
*can be used in combination with statins

69
Q

What is recommended as first line therapy?

A

Statins due to being more efficacious

70
Q

Hypolipidemic Agents : Fibrates currently available

A

Fenofibrate (Antara, Lofibra, TriCor)
Fenofibrate acid (Trilipix)
Gemfibrozil (Lopid)

71
Q

HMG-CoA Reductase Inhbitors (aka STATINS)

A

First drugs specifically designed to inhibit a specific enzyme
*Lovastatin was put on fast track for drug development

72
Q

What were statins developed from?

A

Developed form fungi as was penicillin

73
Q

What are statins most effective at doing?

A

They are most effective for lowering plasma LDL and total cholesterol. They also reduce TAG

74
Q

How are Statins tolerated?

A

Generally tolerated better than other hypolipidemic agents

75
Q

What is the mechanism of action of statins?

A

Specific inhibition of HMG-CoA Reductase, the rate limiting enzyme for cholesterol synthesis

76
Q

What does decreased hepatic cholesterol lead to?

A

Increased production of hepatic LDL receptors, decreasing plasma LDL cholesterol

77
Q

What does doubling the dose of statins cause?

A

In general each doubling of the dose of Statins decreases plasma cholesterol by 10%. However, increasing the dose increases the side effects.

78
Q

How are statins transported?

A

Most statins are actively transported into the liver producing higher concentrations in the liver

79
Q

What tissues are side effects seen in with statins

A

Extrahepatic tissues

80
Q

What is the determining factor of most side effects for statins?

A

Most side effects of statins are directly dependent on the dose. Higher doses mean more severe side effects

81
Q

What is the liver damage that some statins cause credited to?

A

Increased blood transaminase

82
Q

What are the progressive muscle side effects associated with statins?

A

Myalgia, myopathy, and rhabdomyolysis, sometimes leading to kidney failure (myoglobinuria, brown urine)

83
Q

What impact to statins have on blood glucose?

A

Increase blood glucose, increased glucose latex hemoglobin A 1c values

84
Q

More aggressive therapy equals

A

Greater side effects (baycol problem)

85
Q

What do some patients experience in statins?

A

Short-term memory loss

86
Q

Currently Available Statins

A

Lovastatin (Mevacor)
Simvastatin (Zocor)
Pravastatin (Pravacol)
Fluvastatin (Lescol)
Atorvastatin (Lipitor)
Rosuvastatin (Crestor)
Pitavastatin (Livalo)

87
Q

What is JUPITER and it’s purpose?

A

Justification for the Use of Statins in Primary prevention: an intervention trial evaluating Rosuvastatin.
-designed to determine if patients with no evidence of pre-existing cardiovascular disease and low to normal LDL-C but elevated C-reactive protein (CRP) with CRESTOR 20mg once daily would reduce major cardiovascular events

88
Q

CRP is recognized as a marker of

A

Inflammation and is associated with an increased risk of atherosclerotic cardiovascular events

89
Q

What i it’s efficacy of statins?

A

PCSK9 limits efficacy of statins

90
Q

PCSK9 =

A

Proprotein Convertase Subtilisin Kexin, type 9

91
Q

What are the two PCSK9 inhibitors?

A

Alirocumab (Praluent)
Evolocumab (Repatha)

92
Q

What is the method of action of the two PCSK9 inhibitors?

A

They dramatically lower cholesterol. They can be used in patients who cannot take statins. They are effective in familial hypercholesterolemic patients. No data yet on CHD as Phase III not completed

93
Q

What type of drugs are the two PCSK9 inhibitors?

A

They are monoclonal antibodies that bind to the active form of PCSK9 in the blood and prevent proteolytic cleavage of hepatic LDL receptors

94
Q

What is the newest PCSK9 inhibitor?

A

Leqvio (inclisiran) approved in December 2001

95
Q

What type of drug is Leqvio (Inclisiran)?

A

First siRNA drug. Small interfering RNA blocks synthesis of PCSK9 in the liver by binding to mRNA

96
Q

How is Leqvio (inclisiran) administered?

A

Subcutaneous injectiongiven by a healthcare provider with an initial dose, then again at three months and then every six months

97
Q

What percentage reduction in LDL cholesterol is seen with taking Leqvio (inclisiran)?

A

50% reduction in LDL cholesterol

98
Q

What does Leqvio (inclisiran) do to PCSK9 levels?

A

Reduces both Nitra- and extracellular PCSK9 levels. (Monoclonal antibodies reduce only extracellular PCSK9)

99
Q

What is the structural composition of hypolipidemic agents that are fish oils?

A

Very long chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)

100
Q

Where are fish oils primarily found?

A

Cold water marine fish (not MS catfish)

101
Q

What do fish oils reduce?

A

They reduce plasma TG, decrease VLDL synthesis

102
Q

What is the FDA approved fish oil?

A

Lovaza (omega-3-acid ethyl esters) is an FDA approved fish oil recommended to be taken 4 grams/day for hypertriglyceridemia

103
Q

What can fish oils be used for external to hyperlipidemic agents?

A

May be used as anti-inflammatories
*fish oils do not lower cholesterol

104
Q

What is Niacin?

A

Niacin is a B vitamin with MDR of 15mg, but hypolipidemic dose is about 3 grams, which can cause flushing

105
Q

What does Niacin do?

A

Niacin decreases TAG and increases HDL cholesterol.

106
Q

What is the MOA of Niacin?

A

Mechanism of action is to inhibit hormone sensitive lipase (adipose) decrease FA release and decrease VLDL synthesis

107
Q

What preparation of Niacin shows better response?

A

Sustained release preparations show much better response

108
Q

What are the Niacin preparations available in the US?

A

Polygel extended release niacin (SLO-Niacin)
Prescription extended release niacin (Niaspan)

*Dietary supplement niacin must not be used as a substitute for prescription niacin. They are not regulated by the FDA

109
Q

What are Bile Acid Sequestrants?

A

These are insoluble anion exchange resins. They are not absorbed from the intestine. They bind bile acids, not cholesterol

110
Q

What is the mechanism of action of Bile Acid Sequestrants?

A

MOA is by inhibiting the reabsorption of bile acids blocking enterohepatic cycling. This in turn leads to increased synthesis of cholesterol and increased production of LDL receptors

111
Q

What is the nature of drug interactions with Bile Acid Sequestrants?

A

Greatly decrease the absorption of negatively charged drugs (thyroxine, digoxin, thiazides, warfarin, etc.)
*side effects are mostly GI

112
Q

What are the current Bile Acid Sequestrants available in the US?

A

Cholestyramine (Questran, Prevalite, Locholest)
Colestipol (Cholestid)
Colesevalam (WelChol)

113
Q

What are the antioxidants?

A

Probucol (no longer available in U.S)
Vitamin E (highly advertised but is no longer recognized as having beneficial effects)

*antioxidants were initially thought to be useful but clinical trials proved otherwise

114
Q

What are cholesterol absorption inhibitors?

A

They are the newest class of lipid-lowering agents and include
Ezetimbe (Zetia)

115
Q

What is the MOA of cholesterol absorption inhibitors?

A

Inhibits the intestinal cholesterol transporter without affecting FA uptake.

116
Q

Why should cholesterol absorption inhibitors not be confused with bile acid Sequestrants ?

A

Cholesterol absorption inhibitors have a different mechanism of action and fewer side effects

117
Q

What do cholesterol absorption inhibitors do?

A

Effectively lower LDL-C
Produces additional lowering of LDL-C with STATIN

118
Q

What side effects are seen with the use of cholesterol absorption inhibitors? And in combination with statins?

A

Side effects of tiredness, stomach pain when used alone, myalgia in combination with statin

119
Q

Do cholesterol absorption inhibitors decrease cardiac events?

A

No evidence yet that they decrease cardiac events (trials currently underway)

120
Q

What are the cholesterol ester transfer protein inhibitors (CETP)?

A

Trocetrapib, dalcetrapib, evacetrapib, anacetrapib & obicetrapib

121
Q

What do cholesterol ester transfer protein inhibitors (CETP) do?

A

They inhibit transfer of cholesterol esters from HDL to LDL
Clearly shown to lower LDL-C and raise LDL-C

122
Q

What are FDA implications for cholesterol ester transfer proteins inhibitors?

A

Not approved by FDA yet (not sufficient > ASCVD)
Obicetrapib is still in phase III clinical trials

123
Q

What is the FDA implication for siRNA to lower cholesterol?

A

Recently approved by FDA for homozygous familial hypercholesterolemia ONLY

124
Q

What is the drug name do the siRNA used to lower cholesterol?

A

Mipomersen (Kynamro)

125
Q

What does mipomersen (Kynamro) do?

A

It is a modified antisense RNA which inhibits ApoB gene expression. (Modification prevents metabolism of the drug by nucleases

126
Q

What is the method of action of mipomersen (Kynamro)?

A

Blocks the synthesis of VLDL (endogenous pathway) because of lack of ApoB proteins to make VLDL

127
Q

What is the current warning for mipomersen (Kynamro)?

A

Risk of hepatotoxicity
Increased hepatic lipids and plasma transaminases

128
Q

How is MTTP (Microsomal Triglyceride Transfer Protein) used to Lower Cholesterol?

A

MTTP transfers hepatic TG into the endoplasmic reticulum for packaging into VLDL particles

129
Q

Which MTTP drug was approved by the FDA?

A

FDA approved lomitapide (Juxtapid). Initially approved for Homozygous Familial Hypercholesterolemia

130
Q

What are the side effects of inhibition of MTTP to lower cholesterol?

A

Elevated aminotransferase levels and fat accumulation in the liver

131
Q

What are the ATP citrate lyase (ACL) inhibitors?

A

Bempedoic acid (Nexletol, Nilemdo)

132
Q

What is the therapeutic effect of ATP citrate lyase inhibitors?

A

LDL down, HDL up TG down

133
Q

What is the mechanism of ATP citrate lyase (ACL) inhibitors?

A

-Adenosine triphosphate-citrate lyase (ACL) inhibitor (cholesterol synthesis upstream of statins)
-the enzyme ACSVL1, required for bempedoic acid activation, is not present in the skeletal muscle
-CRP down
-once-daily oral drug

134
Q

Drug Combinations for hyperlipidemia?

A

Statin + bile acid sequestrant
Statin + fibrate
Statin + sustained release niacin (niacin + lovastatin, Advicor®)
Statin + cholesterol absorption inhibitor (simvastatin + ezetamibe, Vitorin®)
Bempedoic acid + ezetimibe

Pharm Test 4 (2 decks)

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